The Circuitous Route by a Group of Novices to a New FDA Approved Cancer Therapy: HOW DID WE DO THIS? 1432798731, 9781432798734

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THE CIRCUITOUS

ROUTE BY A GROUP OF NOVICES NEW

TO A

FDA APPROVED

CANCER

THERAPY

HOW DID WE DO THIS?

“THOMAS J. DOUGHERTY, PHD

The opinions expressed in this manuscript are solely the opinions of the author and do not represent the opinions or thoughts of the publisher. The author has

representedand warranted full ownership and/or legal right to publish all the materials in this book. The Circuitous Route by a Group of Novices to aNew FDA Approved Cancer Therapy HOW DID WE DO THIS?

All Rights Reserved. Copyright © 2015 Thomas J. Dougherty, PhD v1.0 Cover Photo © 2015 thinkstockphotos.com. All rights reserved - used with permission. This book may not be reproduced, transmitted, or stored in whole or in part by any means, including graphic, electronic, or mechanical without the express written consent of the publisher except in the case of brief quotations embodied in critical articles and reviews. Outskirts Press, Inc. http://www.outskirtspress.com

Outskirts Press and the “OP” logo are trademarks belonging to Outskirts Press, Inc. PRINTED IN THE UNITED STATES OF AMERICA

outskirtspiess 3

DENVER,

COLORADO

To my parents Joseph and Norma Dougherty

who encouragedme to follow my dreams.

Author's

Note:

How Naive can you get? How did |ever think that someone with no background in medicine or biology, let alone cancer, could possibly develop a new cancer treatment? Nonetheless, when |joined a cancer center in Buffalo following

ten years in industry, |knew |could do this-NO DOUBT AT ALL! |had NO idea what |

was getting in to! This book describes the ups and downs with the FDA, the lack of assistance and skepticism of scientific and medical staff at my institute and the sometimes really offensive public comments from attendees at national and international scientific meetings even when |presented positive results of our preliminary studies. Finally, with the help of the forward-looking and open-minded Chief of the Surgical Staff, anew cancer therapy came into existence!

In 1970 in Buffalo, New York at a cancer center then known as Roswell Park Memorial Institute (later Roswell Park Cancer Institute), | found

—entirely by accident, that cancer cells could be destroyed when they were treated with a light absorbing drug and exposed to light. This eurekamoment evolved into an obsession to create and make available to cancer patients, an effective new treatment based on this concept. This occurred

in 1973 when we treated our first patient with Photodynamic Therapy. This is process now referred to as Translational Research, taking a research

finding from the Benchto the Patient.This was the first time that this occurredat Roswell Park so we had to figure out how to do it on our own! Serendipity, or what some might call “dumb luck,” has been a constant companion in my professional life, and |owe “him/her/it" at least a few knowing nods of acknowledgment. |like to think of myself as an accidental pioneer, whose brush with serendipity led him on an exciting and sometimes frustrating quest through

challenging terrain, often without benefit of a reliable guide. This odyssey, fraught with detours and dead ends, steep hills and learning curves—was a testament to the famous axiom of Murphy's Law: Whatever can go wrong, will. Still, there is no doubt that while PDT came about as a result of an unbelievable series of unplanned and unexpected events, |can say without reservation that every step and corresponding misstep were, in the long

run, steps in the right direction. |recently came across a definition of serendipity that |feel best captures the essence of this great adventure: “if your heart is open, if it is free of meanness, destiny takes us to wonderful places.” (1) This is my story—a travelogue of sorts—of the development of PDT, the quarter-century journey to obtain FDA approval and the wonderful places destiny has taken me. My narrative here ends ona satisfying, although not definitive, note. There’s certainly much more to be written and logged by the next generation of PDT explorers and innovators. More importantly, the genuinely happy endings exist in the countless unpublished sidebar stories of cancer patients who have benefitted—and will continue to benefit—from this treatment.

While there are many people to thank, |would like to especially recognize three important players in this saga: Pastor Nathaniel Preisinger of the Parkside Lutheran Church in Buffalo, who unknowingly

gave me the extra push |needed to share my story; the late Arnold Mittelman,

MD, of Roswell

Park Cancer Institute, one of the true heroes and visionaries behind PDT’s advancement; and Yosihiro Hayata, MD, of the Tokyo Medical School in

Japan, who elucidated, early on, some of the most effective applications of this treatment. In no small measure, their friendship and faith in me helped illuminate the way, and |am most humble and grateful for their support. Thomas J. Dougherty, PhD Buffalo, NY

(1) White, Randy Wayne. Gone (A Hannah Smith Novel). New York: G.P. Putnam’s Sons, 2012.

Contents Prologue Chapter

1: Let There Be Light: Photodynamic

Therapy

Chapter 2: Life Before PDT Chapter 3: Photochemistry & Librettos: The DuPont Years (1960-1970) Chapter 4: ACancer Researcher at Home...and

Abroad

Chapter 5: Seeking Federal Funding: My First Grant Application Chapter 6: OT Mice and Men: Success from a Failed Experiment

Chapter 7: Hematoporphyrin Derivative: (HpD) as aPDT Agent? Chapter 8: Running Interference: A Clash of Opinions? / Chapter 9: "Elegant But Impossible”: The Best Backhanded Compliment

|Ever Received

Chapter 10: New Directions, New Staff and Graduate Students: The PDT Program Expands

Chapter 11: Preparing for Clinical Studies Chapter

12: Lesson 1: AMouse Is Not aHuman

Chapter 13: Buffalo, We Have a Problem!—The FDA Sets Us Straight Chapter 14: The Dog (and Cat) and Pony Show: Pet Projects Chapter 15: Launch of the First PDT Company: We Will Need Money Chapter 16: From HpD to Photofrin-A Patent? Chapter 17: Expanding the Applications Chapter

of PDT: The Japanese

Connection

18: The Trip to China

Chapter 19: Patents and Patience Chapter 20: The Big Leagues: Partnering with Jonnson & Johnson

Chapter 21: The Oncologic Foundation of Buffalo Chapter 22: 1990: J&J Drops aBomb

Chapter 24: Search and Rescue: Is Anybody Out There? Chapter 24: The Holy Grail: Our First US-FDA Approval

Chapter 25: HPPH: Our New Photosensitizer (HPPH) Chapter 26: Licensing HPPH: Here We Go Again!

Chapter 27: Light at the End of the Tunnel: Photolitec Chapter

28: Expanding

Epilogue Acknowledgments

PDT to New Cancer Applications

and Developing

a PDT Induced Cancer Vaccine

Prologue “The harder|work, the luckier |get.” ~Samuel Goldwyn

Before commercialization of any new medical treatment or technology, certain national standards must be met: promising basic and clinical research must be conducted, extensive safety and efficacy testing must be done, and finally—and what may be the most challenging hurdle—approval must be granted by the US Federal Drug Administration

(FDA) which, as the reader will discover from the experiences detailed in this book, is no hop, skip and

a jump to the public marketplace. FDA approval is the culmination of years, sometimes decades, of intense research and teamwork—demanding

of

researchers the patience of Job and the unwavering belief that they have something important to contribute that would ultimately make a difference in the lives of patients. In 1994, more than 20 years after the start of its development, Photodynamic Therapy (PDT) received its first FDA approval for the palliative treatment of advanced esophageal cancer. PDT is a targeted cancer treatment, which means that it “targets” only tumor cells for destruction without

permanently damaging surrounding tissue. The treatment combines a nontoxic photosensitive drug that accumulates in tumor tissue, with a red laser light that destroys the tumor. Because PDT is classified by the FDA as a “dual treatment”—using both a drug (a photosensitizer) and a device (a laser) to work—two separate FDA approvals are required. Photofrin, the photosensitizer that we developed at Roswell Park Cancer Institute, is the PDT drug that has been approved by the FDA to treat or relieve the symptoms of certain types of cancers, including late-stage esophageal cancer, Barrett's esophagus (a pre-cancerous tissue), and

early-stage and advanced lung cancer. These approvals indicate that the FDA considers PDT to be both safe and effective for these specific types of diseases

Photofrin-based PDT is also available as an “off-label” treatment for many other types of cancer, including those of the skin, lung, breast, the female reproductive system, esophagus, pleura, head and neck. Off-label means that while a treatment may be approved by the FDA for one type of

cancer, it may be used, based on strong evidence reported in peer-reviewed medical journals, for a different type of cancer without FDA approval or data from clinical studies. There is adownside to pursuing this avenue. A treating physician can risk a lawsuit if something goes wrong and may have diticulty receiving reimbursement trom insurance companies. Over the years, PDT has also been approved by national agencies in many countries for specific types of cancer—in Canada, for bladder and esophageal cancer; in The Netherlands, for lung and esophageal cancer; in Japan and Germany, for early-stage lung cancer; and in France, for earlyand late-stage lung cancer. This book tracks my experience with the long and arduous—and often, serendipitous—process involved in garnering FDA approval for PDTnecessary to make the treatment available to cancer patients.

CHAPTER T

Let There Be Light:

Photodynamic Therapy What is photodynamic therapy (PDT)? As a cancer treatment, PDT requires the combined eftect of three essentials: oxygen, a light-absorbing drug called a photosensitizer, and a tissuepenetrating light source. Here's how it works: A photosensitizer,

injected into the bloodstream,

is taken up by both normal and cancerous tissue. Within 24 to 72 hours,

it concentrates in the tumor tissue at higher levels than in the normal tissue. The tumor is then exposed to red laser light delivered through fiber optics. The drug absorbs the light, becomes “excited” (excess energy), transfers the excess energy to the oxygen in the tissue converting it into a highly

reactive form of oxygen that attacks the tumor and under ideal conditions, shrinks or destroys the tumor (See photos below). The photodynamic cancer treatments that have been approved by the FDA use the photosensitizer Photofrin® that was developed in my laboratory at Roswell Park

CancerInstitute beginningin 1970.

pee

sitizer

Sequence of PhotodynamicTherapy

_

111m7 a

>

Light Delivery -_-

Lee = a

abaenes

gets Laser delivers monochromatic |liq ht

7 ce

7; =

re

nt

ofphotesensitizer-specific = “i

wavelengththroughopticalfibers

=

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- ik,

a §5 ==

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NE

=

Se

Dr Anne-Marie Regal Inserting the Optical Fiber into a Tumor Obstructing the Airway in this Patient, in preparation for PDT Treatment( the laser is not on at this time). The PDT Treatment

The Fiber is Inserted into the Tumor. The Laser is on causing Red Laser light Distribution Throughout the Blockage. The Small Black Areas on the Right are the only remaining open airways. The Treatment Time (the time the laser is on) is 8-12 Minutes.

The Blocked Airway Two Days After Treatment is Completely Open Allowing Greatly Improved Breathing for the Patient

The fields of cancerbiology, photochemistryand radiationbiology—aswell as the developmentof advancedimagingand lasertechnology—have greatly expanded the potential of PDT both as a curative and palliative treatment option for thousands of cancer patients.

In adaition to directly killing cancer cells, PDT can shrink or destroy tumors in two other ways. The photosensitizer can damage blood vessels in the tumor, thereby preventing the cancer from receiving necessary nutrients. PDT also may activate the immune system to attack the tumor cells.

PDT is generally an outpatient procedure,and has become a viable option for many cancer patients for whom surgery is impossible, or who cannot tolerate additional chemotherapy and radiation therapy and their deleterious side effects.

Becausethe photosensitizercan remain in the skin for quite some time, PDT’s major side effect is ahypersensitivityto the sun and other bright light. Because of a high risk of phototoxicity, which can result in severe sunburn, redness and swelling of the skin, patients are required to avoid

direct sunlight anywhere from three to four days to four to six weeks after injection (depending on the photosensitizer used). Other heat and bright light sources—such as a dentist's lamp or physician’s examining light, spotlights and floodlights, and cone- or helmet-type hairdryers—must also be

avoided during recovery. Sunglasses, dark-colored clothing, long-sleeved shirts, hats, gloves and long pants must be worn to protect the skin when the patient is outdoors.

CHAPTER 2

Life Before PDT |was borne in the Nickel City—Buffalo, New York—and attended elementary school, high school and college in the city where |was born and raised, and where |happily reside today. I’m not going to bore you with a history of my personal life, but |will say that |lived a relatively normal middle class

existence. My childhood was happy, and my close-knit family has always been loving and supportive. It was in my freshman year in high school that |decided to pursue a PhD in chemistry. Two years later, as |sat bored and uninspired in my first chemistry class, |wondered if my career decision had been a tad premature. |could always switch to physics, |reminded myself, as |tried to stay alert while my chemistry teacher droned on. It is hard to be excited about chemistry when your teacher is both unenthusiastic and missing-in-action. On lab days, after assigning our day’s project in his flat-line monotone, our teacher had the peculiar habit of vanishing. Today, |can only surmise that he wanted to be as far away as possible from “children” playing with dangerous chemicals. Even the senior student assistant would retire to the small adjoining office during lab time. Despite a lack of proper supervision and motivation, we all managed to survive this class without blowing up the lab. College chemistry was a quantum leap better. At Canisius College, a small Jesuit school, our chemistry professor was both engaged and engaging, and was graciously approachable. During labs, he would walk around, supervising our work and answering our questions. His passion for chemistry

was contagious, which made me more determined than ever to pursue chemistry as a career. He also suggested chemistry programs at graduate schools where he thought |would excel. |was accepted by three universities, but chose The Ohio State University (OSU) in Columbus, Ohio. It would

be my first time away from home. One of the reasons |chose OSU was the opportunity to work with Harold Shechter, PhD, a pre-eminent organic chemist whose work |greatly

admired. ProfessorShechter is internationally recognizedfor his contributionsto organic chemistry,and some of his researchplayed an instrumental role in the development of the propellants used in the Polaris submarine missile system. Professor Schechter was a superb lecturer, and in my opinion, unequalled in his mastery of subject matter, his flair for the dramatic and his captivating delivery. As one of his former students so eloquently described his lecturing style: “He had the unique ability to construct a narrative that was as compelling as a novel.” (2) |could not have asked for a better dissertation advisor and, in my later years, amore supportive colleague.

At OSU, first-year graduate chemistry students are required to take advanced courses before beginning their independent research. There were courses in kinetics (how fast and by what path reactions between molecules occur) and thermodynamics (the study of the energy involved in these reactions)—both hard-core courses not intended for the faint of heart or the unprepared. |and most of my fellow grad students had not been exposed

to these subjects as undergraduates; a few had, particularly those who had attended the “higher power” schools, such as Harvard and MIT,so naturally they were ahead of the game.

After the first test in thermodynamics—themore difficult of the two courses—eachstudent was requiredto receive his/her grade directly from the professor in a one-on-one meeting. For most of us, this carried adouble whammy: not only did we think we had done poorly on the test, but the

“bearer of bad news” was a no-nonsense, no-excuses professor who lacked a sense of humor. In other words, scary as hell! One by one, students filed into his office for their face-to-face meetings—and exited silent and blank-faced! When it was my turn, |entered the room and sat directly across from the professor. Waving my exam, he pulled no punches and told me how bad it was—pointing out my mistakes. |was dismissed without knowing my grade, and |thought the worst. But when the grades were posted, |discovered, to my great astonishment and relief

that |had passed! At the end of the quarter, the number of chemistry grad students who had entered the program with me was cut in half. It became apparent that these difficult classes were given at the start of the academic year to “weed out” those students who predictably wouldn't last. After completing these courses, |focused on my research, which involved making a group of similar compounds of increasing size and studying

the rate of their reaction with water. The intent was to see if the reaction rate changed with size and, if so, to explain why. My early research in synthetic and theoretical chemistry would become essential to my future as a cancer researcher.

After three-and-one-half years, |felt that my research was ready to be written up for my doctoral thesis, and |made an appointment to talk to Professor Shechter. |knew he had a habit of “hanging on” to graduate students—keeping them busy with various research projects. He had, in fact, done this to me. But |was anxious to finish up and get on with my career. |summoned my courage, made my way into his office and told him |was ready to begin writing my thesis. He agreed, and encouraged me to begin. In 1960, |graduated with a PhD in Physical Organic Chemistry. Several years later, Professor Shechter arranged for me to receive the Sullivant Award from The Ohio State University. This is OSU’s highest honor, given to former students for “accomplishments in keeping with the highest standards of the University.” There was a dinner and awards presentation in the evening, and the next day, |addressed an audience of about 1,000 mid-year graduates and 8,000 additional

attendees! (All this without Power

Point!) Knowing full well that no one would rememberwhat |said 10 minutes after leaving the auditorium, |told a fewjokes and kept my remarks short. In any event, |was humbled and grateful for this important recognition, and Professor Schechter’s faith in me. Sadly, my former mentor passed away in 2010. |have recently learned that OSU will honor him by creating and dedicating laboratory space in his name in the new Chemistry-Biological

and Engineering Building.

(2) Excerptedfrom Development brochure,Harold Schechter:An Icon in ChemistryTeachingand Research,The Ohio State University, College of Arts and Sciences.

CHAPTER 4

Photochemistry & Librettos: The DuPont Years (1960-1970) After receiving my doctorate, |returned home and took a position as a chemist at a branch of E. |.du Pont de Nemours and Company (commonly referred to as simply "DuPont") in Tonawanda, New York—a 15-minute drive from Buffalo. At DuPont, |had my first brush with serendipity. |just happened to be in the right place at the right time. |was assigned a project that required some knowledge of light reactions. Of course, |had no prior knowledge of any aspect of photochemistry since it was not part of my college curriculum or grad school training. The most important person |met at DuPont was a consultant named George Hammond, PhD, who was chairman of the Chemistry Department at

California Institute of Technology and was considered to be the world’s authority in the new, but burgeoning field of photochemistry. Dr. Hammond would periodically visit the Tonawanda site, and meet with scientists to discuss research projects. |was usually the first in line! |had been assigned a project to determine why a new plastic siding material DuPont had developed degraded over time when exposed to the outside environment. One reason, |hypothesized, was frequent exposure to sunlight.

My first meeting with Dr. Hammond was daunting. He was the number one scientist in photochemistry—often called the “Father of Organic Photochemistry”—was

widely published, and the recipient of many awards, including the Priestley Medal (the top award in chemistry) and the

National Medal of Science. |was fresh out of graduate school and, while | knew of him, | had never before met such a famous scientist.

|was quite

nervous at our first one-on-one meeting. However, he immediately put me at ease with his friendly, disarming manner.

By our fifth meeting, |was on a first-name basis with George. He and |met to discussthe results of one of my current projects—a clever little experiment, |thought, that | couldn't wait to share. The project required an elaborate piece of equipment involving a high-vacuum system that contained a light source and other components that had been built by our very talented glass blower. A lot of time and effort went into project. However, |thought it was worth it because this experiment might resolve the issue of which of two possible mechanisms was causing the degradation of the building material—the light itself or light plus slow oxidation from oxygen in the air. The approach |took was to isolate the light from the air

(which is why the high-vacuum system was necessary). |described the equipment and the results to George, whose initial reaction was no reaction. Then he looked me straight in the eye and declared, “That's a T----- up experiment!” |nearly fell off my chair. Here was a man |greatly admired who had never even sworn in my presence, berating my work with a single sentence! It took some time to regain composure; |was both shocked and crushed by this unexpected response trom the expert in

the field.

George then told me why he did not “like” the experiment. |listened intently, immediately recognizing a major flaw in his argument. “No, you're wrong!” |blurted out! When |explained what he had missed, he admitted that |was right.

|felt vindicated! |went on to have a good working relationshipwith Georgeand, thanks to him; |came away from DuPontwitha solid foundation in photochemistry. This was to become critical in the next big step of my career. Years later, several Tormer students, including me, were invited to a special reception honoring George. We were asked to relate a personal

anecdote that gave a human face to our professional relationship with our former mentor. |shared the now-infamous “F-word” incident, and the audience, including George’s wife, roared with laughter. Judging from the redness in his face, |would say that George was more embarrassed than amused, but it was all in good Tun. When |was hired, DuPont also recruited several other newly-minted PhDs, so there were ample opportunities to make new friends and cultivate new and mutual

interests.

One of these young PhDs was James Dunphy,an opera buff who introduced me to this fascinating art form. Hailing from Boston, Jim had once worked part time at the Boston Pops concerts. His job was to walk on stage carrying a large sign that announced the next piece of music. For this, he

got to stand in the back for the entire concert. Jim had made several attempts to get me interested in opera—but made the rookie mistake of starting my operatic education with the

indomitable Richard Wagner. For those not familiar with opera, think of the music that the Robert Duvall character blasts from the helicopter as bombs drop and bullets are sprayed in that famous scene from the movie Apocalypse Now. |told Jim that Wagner was bit heavy for my first exposure to opera.

Jim suggested something lighter: La Boehme by Giacomo Puccini. | immediately fell in love with its lyrical score and universal themes of love, friendship, struggle and loss. To me, it was the antithesis of Wagner. Today, no matter how many times |hear the music, tears well in my eyes in the closing scene when the distraught Rodolfo learns of his lover’s death and wails “Mimi” over and over again. |came to enjoy many other operas by Puccini, Verde, Schubert and Mozart, and in time, |even returned to Wagner and bought the entire 16-hour Ring Cycle. Speaking of opera and Wagner, another friend of mine from DuPont, Jim Kane, and |travelled to New York City to catch a performance of Mozart's The Magic Flute—a magnificent opera—at the Met. Later, while dining at an upscale restaurant, Birgit Nilsson, the leading Wagnerian soprano

of the day, walked in with a few friends. Jim dared me to ask her for an autograph. |ran out to the car, grabbed the playbill, went over to her table and asked her to autograph her picture. She graciously signed it with the comment, “Oh! That awful picture.” |had the autographed page framed and have it to this day, 50 years later. DuPont eventually shut down its Tonawanda laboratory, but before it did, |had been seriously considering leaving the company, and forgoing a career in private industry. As a native Buffalonian, |knew of Roswell Park Memorial Institute (but not much else!), and thought | might like to do research there to find new ways to treat cancer (a little naive, I’ll admit). In 1970, DuPont offered me a position at their corporate headquarters Wilmington,

Delaware, but |turned it Gown and decided it was “now or never” to make my move.

in

CHAPTER 4

A Cancer Researcher

at Home...

and Abroad |had discussedmy intention to leave DuPont with GeorgeHammond,who collegially offeredto write a letter of recommendationto a scientist friend of his at Roswell Park Memorial Institute (Hereafter, referred to as “Roswell Park”). That friend was David Pressman, PhD, Director of Biochemistry Research and Associate Director for Scientific Affairs. An early pioneer in cancer immunology, Dr. Pressman had studied with Linus Pauling, PhD, arguably the most famous scientist in the world and the only person to be awarded two unshared Nobel Prizes (Chemistry, 1954 and Peace, 1962). |got the interview with Dr. Pressman and was offered a starting position, with a salary paid from a National Institutes of Health research grant. Dr. Park, a local surgeon, established Roswell Park Memorial Institute in 1898 at the University at Buffalo with a $7,500 grant from the New York

State Legislature. In 1992, the Institute’s name was changed to Roswell Park Cancer Institute to better reflect and define its role in the international

oncology arena. |knew that Roswell Park conducted cancer research. |later discovered, however, that it was much more than a research facility. Patient care and

public/professional education anchored its three-part mission. At the time, Roswell Park was considered one of the top three cancer centers in the world, standing shoulder to shoulder with MD Anderson Cancer Center in Houston, Texas, and Memorial Sloan Kettering Cancer Center in New York City. This information played a large role in my applying to this world-class institution. Today, Roswell Park Cancer Institute is among the 40+ National Cancer Institute-designated “Comprehensive Cancer Centers” in the United States. My first experience with cancer was when |was 16. My grandmother, who lived with us, developed breast cancer and, since |had just received my driver's license, |was ‘elected’ to drive her to Meyer Memorial Hospital five days a week for radiation therapy. Meyer Memorial Hospital was an old hospital in the center of the city. While |enjoyed being able to drive the car—a new experience for me—! hated sitting for hours every day in that dark, dungeon-like waiting room in the hospital basement where the radiation therapy department was located. Frankly, it gave me the creeps. The

impression |got was that cancer was not only a horrible disease, but its treatment was just as bad. Stepping on the Roswell Park campus for the first time in February of 1970, all those memories came rushing back. Dr. Pressman’‘s office was in an old, dreary red brick building—not exactly what |was expecting—and it was not much better on the inside. |should note that the “old” Roswell Park bears no resemblance to the beautiful, modern campus of today. |was hired by Dr. Pressman to work with the late Charles Wenner, PhD, head of the Cellular &Molecular Biology Laboratory. Dr. Wenner was in need of someone who could look at the cell membrane using nuclear magnetic spectroscopy. This method, which |had been introduced to at DuPont

(there’s that old serendipity again!), was later developed into molecular resonance imaging (MRI), acommon diagnostic tool for cancer and other diseases. |was given a tiny, dingy office in the Gratwick Science Building. When |turned on the lights each morning, the cockroaches scurried for cover.

|soon learned the differences between working at an academic center and working in the private sector. The most notable was compensation. My starting salary at Roswell Park was less than half of my salary at DuPont. |was young and naive in those days, with the most modest of salary

requirements since |was living at home with free room-and-board. |also learned that in order to become a permanent employee, |had to take a State civil service exam. Roswell Park was then part of the New York

State Departmentof Health, and bound by the rules, regulationsand redtape of a large bureaucracy.The examwas for a starting chemistjust out of college without an advanced degree. At this point, my bruised ego was getting the best of me, and |nearly turned down the position, but |took the exam and easily passed. |also had not realized that to do any type of independent research, it is absolutely necessary to get your own grant funding (usually from the

National Cancer Institute, an agency of the National Institutes of Health). These highly competitive grants were renewed every three years (today, it’s every five years). If your grant was not renewed, your ability to continue your research was impacted and your work often came to a grinding halt, because your technicians’ salaries (and often your own) were supported by these funds.

At that time (and it is far more difficult today), the chances of getting a federal grant for a research proposal was roughly 20%. If the proposal was not accepted, the principal investigator had an opportunity to resubmit his/her application, after making any changes suggested by the reviewers. However, if you were lucky enough to obtain a state-supported position (offered to me after passing the civil service test), your salary was covered, but you would still need outside funding to adequately statt your Lab. It was clear that if | were to succeed at Roswell Park, |would need my own research project and my own grant dollars, particularly once | completed my short-term project with Dr. Wenner. Serendipitously (there's that word again!), an opening occurred in the Department of Radiation Oncology. Charles “Chick” Helmstetter, PhD, was head of the science division in the department, and had just been promoted to head up one of Roswell Park’s biology departments. This left a vacancy, and Chick, who was familiar with my work, suggested |replace him. |had a brief interview with the department chief, John Webster, MD, and |was

hired. Dr. Webster would turn out to be a strong supportive ally as |began my career in cancer research. In my new position, |soon discovered that |was not just head of the department's science division, but also chief bottle washer, janitor and sole staff member as well! Along with these new responsibilities, |was given a small office and lab.

A few months later, |was one of three Roswell Park researchers invited to attend an important international cancer meeting in Florence, Italy. This meeting attracted physicians and scientists from all over the world. |was both nervous and excited about the trip since |had never been to Europe. In

fact the only country |had been in outside of the US was Canada,just overthe borderfrom Buffalo—mainly to go to their nice beaches.

My Roswell Park traveling companions were Moshe Friedman, MD, a radiation oncologist, MD, and his wife Marie; and Charles West, MD, Chief of

the Department of Neurosurgery. We decided to leave early so we would have time to do some sightseeing. We flew into Rome and took the train to

Florence where we rented a car to travel along the Mediterranean Sea to Monaco. Moshe insisted on driving the small Fiat, despite the fact that he had never driven a stick-shift car before. Born in Romania, Moshe was not only an excellent physician but had a delightful sense of humor.

|owned a car with a stick shift and offeredto drive, but Mosheinsistedon taking the wheel. His wife served as navigator.Eachtime Moshestarted in first gear, the car stalled. “Let the clutch out more slowly,” | instructed him. Suddenly we were jerking along, but at least we were moving. We entered a busy traffic circle, and the engine was racing considerably. |suggested he might want to shift into second gear! That solved THAT problem, but we became miserably lost. When the traffic came to a stop, Moshe said that he would ask the driver in the car ahead of us for directions. Marie

pointed out to her husbandthat he did not speak Italian, but he said that it was similar to Romanian—anotherRomancelanguage—sohe should have no trouble. When Moshe returned to our car, Marie asked what the driver had said. Moshe just smiled, shrugged, and said, "I don't know!” We finally

did find our way out of the city and headed north to the Mediterranean. |do not recall the first small harbor town we stopped in but it was quite beautiful—its colorful houses dotting the hills. We spent the night there and woke up early to the sounds of bicycle bells. Each morning, bicycles transported freshly baked bread, which |couldasmell from my room, to the stores and restaurants in the town. What an intoxicating way to wake up.

An unfortunate experienceoccurredin Florence when Charley West and |were searchingfor the Galleria dell'Accademia,the art museumthat is home to Michelangelo's statue of David. We had a map, but it wasn't much help. Charley stopped a person on the street to ask for directions. The individual walked right past him without acknowledging his presence. The next person Charley asked did the same thing. When |asked a third person

for directions, he gladly obliged. The only difference was that |am white and Charley is black. |like to think this occurred by chance, but |doubt it. As an aside |should note that since that time |have traveled to many countries, including, Japan, China, Australia, New Zealand, France, Austria, South Korea, England, France ,ltaly, Germany and Switzerland,

some many times, mainly to consult and/or lecture on PDT.

CHAPTER 5

Seeking Federal Funding:

My First Grant Application After returning from Europe, |realized that there would be no career if |didn’t obtain a large federal grant to support my research. |submitted a grant application to the National Cancer Institute (NCI), the arm of the National Institutes of Health (NIH) that coordinates the National Cancer Program in

the United States. You might ask: How could someone with absolutely no knowledge of cancer and no experience in writing a grant proposal pull this together? It wasn't

easy! Luckily the project |was assigned to with Dr. Wenner did not consume all my time and |could work in the library at any hour of the day and on weekends.

Consequently, most of my first year at Roswell Park was spent in its Medical & Scientific Library. Back then—and perhaps this still holds true today

—this well-stocked library boasted the largest collection of cancer-related materials in New York State. My time there was spent learning as much as |could about the hundreds of diseases known as cancer—and how effective existing treatments were in curing or at least relieving the symptoms of these diseases.

After sitting through pages and pages of literature, |chose to concentrate on a problem relating to radiation therapy. There was a longstanding problem with radiation treatment called the “oxygen effect.” It had been known that tumors generally have areas where the oxygen supply is low

(hypoxic), resulting in the inability of radiation to effectively destroythe tumor. |reasoned that if there was a compound that would generate oxygen during radiation, we might be able to overcome the problem of hypoxia. The first step was to make a non-toxic compound that would localize in the tumor and produce oxygen following radiation. Studying the

literature, |decided to focus on a certain type of oxygen-containing compound that might release the oxygen when exposed to radiation. This is where my knowledge of chemistry was helpful. |filed my very first NCI grant application, which detailed my radiation sensitizer approach. My application was routed to the NCI's Radiation Study Section, one of many specialized groups that review grant applications. The 10 to 20 reviewers in these groups assess the importance and relevance

of each grant application and vote on whether the grant should be funded. Two or three members—who are considered to be most familiar with the subject of the grant—are designated “primary reviewers.”

To my great surprise, my grant was funded for three years. | used these funds to purchase materials and equipment and hired a technician. Unfortunately, like me, my new technician had no prior experience in the type of experiments the research required. The then-Director of Roswell Park,

George Moore, MD, came to my rescue in another moment of serendipity! |ran into Dr. Moore one day in the hallway and he asked about my research. |guess he thought it was worth doing because he not only allowed me use of his laboratory but he also made available to me one of his technicians, who taught me cell culture techniques (growing cells on a plastic plate under sterile conditions)—a skill essential to my work.

CHAPTER 6

Of Mice and Men:

Success from a Failed Experiment Skipping over the chemistry (it wasn’t very interesting anyway); |did in fact make acompound that generated oxygen using the same type of radiation used in treating cancer. However it was obvious, even to someone as green as |was that the drug would have to be safe in humans. How does one determine this? We

tested both normal and cancer cells in a culture. My wonder drug killed the cancer cells—right along with the normal cells! The drug would be too toxic for patient use! It was clear that this project was not going anywhere. But, in fact, this failure was a blessing in disguise! While testing the toxicity of the radiation sensitizer, |was shown a method called vital staining that tested the viability of cells in culture. The method requires the use of a light-emitting,

non-toxic compound called fluorescein. Only the live cells remaining after adding the photosensitizer

emit the light; the dead cells do not. Thus the number of live cells and dead cells can be compared under a microscope to determine the degree of toxicity. During my learning process, a technician warned me not to leave my cultures in the light after adding the fluorescein because all the cells would die!

|immediately wondered: Had anyone applied this concept to treat cancer? |prepared a new culture of cancer cells, added fluorescein, and then placed the culture plate on the windowsill (it was a sunny day). Sure enough, all the cells died! To be sure that it wasn't the heat killing the cells, | repeated the experiment without the fluorescein, and all the cells survived! |repeated this experiment over and over to convince myself that |wasn’t delusional until one of the researchers in an adjacent lab chided, “All right already, it works! Move on!”

Back to the library! Since this was the early /Os, |did not have a computer so |searched for information the old-fashioned way—poring over relevant cancer and chemistry literature. |found a reference to a process called the photodynamic effect in a 1900 paper published by a German researcher named Oscar Raab, who described the destruction of paramecium (a single cell organism) when the organism was exposed to a certain dye and light. That was all |found. Of course that does not mean that relevant information didn’t exist: in fact, over time, |discovered that others had tried

this approach but it was never pursued as a viable therapy, partly because the most important variables had not been optimized.

|knew going in that no one would accept the promise and potential of this therapy without sufficient animal data. Of course, like everything else

back then, |did not know the first thing about doing experiments using laboratory models.

|again relied on the generosity and patience of several Roswell Park faculty and staff. Theodore S. Hauschka, PhD, Director of Experimental Biology was one of the world’s leading experts in developing strains of syngeneic mice (mice with the same genetic makeup). He willingly lent me his lab and his technicians to show me the ropes. Several mishaps occurred; some of the mice escaped from their cages as |was learning to handle them.

lt was great entertainment for Dr. Hauschka and others in the lab to watch me chasing the liberated mice as they raced across the floor. My outbursts

drew roars of laughter: / got one! Oops,it got away! |caught one, but it’s trying to bite me! It was a comedy of errors. Finally a colleague showed me how to properly handle mice and how to painstakingly implant a small piece of tumor under the skin, which, after a few days growth, would be ready for treatment. |eventually got the hang of it!

CHAPTER 7

Hematoporphyrin Derivative: (HpD) as a PDT Agent? We determined that for PDT to successfully destroy tumors without irreversibly harming the surrounding normal tissue, three conditions had to be

caretully controlled: « The photosensitizer dose (fluorescein, in this case) « The light dose, which, in these very early tests, was a slide projector (and later a small xenon arc lamp) fitted with optical filters to emit only the

green light which is best absorbed by the fluorescein.

«The time interval betweendruginjectionand light delivery. Our early PDT treatments caused the tumors in the mice to grow more slowly than those in the non-PDT treated mice, but after a few weeks, the treated tumors resumed their normal growth rate. Nonetheless |was able to get our manuscript accepted for publication in the Journal of the National Cancer Institute in 1974—\the first published paper describing PDT as a potential cancer treatment.

But simply slowing down tumor growth was not our goal, and |wondered why fluorescein did not work as well as |had expected. From the photochemical literature, |learned that the green light needed to activate fluorescein does not penetrate tissue very deeply. What was required was a photosensitizer that could be activated by red light, the most tissue-penetrating color in the visible spectrum.

Do you remember when you were a child and shonea flashlight through your hand and saw red light on the other side? This is not blood as some thought; it was red because only red light can go through your hand. The other colors that make up the white light from the flashlight are absorbed

within the tissue. |needed a compound that absorbed red light! At this time, another accident of fortune occurred. |attended a dissertation defense at Roswell Park, which was also attended by a University at Buffalo biochemist, Michael Anbar, PhD, who |had met briefly before. We chatted after the presentation,

dilemma of finding a tissue-penetrating

and |described my research and my current

photosensitizer. He told me about a group at the Mayo Clinic that was working on early detection of cancers

(when they are more likely to be curable) by using the red light-emitting properties of a material called hematoporphyrin derivative (HpD). HpD is a

member of a class of molecules that are capable not only of light emission, but also of inducing a photodynamic effect that can potentially destroy

cancer. Since HpD absorbs light in the red portion of the light spectrum, it likely would induce the lethal photodynamic effect at depth. This was just what |needed! |found publications from the Mayo Clinic team describing their use of HpD for detecting cancers. By examining tumors that had been surgically

removed, the researchers found that the HpD injected into patients the day before surgery had collected in tumors and emitted the red light as expected. However, before they could administer HpD to patients, the researchers needed FDA approval for this ‘new drug.’ They filed an IND

(Investigational New Drug) application with the FDA, adocument that, among other things, must include the results of preclinical toxicity studies to prove that HpD is safe.

The HpD used in these studies was prepared at the University of Minnesota by Professor Sam Schwartz. A physician who also dabbled in chemistry, Dr. Schwartz was making novel types of porphyrins from hematoporphyrin, a material derived trom blood. A new material resulted but

interestingly, neither the Mayo scientists nor Professor Schwartz knew the structure of this modified HpD so they called it simply hematoporphyrin derivative, or HpD. As it turned out, HpD would be a game-changer in our advancement of photodynamic therapy. |was not sure how to make the HpD and, considering my past experiences, |was reluctant to just go ahead blindly. | knew from the Mayo reports that it was derived from hematoporphyrin treated with a mixture of two acids—acetic acid and sulfuric acid. However, no details of the actual preparation were available. After several failed attempts, |obtained a material that seemed close to the HpD reported in the literature.

At this time, | recruited two colleagues trom DuPont—Donn Boyle and Kenneth Weishaupt—to work in my lab, and we continued to research different ways to synthesize the HpD until it could be reproduced and tested in a mouse breast tumor model. After playing around with various

HpD dosages, time intervals, light wavelengths and red light doses, we were able to move to the next step: a large animal study to determine the effectiveness of this treatment. We found that, in some of the mice, the tumor had been completely eradicated, and the mice were cured. We wrote up the results, and our second PDT paper was published in 1975 in the Journal of the National Cancer Institute. |remember that one of the reviewers questioned our use of the word “cure” in that paper. In mice it is acceptable to consider 90 days without recurrence a cure. However the reviewer had a point. It could be misconstrued that a cure would occur in humans as well. There was a long way to go to prove that.

CHAPTER 8

Running Interference:

A Clash of Opinions While the research was going well, |was continually butting heads with the newly appointed Director of the Radiation Oncology Department. For one thing, he insisted that his name appear on all of my publications. By this time, |was publishing PDT papers in several peer-reviewed

journals. |pointed out to him that he had not contributed scientifically to my research. He countered that as department chief, he had the right to have his name on all publications originating in his department. Roswell Park was then associated with both the New York State Department of Education (through its affiliation with the University at Buffalo)

and the Department of Health. |obtained a copy of the University rules on authorship, which clearly stated that in order to be included as an author an individual had to have to contribute directly to the research. |sent the “rulebook” over to my department head and heard nothing further. He was, however, rather chilly toward me after that, and was clearly not supportive of my research, especially after | had changed my focus from ionizing radiation to light-activated

therapy. He later got back at me

during a visit from Eric Hall, PhD, a well-known radiation biologist at Columbia University and the author of what was generally considered the’ bible’

in the field. |was still doing some teaching in this area and was very much looking forward to talking with him. Dr. Hall was curious about PDT, and | happily gave an overview of our work. My department chief, who interrupted us, told Dr. Hall that PDT was going nowhere and then changed the topic to a project he was interested in. It was hard enough to convince scientists and physicians (both inside and outside of Roswell Park) that |was not on some quixotic quest, tilting

at windmills, without my department chief publicly torpedoing my research! A few months later, |was invited to present a lecture on PDT at the University of Rochester. Since by that time we had clinical as well as animal data, both were included in the presentation. |had already started the lecture when in bursts the head of the Department of Radiation Oncology at Rochester, noisily taking a seat in the front row. |knew he wasa close friend of my department chief and felt somewhat uncomfortable. Undaunted, |proceeded to share our PDT clinical results, with before and after pictures of patients—all of whom had exhausted all possible treatments before

receiving PDT as a last resort. Many of the patients had advanced breast cancer—some with lesions that had spread to the chest wall. Our results indicated that PDT was highly effective in removing these cancers; however it did not prevent new lesions from appearing Later.

CHAPTER 8

Running Interference:

A Clash of Opinions While the research was going well, |was continually butting heads with the newly appointed Director of the Radiation Oncology Department. For one thing, he insisted that his name appear on all of my publications. By this time, |was publishing PDT papers in several peer-reviewed

journals. |pointed out to him that he had not contributed scientifically to my research. He countered that as department chief, he had the right to have his name on all publications originating in his department. Roswell Park was then associated with both the New York State Department of Education (through its affiliation with the University at Buffalo)

and the Department of Health. |obtained a copy of the University rules on authorship, which clearly stated that in order to be included as an author an individual had to have to contribute directly to the research. |sent the “rulebook” over to my department head and heard nothing further. He was, however, rather chilly toward me after that, and was clearly not supportive of my research, especially after | had changed my focus from ionizing radiation to light-activated

therapy. He later got back at me

during a visit from Eric Hall, PhD, a well-known radiation biologist at Columbia University and the author of what was generally considered the’ bible’

in the field. |was still doing some teaching in this area and was very much looking forward to talking with him. Dr. Hall was curious about PDT, and | happily gave an overview of our work. My department chief, who interrupted us, told Dr. Hall that PDT was going nowhere and then changed the topic to a project he was interested in. It was hard enough to convince scientists and physicians (both inside and outside of Roswell Park) that |was not on some quixotic quest, tilting

at windmills, without my department chief publicly torpedoing my research! A few months later, |was invited to present a lecture on PDT at the University of Rochester. Since by that time we had clinical as well as animal data, both were included in the presentation. |had already started the lecture when in bursts the head of the Department of Radiation Oncology at Rochester, noisily taking a seat in the front row. |knew he wasa close friend of my department chief and felt somewhat uncomfortable. Undaunted, |proceeded to share our PDT clinical results, with before and after pictures of patients—all of whom had exhausted all possible treatments before

receiving PDT as a last resort. Many of the patients had advanced breast cancer—some with lesions that had spread to the chest wall. Our results indicated that PDT was highly effective in removing these cancers; however it did not prevent new lesions from appearing Later.

During the Q&A, my ‘friend’ in the front row stood up and declared that my research offered nothing that hadn't been done before with radiation

therapy. When | reminded him that our patients had failed radiation therapy as well as other standard treatments, he huffed out of the room! | surmised—perhaps unfairly—that my department chief had gotten to him!

CHAPTER 9

“Elegant But Impossible”:

The Best Backhanded Compliment |Ever Received Three years had passed quickly since |received my original National Cancer Institute grant for the radiation sensitizer project, and my funding would soon come to an end. It was time to write a new grant to support the PDT Program. In 1973, |submitted my grant proposal to the NCI Radiation Study Section—the same review section that had approved funding of my first grant. As may be obvious, the members of this review group were radiation physicians and scientists but |thought that PDT was a good fit since it is, in many

ways, related to radiation therapy. |was more than a little concerned about acquiring funding this time around. |had run into much skepticism about PDT from many people, even from my colleagues at Roswell Park. The most negatively biased were radiation physicians and scientists—not because they did not trust the data but

because they considered PDT to be in direct competition with ionizing radiation. My PDT grant would not be an easy Sell, particularly to this group of reviewers, but |was still a bit taken aback by their response. My grant proposal was rejected outright!

|read with some amusement one reviewer's succinct comment: An elegant idea, but everyoneknows that visible light does not penetrate tissue, so no therapeutic effect is possible. That was the best backhanded compliment |had ever received. It hadn’t occurred to me that the basic premise of our

proposal—that light could penetrate tissue—would be contested. After all, we were all kids once playing with flashlights, and observing with awe and delight the red light—the very wavelength used in PDT—that shone right through our hands. While it is true that the light is reduced as it penetrates tissue, |Telt that we had resolved that issue by devising and using state-of-the art lasers that delivered light through fiber optics that can be strategically placed inside the body to reach most cancers.

We had the data, of course, but obviously didn't explain our results well enough. |expected the reviewers to accept our claims at face value, and they hadn't. My nonchalance in making certain assumptions was interpreted as intellectual arrogance—a misunderstanding |would not allow to happen again.

The reviewers weren't the only “Doubting Thomases” who questioned our claims. Gerald Grindey, PhD, one of my Roswell Park colleagues was one such disbeliever, so, to change his attitude, |suggested that he conduct his own experiments independently. We supplied him with HpD and a light source, and he treated his own implanted mouse tumor models using our parameters for dosages and time intervals. Our research had demonstrated

that it took from one to three months to ensure that the tumors showed no signs of regrowth. After one month, Jerry admitted that he had been wrong, saying simply, “Well, I’ll be damned. It really does work!’ This was helpful because we now had unbiased independent confirmation that Jerry was more than willing to share with his fellow skeptics. |did not let the reviewers’ impressions go unchallenged. |marched over to the library and found a photograph from the Mayo Clinic showing red light traveling through an entire human breast! This type of trans-illumination

had been tried by researchers in an attempt to find breast cancer at

an early, more treatable stage. Although the use of PDT as a method for early cancer detection was subsequently abandoned for being ineffective, | made my point: red light does penetrate human tissue. The following year, |rewrote the grant, this time including extensive explanations and photographs to support our claims. And this time around,

|requested that the Chemotherapy Study Section, not the Radiation Study Section, review the grant proposal. |was hell-bent on making believers of them all and |did; the grant was approved for funding. Ironically as PDT progressed and presentations and published papers demonstrated its wide application, Frank Mahoney, MD, head of the NCI Radiation Study Section, asked that future PDT grant applications be forwarded to his section—the study section that had rejected my first PDT application—for review. He, too, becamea believer. Our grants began to be funded more frequently, and Dr. Mahoney provided important input on PDT to the radiation doctors who dominated this study section. And eventually, PDT investigators were added as primary reviewers for PDT grants. Even so, with only two or three PDT experts within the larger voting group, PDT grants had a hard time in this section, especially when funds were tight. However, |am proud to say that my research team at Roswell Park continuously received sufficient funds to continue our PDT studies.

CHAPTER T Q

New Directions, New Staff and Graduate Students:

The PDT Program Expands Our federal grants allowed me to add additional support staff to the PDT Program. In addition to my lab techs Kenneth Weishaupt and Donn Boyle, | was now able to take on my first PhD graduate student, Chuck Gomer. Neither Chuck nor |knew anything about drug development—two babes in the woods! By the time Chuck arrived, |had already been studying HpD as a photosensitizer for PDT. Chuck’s main project was a pharmacokinetic one—to determine the uptake of HpD in blood, its clearance rate from blood and distribution in animal tissues and mouse tumors. This was the first time this had been done and it revealed highly pertinent information for future clinical use. Based on the Mayo Clinic data, HpD was assumed to be a tumor-selective drug; Chuck actually discovered that HpD could be found in almost all organs, several with higher absorption levels than the tumor. This was critical information since the light activation would need to be as selectively delivered to the tumor as possible to avoid normal tissue damage. We learned, too, that patients would need to protect themselves trom bright light, especially sunlight, until the HpD had cleared from the skin. Chuck did this work pretty much on his own. Chuck's independence and boundless imagination continued during his professional career, resulting in many original publications

and

recognition in the PDT arena. He was also a Ttrequent reviewer in the NCI Radiation Study Section to which most PDT grant applications were

submitted. He has been head of the school board in his community and recently has become Head of Faculty at the University of Southern California. lt takes a special type of person to benefit from a hands-off method of teaching. |should note that |was a beneficiary of this approach during my graduate research at OSU. My preceptor had 17-20 graduate students under his wing and most of his time was devoted to closely mentoring those

nearing completion of their training. For the new students, he would define the project and then it was sink or swim; some sank, others perfected the buttertly- and back- strokes! Often, the more senior graduate students would help the newer students become acclimated and teach them the basics. If you really got stuck you could always go to your preceptor, just not too often. At Roswell Park, |selected grad students with the right mix of talent, resourcefulness, and curiosity, and while my mentoring style was not entirely “sink or swim,” (|was always available for questions and support). |did expect each student to contribute their own ideas and insights and to be as self-

sufficient as possible. As a result, each of my grad students rose to every challenge, and over the years their value to our team—and their continued contributions to the Photodynamic Therapy field—proved immeasurable.

With continuous NCI funding and help from the Oncologic Foundation of Buffalo (see Chapter 21), we were able to keep our program going,

without any lapses,for over 30 years. Ultimately, with this funding we were able to significantly expand our PDT Program, adding senior and junior faculty as well as support staff, such as research nurses, laser operators, secretaries, and technicians thereby increasing the number of grant applications and new PDT studies; and expanding research opportunities for agrowing number of master’s and doctoral students interested in PDT research. With these increased funds, we

were able to spend most of the next few years optimizing PDT treatment for a variety of different types of implantable tumors in rodents. As we advanced in using more sophisticated equipment in applying PDT, it was clear that we needed a physicist. As it turned out, Bill Potter was a physicist was already an employee at Roswell Park, working with a group doing research using x-ray equipment? His position was funded by a grant

and his tunds were running out. |recruited him to our PDT team. An expert in electrical and optical technology, Bill quickly became indispensable in maintaining and repairing the lasers used in both our basic science and clinical studies.

That chance meeting of Dr.Smith in the airport wasn’t the only stroke of luck for us in 1981. BarbaraHenderson,PhD,joined out PDT team that year. She basically just appeared one day. |noticed ayoung woman sitting alone in a vacant office. |had no idea that she was, where she came from and what she was doing in our department; |just assumed that our department chief had hired her. He did, of course, but he failed to introduce her to the team, so we all thought she was working directly with him on a project. |must admit that |pretty much ignored her. After a while, |noticed she seemed to be doing very little. Finally she approached me and asked why she was not part of our group. Apparently, this was the intention all along.

Her recruitment turned out to be one of the best things that could have happened! An outstanding scientist, Barbara quickly found her own niche by launching a study of the mechanisms of PDT, an area that had been largely ignored up to that time. Her work, for example, demonstrated conclusively that PDT with the photosensitizer HpD produces a vascular effect that damages cells, which ultimately die due to a deficiency of oxygen and nutrients. This information

would later form the basis for QLT, a start-up company in Vancouver, Canada, that develops PDT for the treatment of

macular degeneration (see Chapter 23).

As time went on, Barbara obtained several major research grants and supervised many graduate students, becoming a key member of our team. In fact, she took over as head of the PDT Center when | retired in 2002 and did an exemplary job with a program that expanded considerably under her leadership.

CHAPTER T T

Preparing for Clinical Studies |am about to tell you more than you ever wanted to know about how a new drug or method goes from inception to actually treating patients. |think you will be impressed by the rigor required of the FDA, before this can happen. After treating hundreds of mice with PDT, and accumulating a considerable amount of scientific data, it seemed time to consider doing a phase | clinical trial on the treatment’s effectiveness in humans. There are three phases of clinical trials required by the Food and Drug Administration (FDA)

to bring a new drug to commercialization. « Phase I: A new drug or treatment is tested in a small group of people for the first time to evaluate its safety, determine safe dosages, and identify side effects.

« Phase Il: Based on the information from the Phase |study, the drug or treatment is given to a larger group of people to see if it is effective and

to further evaluate its safety. « Phase III: Assuming all goes well up to this point. The drug or treatment is given to large groups of people to confirm its effectiveness, monitor

side effects, compare it to commonly usedtreatments, and collect informationthat will allow the drug or treatment to be used safely. Phase Ill studies are often carried out in several medical centers, each following the same protocol provided by the sponsor—generally a commercial drug company that has developed the drug in-house or acquired the rights to the drug from an academic institution or a smaller company. These studies are generally very expensive and require several years to collect sufficient clinical information to convince the FDA that the drug or

treatment is both safe and effective for commercialization. This is where patents for the drugs become critical—a subject that will be discussed in greater depth later on in this book (Chapter 19).

Our vast experience with PDT to treat breast cancer in mice led me to believe that this disease would be a good starting point for us. |approached Thomas Dao, MD, the head of the Breast Surgery Department at Roswell Park, and shared with him our laboratory data. He seemed amenable to collaboration.

His group was studying breast tumors in rats, so he suggested we use PDT on these larger rodents first to determine if we would get a similar

response.The rat tumors measured about 1.5 inches—significantly larger than our mouse tumors, which were less than one-quarter inch. This afforded us a challenging opportunity to prove that PDT was as effective on larger tumors.

The Breast Service technicians provided us with tumor-implanted

rats. We let the tumors grow to a specified size and found that a longer time of

iilumination was necessary to obtain complete tumor eradication. Demonstrating that PDT was potentially useful for treating breast cancer, |sent the data to Dr. Dao, who, for some reason, never got back to me and could not be reached when| called him.

This was the first time |learned that if a physician is not interested in PDT, it's awaste of time to try to convince him/her otherwise, no matter how compelling the laboratory results! With considerable trepidation, |approached other members of our clinical faculty to initiate a clinical trial, but |had no takers. They had their own

projects and preferred to continue these rather than take on another project of “dubious merit.” |had learned that Arnold Mittelman, MD, Chief of the Colorectal Service at Roswell Park and a brilliant surgeon, had a very large grant from the National Institutes of Health that supported the entire surgical staff covering all of the cancer specialties—for example, urologists, brain, esophagus,

colo-rectal and so on. This gave Dr. Mittelman considerable leverage with the surgical teams. Erudite and thoughtful, Dr. Mittelman was a true visionary who always saw the bigger picture, thank goodness! |met with Dr Mittleman, expecting the same cold shoulder |received from other clinicians. When |explained our PDT results in animals, and our

desire to take this treatment beyond the laboratory and into the clinic, he responded enthusiastically and without hesitation: “Sure, let's do it!” There is no doubt that there would have been no PDT Cancer Therapy, anywhere in the world, without Dr. Mittelman’s involvement direct involvement!

The first step in initiating a clinical trial is to prepare a detailed description of the study, referred to as a clinical protocol. The protocol must spell out the background of the disease to be treated and the rationale for the study. It must describe exactly how the treatment will be delivered to patients, and list all possible known side effects of the treatment, no matter how remote the possibility of them occurring. Once written, the protocol

has to be approvedby an in-house committee of experts referredto as the Internal Review Board (IRB). Once again, the learning curve was steep. |certainly had no idea how to write a clinical protocol! The head of our IRB at that time was Harold O. Douglass, Jr., MD, and Associate Chief of Surgical Oncology, who was kind enough to serve as my mentor in the preparation of this comprehensive

treatment plan. He even shared with me samples of other well-written protocols that had been approved. Our first protocol was very broad, allowing PDT treatment for patients with any type of solid tumor, such as those of the bladder, lung, breast and prostate, while excluding blood cancers such as leukemia. Assuming approval by the IRB, the protocol becomes just one component of a much more extensive document to be sent to the FDA—an IND (Investigational New Drug) application. This “next step” can be quite expensive since, in addition to containing everything known about the drug, the IND application mandates a large toxicity study in animals, which alone can cost up to $200,000.

However, we thought that we were exempt from filing an IND application with the FDA, since we were treating only patients within the State of New York (intrastate) and the FDA has jurisdiction novices, often shooting in the dark.

only over interstate studies. This mistake would later come back to haunt us. As |have said, we were

CHAPTER T 2

Lesson

1: A Mouse Is Not

a Human

In 1976, Dr. Mittelman aggressively began recruiting patients for our PDT Phase| clinical study, assigning one of his research fellows, Jerry Kaufman, MD, to assist him. This led to a rapid accrual of patients.

Because of his large NIH grant, which funded most of the other surgeons’ studies, Dr. Mittelman had unlimited access to both surgical and chemotherapy patients (who at that time were treated by the surgeons. The patients enrolled in our study had advanced disease and had failed all conventional

treatments.

Dr. Mittelman and | meticulously described PDT to potential study participants, describing what they could expect before, during and after treatment. The patients, and their family members, were encouraged to ask as many questions as they had. If they said that they understood he asked them to sign the requisite patient Consent Forms, which outlined, in simple, easy-to-understand

language, all aspects of the study included all

possible side effects. |was present to help with any technical questions about PDT. Patients understood that PDT would not be curative because of

the advanced stages of their diseases. Nonetheless they were willing to try PDT for the benent of future patients—not an uncommon response trom late-stage patients who enter clinical studies. |saw this in our first patient and most of the others we treated with advanced disease. In 1974, we treated our first patient—a middle-aged woman with colon cancer whose disease no longer responded to standard chemotherapy.

Her cancer was so aggressive that it had protruded through the skin, causing lesions on the right side of her body. This patient had altruistic reasons for enrolling: she wanted to help advance science and medicine so that future cancer patients would not have to suffer. We went over the patient

consent form with her and explained everything we knew about PDT. The Study Protocol spelled out how we would administer the treatment; our calculations of the conditions (HpD dose, Light dose etc.) were based

on our experiments with animals. We assumed we could use the same conditions to treat humans taking into account the difference in drug clearance between animals and humans. We expected to spare normal tissue as much as possible although some was purposely included in the area exposed to the light since it rarely was possible to know the exact extent of the cancer. We quickly discovered that humans are not mice! The entire treated area, including some normal tissue, became badly damaged, resembling a severe burn. Our patient had been over-treated and was in terrible pain. She was given barbiturates to provide some relief. With a heavy heart and guilt, |returned to the hospital in the evening to check on the patient. Surprisingly |found her sitting up in bed, alert and comfortable. |apologized

for causing herto suffer. She took my hand and said to me, “I know that this treatment will not cure me, but if it will help other patients in the future lam more than willing to accept the pain."

Here she was, comforting me when |was there to try to comfort her! Learning from our mistakes, we quickly adjusted the treatment parameters to ensure that this would never happen again. What did we learn from our Phase |study? The most important lesson was how to use PDT optimally. We determined the correct dose of HpD, how long to wait before the light treatment and how much light is required. In addition, we found that PDT could be carried out up to three or four days

after injection of the HpD. This is not true for most of the newer PDT photosensitizers since they clear from the tumors a short time after injection. While toxicity was the main objective of this Phase |study, we also got an idea of how well PDT worked by observing the tumor response. These data were critical in treating future patients. For example, skin cancers on the face (a common site) that are generally treated surgically often leave scars. We found that PDT can cure these cancers without scarring. PDT is now routinely used to treat skin cancers caused by sun damage, provided the lesions are not deeply embedded.

When the results of these early trials were published in journals or presentedat national and international meetings, interest among scientists and more importantly, physicians, grew. Physicians would approach me at meetings and ask how they could get involved. After about two years we had assisted more than 20 cancer physicians in setting up their own PDT centers. This was of great help in spreading knowledge of and use of PDT.

Through their efforts, progress was accelerated. Down the line, they introduced new indications for PDT that we were not doing at Roswell Parktreatment of brain, esophageal and lung cancers, for examples. Ultimately their published research expanded the field and played a critical role in convincing others of PDT's legitimacy and wide application.

CHAPTER T 4

Buffalo, We Have a Problem!-

The FDA Sets Us Straight After treating about 30 patients between 1976 and 1978, |presented the results of our study in 1979 at a special workshop funded by the National Institutes of Health in Washington, DC. Several representatives of the US Federal Drug Administration were in the audience. When | returned home, | received a phone call from an FDA representative, who had heard my presentation. He asked me why we hadn't submitted an Investigational New Drug (IND) application (see Chapter 11) for the study |presented. My reply was that the entire study and all patients

were from New York (intrastate) and, it was my understanding that the FDA had jurisdiction over interstate studies only. His response was “Where did you get the bottles for the drug?” He might as well nave said “Got’cha!” We subsequently filed an IND application, and the FDA allowed us to continue with the patients we had already treated but required details and specific approval for any new patients we proposed to add. This slowed down patient accrual, but we couldn't complain: the FDA agreed to all our requests. We did have one break here. As we prepared the IND, |remembered that it is possible to cross-reference an existing IND with permission from the holder. The Mayo Clinic had an HpD-IND on file with the FDA for using HpD for tumor detection. They allowed us to cross-reference their IND with the

FDA (that allowed the FDA to apply their information to our IND since we were using the same drug, (HpD), This precluded us of the necessity to re-do all the toxicology on HpD, This information, together with our clinical data, expedited the IND process that not only takes a very long time but is very expensive. The FDA allowed us to re-start our clinical study in 1980.

CHAPTER T 4

The Dog (and Cat) and Pony Show: Pet Projects In 1979, my team and |met with Richard “Dick” Thoma, DVM, a local veterinarian, who was considering using hyperthermia to treat cancer in dogs and cats. He sought us out after learning that hyperthermia, an experimental therapy that elevates the body's temperature to fight diseases, was being Studied and tested at Roswell

Park.

Another rare and serendipitous opportunity presented itself, and we seized upon it. We offered Dick what we felt was a safer, equally effective alternative to hyperthermia—PDT.

Impressed with our scientific and clinical data, he agreed, and thus began a longtime friendship and mutually

beneficial professional collaboration. It is important to clarify that the dogs and cats we treated with PDT were not lab animals; they were, in fact, Dick's “patients"—family

pets.

Since veterinary offices and clinics do not have the equipment necessary for PDT, Dick brought his animals to Roswell Park for treatment. This presented some logistical problems since our clinical lasers were housed in patient care areas—the kind reserved for humans!

We decided that we would sneak in the animals after-hours, and treat them in a radiation therapy room adjacent to where one of the laserswas located. After each treatment, we meticulously washed down all areas with alcohol. PDT was provided at no cost to—and with full consent of—the pet owners.

Late one afternoon, Dick was bringing in a dog for treatment. |met Dick at the backdoor,which was our custom. It was a sunny day and Dick had forgotten to remove his sunglasses when he entered the elevator that would take us up to the treatment area. Before the elevator door closed, someone else got in—the Director of the Institute Gerald P. Murphy, MD! Dick quickly drew the dog closer to him. With his dark glasses on and his “service dog” at his side, Dick could easily be mistaken for a blind man, and |believe that Dr. Murphy was convinced that he was. After exiting the elevator, Dick and |laughed heartily at our narrow escape. The first cat we treated was named Brandy—not the friendliest feline either. She had developed an unknown malignant tumor in her neck, which had not responded to conventional treatment and continued to grow. Two days after we injected her with the HpD (about 25 mg for a 10-pound cat)

we delivered the activating light by inserting the laser fiber directly into the tumor (the tumor was too deep for the light to reach from the surface). We had not yet done this in human patients, but this experience provided essential information that we would later use when treating human patients

with deep or large tumors. Following treatment, Brandy was returned to Dick's clinic for observation. After one week, the x-ray scan revealed no change. Had we failed? Not entirely. The tumor had indeed stopped growing. After one year, the tumor still had not progressed, and the ornery cat lived out her natural life.

We continued to smuggle in cats and dogs into Roswell Park for about a year, and then decided, for convenience sake, to install a laser in Dick's

animal clinic. Over the next two years, we treated about 100 cats and dogs with at least 25 different cancers—achieving an 89% positive response

and a 59% complete response (one year or more without recurrence in cats and dogs is considered a cure). These animals had no available treatment options and would most likely have been euthanized, so we believed that we had successfully established a role for PDT in veterinary medicine. Dick and |published our results in the journal, Veterinary Medicine, in19853. That publication elicited great interest among veterinarians. |was contacted by two academic veterinarians who wanted to try PDT on their

cats and dogs in research studies, presumably funded by their universities. |supplied Photofrin (the purified form of HpD, which we were now using exclusively) from our lab and they used their own lasers. The results they achieved were similar to those we had found in our study. In 1994, we began collaborating with Michael Magne, DVM, from the University of California, Davis Veterinary School. He planned to treat pet cats with facial skin cancer. While surgery or radiation therapy may have been possible, PDT was preferred for two reasons: it could be delivered in a single treatment, not the multiple treatments required by radiation, and it eliminated the possibility of any facial dishgurement that would have been caused by surgery. For several cats, we used our new photosensitizer, HPPH (see Chapter 25)—again using parameters determined for our human patients. The difference, before and after treatment, can be seen in the photos below.

Cat before Treatment

igh

Cat Four Weeks after PDT Treatment (Photos Compliments of Dr Magne)

Dudley McCaw, DVM, a veterinarian at the Veterinary College at the University of Missouri, also inquired if PDT could be used to treat eyelid cancer in horses—a common, but serious problem that, if left untreated, could result in the removal of the eye or euthanasia. We had had some experience

by then using PDT in combination with surgery to destroy residual cancer cells in certain patients when surgery alone was not effective. But this was a “horse of a different color", as they say. The first problem was that PDT photosensitizers generally require intravenous injection in order to circulate throughout the whole body before localizing in the tumor. Dr. McCaw wanted to use HPPH, the new experimental photosensitizer we had developed (see Chapter 25). A derivative of chlorophyll, HPPH avoids the long four- to six-week period of skin photosensitivity associated with Photofrin and HpD while producing similar treatment results. Unfortunately, we realized that there was not enough HPPH in the world to inject into a horse! |suggested that we develop a formulation that could be applied directly on the eyelid. |had actually never done this with either Photofrin or HPPH. One possibility was to dissolve the HPPH in dimethyl sulfoxide, an excellent tissue-penetrating solvent already used on horses to relieve joint pain in their legs. |“gquesstimated”the dose of HPPH, when to apply the light treatment and the proper light dose to use. After several months, | received, the before and after treatment pictures from Dr. McCaw. These photos, taken at various time intervals, clearly demonstrated the complete eradication of

the tumor. The cancer would have returned if surgery alone had been used. These results, which were later confirmed by biopsy, were replicated in eight more horses over a period of a few years and published in the journal, Veterinary Ophthalmology in 2008.

. fH

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: h — -

-

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a Horse with Eyelid Tumor Before PDT Treatment

Horse Six Weeks After Partial Surgery Followed By PDT (Photos Compliments

of Dr McCaw)

CHAPTER T 5

Launch of the First PDT Company:

We Will Need Money By 1980, it was becoming blatantly obvious that we needed guidance, expertise and direction to handle the complicated business end of drug development—services that, unfortunately, an academic center like Roswell Park was incapable of providing. We needed crucial information on patents, licensing and federal approvals if we were to move PDT forward. One day, while Ken Weishaupt, Dick Thoma and |stood in the hall outside an animal treatment room, Ken innocently posed the question: “Why

don’t we just start our own company?” We looked at each other, smiled, and in amoment of clarity and confidence, |said, “Why not?” We were adamant about taking control of a situation that seemed to be stuck in neutral. Our company would manufacture and supply HpD (and later its purified form Photofrin) to investigators both inside and outside Roswell Park. Admittedly, there wasn’t much of a market, but we had loftier

plans to get the attention of acommercial drug company to help us get to the next level of testing and FDA regulatory approvals. Essentially, we had a Field of Dreams mindset: Build it and they will come. The first thing we did was to hire an attorney to set up the company; the second was to scout locations. Dick mentioned that there was a small

liquor store for rent near his veterinary clinic in Cheektowaga, a Buffalo suburb. When we looked at the building, we realized that it was going to take plenty of work and money to convert it to an FDA-approved pharmaceutical facility. Undeterred, Ken enlisted the help of his father and the two of them got to work. Ken had a contact that was familiar with FDA requirements, and

he steered us to a company that sold self-contained clean rooms (a sterile environment essential for production of drug products). The next step was to find seed money for our little “start-up"—we estimated that we would need a “mere” $100,000. Ken approached a local bank, described our needs and convinced them to loan us $60,000; we offered up our homes as collateral. In addition, we contributed what we could and a few kind-hearted friends, who saw hope in our research, made small investments as well. Over the next several

months, |watched in amazement as Ken and his dad converted the rundown liquor store into an” FDA-compliant” drug manufacturing plant—with considerable help from the local FDA staff |should add.

We called our company Oncology Research and Development (ORD). Up and running in a record amount of time, ORD was the first spin-off company resulting from research initiated at Roswell Park Cancer Institute. This was at a time when the now ubiquitous term “translational research” —the bench to bedside transfer of new treatments and technology was non-existent!

We created a small board of directors consisting of Dick Thoma, Ken Weishaupt and his wife, Cheryl, me and a local attorney whose primary job

was to keep us outofjail. We also hired three staff members: a secretary and two technicians.

Unable to balance work at both Roswell Park and ORD, Ken left the cancer

center to become our full-time CEO, while |remained at Roswell Park and served in a consulting role to our tleagling company. The local FDA office kept a very close eye on us, with frequent inspections of the site. At each inspection, they would unroll a foot-long list of deficiencies, which invariably called for additional staff, better equipment and money we didn't have. While we balked at their overzealousness, we

soon came to realize that we owed these local representatives a large debt of gratitude for slowly bringing us in compliance with FDA regulations rather than just shut us down. |think that they actually believed in PDT and were helping us novices as best they could to bring It to fruition.

Still, it was clear that we needed money—and lots of it—to survive. As will become apparent we really were novices in this area!

Somehow a member of the Hunt family of Texas—! think they own the state—got wind of our company and our research. One of its younger members came to Buffalo and offered a nominal amount of money to acquire a 51% share of our company. Welcome to the shark tank! We countered with an offer of a greater investment for a smaller, non-controlling interest. Negotiating was out; the original offer was firm. We naturally turned it down, and, of course, that was the last we heard from the Hunts.

|conveyed our financial woes to a physician friend of mine, who suggested that we contact Abe Feldesman, an attorney from Detroit. Intrigued by our work, Mr. Feldesman flew to Buffalo where we showed him around our little company and filled him in on our plans. He said that he might be interested in investing, and invited Ken Weishaupt(CEO of ORD), Dick Thoma (the VET) and me to his home near Detroit to continue discussions. Big mistake! When we arrived, we discovered that his home was a huge old mansion, beautifully

refurbished, on the shores of Lake Michigan.

Mr. Feldesman introduced us to an advisor and friend of his, who, he said, would be part of the conversation. That night, we were wined and dined,

and treated to a performance by the Detroit Philharmonic Orchestra. We stayed overnight and after breakfast the next morning, the negotiation finally began. When an offer was put on the table by Abe and his ‘advisor’ it consisted of a small amount of money for a modest share of the company and provide assistance in obtaining FDA approval for PDT. My group met in private and we all agreed that the offer, while tempting, was in misalignment with our ultimate goals. Our potential investors had no experience in the drug approval process, a critical component that would make our treatment available to those who ultimately stood to benefit—cancer patients. We politely refused the offer and returned home. Weeks later, we were informed that our company was being sued by Feldesman for breach of contract! We had not signed anything! He claimed that Ken had promised him a large share of the company, an assertion that Ken vehemently denied. This could become a problem with any potential

future partners. We decided to settle out of court after we finally had some money from the Agreement we ultimately signed with a” legitimate” partner. This company did not turn out so great either as will be described in Chapter 20. It finally dawned on us that we had no idea how to negotiate an agreement with potential investors. At the suggestion of my brother, who had considerable experience in this area, we expanded our small board of directors to include Stan Ray, a businessman from Florida, and Richard Thompson, a lawyer from Lincoln Nebraska who was adept at negotiating corporate deals.

Some of my ORD partners were pushing for an Initial Public Offering (IPO) that would allow us to sell stock in our company to the general public at an initial predetermined price and then hope that sufficient funds could be obtained to keep us alive. |thought this “survival strategy” was a bit reckless, especially since we would have to convince investors that the company was worth the price, with the underlying expectation that the stock would, over time, increase in value. One of two things could happen: the plan could succeed, with the initial stock price increasing rapidly (or at least

staying near the initial cost the day it is offered), or it could flop and the stock would not sell at the initial price and sink like a stone along with ORD! Rather than go this route some of us, including me, preferred to partner with a pharmaceutical company to sign a licensing agreement for our patents or Tor an outright purchase. However we unanimously agreed to explore all possible options, including an IPO. We set up a business meeting with Lehman Brothers, a well-

known, global investment firm in New York City (who went down in 2008 along with many otherswhen the economywent bust), to see if they would be interested in sponsoring the IPO. They arranged for a limousine to take us from the airport to their plush corporate offices near Wall Street. Lehman Brothers had already done their due diligence on our company prior to this meeting, but they still had many questions: What is the market for PDT? How many others are currently involved in its research and development? The bottom line was that we were too small for them to bother with!

Our search for a major pharmaceutical company began, but was not going very well—they all wanted patent coverage! We should have realized this before approaching the companies. At this time we had NO patents because the photosensitizer (drug) we were using for PDT, HpD, had been in the literature for several years due to the Mayo Clinic attempts to use it for tumor detection as described in Chapter 7. We did get around this problem

as described in the next Chapter 16.

CHAPTER T 6

From HpD to Photofrin-A Patent? lf we were going to move PDT along—with the ultimate goal of FDA approval—it was clear that we would need a patent. A patent offered the best chance of partnering with a pharmaceutical company that would Nave the experience, resources and deep enough pockets to move PDT to the next level.

As previously mentioned, cancer centers—even National Cancer Institute comprehensive cancer centers such as Roswell Park—lacked the

expertise needed to effectively navigate the precariously nuanced terrain of drug development. At that time, there were no such things as inhouse tech transfer offices, translational research teams or legal counsel savvy enough to unravel the Gordian knots of red tape that impeded the

introduction of a new drug into the public marketplace. And, as often as we were prone to travel this way, flying by the seat of one’s pants is by far the least optimal mode of getting from Point A to Point B.

We would need to conduct phase III clinical studies to meet the rigorousstandards set down by the FDA, but we obviously could not afford the hundreds of millions of dollars that such large clinical studies would cost, nor did we have the know-how to coordinate these studies. We definitely needed a patent—without one no pharmaceutical company would touch PDT and provide the expertise we so desperately needed. But what to patent! |decided to try to isolate the “active” component of HpD ( we already knew that at least half of HpD was inactive as a PDT

agent) and identify its structure. This will be patentable since it is anew compound not previously known. Others had travelled this road, providing clues along the way. David Kessel, PhD, apharmacologist at Wayne State University in Detroit, was the first to suggest that HpD contained some linked molecules of the porphyrins in HpD. But what were they? That is what we will determine-we hope! | attempted to separate the HpD components by column chromatography—a

method used to isolate individual chemical compounds from

mixtures of several compounds. My experience with this separation method was sorely lacking and my best attempts proved to be futile. Time and time again, |tried, unsuccessfully, to separate these materials |was frustrated and disappointed, not knowing how to proceed...until

achance meeting

in an airport in 1981 pointed me in the right direction. Returning from a meeting of the American Society of Photobiology in California, |grabbed the last remaining seat in the airport waiting area

near my gate. In the seat next to mine was Stanford University Professor Kendrick Smith, coincidentally the founder of the American Society of Photobiology. |barely knew him, but we struck up a conversation, and |mentioned to him the difficulty |was having separating the components of HpD using standard chromatographic columns. |also mentioned that David Kessel’s research pointed to the fact that HpD may contain some linked

molecules of larger size than those used in making HpD. Dr. Smith suggested that if this was indeed the case, |should try size-exclusion columns that separate molecules by size—something |had not considered, in fact did not even know about! |couldn't wait to return to the lab to try out this approach. To my astonishment, it worked! There was an immediate separation of HpD into two

spots on the column, one brown and one red. Examining the fractions by several analytical methods, |found that the red material was mainly the

chemicalswe started with to makethe HpD. This fraction was completely inactive as aPDT agent whereasthe brownfraction was highly active. Now |had the unknown active component of HpD that opens the possibility of obtaining a patent for anew PDT photosensitizer—provided

we

could also determine its structure. Using well-known analytical methods, |found that it appeared to be a dimer (two molecules linked together) as well as the structure of the molecules joined together. This provided the basis of a new patent that was issued by the US Patent Office in 1982 not without considerable problems (Chapter 19). We named the new compound Photofrin (a combination of photo and porphyrin). This is the compound, that several years later, would be approved for

PDT in the treatment of esophageal cancer by the US FDA and health agencies throughout the World. This FDA approval was for esophageal cancer only, since this was the only Phase III clinical trial provided to the FDA for approval. For approval to treat other types of cancers a new Phase III clinical trial must be carried out for that particular cancer and submitted to the FDA for approval. This

is true for all new applications of PDT as well as for all new photosensitizers for PDT (see Chapter25) . This process is not just for PDT, but for all new drugs. This is the way the FDA system works-an4d It is the proper way! |think that you can appreciate how expensive this process becomes—a clinical

trial of this type can easily take five years and cost several millions of dollars. PDT using Phototrin currently is approved in the US and abroad for six types of cancer—with more to come!

CHAPTER T 7

Expanding the Applications of PDT:

The Japanese Connection In 1980, a group of lung surgeons from the Tokyo Medical College in Japan paid us a visit. Intrigued by the early promise of HpD-PDT, our visitors,

led by Yoshihiro Hayata, MD, Protessor and Chairman of the Department of Surgery were interested in learning it PDT could be used to treat various types of lung cancers. This meeting would lead to a milestone in the advancement of PDT. Dr. Hayata said that he would test PDT in humans if |would supply the HpD. The Japanese already had access to some of the most advanced lasers in the world. For me, this collaboration was a no-brainer.

As it turned out, our Japanese collaborators were the first to demonstrate PDT's effectiveness in lung cancer: both as a palliative treatment for obstructive lung tumors and as a potentially curative therapy for early-stage lung cancers. They used PDT to remove blockages in the airways for patients with advanced disease thus restoring their ability to breathe more easily and for patients with early stage cancers where the intent was a cure. The laser light was delivered through a fiber optic cable threaded through the biopsy

channel of a bronchoscope to deliver the laser light inside the bronchus directly to the cancer site as shown in Chapter 1. While we had always thought this might be a possibility, this was the first time it had ever been done, and it confirmed for us PDT's seemingly limitless possibilities in tackling other internal cancers such as those of the esophagus, colon, stomach, and bladder.

In fact, the Japanese team put PDT’s utility to the extreme test in the rare case of one patient who had developed early-stage lung cancer in both lungs. Surgery was not possible. While a patient can live with one lung, he/she obviously can’t live without both! Radiation therapy was ruled out because it could not be administered to both lungs, and chemotherapy was known to be ineffective. The patient essentially had no options.

Both tumors were treated on the same day with PDT and both were completely destroyed. The patient went on to lead a normal life, a rarity for most lung cancer patients. Following the initial results from the Tokyo group, Oscar Balchum, MD, the Hastings Professor of Medicine at the University Of Southern California School Of Medicine, also began applying PDT to lung cancers, especially those obstructing the airways. His results led to a large clinical

trial eventually leading to FDA approval for both early stage (for cure) and advanced stage (for palliation) of lung cancer.There were now three FDA approved applications of PDT. There were more to come.

When| first met Oscar at his office at aLos Angeles hospital, |was taken aback. Despite his global reputation, his “office” was a small cubicle with a desk loaded with papers. My discussion with him was not encouraging and |came away certain that he would not do anything with PDT. |was wrong! Oscar would wind up treating more lung cancer patients with PDT than any other physician in the United States. Together with Dan Doiron, then a

graduate student in physics at UC Santa Barbara who had done part of his graduate training at Roswell Park, Oscar learned all there was to know about PDT treatment for lung cancer. Dan was able to set up the laser and fiber delivery systems and calibrate the proper conditions for treatment. They made quite a team!

CHAPTER T 8

The Trip to China One day in early 1983, |was sitting at my desk reading a recent paper on PDT and the phone rang. It was Joseph Saunders, PhD, from the Office of

International Affairs at the National Institutes of Health (NIH). |could not imagine why he would be calling me. He explained that the United States had a program with China to exchange medical/scientific

knowledge and personnel. The host country could

select the program in which they were most interested. He told me that China was interested in PDT, and requested a visit from Roswell Park personnel working in this area, specifically me. The United States government would cover travel costs and the Chinese would cover all in-country expenses.

|had been communicating with a group of physicians at the Chinese Medical Center in Beijing, who had treated patients with PDT on their own. Sharing some of their data, they sent me a picture of a patient who had been treated with PDT for a large tumor on his lip. The patient had responded quite well. |told Dr. Saunders that |would give this request some thought and respond within a Tew days. Since the Chinese group wanted us to show them how to treat esophageal cancer—endemic in certain regions of their country—!I needed a PDT oncologist who had experience with this disease. That person would be James McCaughan, Jr., MD, from the Grant Laser Center in Columbus, Ohio.

|also wanted someone who was familiar with both PDT and HpD manufacturing. Ken Weishaupt, who had prepared the HpD for all of our studies at Roswell Park as well as for all outside investigators, fit the bill. Once Jim and Ken agreed to accompany me, |informed the State Department that we would participate in the program and arrangements for the trip proceeded. Ken contacted

Rich Newberg, a reporter ( now Senior Correspondent)

at the local CBS affiliate; WIVB in Buffalo, who thought this would make

a great publicity piece for Western New York audiences, with the potential to “go national.” The station manager agreed, and gave Rich and his cameraman, Mike Mombray, permission to accompany us overseas to cover the story. We did not know that Rich and Mike intended to bring their wives and about 100 pounds of equipment! Consequently, we ended up traveling with six people and way too much baggage. It was a problem at every

airport, but we managed—afterpayingthe extra baggagecost ( by Rich). A few months later, we were on a plane headed for Beijing—about a 20-hour trip, including layovers. Four Chinese government officials met our plane and escorted us to two limousines waiting to take us to our hotel. |was immediately escorted to one of them, while my five travelling companions—and

the equipment—were

crammed into the second vehicle. | thought this arrangement was odd, and wondered if | was being

kidnapped! |sat alone in the back seat; the two men in the front did not say a word during the rather long ride. No doubt there was a language barrier. It would be a long, tense ride.

Our hotel, most likely amagnificent grand dame in her heyday (probably left over from the English), was dirty, rundown and shabby—a mere shadow of her former grandeur. There was some confusion at the front desk when we arrived,that we could not understand. A hotel employee, who luckily spoke English, explained that she would let us Know when our rooms were ready. After wnat felt like an interminable wait, we were taken to our rooms. Mine was large enough to fit all of us! My companions’ rooms, however, were much smaller. The special treatment |was receiving was beginning to make me uncomfortable and embarrassed. Early the next morning, we went to one of the largest hospitals in China. There, Jim McCaughan would be treating esophageal cancer patients with PDT while our host doctors observed. As we headed to the elevator, we passed a large room where people were mixing various herbs for patient

treatment. We asked if we could stop and watch, but were told in no uncertain terms that we were pressed for time, and needed to keep moving. My previous contact in China, Dr Ha, later shared with me that Chinese doctors are reluctant to allow Western foreigners access to traditional Chinese

medicine practices, such as herbal medicine, massage and acupuncture, for fear of being ridiculed. We were immediately taken to the treatment room where Jim proceeded to explain how PDT was used in esophageal cancer and then treated

a patient whom the Chinese doctors had chosen and was ready to go. Jim explained each step as he proceeded with the treatment, allowing me to assist him (below).

Preparing for PDT Treatment of a Chinese Patient with Esophageal Cancer (Jim left, me right) Following the treatment Jim asked if he could see a patient undergoing acupuncture. After much pleading by Jim, he and |were allowed to

observe an acupuncture procedure that afternoon. The patient was already under treatment when we arrived. Several needles had been strategically placed at several points on his body. It was both fascinating and surreal, made even more so, by the smoke emitting from the tips of the needles that were being heated by training a low power laser beam at their tips (with punk material at the tip) to enhance the treatment’s effectiveness. At that time acupuncture was considered to be “snake oil” in the US. That is no longer the case and it is used quite extensively here, although still has many skeptics.

The next day, | presented a lecture to a group of physicians—most of whom did not understand English. This required translation after every few sentences. While |understood the necessity for this, it was challenging to speak, then stop, then speak again, in intervals that sometimes lasted minutes. This start-stop way of lecturing threw me off my stride, especially since |was speaking extemporarily from slides and not using notes. |also felt that at this rate, we would be in the lecture hall forever.

|was not far into my talk when the lights suddenly went out! Since it would take too much time to restore them, the remainder of the lecture was cancelled and we returned to our hotel. This was fine with me. We all had been run ragged and welcomeda rest. A series of unsettling incidents occurred during our stay in Beijing. One day, when we were being driven to a hospital for a PDT session, one of the

wives askedto be taken back to the hotel as she was not feeling well. When she enteredher room,she found three “cleaning ladies’” in the bathroom. She thought this was strange since there was only one cleaning rag among them. They quickly left. Later that day, |suggested going for a walk, since it was a warm day and the hotel was located in a lovely, upscale area. Four of us went out and

|noticed we were being followed from acrossthe street by two of our “hosts”. Annoyed, |went over and asked them not to follow us. While they did leave, |am sure that we were still being followed, albeit more discreetly. They were probably just keeping us safe. While in Beijing, Rich had a breakfast meeting with the CBS international correspondent at a restaurant in the Beijing Hotel. They sat in the middle of the huge, but nearly empty restaurant. The correspondent confided that he was constantly being watched, and wanted to take no chances with anyone spying on their conversation.

We were all sufferingfrom a healthy dose of paranoia,but the trip was about PDT and how its use and application could benefit cancer patients. Sometime prior to our trip, Dr. Ha had sent me photographs of a patient he had treated with PDT. This patient, a farmer, had a large cancer on his right hand that was recommended be amputated! If this were to occur he would not be able to continue his only source of food and income since his

left hand had been injured previously. |!am not sure how it came about but he had PDT instead. The tumor responded completely saving his hand. Rich Newberg and his camera man Mike Mombray obtained before and after treatment photos to prove the outcome.

We were told that the patient lived in a rural area and could not afford to travel into the city. Not to be deterred, Rich suggested that we go to the patient. “Impossible,” exclaimed our hosts. The patient's farm was near a military installation, and no unauthorized persons were allowed in the area. After considerable

discussion,

acompromise was reached. Our hosts would bring the farmer to a site near his farm (actually the government's

farm)

and we would meet him there.

Jim met the farmer and engaged him in a long, translated discussion about his care and treatment. Jim was satisfied that the tumor was indeed

gone—another major success for PDT. As we traveled from city to city within China, seeing and treating cancer patients, we would usually end up dining with local political leaders at small banquets. The wives were never invited. At our first feast, we were served an alcoholic drink called moutai, along with a wine of some sort. These were meant for toasts—of

which there

were many. We were told that moutai was a bit like gin, but would not give you a hangover no matter how much you drank. Moutai was like no gin

that |had ever tasted; it emitted a pungent odor and tasted like gasoline. |would stick to the wine for the toasts. Jim was seated next to the mayor of the city. An outspoken, no-holds-barred type of guy, Jim would fill up any conversational lulls with comments and questions that could be construed as less than culturally sensitive. For example, Jim mentioned that he had seen many billboards promoting the

“One Family, One Child" message. |could see where this was going and gave Jim a kick under the table, which, of course, he ignored. As expected, Jim turned to the mayor and asked him how many children he had. “Four”, replied the mayor. Pressing on, Jim asked how this could be when citizens were allowed only one. The mayor laughed and said something in Chinese that was, of course, not translated for us. Just as well. Upon returning to Buffalo, Rich Newberg prepared a mini-documentary of our trip entitled “On A Beam of Hope,” which ran on WIVB-Channel 4

in Buffalo and also was picked up by several CBS affiliate stations outside of Buffalo. Roswell Park’s Medical & Scientific CommunicationsOffice was subsequently kept very busy with the influx of calls and interview requests from local, national and international media outlets that were interested in giving voice to our story. For example, |was invited to participate in a live local TV Call-In Program, where after a short description of PDT, people could call in with

questions. There were many calls, usually asking if a cancer patient, often themselves, could be helped by PDT. Most of these patients had been treated previously or currently being treated. The answer |usually gave was, either it was not possible (if |knew this from experience), or they should call Roswell Park for consultation with a physician. This is a situation where |must be very careful to explain that |am a PhD doing clinical cancer research, not an MD who treats cancer patients, both of whom carry the title "Doctor".

As an aside, in England MDs often are referred to as Mister and PhDs have the Doctor title! In fact the Doctor title originally referred to a person who has achieved a high degree of learning—that of course would include MDs.

CHAPTER T 9

Patents and Patience |noted in Chapter 16 that a patent would be crucial to the future of PDT. The basic reason for obtaining a patent from the US Patent and Trademark Office (USPTO) on any new invention is to protect the inventor, who owns exclusive rights to his/her invention for 20 years. During that time, no other person or company can use the patented invention without first obtaining permission from the patent holder or holders—often requiring a payment.

A patent consists of three main parts: 1. An Introduction that describes the need and rationale for the invention

2. A detailed Description of the invention

3. A Claims section that meticulously outlines the specific protections for the invention—this is the most critical portion of the patent since the patent will cover only these claims. Most often the claims section will be prepared by a Patent Attorney. The application

is submitted, with a fee, to the USPTO—often

with simultaneous

submissions to various other countries. After

patent examiner will respond, often accepting some of the claims and rejecting others. This begins a back-and-forth

afew months, a

process between the examiner

and the attorney(s) representing the individual or company. The attorney will try to refute the basis for the rejection-not always successfully. The initial patent, good for 20 years from the date of submission, may be extended if the FDA approval process, when it occurs, is very lengthy. The extension is determined by the Patent Office with consideration of the patentee’s request. There was a patent process of sorts in place at Roswell Park—and the University at Buffalo—for staff and faculty inventors seeking patents. It was, however, clumsy, inefficient and frustratingly

slow. Roswell Park would forward the patent information to the Patent Corporation, in New York City, a

company that would obtain the patents for clients. After reviewing the information, the company would agree to prepare the patent—for a fee and possibly royalties, or decline to proceed. In the US, if the information in the patent has been disclosed publicly in any way, the patentee has only one year to Tile for the patent and have it accepted for consideration by the USPTO; after that, the patent application is rendered invalid since it is now considered to be in the Public Domain.

In 1979 |had given a presentationat a national meeting describingthe structure of the active component of HpD (Photofrin)—the basis for our patent application. The 12-month countdown began. Roswell Park sent all of our information to the Patent Corporation to prepare and submit our

patent application to the USPTO. After

11months of foot dragging, we learned that the Patent Corporation had declined to proceed with our patent!

For all practical purposes, this decision could mean the end of PDT and our company. Devastated and angry, a few of us got together to discuss our

next steps. Time was running out. Vocal and decisive, Ken Weishaupt announced, “The hell with Roswell”. We'll apply for the patent ourselves.” We hired an outside patent attorney—paying him out of our own pockets—and spent hours bringing him up to speed on our “invention.” Losing no time, he filed a rather short patent application ( referred to as a Provisional Application) to the Patent Office on our behalf that was accepted by the Patent Office—one week before the one-year deadline! This initial Provisional Patent sets the beginning date for the 20 year patent protection,

duringwhich no others can obtain similar patents. A short time later amuch more extensive final patent must be sent to the Patent Office to secure all the claims and constitutes the final patent

to be issued. This initiates considerable interaction between the patent attorney and the individual assigned the patent at the Patent Office. The entire process trom the initial filing to issuance of the patent by the Patent Office can take several years-but we are protected in the meantime by our initial filing. Finally in 1982 our very first patent was issued! The claims in our patent had been considerably reduced to 5 claims among the initial filing of 120 claims initially filed. application that we filed contained more than 120 claims. We included everything we could think of; most applications

contain anywherefrom five to 20 claims. Howeverthe remainingclaims turned out to be extremely helpful in the future sincethey provided basisfor obtaining several new patents-each one extending the time Tor keeping PDT under our wings. Our first patent was issued in 1982. We thought we were off and running. Not quite! About this time, officials at Roswell Park became aware that our company had obtained the PDT patent that their surrogate, the Patent

Corporation,had rejected. |think they also finally becameawarethat PDT was a potential new way to treat cancerand that they had missedthe boat! Despite of their failure to receive the patent—and despite the fact that our company had retained its own patent attorney and covered all related costs—Roswell Park decided that it was the rightful owner of the patent! This decision was based on the fact that |,as an employee of Roswell Park,

had signed an agreement when| was hired that specified that all information coming out of my research belonged to them. The fact is, through an oversight on Roswell Park's part, |never signed that paperwork! Rather than fight over this issue, we agreed to return the patent to them, provided that they would license it back to our company for a minimum fee. We had no more funds to hire an attorney anyway and planned all along to carry

out the clinical trials at Roswell Park. They agreed and we were back on track.

CHAPTER 20

The Big Leagues:

Partnering with Johnson & Johnson In late-1983, at aPDT meeting in Santa Barbara, California, |was approached by a young woman who introduced herself as Linda Cahill, head of the New Venture Group at Johnson

& Johnson

(J&J).

She told me that J&J

might be interested in acquiring our company, Photofrin Medical, Inc. (PMI).

That question was certainly an attention-getter! |told her she would need to talk to our business people, who happened to be standing at the back of the room. She strolled over and made her pitch that, of course, was received with great interest, although no one let her know that.

To us, Johnson & Johnson represented the major leagues and afforded an opportunity that would be impossible to resist! Wasting no time, we

called a meeting of our board of directors that convened in Lincoln, Nebraska—the newly relocated main office of PMI and board member Richard Thompson's hometown, while our manufacturing plant remained in Cheektowaga, NY. There were two items on our agenda. First, we had to decide whether to continue to negotiate with Cooper Medical Corporation's laser division, Lasersonics. They earlier had expressed an interest in purchasing PMI, but had made a less than attractive offer; and second, we needed to brainstorm a preliminary

position in our negotiations with J&J.

A masterful negotiator, Dick Thompson suggested that we use J&J's interest in buying our company to leverage Cooper Medical to raise their offer. Since J&J was not aware of its competition, Dick thought we should play one company against the other! This did not sit well with me and other

board members who saw this as a risky business practice that could easily backfire, leaving us with no takers and returning us to square one. In our

naivete, we didn't realize that this leveragingstrategy is acommon—andoften effective—way of doing business. Even so, |doubted that Cooper Medical would up its offer. (Its CEO had said as much to me.) We tabled any further discussion of this matter and

moved on to the second agenda item. Our first meeting with J&J was at Roswell Park. Four executives from J&J's Ethicon division—which makes sutures and similar medical productsflew into Buffalo by private jet. It seemed odd to me that Ethicon, that had no drug development experience, would be the division that J&J envisioned as a good fit for our company. Still, it was J&J, and we were excited to hear them out.

Ethicon's vice-president of finance, vice-president of research and development, medical director and attorney attended the meeting. Sitting next to me on our side of the table were Stan Ray, Ken Weishaupt, Dick Thompson, our patent attorney and Michael DeLellis, the local head of Health Research Inc., the not-for-profit corporation representing the interests of Roswell Park and the New York State Department of Health (DOH). The mission of Health Research, Inc. is to “assist DOH and Roswell Park to effectively

evaluate, solicit, and administer external financial support

for DOH and Roswell Park projects, and to disseminate the benefits of scientific expertise through programs such as technology transfer.” As

previously noted, Roswell Park owned the patents on PDT and therefore had a strong vested interest in the outcome of this meeting. As long as |

remainedemployed there, Roswell Park and Health Research,Inc.would have to sign off on any deal. At this first meeting, |presented a comprehensive overview of PDT and its current status. The Ethicon representatives asked many questions and

appeared satisfied with our answers. They indicated that they would give us their decision in about amonth whether negotiations would commence. Shortly after, J&J invited me to give a similar PDT presentation to its board of directors—an intimidating experience, to say the least. In a Spacious, well-appointed

conference room, |gave my spiel to about 25 members of the company, including the heads of the various divisions. As | looked

around the room, |could spot the skeptics—the frowns on their faces gave them away!—and sure enough, they were the ones asking the most difficult questions during the Q&A. |left, clueless as to whether J&J planned to strike a deal with us. A few days later, |received a call from Linda Cahill, informing me that J&J

had decided to negotiate. She also shared that the vote of the board

of directors was not unanimous, but the president of J&J was in our corner, and that was all that counted! As things were coming to a head, we now had to make a decision to: to continue discussions with Cooper Medical or commence negotiations Johnson & Johnson? We discussed the pros and cons for each—with the financial package being a large consideration. Frankly, |was surprised that Cooper was still acontender, but Dick Thompson supported them, something |could not understand and that Dick did not explain to my satisfaction.

A lengthy, heated debate ensued, until finally, avote was suggested. |objected and told the group that if they chose Cooper, |was out! With all due modesty, |knew that without me, they had nothing. J&J was chosen and negotiations with the corporate giant began. J&J's well-oiled legal machine clicked into high gear, preparing the first draft of the Purchase Asset Agreement in a surprisingly timely manner. | surmised that since they had done this many times before, J&J probably had legal templates of every kind at the ready. Dick Thompson and a lawyer friend of his scrutinized the proposal and made several changes. You can imagine what this document looked likepages and pages of lawer talk and ambiguous wording! Ken, Stan and| also read it, confounded by the legalese and missing the hidden traps in the small print. A year-long “ping-pong tournament” followed between our lawyers and theirs until we finally reached a consensus.

On December 31, 1984, nearly one year after starting our negotiations with J&J, we signed the final document, which includeda licensing fee that was wired to PMI that day, future royalties of 5% for US and foreign sales, and a 10% royalty for sales in Japan—the second largest market after the US (This was one of the “sleeper” sections our attorneys had missed and hinged on the placement of a single comma! We wound up receiving no

royaltiesfrom Japan.) There were countless provisions, conditions and timelines in the final agreement relating to material transfer, journal publications, and distribution

of additional funds to PMI and Roswell Park, among other considerations.

Distribution of the initial payment included the three major shareholders in PMI—Ken Weishaupt, Dick Thoma and I, as founding members of the company. Dick Thompson, because of his pivotal role and significant contributions, was the fourth major shareholder. In addition there were a few small investors. Funds were distributed accordingly.

J&J set up a freestanding company called Photomedica Inc.—a name similar to Photofrin Medical Inc., the name we had used. The acronym PMI was kept to avoid confusion. George Braun, a former vice-president at one of J&J’s larger divisions, was appointed president of PMI and remained at J&J. J&J also acquired space within five miles of Roswell Park to continue basic research studies of Photofrin. J&J wanted all Photofrin research to be as confidential and contained as possible to eliminate leaking of “trade secrets.” Continuing our Photofrin research at Roswell Park was now out of

the question—theoretically. It turned out that J&J’s reason for moving outside of Roswell was not very successful-our Roswell group and those at the J&J lab nearby had manyjoint meetings since pertinent information was occurring in both places. PMI (J&J) received it all. J&J converted the new space into two laboratories, a conference room, a reception area and offices. Ken Weishaupt, who had served as the president of Photofrin Medical, was appointed director of the new facility. Ken and | assembled an outstanding team of innovative researchers: chemist Ravindra Pandey, PhD, biologist David Bellnier, PhD, (the second student of mine to receive his PhD degree from Roswell Park ) and biologist

Kwan Ho, PhD. Three techs and a secretary were added to the mix. Seeking to recruit an outstanding chemist for the new J&J lab, |had contacted Kevin Smith, PhD, a well-known chemist at the University of California Davis, for arecommendation. Once again, we had a lucky break! Kevin suggested one of his postdocs, Ravindra Pandey, PhD, whom he

described as “the best porphyrin chemist |have ever known.” (Porphyrins are the basic building blocks of most PDT photosensitizing agents including Photofrin). This endorsement amazed me because |thought Kevin was the top chemist in this field! Ravi came to Buffalo for an interview and Ken and |hired him on the spot. Kevin’s endorsement of Ravi was not the least bit exaggerated and Ravi became an essential member of our team at the J&J lab and later at Roswell when J&J shut down their lab here.

There is also no doubt that David Bellnier, my secondstudent to receivea PhD at Roswell, belonged on the J&J team. We hired him also after the J&J lab was closed. He is a very inventive scientist, and probably the most meticulous researcher in our group. After signing the agreement, there was still the question of maintaining our Photofrin manufacturing facility in Cheektowaga, NY. J&J agreed that since this building was already FDA-approved and carrying out Phase II clinical trials at Roswell Park that it should remain operational. We were

relieved; we had 10 employees at the facility and no one was keen on relocating to New Jersey, J&J's headquarters. But it wasn’t long before J&J sent out a team to inspect our facility. The “inspectors” reported that it was not up to J&J’s standards and, in what |would call an imprudent, kneejerk move, they decided to shut us down and transfer all the equipment to their New Jersey-based Ortho Diagnostics

division, in Raritan, NJ that manufactured needles, syringes and blood related diagnostic systems. We wondered what this had to do with drug

manufacturing! The move to Raritan, New Jersey proved disastrous! George Braun assembled his own production crew from the various divisions of J&J. Of all the original employees at our plant, only Ken Weishaupt was asked to stay with the company to serve as director of the scientific lab in Buffalo. |was offered a “strings-attached” consulting

position with a modest retainer. |refused it and gave them two options: They could double my consulting fee, strings and all, or |would stay on as an unpaid consultant without the entanglements. They chose the former.

When the J&J-PDT company (Photomedica) relocated, Ken and |met with the newly assembled, very green staff several times to meticulously review every step of the manufacturing process. We assumed that they were familiar with the sterile procedures required to manufacture an injectable drug. We were wrong! Their first batch of Photofrin did not pass sterility testing, and bottles (that had been overfilled) cracked when the material was frozen (required

for long term stability). Any high school science student knows that water expands when frozen! Their second and third attempts also failed—because

of lack of sterility. By this time, they figured out that their facility was contaminated. To make matters worse, the residual Photofrin, from the remaining material at Photofrin Medical, was running out. J&J's inexperience in drug

manufacturing and its ignorance of FDA Drug Regulations caused a serious several-month delay in Photofrin production at their facility. Our PDT clinical investigators,

many of whom were smack dab in the middle of their PDT treatment studies, became concerned; a few were furious!

Dr. Jim McCaughan, a surgeon from Columbus, Ohio (who, as you may recall from Chapter 18 accompanied us to China) raised Cain. He had the largest pool of patients using PDT, and he complained loudly and frequently to J&J about the potentially critical shortages of Phototrin. He reminded them that this never happened when Photofrin Medical was supplying the drug! He even convinced one of his patients to call the CEO of J&J to ask

why she could no longer be treated with PDT. J&J did get back on track—setting up a facility in compliance with FDA stanaards for a “clean room” and properly sterilizing the equipment. |

couldn’t understand why they didn’t elicit help from their own in-house experts before attempting to manufacture Photofrin in a less than optimal environment. |guess our little know-nothing company in Cheektowaga really wasn’t up to J&J standards—our facility was clean and FDA-approved! One of J&J's first decisions was to abruptly stop supplying Phototfrinto all of PMI’s current clinical investigators. As company advisor, |strenuously objected, noting that these investigators were treating patients in their studies and shutting them off would create havoc—relegating patients to treatment

limbo.

J&J responded that they needed to have complete control over Phototrin or risk negative outcomes or treatment-related adverse reactions that they would need to explain to the FDA. |suggested conducting their studies with the PDT-experienced physicians who were already onboard, then

phase out their studies when they were completed. They agreed to this approach, despite reservations. As described in Chapter 11, FDA approval for a new drug requires a Phase III Clinical Study. PMI had conducted trials at Roswell Park that yielded promising results for two types of cancers—early-stage

for Phase IIItrials.

bladder cancer and advanced lung cancer. These two studies were selected by Photomedica

The goal for the bladder study was cure; the goal of the lung study was to compare the effectiveness of PDT and radiation therapy with radiation therapy alone. This was to determine if PDT added any benefit to radiation treatment alone (it was already known that radiation rarely removed the entire obstruction).

The bladder study was conducted at several cancer centers, including Roswell Park, Mayo Clinic, and Grant Laser Center. The accrual of patients was slow across the board.

Some degree of shrinkage in the bladder had been expected among participants, particularly for those who had been previously treated with chemotherapy. The normal adult bladder can contain up to 15-16 ounces while a previously treated bladder (usually by chemotherapy) may reduce this number to 6-7 ounces. Since PDT may decrease bladder size even further, those with small bladders were excluded from the study.

After a year, we discovered that two of the 30 study participants had experienced irreversible bladder shrinkage following PDT. One had a pre-

existing condition—a small bladder—that should have disqualified her from the study. We could not explain why the second patient had bladder shrinkage. Consequently, PMI terminated the study, despite the fact that PDT was successful in destroying the early stage disease in most of the patients.

Abruptly ending the Phase IIIclinical trial was unusual—and unexpected—to say the least. The risk and identification of side effects are part of all clinical testing. When an unknown side effect occurs during a trial, it is standard procedure to add that side effect to both the protocol and the patient

informed consent that newly-enrolled patients sign before treatment.

Clearly the PMI crew had little or no experiencewith these types of clinical trials, and coming face to face with that reality would force J&J to reevaluate their decision to partner with us.

The lung study was launched,and did continue with excellent results but was not completed by the time J&J divested itself of PMI. |came to have a personal interest in the lung study several years later when my brother, a former smoker who had not smoked in 45 years, developed a late-stage lung cancer. He had taken up smoking in the Navy where cigarettes were free and everyone smoked. When he was 6/7years old, he developed a cough that would not go away after a series of antibiotics. Since we lived 2000 miles apart, |was only aware of this when we talked

on the phone. It took me several months before |realized that this could indicate blockage due to a lung tumor and encouraged him to be examined by a thoracic oncologist. Atumor blockage was found in his lung; it was advanced stage cancer. |located a lung clinical trial sponsored by the National Institute of Health. One of the participating centers was in Denver, Colorado—just 20

miles from my brother’s home. He was examined and found to qualify for the study and by chance—it was a randomized study—nhewas entered into the experimental arm of the trial with the new drug treatment being studied. At first, things went well; His tumor was shrinking and he had few side etrects.

Unfortunately after about six months, his kidneys were found to be damaged, a life-threatening situation that can lead to the shutdown of all internal organs. He died two days later.

His death affected me profoundly. |felt guilty for getting him into the trial and for not recognizing the cause of his cough earlier. The reality is that for most cases of lung cancer, by the time a symptom is noticed, the tumor is advanced and incurable. While my brain knows this as fact, my heart refuses to accept it. |set up an Endowed Memorial at Roswell Park in my brother's name with the earnings going to lung cancer research. This did not ameliorate my guilt or lessen my grief, but it may help someone else’s brother, sister, mother or father.

CHAPTER 27

The Oncologic Foundation of Buffalo Meanwhile, while Johnson & Johnson had taken over the commercialization of PDT, research continued at a high pace in our PDT group at Roswell Park. It was always my intention to use my share of the J&J licensing agreement funds—about $700,000—to

provide Roswell Park's PDT staff with a

stable source of funding during gaps between grants. Continued funding would allow our work to sustain its momentum during revenue shortages, and eliminate the frustrating practice of hiring and then laying off trained staff—an unfortunate byproduct of the funding peaks and valleys experienced with NIH funding or any other source for that matter.

In 1985, with my portion of the J&J licensing fund, |established the Oncologic Foundation of Buffalo (OFB), a public foundation under New York State Regulations. The original purpose was to Tund PDT research projects at Roswell Park. It was later expanded to include PDT research in any institution.

A board of directors was formed, consisting of Ray Reichert Esq, an attorney who all the leg worked for setting up the foundation (at a reduced fee), Reverend John Buerk, Ken Weishaupt and me. We invited our investment adviser, James Sexton, a local vice-president

at Smith Barney, to attend

our quarterly meetings, and gave him carte blanche to invest the foundation's funds—with an eye toward conservative investments. Thanks to Jim Sexton and the growing stock market during the 1990s, my initial investment ballooned to over $3.5 million—allowing

us to

expand our grants not only for PDT, but also to other cancers and health-related projects at Roswell Park and elsewhere. Our grants have supported an important program at The Cancer Wellness Center near Buffalo, that among other programs teaches medical students at The University of Buffalo how to deal honestly and compassionately with terminally ill patients (not covered in most Medical Schools), and where newly diagnosed patients can find emotional support from cancer survivors. Among others are, the American

Brain Tumor Association

(brain cancer), the Hauptman Woodward

Medical Research Institute (cancer protein

research), cancer programs at several Veteran Hospitals (mainly urologic cancers), the University of South Florida (breast cancer research) and have

enabled my alma mater, Canisius College to renovate biology labs and provide tuition assistance for science majors. Ironically, after |had set up the foundation

with my share of the J&J funds, Roswell Park officials informed me that |could not use these funds

for “personal use” because of a “conflict of interest.” |was happy to inform them that even before we had an Agreement with J&J, it was my intension to use this money to established a Foundation for cancer research, in compliance with New York State law that would require me to give up all rights to the money.

While OFB was of considerable help, our PDT group at Roswell received most of our funding from the National Cancer Institute. The grant funds

were used to support research staff, technicians and administrative staff. The NIH grants typically continue for five years at which time they must be renewed competitively, with no assurances or guarantees—the main reason OFB came into existence! In 2014, we will be submitting our next five-year grant proposal for renewal which if funded will mark the start of 25 consecutive years of

uninterruptedfunding for our PDT program.This has never before been accomplishedat Roswell Park. If you have not noticed, |am bragginga bit about this—not just for me but for all those who have contributed to this success, especially Dr. Barbara Henderson who has been the main force behind this endeavor for many years,({these grants are a special type that include a group of many researchers with different specialties, all directed to one program-PDT in our case).

CHAPTER 22

1990: J&J Drops a Bomb Approximately

five years after acquiring our company, Johnson & Johnson announced it was dropping PDT altogether, with no plans to sell

Photomedica to any other company. To us, it was a shock of seismic proportions. No one—not even the J&J folks at PMI in Raritan saw it coming. Hindsight being 20/20, we should have seen the handwriting on the wall. During the late 70s and 80s, J&J gobbled up a vast variety of small

companies to break out into new fields. Its overconsumption led to a bad case of indigestion and it began to divest itself of many of these companies. PMI was an easy target for divestment not only because of the bladder clinical study issues, but because J&J had essentially bitten off more than it could chew. Its’ personnel lacked knowledge of and experience with new drug development and the approval process through the FDA, and had

never been in the drug field previously to ever be able to make PMI a success. J&J failed at its own internal due diligence, the intensive and thorough examination of acompany’s ability to carry out a proposed new project.( Note their difficulty in obtaining sterile Photofrin described in Chapter 20). But J&J wasn’t the only one at fault. There was a lack of due diligence on our part as well. We were blinded by J&J’s interest and its “star-quality.”

But the bottom line was that J&J, with all of its hundreds of products, had only one injectable drug and PDT had not even been incorporated into that division! We were established as a stand-alone company so if PDT failed it could not be blamed on any existing J&J division. Now what?

Dr. Jim McCaughan to the rescue again! Jim's reaction was that J&J could not just shut down PMI and walk away! We all felt that it was J&J’s responsibility to find a qualified company to purchase PMI. It’s true that asqueaky wheel draws attention, and the noise from this particular wheel

was deatening. Jim insisted on meeting with J&J’s President and CEO-he had his own agenda and would not be denied. They gave in and Jim got his meeting From Jim’s own account of what followed, here's what transpired. He started by telling them how stupid they were for abandoning PDT—tthis was a great cancer treatment that they should recognize. He threatened to attend J&J’s upcoming Annual Meeting and if denied would “camp out” with one of his patients, who had been successfully treated with PDT. To prove that he was not bluffing, Jim showed them the hotel reservations he had made for himself and his patient at aNew Brunswick hotel. If he was barred from the meeting, he warned he would hold a press conference and accuse J&J of discontinuing an effective treatment that was a last-resort for many desperate cancer patients. His patient would provide a testimonial

to the therapy’s effectiveness, and if need be, Jim would organize a small army of patients to share their success stories. J&J executives envisioned a major PR nightmare in their future.

CHAPTER 25

Search and Rescue: Is Anybody Out There? The upshot of Jim McCaughan’s well-orchestrated, one-man advocacy campaign, was that J&J agreed to seek a qualified buyer for Photomedica. The search for a “Big Pharma” company to rescue PM! commenced. J&J invited me to be part of their "Dog and Pony Show.” At times, |felt like Sisyphus, pushing a boulder up a mountain, only to nave it roll back on me.

For example,J&J managedto set up a meetingwith Bristol Meyers,a major player in the development of cancer drugs. Infront of an audienceof about 20 scientists and physicians from Bristol, |began to explain the basics of photodynamic therapy and describe its successes.

My presentation fell on deaf ears. No one was paying attention. Some talked to the person next to them; some checked their watches; others dozed off. And while |guess |should be grateful that |wasn’t booed off the podium, the reception was chilly at best. it got worse! J&J had brought one of its medical doctors to present the clinical data, gleaned primarily from published studies and covering a wide range of potential uses of PDT when someone in the audience stood up and challenged the authenticity of the data. Ashouting match ensued. More negative comments followed, and it was clear that this audience of “cancer experts” was not buying anything we were selling.

We continued our quest, making presentation after presentation, all the time wondering if anyone out there was really listening. Then finally, we got a nibble! Lederle Laboratories, a division of American Cyanamia Company that specialized in cancer research, expressed an interest in buying PMI. To me, this union would be perfect. Negotiations went into full swing, and progressed steadily, but at the last minute, Lederle pulled out. They offered no explanation. We were stunned and confused.

Smaller companies were making overtures to buy PMI, but |was not interested. |felt that they lacked the necessary experience in FDA drug approvals and |could see no way that they could obtain sufficient funding to carry out the very expensive Phase III clinical trials required for FDA

approval. Just when we were ready to give up, J&J said that they had received an offer that they wanted to present to the shareholders of our original company. In fact, as the original Agreement stated, sign-off of any sale by J&J to another company required only my signature for approval, which | had forgotten

until | re-read the document when the transfer process began ( (this was not a position |was comfortable

with). We met at J&J’s

headquarters in New Jersey to learn more. To our great surprise, QLT of Vancouver, British Columbia, Canada, had made the offer to J&J. QLT was a company we had ruled out from the

beginning because they were a new start-up company with no experience or funding to carry PDT forward. However there was a sweetener to this

deal; QLT would be partnering with a “large” pharmaceutical company with considerable experience in drug development. Naturally my first question was “What company?” The J&J people refused to tell us until after we had signed the deal. How could they expect us to sign the agreement blindly? They left our group alone to discuss the offer. We unanimously agreed that we could not sign the agreement without knowing the name of the

other company. The J&J group rejoined us, and we told them our decision. At this point, Verne Willaman, the J&J vice-president overseeing the sale of Photomedica, called me into his office for a private meeting. Since my

sign-off was a condition of any deal, he knew mine was the only mind that would need changing. Closed doorsor not, my position was firm. Willaman insisted that if |did not sign the agreement, J&J was prepared to shut down Photomedica completely—and that would be the end of PDT. There was credence to this threat. If J&J bailed no other company would likely touch PDT. | left his office and conferred with our group. It was clear to all of us that J&J had the upper hand. Strong-armed and cornered, with way too much invested and way too much to lose, we reluctantly

signed the agreement. Only then were they willing to reveal this phantom company to us. When Willaman told us it was Lederle, we were floored—and

relieved! This seemed to explain why Lederle had backed out of our original

acquisition negotiations. Apparently there were some attractive financial benefits to Lederle in partnering with QLT, although | never did really understand

it.

To this day, |still do not understand J&J’s “cloak-and-dagger”

handling of this sale. If J&J had simply told us that QLT's silent partner was Lederle,

we would havejumped at the deal! As it turned out the arrangement between QLT and Lederle was to become critical to the advancement of PDT. Lederle was a major company in cancer drugs and knew all the ropes, including the fastest, most direct ways to obtain FDA approval. For QLT, Lederle was a true collaborator in every sense of the word, bringing the smaller company up to speed on drug development and the nuances of the FDA approval process. At the time, the CEO of QLT was Julia Levy, PhD, who would later become a good friend of mine. Julia was one of the three individuals from the University of British Columbia , who had set up their own photodynamic therapy company (QLT). One of the UBC chemists had developed a

photosensitizer that they thought would be as active as Photofrin against cancer while reducing the four-to-eight week hyper-photosensitivity period in patients. QLT’s photosensitizer had been shown in animals to possibly control age-related macular degeneration, the major cause of blindness in people

over the age of 50. How does PDT work in this disease? Macular degeneration is caused by damage to the retina, the light-sensitive layer of tissue that lines the eye's inner surface. Blood is supplied to this area by the choroid, a network of blood vessels that rest in back of the retina. Leakage of blood from these vessels results in loss of sight. PDT closes off these vessels, thereby stopping the progression of the disease. QLT's research turned to this indication

and led to FDA approval in 1992. Almost overnight, QLT stock skyrocketed from a few dollars to over $70 per share.

CHAPTER 24

The Holy Grail: Our First US-FDA Approval In 1994, the QLT/Lederle group obtained the first FDA approval for PDT which was for treatment of obstructing esophageal cancer. After years of searching and researching, we had finally found the Holy Grail...or at least a huge chunk of it! |admired the seamless way the QLT/Lederle team efficiently maneuvered through the entire process, from designing the Phase III clinical trial, monitoring the 11 study sites participating and meticulously collating the data on the 220 participating patients. Using Photofrin as the photosensitizer, the esophageal trial compared PDT's safety and effectiveness against laser thermal ablation, the then-

current standard of care. The results were compelling—PDT was found to be as effective as laser thermal ablation in opening the esophageal obstruction but with shorter treatment time and reduced risk for complications. On September 12, the data were presented to the Oncologic Drugs Advisory Committee, whose members are selected by the FDA Commissioner or his/her designee. According to FDA regulations, this committee reviews and evaluates all data concerning the safety and effectiveness of new investigational human drug products and makes a recommendation to the FDA Commissioner for or against approval. The FDA technically does not have to accept the Advisory Committee's, but this rarely occurs. The PDT panel consisted of 12 voting members—a homogeneous group of cancer authorities, including oncologists and scientists, as well as a

Statistician, and a lay ombudsman. Since these meetings are open to the public, several staff members from Lederle and QLT attended. Bill Potter, the physicist on the PDT team, and

|represented Roswell Park. As you can imagine, |was extremely anxious about the outcome since this was the culmination of my longtime obsession

with PDT—hands-down the most emotional roller coaster ride of my life! The meeting started out fine. QLT staff described their role in designing and managing the clinical trial. Then, Charles Lightdale, MD, from Columbia University, one of the 11 participating study sites, delivered acomprehensive overview of the results. Finally, amember of the FDA shared

his perspective on PDT—which was very supportive. The panel members, well-versed on the subject of PDT, asked the presenters many questions, and appeared satisfied with the responses. It

seemed like things were moving smoothly, so |relaxed a bit and took a deep breath! My complacency was premature. A surgeon from California—the most influential person on the review panel—addressed his question to Dr. Lightdale. It went something like this:

Now let me get this straignt. You want me to believe that a treatment that results in a patient naving considerable post-treatment pain and a long

and miserable recovery...and that poses a risk of severesunburn unless the patient is well-protected from sunlight for four to eight weeks—a significant time of their remaining survival... is really better off than having laser ablation? Is that what you are telling me? At this point |looked at Bill and said, “We're doomed! They're not going to approve it!” He nodded in agreement. Our hopes were fading. Dr. Lightdale responded that if he had a tumor blocking his ability to eat—and perhaps even the ability to swallow—he would not prefer a treatment ( that could perforate his esophagus, possibly resulting in death. He would not opt for multiple treatment sessions to keep his esophagus open (PDT is administered in a single session) and that as a treating physician, he would much rather use PDT to avoid the smell of the patient's

burningflesh. He also made the point that each laser thermal ablation session takes as long as an hour or more, while one PDT application takes about 12

minutes. Depending on the length of the obstruction, multiple 12-minute light treatments may be necessary during a single procedure. However larger tumor obstructions also increase the time of the “burning laser” method as well. Seemingly satisfied, the surgeon who had asked the question had no follow-up. Hope returned. |whispered to Bill that maybe we had jumped the gun and that we still had a fighting chance. But it was not over yet! It was now the statistician’s turn to comment, and his statement caught us all off-guard. In his opinion, he declared, the data presented were not

Statistically significant because there were insufficient patients in each arm of the trial. It the clinical trial was not statistically significant, it would fail to prove that PDT was at least equal to or better than the current treatment, and there would be no FDA approval. Expanding the number of patients in each arm would require several more years (it had already taken four years to get the data presented), and would be very expensive. There was a real possibility that OQLT/Lederle would drop PDT altogether rather than put in considerable more money and time to continue the trial. Since there was only one statistician on the committee—and QLT/Lederle did not have one present—there was no one in the room to refute or address the concerns he raised.

The discussions and questions continued for another half hour (it had already gone on for several hours), at which point the committee was

ready to vote on their recommendation.My stomachwas in my throat. Bill and |were convinced PDT would go down. The ballot votes were collected and counted, and the result was announced-PDT was recommendedfor approval!! The vote was 11 to one—the single “no” vote was cast by the statistician! Even the skeptical surgeon had voted yes. By then, Bill and |were so emotionally drained that the only reaction we could muster was stunned silence. It was Stu Marcus, MD, the Medical Director at Lederle, who snapped us out of our catatonic state with a tap on the shoulder and some encouraging words. “Be happy,” he said. “It’s been approved!” And so it was, and our long, long journey in the wilderness had led us to our first oasis. A few months later, we received the official notice from the FDA that PDT had been approved for the palliative treatment of obstructing esophageal cancer. It was the very first approval for PDT in the US!

However, this was not the first health agency approval in the world. In 1993, the Canadian Health Agency approved Photofrin-PDT for the treatment of superficial bladder cancer. Its Phase III clinical study was essentially identical to the one that Johnson & Johnson had abandoned earlier.

The Canadian study produced no unexplained side effects and no irreversible bladder shrinkage. This demonstrates how treatment techniques and results can vary among physicians, even when they are following the same methods spelled out in detail in the protocol. The Canadian Health Agency also approved Photofrin-PDT for treatment of obstructive lung cancer based on results of a study of PDT versus radiation therapy. The US also lagged behind Japan, where theyhad obtained health agency approval for early-stage lung cancer. Over the years, PDT has also been approved by health agencies throughout the world for a wide variety of cancers. For QLT/Lederle there was still much to be done before patient treatment could proceed. The FDA would need to conduct an on-site-visit to

inspect and approve the drug manufacturing facility at Lederle. Admittedly, this was not the first time Lederle had gone through this exercise but the manufacture of each new drug has its own methods so there is always something for the FDA to find out of compliance; which, of course, they did! They also would need to train representatives of Lederle who would be marketing Photofrin to individual hospitals. These details took about a year to be ironed out. The first commercial bottle of Photofrin was sold for patient treatment for about $2,000 in April 1995. Keep in mind that the 1994 FDA approval covered PDT's use for only one type of cancer. Each new type of cancer to be treated with PDT required new clinical trials for that particular use and rigorous Advisory Committee reviews to obtain FDA approval for that indication—so this process was

tackled several more times over the years. All of these studies were successTul. Today, In addition to the first approval, PDT has also been FDA-approved in the United States for obstructing lung cancer (palliation only), earlystage lung cancer (the first approval for cure) and pre-cancerous esophageal disease to prevent development of cancer. And in spite of the fact that all patents on Photofrin have terminated ( the 20 year exclusivity has passed) the company that markets Photofrin

today—lllinois-based Pinnacle Biologics , recently has applied for health agency approval for Photofrin-PDT for the treatment of cholangiocarcinoma, an incurable cancer of the bile duct, and other applications. These will be carried out in Germany, France and the United States. Roswell Park will be

a participating center. Once a drug is FDA-approved, physicians are free to use it for any type of cancer that they believe will respond to the treatment. This is referred to as “off label use”. However, not all insurance companies will cover the costs for patients who receive investigational or “experimental” drugs. Often

the first denial can be reversed by supplying journal articles indicating that is useful and safe for the use that is planned. Of course it also helps if PDT will be less expensive than the alternative.

The USFDA as well as health agencies in other countries, do not allow companies to advertise the unapproved drugs “off label” uses either broadly or even to individual doctors. Therefore, any company that wants to advertise and sell these drugs needs to go through the expensive approval

process.

Now might be the perfect time to pay tribute to our doggedly persistent research nurse, Michele Cooper RN, who would never take no for an

answer from an insurance company. She would comb the PDT literature and find articles in peer-reviewed journals to support PDT's effectiveness in certain cancers, and then forward them to insurance companies. Michele’s tenacity usually paid off, and almost all the insurance companies she

contacted provided reimbursement. Michele was our secret weapon; she continually contributes her wisdom, talent, compassion and resourcefulness to the welfare of the PDT patients under her care. She also She also has an excellent memory of all our patients even those dating back many years. This often is very helpful when a new patient arrives on the scene with an unusual problem to one we had treated in the past for which we have the records to see how it was done and the outcome.

CHAPTER 25

HPPH: Our New Photosensitizer

(HPPH)

A Case of Reverse Serendipity In 1995, |was slowly returning to my PDT researchat Roswell Park, but that wasn’t the only hat |wore. |continued working with the clinical faculty, initiating many PDT protocols, dealing with our Institutional Review Board (IRB) and being the point person for our FDA applications. Up until 1995, we had focused a large part of our research and clinical protocols on Photofrin. That is not to say, however, that Photofrin was a one-trick pony.

We were continually synthesizing and testing new PDT drugs that could be used therapeutically, both for cure and for symptom palliation in cancer patients. We hoped that newer photosensitizers would improve on Phototrin’s shortcomings, by providing deeper light penetration through tissue (for larger tumors), shorter skin retention (to minimize sun photosensitivity), and more efficient formation of singlet oxygen, the effective toxic agent

produced when activated by light. One of the most promising photosensitizers we called HPPH( an abbreviation for a long chemical name) based on animal studies and numerous

Phase I(safety) and Phase II (efficacy) clinical trials carried out at Roswell. Fortunately, our lab boasted the top chemist in porphyrin chemistry. As you may recall, Dr. Ravi Pandey originally had been hired to work in the

Buffalo-based Johnson & Johnson lab. After that facility was closed in 1990, Ravi came to Roswell Park as head of our chemistry group. We thought HPPH, Ravi’s brainchild was ready for Phase III clinical trials( the final Phase for FDA approval), and once again, we found ourselves in

need of a company to license our patents and complete the FDA approval process. As noted previously this is the clinical trial with a large number of

patients from several clinical institutes and hospitals required for FDA approval and with very high costs-well beyond our capability. My team and |were far more business-savvy than we had been 20 years ago in understanding and completing the multi-step process required to obtain FDA approval. We knew the drill by heart: collect the necessary toxicological, pharmaceutical and animal data, carry out a clinical protocol to

use HPPH-PDT to treat the cancer,and file an InvestigationalNew Drug (IND) application with the FDA. My partners in this effort, who each deserve more than a passing acknowledgment for their Herculean efforts and Job-like patience, were Dr. David Bellnier, Dr. Barbara Henderson, and Bill Potter. Since the bulk of the clinical data gathered with HPPH was in the area of dermatologic oncology

we chose that clinical trial for the Phase IIIstudy.

Unfortunately, just as we submitted the first IND for HPPH, the rules changed. The FDA had added a dedicated section for Dermatology that was separate from the Oncology Section that had reviewed all of our previous applications. Our IND application was forwarded to this new section. Trouble ahead!

You could say that this was a case oT reverse serendipity—events coming together to produce an unexpected negative result! Unlike the Oncology Section that was very familiar with PDT, members of this new group had no understanding of the basics of the treatment. They were skeptical of treating non-life-threatening

diseases, such as skin cancer, with an injectable drug—dermatologists

normally do not inject

drugs. In essence, we were starting from square one! This process took a ridiculously long time. The study’s principal investigator Allan Oseroff, MD, PhD, Chair of Roswell Park’s Dermatology Department, and |spent the next several years educating this new group about PDT. We had treated many skin cancer patients with Photofrin-PDT

and all the information was at the FDA Oncology Section which we suggested they consult—apparently they did not. Like many bureaucracies, the various FDA sections did not communicate with each other, much less share information and data. Many of the answers to the questions the members

oftthe Dermatology Section asked us—over and over again—were available in the Oncology Section. Letters were shot back and forth, conference calls were placed that went on for a long time—we were frustrated and disappointed. We finally got our approval to initiate clinical trials in 2000—five years after we had submitted our IND application! It took stubbornness and unshakable resolve to stay the course, but we believed that HPPH-PDT was the best way to treat most skin cancers and possibly other cancers as well.

Those five years of waiting weren't wasted. When it was clear that our communications with the new Dermatology Section were going to go on for a long time, |approached Hector Nava, MD, Chief of Gastrointestinal Endoscopy at Roswell Park, about putting together an HPPH-PDT protocol and IND for obstructing esophageal cancer. He agreed to do so. We knew that the FDA's Oncology Section would review this protocol. The IND was

approved within one year and we began our first clinical study using HPPH, while still fiddling around with the Dermatology Section ( They finally approved our study and we began treating dermatology patients, long after we had already obtained the information regarding the safety and

efficacy of HPPH we needed to begin clinical trials.) One of the hardest-working physicians |have come across, Hector was quick to embrace PDT asa palliative treatment for advanced esophageal cancer. Patients with this cancer generally have metastatic disease and are poor candidates for surgery. For this type of cancer, the light delivery is directed from the laser to the treatment site througha fiber optic light delivery cable threaded through an endoscope as described in Chapter |.We found that PDT destroyed most of the tumor blocking the esophagus and generally restored the patient's ability to swallow food and fluids, the best outcome expected with these patents.

This application to initiate a clinical trial (the IND) for Photofrin-PDT,was the first to be approvedby the FDA, and Hector played a major role in this milestone. He went on to use PDT for earlier stage, non-obstructing esophageal cancers, and was the first to use it to treat Barrett's esophaqus, a pre-cancerous condition caused by frequent acid reflux that, in its most advanced stage, can lead to cancer.

CHAPTER 26

Licensing HPPH: Here We Go Again! After treating many patients with skin and esophageal cancers with our new photosensitizer, HPPH, we were ready to partner with a pharmaceutical company to complete the last step to FDA approval, as we had done previously with Phototrin. In earty 2000, |was contacted by an individual trom Light Sciences Inc. (LSI)—a relatively new PDT company that was interested in obtaining the rights to HPPH. A meeting was set up. LSI executives came to Roswell Park and briefed us on their company and future direction. It was a compelling presentation,

and they seemed serious about developing HPPH. Licensing negotiations began. After the usual back and forth between our respective lawyersthat took the better part of a year, a final agreement was drawn up. In the dead of winter on January 2, 2001, the president of LSI and his executive entourage returned to Buttalo and an official “Agreement Between The Parties” was signed by both sides. The agreement contained an upfront payment of $2.5 million as well as research funds to our PDT group at Roswell Park of $500,000 per year

for five years to continuestudying HPPH as well as other potential new photosensitizers.All of the data would belong to LSI. After everyone had signed the agreement, the president of LSI dropped a bomb: The company already had a PDT drug in development! It was obvious that HPPH would compete with that drug. We were none too happy and complained that it would have been nice if they had informed us of

this before we signed the Agreement. They assured us that HPPH would be their “lead drug” for development and their other drug would be relegated to the back burner.

Naively, but with a grain of skepticism, we accepted their explanation, After all, the Agreement they just signed would cost them a large amount oT money. During the five-year period of researchfunding, our group had accumulated extensive data relating to HPPH, which would be mandatory for FDA approval. We provided monthly reports to LSI and they seemed happy with the results.

Strangely, they gave us no teedback on their progress with HPPH. We had supplied them, and continued to supply them, with the necessary chemical, biological and clinical information and they were supposed to be using this information to prepare the FDA document necessary to begin clinical trials-the IND described previously (Chapter 11).

We soon learned that they had no information to share! It became obvious that HPPH was not their lead product, and that they were investing all their time, resources and attention to their original drug—the drug that was allegedly simmering on that back burner.

Luckily for us, the Agreement we signed stipulated that if we felt that sufficient progress was not being made on HPPH over a reasonable period of time, our partnership could be dissolved. We requested that LS! return the HPPH rights to Roswell Park, which they did without argument. The LSI

individual who had first contacted me apparently fought to develop HPPH, an action that cost him his job! So why did they want HPPH in the first place? My guess is simply to keep a competitor off the market. |believe that LSI recognized HPPH as an excellent PDT photosensitizer, and, if developed by another company, would vie for the same market as their drug. So they kept it “on ice” for five

years. When we re-acquired the rights to HPPH, there were only five years left on the patent. In the time it would take to acquire FDA approval for commercialization (about five years), no exclusive patent protection time would be remaining, making it virtually impossible for any company to earn back their development

costs, much less make a profit. Therefore HPPH was dead in the water!

Incidentally, after 14 years, their infamous “back-up” drug is still without FDA approval. LSI’s attempt at FDA approval was denied in 2011. Since we were not able to license HPPH in the US, we decided to go overseas, and approached companies in India and China. Interest in Asia was high, and we received positive responses from a company in India and two in China. Our potential partners believed that our existing clinical data on

HPPH might be sutncient for approval in their countries. Appropriate Licensing Agreements were initiated with rights limited to their respective countries only and with different aspects of HPPH for the two Chinese companies-one for treatment and one for detection (Ravi Pandey had modified HPPH to act as a means for detection of cancers). Upfront payment from the Indian company was modest. When we met with representatives of one of the two Chinese companies, their president looked over our suggested Agreement and signed it on the spot! The agreement with the other Chinese company was signed in a Tew weeks. Rights to HPPH were limited to their countries only since we wanted to be free to continue seeking partners in the US and other countries. Unfortunately to date, none of the three companies has received health agency approvals for HPPH. The Indian company apparently has abandoned HPPH since their initial contact with their Approval Agency was not receptive to using only the clinical information from the US and they would need to carry out clinical studies in India.

One of the Chinese companies asked for more information requested by their Approval Agency that we provided to them. No response so far after six months. The other Chinese company appears to be moving right along with the cancer detection property of HPPH. Ravi Pandey is communicating

with them frequently. In retrospect, we should have enlisted the aid of consultants with expertise in Asian business affairs, but we naively proceeded on our own. Another

lesson learned!

CHAPTER 27

Light at the End of the Tunnel: Photolitec |retired from Roswell Park Cancer Institute in 2002, maintaining the title of Chief Emeritus of the Photodynamic Therapy Center and Professor of Oncology. |continue to work as a Volunteer at Roswell Park several days a week doing pretty much what |had been doing previously. Much of my time

is devoted to reviewing PDT-related manuscripts for various medical journals, consulting for our PDT staff and, and now, writing this book. Looking back to the early 1970s when |submitted my first National Institutes of Health (NIH) research grant, |am keenly aware of the stunning

changes in today's academic research milieu and the lack of federal dollars available for important, potentially game-changing cancer research. In the wake of sharp reductions in the size and number of NIH grants, only proposals that receive review score in the top 8-10% have a chance of

receiving funding—years ago, that figure was as high as 20-30%. That means that the majority of high-quality, once-fundable grants submitted to the NIH will receive no federal support, which, of course, will stall or thwart any innovation or advancement that the proposed research would generate.

Beneficiaries of such advancements—current and future cancer patients—will be the ones who will be directly impacted. Today, academic research centers, such as Roswell Park Cancer Institute, have faced this problem head-on by encouraging their pioneering scientists and physicians to form their own start-up companies especially for Translational Research—'bench to bedside’. What a difference 20 years can make! Roswell Park has made a commitment to its faculty and staff to direct more funds and resources to new products/applications

as quickly as possible.

As of 2014, Roswell Park boasts 13 biotech spinoff companies—forming

strategic partnerships with investigators and centers throughout the

world. Roswell Park provides up to $200,000 in ‘seed’ funding for these new life sciences companies, and in return, receives 25% equity. Each company must then seek the remaining funding necessary to bring a new drug or technology to market, and support may come from a variety of sources: venture capitalists, private investors, philanthropy or companies interested in the product. The PDT Center capitalized on this emerging national trend by forming its own start-up company-Photolitec,

established in 2010 by Dr. Ravi

Pandey. Ravi is the Chief Scientific Officer, while retaining his title and responsibilities at Roswell Park. |am a member of the board of directors and also serve as technical

consultant.

As certain gardeners seem to nave a “green thumb,” Ravi is achemist with a “green hand.” He has devised more than 1,000 new compounds as potential PDT photosensitizers. HPPH (described in Chapter 25) is just one of his compounds that were developed as a treatment for skin cancers. Ravi's new generation of synthesized compounds has dramatically enhanced the quality of life for PDT patients, reducing skin photo toxicity from several weeks to three or four days.

Using advanced proprietary technologies licensed from Roswell Park, Photolitec strives “to develop and commercialize the next-generation of multi-functional

agents for cancer imaging and phototherapy.” Its objectives are to:

« Create promising new cancer treatment opportunities for patients.

« Study ways to improve the effectiveness of PDT and expand it to other cancers.

« Develop new era PET imagingagents for tumor imagingand monitor tumor responseafter surgery or chemotherapy. «Advance the company’s researchand develop new products. «To move “from bench to bedside” or from laboratory experimentsthrough clinical trials to actual point-of-care patient applications.* *Excerpted from the Photolitec website: http://www.photolitec.org/

All patents have been transferred trom Roswell Park to Photolitec, thus allowing the company complete freedom to deal with companies both in

the US aswell as thoseoutsidethe US. Those of us at Roswell Park who have been around long enough, can easily grasp the almost “night and day” contrast between the means of formation of the first PDT company, Oncology Research and Development (ORD), (later changed to Photofrin Medical,Inc) and the most recent, Photolitec. ORD was formed out of an urgent necessity because Rowell Park, through its representative in New York City, had turned down our first PDT

patent. This situation led a small group of novices to branch out on its own, file and pay for the patents and to raise start-up funding—all in a very

short time. The formation of Photolitec, on the other hand, was encouraged by Roswell Park, which provided start-up funding. Further, all the pertinent patents, of which there were many were turned over to Photolitec without charge. Photolitec has experienced, knowledgeable people populating its board of directors while ORD had well-intentioned

neophytes making its

business decisions. PDT was FDA-approved and a well-known effective cancer treatment long before Photolitec was established. ORD was established betore PDT was hardly known, let alone an approved cancer treatment.

Despite major differences, some things never change, even in today’s academic research climate. First and foremost is the challenge of obtaining FDA approval. A second hurdle is to keep the company viable, well-staffed and productive through a steady funding stream.

CHAPTER 28

Expanding PDT to New Cancer Applications and Developing a PDT Induced Cancer Vaccine The clinical uses of PDT are expanding to new types of cancers and quite surprising, development of a cancer vaccine resulting formed by the patient's

cancer itself. This immune induction is a relatively new characteristic of PDT not previously known, but that clearly aids in its efficacy. Currently there are several new studies for using PDT to extend the lifetime of patient with lethal cancers such as cholangiocarcinoma, a cancer

of the bile duct-critical in food digestion.This cancer is incurable but PDT has been found to greatly increasepatient survival from a few months to more than one year-and longer in some patients. It is currently in clinical trials aimed at FDA approval.

Further there is a clinical trial underway to study PDT to treat tumors of the larynx. Numerous preliminary studies have indicated that PDT may be superior to radiation therapy (the current treatment) and with fewer side-effects. These studies are sponsored by Pinnacle Biologics, Inc., in Bannockburn.IL, the company that produces and markets Photofrin, the first PDT drug discovered and developed in my laboratory at Roswell Park Cancer Institute.

Epilogue The development of photodynamic therapy has been an incredible journey even with all its ups and downs. Today, PDT is being used to treat a large number of cancers and some benign conditions. My companions on this adventure have been scientists, physicians, nurses, friends and family—but truth be told, the powerful gusts of wind beneath our wings have most certainly been our patients. This final chapter acknowledges the thousands of PDT patients, both in the United States and abroad, whose courage, altruism, trust—and a strong belief in the advancement of science and medicine—helped us launch a new therapy. Our patients are both the heroes and pioneers of this story, the men and women who were on the frontlines in every battle we fought—both big and small—over the years. Theirs are stories of hope and triumph.

A Few Examples Patient KS |can |recall many of the PDT patients treated at Roswell Park—patients like KS, ayoung woman with a bone cancer that had been surgically

removed, but had, unfortunately spread to her lungs. She was initially treated by anon-Roswell Park surgeon, who removed every cancer nodule from her lungs but found that after a few months, the tumors had recurred. He again removed the tumors and again, they recurred. She had been told that they could do no more or her and her remaining lifetime was short. As a last resort she was referred to Hiroshi Takita, MD, an outstanding

thoracic surgeon, at Roswell Park Cancer Institute, with a reputation of

doing very aggressive surgery, Dr Takita also tried to surgically remove all the lesions on her lungs-all the tumors returned.

Dr.Takita, who had been using PDT successfullyto destroy canceroustumors within the airways of the lung (a procedurenot requiringsurgery), had an idea that had never been tried before. He suggested surgically removing the lung lesions, but this time, while the lungs were still exposed, treating the lungs with PDT. It was apparent that the surgery was not removing all of the tumors either because they were too small to see or deeper

than the surgeon could see (the margins and depth of the tumors were not well defined and it would be dangerous to just remove more lung tissue blindly). However PDT could be used on all the surgical sites as well as the untreated portions of the lung and the PDT effect would penetrate more deeply than the surgery could go safely and more broadly. The intent was to clean up all the invisible remaining cells At the first follow-up

visit at 3 months to assess the result, there was no evidence of recurrence nor was there at 6, 12 and 24 months and every

follow-up thereafter. It appeared that the combined treatment was far superior to surgery alone.

This lovely young lady was married shortly later and now has three children, the most recent about a year ago, 77 years after her last treatment! She sent us a family photograph over Christmas of 2012—three smiling children and one happy mom!

Patient CD One of Dr Hector Nava's most interesting cases was a patient with an esophageal obstruction that was making eating difficult. This was found to be caused by a rare slow growing tumor (a tumor that often is not symptomatic). He also had a long history of disruption of the lining of the esophagus caused by frequent acid reflux. This generally is treated by medication for symptom relief since it is abenign situation—unless it progresses to an advanced state when it must be treated due to a risk of causing esophageal cancer. The patient lived in Detroit and was brought to Roswell Park by his son, Robert Lutnick, MD, a radiologist who also happened to live next door to me. Hector determined that the patient could not withstand surgery because of other medical problems, and the lesion would not respond to radiation therapy or chemotherapy which would be contra-indicated for this patient at any rate. Hector asked the patient if he would consider PDT, explaining that we had never treated this type of tumor before and had no idea if it would work on this type of cancer. Since this was his last hope, the patient agreed to try PDT. The patient's son, Bob Lutnick, was present during these discussions and asked many questions. When Hector told him that PDT was developed at

Roswell Park by one of our scientists, Dr.Tom Dougherty, it suddenly dawned on Bob that | lived almost next door to him. He had known that |worked at Roswell Park, but had no idea what |did here. He called me that evening to tell me what was going on. The PDT treatment was carried out just as we would with an esophageal cancer of this size. When examined the two days later, the lesion looked unchanged and the biopsy was still positive for carcinoid-not good news, but time would tell. The patient went home and later returned to Buffalo for follow-up. There was good news and bad news—the carcinoid was gone! However the abnormal area in the esophagus had advanced to the point that it needed to be treated which we did with PDT a short time later. It was successfully removed.

When followed-up by phone the patient said his was fine, with none of the symptoms he had described at his first visit. This was the first time in

years that he could say that. He was happy, his son was happy and so were Hector and |,We had learned something new about PDT that was also seen later for lungsometimes it takes several weeks after treatment for the tumors to finally be totally gone! |continue to be grateful to and humbled by patients whose spirit and survivorship are a testament to all that we have accomplished over the years. I'm looking forward to the next chapter in the PDT story—with patient success stories filling the clinic journals. |have described two of our patients who were among those who were especially notable since they had nowhere to turn; one who had failed previous therapy and would not have survived much longer and the other because health problems precluded other treatments. |cannot describe all of the several hundred patients treated just here at Roswell Park Cancer Institute-among the thousands over the world, or

you would not be able to Liftthis book—and |would be an old man!

Thank you for allowing me to share my adventure with you!

Acknowledgments In addition to those noted in the book, there are numerous others who deserve recognition for their contributions to the successful development and FDA approval of Photodynamic therapy for cancer (and now other applications) Judy Felski, the only secretary who could read my hand writing (no computers in those days). Current and past PDT staff who applied for grants necessary for carrying out PDT research—critical for understanding the mechanism of how PDT works and for initiating human clinical protocols directed toward FDA approval.

All of our current and past PhD graduate students who carried out the scientific studies under the tutelage of the PDT staff. And those who demonstrated the broad use of PDT for many cancers: For example, Paul Muller for brain cancer, Allan Oseroff for dermatology, Unyime Nesyo for bladder cancer, Merrill Biel for Head and Neck Cancers.

|also offer many thanks to my editor, Colleen Karuza. To all those |have left out |offer my sincere apologies.