Industry Explorers Blaze On: R&D Veteran William Comer Of NeuroGenetic

By Wayne Koberstein, Executive Editor, Life Science Leader
Follow Me On Twitter @WayneKoberstein

Industry Explorers Blaze On: A series of stories of longtime leaders, still active in the industry, sharing their historical perspectives on life sciences industry innovation.

The chairman of Bristol-Myers summoned the head of R&D into his office. “Bill, go down and check out the ruckus on the street,” he said. “Something about our new AIDS drug.” When Dr. William Comer exited the front door of the company’s New York City headquarters, he saw a small group of men marching around on the sidewalk, holding signs, blowing trumpets, beating drums, and chanting loudly. The year was 1988, the company chairman was then Richard Gelb, and the group, ACT UP, was new to Comer. He offered his hand to a gaunt, exhausted-looking man who introduced himself as Larry Kramer, widely regarded as the organization’s leader and founder. Kramer said the group was protesting because it believed the company was “sitting on” a compound that could save lives — the preclinical anti-HIV candidate didanosine (2’,3’-dideoxyinosine, or ddI). Comer patiently explained the early status of ddI, and in the end, pledged to make its development “the fastest on record.”Not only that, but he subsequently convinced the activist to join a groundbreaking drug-development steering committee including NIH directors, giving ddI top priority in the company’s pipeline. Bristol- Myers would ultimately fulfill Comer’s promise by taking the drug from early clinical stage to FDA review in only 18 months.

At the FDA hearing, just before the agency’s scientific advisory board planned to adjourn for a final vote on recommending approval of ddI, the chair called a tardy witness. A scraggly figure approached slowly from the back of the room and apologized for arriving late. “I just attended the funeral for my lover,” the man said. Then, in a weak and broken voice, he pleaded for the agency to make ddI quickly available to AIDS patients: “We don’t have 10 to 12 years to wait!”

It was a pivotal moment. Comer says the reviewers looked at each other and, by general acclamation, decided to vote then and there to approve the drug. The persuasive witness, who was also diagnosed with HIV infection, was Larry Kramer. “Because of that experience, I made two resolutions,” says Comer. “One, to employ the same steering-committee model in the company to accelerate development of our top-priority drugs, and two, always include a patient advocate on the team.”

BIRTH OF A SERIES
I first heard the preceding story from Comer at this year’s Biocom Global Partnership conference in San Diego, only because he happened to sit down next to me after his presentation for the company he now heads, NeuroGenetic Pharmaceuticals, which is developing new, unique drugs for neurodegenerative diseases such as Alzheimer’s. He had already caught my attention by saying to the audience, “Prevention is the only way to defeat Alzheimer’s. You can’t cure a dead brain.”

NeuroGenetic’s lead candidate, NGP 555, is a small molecule modulator of the gamma-secretase complex designed to interrupt the early pathway of amyloid formation in the brain. Specifically, the drug redirects production of amyloid proteins from the toxic form deposited in diseased brains (Αβ42) to nontoxic forms (Αβ37 and Αβ38). Key to the therapeutic strategy is treating patients before amyloid plaque reaches critical levels by using cognitive impairment as an early marker of the disease. The same drug mechanism, employing gamma-secretase modulators (GSMs) to inhibit the enzyme γ-secretase in the amyloid pathway, could also apply to other amyloid-based diseases such as cerebral vascular dementia, inclusion body myositis, and Alzheimer’s dementia associated with Down syndrome.

Comer had a lengthy, distinguished career at Mead Johnson and Bristol-Myers Squibb, but the story of his entry into the industry is itself a lesson about the value of spontaneous, unguarded thinking in life, in science, and in business. In 1957, he had just graduated from Carleton College with a degree in chemistry and planned to enter a graduate program at the University of Chicago to pursue a general interest in organic chemistry. During the summer break, he returned home to visit his parents in Iowa City and one day decided to take a walk on the University of Iowa campus. On impulse, he stopped in at the chemistry department, asked to speak with any available faculty, and was ushered into the chairman’s office for an informal conversation. Assuming Comer was there to join the Ph.D. program, the chairman, Ralph Shriner, touted his own project, sketching out his ideas on the office chalkboard, then sought to recruit the young man into it.

But Comer frankly found none of it interesting. Taken aback, the chairman asked, “So what does excite you?” While waiting in the outer office, Comer had read an article in the latest issue of Science about the then-recent discovery of the neurotransmitter, serotonin. “I said it was exciting a single molecule like that works in the brain, the stomach, and in different ways all over the body, and I thought, by making similar molecules with slight differences, it might be possible to find one that works in the brain or in the stomach only.”

"If it isn’t risky, it isn’t innovation!"

Bill Comer

 

 

The field of medicinal chemistry did not yet exist, but the chemistry chairman immediately phoned neighbor John P. Long, the chairman of the pharmacology department. Remarkably, Long had been reading the same article at that moment and said he wanted to speak with Comer immediately.

“He drove all the way across town to Prof. Long’s office, and the three of us sat there all afternoon talking about serotonin,” Comer recalls. “Next morning, the chemistry chairman offered me a teaching assistantship, full ride, in his department, and the pharmacology chairman offered me a research fellowship, and together we designed a program where I could synthesize serotonin analogs in chemistry and test them in animal models in pharmacology. I was naturally thrilled to be offered a package that would pay for my entire postgrad education. I called Chicago the next day and said I would not be coming there.”

For the next four years, Comer took courses on opposite sides of the Iowa campus, majoring in both chemistry and pharmacology, making a few serotonin analogs, comparing them in animal models, and following “an interesting thesis.” After gaining his Ph.D. in 1961, he began interviewing for a job, first mainly with chemical companies and later with pharmas. His last meeting was with the nutritional company Mead Johnson in Evansville, IN. There, echoing his first day at the University of Iowa, one interviewer was head of chemistry, and the other was head of pharmacology.

Comer recounts the meeting: “Mead Johnson had been trying to enter the drug business for about three or four years, and they weren’t quite sure how. I said, ‘Not to be presumptuous, but if you would offer me a job, where would my lab be, who would be my boss, and what project would I work on?’ But they said, ‘Oh, no, you don’t understand. We want you to come and tell us what targets we ought to be working on.’”

THREE STRIKES, YOU’RE IN
At Mead Johnson, Comer’s beginning project focused on the beta-adrenergic system, and it led to a hard lesson in industry thinking at the time. “We had the first beta blocker ever discovered, and as we were starting clinical trials, the head of marketing came in and asked, ‘What kind of patients need their betas blocked, anyway?’ No one had a clear answer at that point, so he killed the project. We were no longer the first beta blocker, and when we launched it a couple of years later, indicated for hypertension, it was already too late because ICI Pharmaceuticals had stepped in with propranolol [Inderal] in the meantime. That was a disappointment.”

Comer’s next project concerned the beta agonists, ultimately used in bronchodilators. Again, the lead compound was first-in-type, initially lacking a defined patient population, but after it showed excellent results in clinical trials, it ran into a toxicology roadblock. “They found some tumors in the second year of a tox study and shut down the whole thing,” he says. “Several years later, I repeated the tox study and showed the tumors were not related to the drug at all. But by then Glaxo and other U.K. companies already had similar drugs on the market as bronchodilators, and they ruled the market for 20 years, just as propranolol had.”

Working with a biochemist friend, Duane Gallo, Comer started a third program aimed at stopping cholesterol formation. “We came up with the first so-called HMG-CoA reductase inhibitors, but just when they were ready for clinical trials, the head of marketing killed the project because we didn’t have a clear plan on how to pursue it clinically or commercially.” Reflecting the times, the marketing head offered no help with forming such a plan. “Marketing was totally retrospective in view, not prospective,” Comer says. “It wasn’t a problem with the people — that’s just what marketing was then.”

OVER TO THE OTHER SIDE
Comer had reached the end of his rope. He started looking for another job. But the president of the company then, Wayne Davidson, offered Comer a new position outside of the research center and with a new title, director of new business development. “You can decide what programs we should work on and license in anything you think is an exciting innovation,” the president said.

During his six-month tenure in the position, Comer licensed in two of Mead Johnson’s biggest-selling products on record, trazodone and cefadroxil, and had them on the market within a year. “The point is this: I had to talk marketing talk, and I had to convince our business people of the scientific merit of going into new areas where all the marketing strategies were not laid out ahead of time.” He outlines the risk-mitigating strategy as a sequence:

1. License in a first-of-type compound.
2. Get it on the market quickly.
3. Make a good business with the product and impress the marketing people.
4. Immediately employ research in finding a better version of the compound — or another molecule with a different mechanism — to attack the same problem. Comer comments: “Research was not intended to be innovative because marketing wouldn’t understand it, but research could make a better product.”

Comer brought those principles with him after they installed him as VP of research, responsible for pharmaceutical discovery. He worked in Evansville for 20 years, staying with Bristol-Myers when it acquired Mead Johnson in 1967. But a seismic shakeup struck in 1982, when Bristol-Myers restructured — combining Bristol Labs, then in Syracuse, NY, with the Mead Johnson group and building a new research center in Wallingford, CT. Comer relocated to New York City to help put the organization together. Under a new head of research, Giulio Vita, formerly responsible for Bristol- Myers’ international group, the company reorganized R&D into therapeutic-area units with discovery through clinical development in each therapeutic area, then a groundbreaking concept in the industry. Comer was responsible for three therapeutic areas.

“I liked the new structure, where you have a group of chemists, a group of biologists, and a group of clinical people all focused in cardiovascular or neuro or cancer,” Comer says. “Every day, the chemists, the biologists, and the clinical people meet together, and all talk about how they can get a product into the clinic, move it through the clinic, and win approval expeditiously.” At the same time, Comer realized Bristol-Myers had one of the slowest records in the industry moving products from discovery through development to the marketplace. “So it became a goal: How can we do it faster? How can we do it smarter?

It was Comer’s job to recruit someone to head each therapeutic area group. At first, he assumed clinical trials experts would make the best candidates, but then he realized such a person would tend to focus primarily on designing trials for maximum speed to market. “An area head must look toward how to design drugs.” Comer decided the best candidate would be a kind of chemist/pharmacologist hybrid.

He says about half of the chosen therapeutic area heads were chemists, but very biologically oriented, actually in a thennascent field that would become known as medicinal chemistry. “We required the TA (therapeutic area) heads to drive projects all the way to the finish line — and to make compounds that had the right properties, metabolic pathways, and so forth. So the pharmacokinetic and pharmacodynamic issues were addressed, hopefully solved, at the very earliest stages of the project.”

After a few years in New York, the company added licensing to Comer’s charges, where he deployed the staff of all Ph.D. scientists in an international matrix, some assigned by therapeutic area, others by geographic area. The idea was to create overlapping “silos” to comb through the territories thoroughly hunting for top-value drug candidates. “It worked out pretty well,” says Comer. “We became known as the company that did a fabulous job of bringing in a lot of new discoveries at a very early stage.

One of the first drugs the company licensed and developed on Comer’s watch was ddI, entering the unknown area of HIV but still within the company’s strong anti-infectives tradition. At first, Comer says, it may have looked as though focusing all resources to speed a single drug along could have derailed his R&D group, but the actual experience ultimately taught the group and company invaluable lessons in how to move new medicines swiftly through the development pathway. One of the last drugs the company licensed and developed on Comer’s watch was the cancer drug Taxol (paclitaxel) — in keeping with Bristol-Myers’ unique oncology franchise. The new knowledge stretched from the corporate to the personal levels, looping back to the moment of truth before the regulatory committee.

“When Larry Kramer made his one-sentence statement at the FDA hearing, it absolutely got ddI approved immediately, and it had all happened in a very, very fast time. That was the key story because it convinced me of the need to have a patient advocate, especially in a very touchy clinical area. It was a first-of-type product in a new market, with nothing else out there that treats the problem. Patient advocates are absolutely essential — and so is total focus by the company on such a top-priority candidate.”

FOCUS IN PRACTICE
So what does it mean for a company to place a single drug in development above all other priorities? Comer describes it as a challenging but rewarding process wherein some players must take a secondary role in the interest of speeding the lead candidate to the market.

“Once a year, I met with the leading scientists and marketing people, largely divided by therapeutic areas — along with preclinical, clinical, and other departments, such as manufacturing and toxicology, that operated independently of the therapeutic-area concept — to prioritize the sequence and budgeting for all the pipeline projects. Of course, everyone wanted their own project to be number one, to be expedited ahead of everything else by manpower and money.”

When the “number-one” concept began to soak in, Comer says the TA heads and project managers feared losing control of their resources to the needs of the lead project. And for ddI, internal resistance was even stronger because the anti-infectives market had slowed. “So it was a painful discussion, a lot of screaming and shouting,” he says, “and once we more or less reached a consensus, we had to completely reorganize our clinical operations to do all of the ddI studies concurrently, not sequentially as usual.”

Comer mediated the practical trade-offs of resources to push the top drug. “Somebody had to be the Supreme Court and make sure anything you could do with people or money, faster, went to that one project. And there were some very painful moments. Of course, when we got a quick FDA approval — going from IND (investigational new drug) to NDA (new drug application) in 18 months compared to an average of seven to eight years — everybody celebrated, because they realized that working together to push one drug forward did not hurt their projects, but it sure benefited the company.”

From that point on, Comer says the company was committed to the “top-priority” strategy, and it repeated its record-breaking performance with the next lead candidate, Taxol, in only 15 months from IND to NDA approval. Industry peers began to show great interest in the company’s historic move to multidisciplinary drug development. As a result, Comer believes, communication among companies and across disciplines inside companies improved generally

Within a few years, many other companies organized their R&D along similar lines. This was the mid- to late-1980s, as a golden age of pharma blockbusters dawned. But it, too, was not to last.

TECHNOLOGY STEERS A NEW COURSE
Licensing in early-stage compounds only worked to Big Pharma’s benefit as long as the compound inventors lacked the large companies’ ability and resources to move drugs through clinical development. Comer sees new technology as responsible for unseating that disparity by empowering academic labs and small companies to take their inventions further. A “systems biology” approach replaced much of the traditional discovery science such as massive screening, allowing more targeted screening based on a mechanistic understanding of disease. Biotechnology even brought a whole new medium of “drug” treatment, genetically engineered proteins, utterly foreign to the pharma establishment.

“With the new tools, you could make more molecules faster,” Comer says. “You could test them faster in preliminary assays and in much smaller quantities. As a result, you needed fewer chemists, fewer pharmacologists, but more molecular biologists and data managers. We could run more programs, but with fewer people.”

Meanwhile, large-pharma company R&D budgets had grown into the multibillion dollar range, mostly shuttled to clinical development while discovery science and other innovative areas suffered big cuts. Why maintain risky, innovative programs inside the corporation when you can acquire the cream of the crop from outside sources?“Many small companies grew out of academic labs, and they would go right to a new target, make fewer compounds, screen them faster, and get there first. More of the Big Pharmas looked to the small biotechs to make the discovery and validate it before a big company would license it in.”
A RETREAT FROM RISK
As the pharma companies reached the cusp of the license-in strategy, they also began to lose the lead in innovation. The total cost of Big Pharma R&D continued to soar despite internal cutbacks, yet the number of breakthrough, big-market drugs steadily fell. New life sciences companies came on the scene to capture markets and imaginations — sometimes reaching full integration at a smaller scale, remaining as prominent divisions inside their new owners, or becoming large companies on their own. Organizational dysfunction usually gets the blame for poor R&D productivity in Big Pharma, but a more likely culprit may be organizational chaos following the sudden, sweeping mergers of the times.

Comer was Bristol-Myers’ top scientist when it merged with Squibb in 1989. By the earliest terms set by the companies’ chairmen, the die was already cast: The remaining part of Bristol-Myers, the majority owner at 60 percent, would take charge of the business, including legal and administration, as well as sales and marketing, worldwide. As the 40-percent owner, Squibb would be in charge of the science.

Squibb imposed its own R&D structure and headed it with an academic professor who had no experience in the drug discovery and development area. Comer was moved to a new role as senior vice president of strategic management, where he put together some of the companies’ best scientists and marketing experts to explore innovation opportunities in key therapeutic areas.

“It turned into a complete mismatch,” he says. “The two company cultures were very different, and their organizational skill levels were very different. I had to move from working in Connecticut and in New York City, down to Princeton, where I must have appeared to be the invading enemy.” Isolated from scientific and strategic business discussions, Comer finally called chairman Gelb to say he was taking an early retirement at age 55. After some 30 years, he was no longer working for Bristol-Myers.

DOWNSCALING TO INNOVATION
About a year previously, Comer’s mother had died of Alzheimer’s disease, thus piquing his old interests in disease mechanisms and neuroscience. He vowed to himself, “I don’t know how, but I’m going to find out what causes this disease and try to help fix what’s broken.” He hoped to apply his record of success in multiple therapeutic areas to finding new approaches and bringing them to the market. But he found little encouragement in the halls of pharma.

“Nobody within the industry was doing anything about Alzheimer’s. I saw some academic programs that seemed to be nipping away at the beginnings of it — especially at UC Irvine, UCSD, and The Salk Institute, all located around La Jolla, CA. I visited California to look around and found a postdoc at UC Irvine, Steve Wagner, working in a program at the heart of the amyloid approach. So he and I started a new company, and we merged it with a Salk development lab in La Jolla to become SIBIA Neurosciences. The people from Salk asked me to be CEO, but I just wanted to do drug discovery in the neuro area, where Salk owned many patents, rather than pursue diverse projects they had under way — and they agreed to that.”

With about 100 people and less than $1 million in cash, the IP all held by Salk, Comer quickly scaled SIBIA down to a workforce of 18, all focused on the neuro candidates. “We built upon our expertise in receptor subtypes and high throughput screening with two corporate collaborations — Lilly and Novartis, and one with Bristol-Myers and Steve Wagner’s group on Alzheimer’s,” he says.

By 1996, SIBIA had scored an IPO and placed five projects into clinical trials. But just as the company began to build a clinical development capability, it received an unsolicited acquisition offer from Merck & Co. in 1999. In need of funds, Salk pushed for the sale. “We were publically traded, but we sold the company for only $100 million, and $22 million went home to Salk, total profit, tax free,” recalls Comer.

Mirroring his earliest days in the industry, Comer was learning how nothing in the life sciences start-up world moves in a straight line. After the experience with Merck and SIBIA, he would lead another company called Neurogenetics, that explored several patented approaches to Alzheimer’s disease from Rudy Tanzi of Harvard along with Steve Wagner. By 2002-2004, a novel and selective approach to prevent Abeta42 and amyloid plaque formation had been discovered. The company became publicly traded as TorreyPines Therapeutics and developed a clinical agent for migraine and chronic pain.

In 2008, the board decided to sell the company with its pain project, but auction the Alzheimer’s project separately. Comer placed the winning bid and restarted the Alzheimer’s project as NeuroGenetic Pharmaceuticals in June 2009 with Tanzi and Wagner as cofounders. Maria Kounnas, the Alzheimer’s project leader at TorreyPines, joined with Comer to further develop the project in preclinical development, pharmacokinetics, and toxicology and select NGP 555 as a preferred clinical agent, which is now in clinical trials.

“We then developed a stable formulation with once-a-day oral dosing; it gets to the brain and has a very specific mechanism for preventing Abeta42 formation. Although our company moves slowly with virtual staff and little money, it has been the culmination of drug development lessons — design experiments to get the most information from the fewest subjects, time, and money; understand any failures and then move on; assume success but expect the worst,” says Comer.

As he once felt about the molecule called serotonin, he now feels about the new gamma-secretase modulators his company is pushing through development and hopefully to patients. “You can’t treat Alzheimer’s or other neurodegenerative diseases in the later stages, when the neurons have all essentially died,” he maintains. “Investors and FDA regulators have also realized you have to prevent the damage, and thus you have to prevent the advanced stages of the disease. But prevention requires early diagnostics. Now, we can measure reduction of disease-related cognitive impairment as early as 26 weeks and measure early stages of amyloid deposits with PET scans.”

So he’s at it again — first-in-type treatment, expedited development, newer drugs in class coming along behind — and practicing a risk-accepting strategy he summarizes as, “If it isn’t risky, it isn’t innovation!” Dr. William Comer is a natural explorer who has found and traversed many new trails in his career, and he is trailblazing on for the industry even today.