By Louis Garguilo, Chief Editor, Outsourced Pharma
In 2001, members of a small biotech from the New York City area traveled to the state capital, Albany, to discuss accessing the state’s new Biotechnology Industry Growth Fund. An economic development official responsible for a portion of that fund met with them but came away skeptical.
Biotech was still a new industry; this company had failed in the clinic and was just getting new compounds into development. Its self-assuredness seemed misplaced. “When would NY residents see any return on investment?” asked the stern official. “How many jobs will your start-up create?
I was that (myopic) state official, and let’s just say I’m thankful for having gained somewhat better instincts over the years. That company, Regeneron, would go on to become one of the most successful biotechnology companies in the world, let alone in New York, where it has created thousands of jobs (see accompanying article on NY). More importantly, Regeneron has provided relief to millions suffering from disease. And further relief is on the way, with potentially three new drug approvals coming soon, more compounds in the clinic, and a pipeline that any biotech or pharmaceutical company would envy.
Constant through Regeneron’s remarkable trajectory has been an outsized assuredness of success, starting from its formation in 1988. How confident has Regeneron been? Well, how many biotechs do you know that purchase a commercial manufacturing facility to control its own production before they have a compound in Phase 2?
Neil Stahl, SVP of research and development sciences and a 24-year veteran of Regeneron, recently told me that level of confidence flows through every scientific decision Regeneron has made and drives the company’s impressive pursuit of medicines into new therapeutic areas. Below he shares more of the story behind Regeneron’s success and tells us why the best is yet to come.
ONE OF THESE DAYS, A COMPOUND WILL SURELY SUCCEED
“We believed from day one we would be one of the most successful science and medicine creating organizations in the world,” says Stahl, mentioning the resolve of founder Leonard S. Schleifer, M.D., Ph.D. president, and CEO; and founding scientist, CSO George D. Yancopoulos, M.D., Ph.D. “Well, maybe George didn’t fully agree. He’s always thought we would be the best.”
That confidence got a boost from the outside when in 1995 renowned scientist and chairman and CEO of Merck & Co., P. Roy Vagelos, upon his retiring from Merck, decided to join Regeneron as chairman of the board. Stahl recalls Vagelos saying at the time he was impressed with the science and energy, and that given the time and money, Regeneron would lead biotech in making important contributions to science and medicine.
Stahl, for his part, had to be force-fed the Kool-Aid to get his initial confidence boost. “I was teaching at UCSF and looking around for academic opportunities,” he says. “I had no idea about biotech, and certainly not in New York, when Len invited me to their labs in Tarrytown. I found this small operation, and my first thought was, ‘No way in hell I would come work here.’” Stahl says that at the time there were only two biotechs that most people had heard of, Genentech and Amgen. Nonetheless, an intense, three-hour discussion of science and what a biotech could accomplish with Yancopoulos was enough to change his mind.
“People told me I was throwing my career away,” recalls Stahl, “but at Regeneron I could see the science came first. We’ve always taken the realistic perspective of how long science takes and for that knowledge to develop and make an impact. We planned the company’s finances to ensure there is always a substantial amount of research going on. We had confidence that if the first compounds didn’t work, one of these days one of them was going to be effective.”
Here’s what that confidence has produced so far: 2008 FDA approval of Arcalyst (Rilonacept) for the treatment of a rare genetic disease; 2011 to 2014 FDA approvals of Eylea (Aflibercept) Injection, Eylea for Macular Edema Following Central Retinal Vein Occlusion, and Eylea Injection for the treatment of diabetic macular edema (DME). Net product sales in the first quarter of 2015 were $545 million, compared to $362 million in the first quarter of 2014, and total revenue increased by 39 percent to $870 million.
Perhaps the most important results — and biggest payoff — from Regeneron’s unbridled confidence to “lead with the science” is in how it has put irons in the fires of an expanding group of therapeutic arenas.
SCIENCE IS THE SNAKE OF SERENDIPITY
Where some might see the mysterious movement of serendipity leading Regeneron from one therapeutic domain to the next, Stahl sees the logical and steadfast pursuit of science. This dedication is without regard for what is paramount in so many other companies: patient population numbers and potential financial returns. “Through our history,” says Stahl, “we have been fearless about entering any new areas if we believe we have some scientific insight to help patients.”
For example, although now famous for eye drug Eylea, Regeneron started with a deep research effort in angiogenesis in oncology to get there. Regeneron cloned a group of new factors with a primary importance in developing and stabilizing blood vessels. To pursue work with these angiopoietins, the company formed an angiogenesis team to study the full processes by which new vessels are formed, how they become pathologic, and the potential to regress them if it was shown they were not wanted in certain areas.
Regeneron had reached the conclusion that macular and endothelial growth factors were probably primary to some diseases, but other factors like these angiopoietins could play a role. With that insight, the company independently engineered the VEGF Trap — a decoy receptor-molecule combining two distinct receptor components and a portion of an antibody molecule called the “Fc” or “constant” region – which became Eylea. “These two pursuits, angiogenesis and this engineering technology, came together for our entering this area of eye disease,” says Stahl.
“This is a vignette of how we entered one area. But the same applies across all of these other therapeutic areas. We’re in a wide diversity of biology areas, but each stems from initial biological insights and the pursuit of the science.”
A great deal of that biological insight stems from Regeneron’s interest in human genetic findings. “Our cholesterol program arose out of the genetic finding that people with a mutation in one copy of the PCSK9 gene have lower LDL,” says Stahl. “In a 15-year observation period, these people also had an 88 percent reduction in cardiovascular disease and appeared to have no ill effects from having a loss of function mutation which inactivated one copy of their PCSK9.” From that key observation, Regeneron moved forward to develop animal models that produced the same results in mice and monkeys, by creating antibody reagents that mimic the blocking function of the PCSK9. With that proof-of-concept, they were then able to show a dramatically lower LDL level in humans. The resultant drug is Praluent (Alirocumab), an antibody targeting LDLcholesterol (LDL-C or “bad” cholesterol) and which is now tantalizingly close to FDA and EMA approvals.
Stahl points out that in Tarrytown, Regeneron has one of the largest mousegenome engineering capabilities in the world. Working with the NIH, Regeneron is in the midst of a “knockout mouse project,” deleting one gene at a time in the mouse genome to help understand how that affects health and disease. Also, the Regeneron Genetics Center was recently opened “to work hand-in-hand with this mouse biology and try to understand if there are other mutations in the human population that tell us about biology and disease.” Now with one of the largest sequencing operations in the U.S., Regeneron expects, by year’s end, to have sequenced 100,000 exomes, which make up 1 percent of the human genome and are expressed as proteins.
“We’ll correlate that with phenotypes to look at susceptibility to health issues such as cardiovascular disease, high blood pressure, and high LDL,” explains Stahl, “and conversely look at general health and a lack of disease, suggesting a protection that we may make use of.”
He concludes: “All of this sequencing is providing new insights that will help us enter more therapeutic areas — like we entered the cholesterol area — based on the pursuit of genetic research.”
THE NEXT SURE THING(S)
Along with Praluent, Regeneron awaits an array of approvals in coming months and years. These include Sarilumab, the company’s antibody targeting IL-6R for rheumatoid arthritis, currently in a global Phase 3 program. The company and its research partner Sanofi plan to present new data and submit a BLA (biologics license application) in the U.S. by the end of this year. Stahl believes Sarilumab will prove useful for other inflammatory and immune conditions as well.
Another compound working through the clinic is “the unprecedented drug Dupilumab, which has shown encouraging efficacy in mid-stage trials for three distinct allergic conditions,” says Stahl. Dupilumab is an antibody that blocks signaling of IL-4 and IL-13 and is currently undergoing study in atopic dermatitis, asthma, nasal polyps in patients with chronic sinusitis, and eosinophilic esophagitis.
However, true to the Regeneron way, Stahl seems more excited — and confident — the further up the pipeline he looks. He says there are “another 15 antibodies in clinical trial, including some based on new platform technologies.” He’s referring to Regeneron’s own approach to the renaissance in immuno-oncology, based on the increasing realization that tumor cells have mechanisms to suppress the immune system. “A variety of molecules that block that interaction and rev up the immune system have been discovered. We are very active in this area,” says Stahl.
This is in addition to what Stahl calls “bi-specific antibodies,” where instead of reliance on endogenous immune response against a tumor, an antibody bridges and creates an artificial immune response. “One arm actually binds the tumor, and the other binds the T-cell — the immune cell — and activates it by clustering a surface protein just as if the cell had been naturally activated by the tumor. It’s a new platform to turn on the immune system and direct it toward the cells you want to kill. We have one bi-specific antibody in the clinic now and five more ready to enter once we are convinced the approach is effective.
“We are just at the beginning of everything we can do with the science and these new drug platforms we’re building. What keeps us coming to work everyday is not what we’ve already done, it’s the exciting stuff still in the hopper.”
REGENERON A NEW YORK EXCEPTION … FOR NOW
Most everyone knows Frank Sinatra’s ode to New York: “If I can make it there, I’ll make it anywhere… .” For the biotechnology industry, though, New York has not been the benchmark, despite respected institutions of higher learning, medical research centers, an active biotechnology industry association, and plenty of funding opportunities.
“Our two founders and executive leaders, Len Schleifer and George Yancopoulos, were born and raised and started Regeneron in New York City,” says Neil Stahl, SVP of research and development sciences, who himself makes the city his home. “It’s frustrating to us that although there is all this scientific talent and great universities, the New York City area is not a bigger hotbed of biotech. We’re dedicated to changing that.”
The scientific talent Stahl mentions resides at places such Cedars-Sinai Medical Center, Columbia University, and New York University (NYU), all ranked by the NIH as leading biomedical research institutes.
Regeneron has collaborations and stays involved with all the universities in the city. “I’m particularly affiliated with NYU and CUNY [City University of New York],” says Stahl. He considers it a company – and personal – mission to visit these universities to tell student researchers about the satisfaction and opportunities of working in the bio industry. “We open their eyes about how we do the science and the possibilities of what they can accomplish when working in large scientific groups,” explains Stahl. “They learn about the resources available and the difference you make in people’s lives doing research and development directly on programs that can lead to medicines. I convince them of this satisfying way to spend their intellectual energy.”
But there’s also the need for the entrepreneurial side as well; science and enthusiasm have to transfer to start-ups to grow a biotech cluster. In this and other measurements, New York has consistently ranked below San Francisco, Boston/Cambridge, San Diego, and Maryland/Washington, D.C., and among a second tier of clusters, including Raleigh-Durham and Seattle, for example. Momentum remains relatively strong in all these other clusters; critical mass has been achieved, and close-knit but broadening networks and infrastructure continue to be built.
New York is experiencing this growth as well. The broadening is recognized in recent surveys of biotech clusters. For example, Genetic Engineering & Biotechnology News (GEN) recently changed its listing for the metropolitan area from “New York” to “New York/New Jersey,” which propels the cluster to third place from fifth, now behind only San Francisco and Boston/Cambridge and ahead of San Diego. This broader measurement presents the cluster as the nation’s largest geographic region. It also helps mitigate what has always been considered – whether in reality or perception – a concern for bio entrepreneurs in New York: affordable and available lab space. According to GEN, the Empire State/Garden State tandem is now tops in lab space among clusters. We’ll have to keep an ear to the ground on the pricing of all those labs.
Moving up to the third largest biotechnology cluster in the U.S. would be quite satisfying for most any city, but hey, this is New York! There are no likable numbers after one. And we can be sure New Yorkers are happy to now have their biotech companies – like some of their sports teams – one happy New York-New Jersey family.