Bio CEO dishes big city mix of business, policy, science

As always, the recent Biotechnology Innovation Organization’s annual BIO CEO & Investor Conference offered a lively mix of tough business and policy topics along with in-depth looks at key therapeutic areas, notably oncology, Alzheimer’s disease and ophthalmology. There were some valuable insights which are worth sharing with a broader audience.

The meeting, held at the Waldorf-Astoria hotel in New York and boasting more than 1,400 attendees, more than 600 of whom were registered investors, kicked off with a look at oncology clinical trial design.

Thousands of failed cancer trials and only a smattering of cancer drug approvals prompted the FDA to adopt draft guidance in 2010 to allow for adaptive study designs and, while a number of studies such as the public-private Lung-MAP study are ongoing, still more work needs to be done to improve the cost efficiency and success rate of oncology drug development.

Preliminary data from a report that BIO expects to release in May shows that, between 2006 and 2015, the success rate of oncology drugs was lower than all other areas. A mere 5 percent of cancer drugs were able to go from phase I to approval, David Thomas, BIO’s senior director of industry research and policy analysis, told the BIO CEO audience.

That rate was even lower than for psychiatric and cardiovascular drugs, each of which have success rates of 6 percent.

When it comes to drugs that make it to phase III, oncology "also is at the bottom of the list," Thomas said, with a one-in-four chance (25 percent) of making it to phase III. Of those that do, only 39 percent move forward to new drug application filing, again lower than other disease area.

One bright spot shows that the use of biomarkers can make a huge difference. Thomas pointed to oncology drug programs that have taken advantage of biomarkers which had a fourfold increase in success. The problem is that only a fraction – roughly 10 percent – of cancer drugs are developed using a biomarker approach.

It's partly an issue of science. “Part of the problem with biomarkers is that we need to validate them, we need to find them,” said Ellen V. Sigal, chairwoman and founder of the Friends of Cancer Research, which moderated the panel on improving clinical trial design in cancer.

In cases in which biomarkers have been identified, great progress is being made. One of those examples is Lung-MAP, a multidrug, biomarker-driven squamous cell lung cancer trial that operates under a master protocol, enrolling patients with a host of mutations such as c-Met, FGFR, PIK3CA, and then matching patients to sub-studies that investigate treatments targeting specific genomic mutations.

Work on Lung-MAP and other such adaptive trials, while promising, also throws into stark relief two of the biggest challenges: a relative paucity of biomarkers and, particularly for small firms, the difficulty in raising cash to support such biomarker discovery.

Drug Pricing vs. Value

A panel of experts also took on the drug pricing vs. value debate, urging the industry to shift its narrative on the topic going forward.

"We have been here before," conceded Ron Cohen, CEO of Acorda Therapeutics Inc. and current chairman of BIO, mentioning Questcor Pharmaceuticals Inc., which earlier was heavily criticized for a dramatic price hike on its drug for infantile spasms in a fuss that quickly blew over. "But now it seems to be sticking, and the overall distribution of rage seems to be wider."

The reasons are many. Scott Gottlieb, resident fellow at American Enterprise Institute, listed four contributing factors: the make-up of Capitol Hill, with more legislators likely to be open to regulating drug costs; the shift in insurance scheme to closed formularies; the government picking up a "dramatically bigger share” of the overall drug spend; and the Affordable Care Act (ACA), which "nationalized" discussions of healthcare costs, resulting in hospitals and drugmakers getting labeled as the "bogeyman."

"I don't see a legislative fix on the horizon" this time, Gottlieb added, referring to the introduction of Medicare Part D in 2006, which helped stave off clamor for drug importation, a move the industry viewed – and continues to view – as catastrophic to innovation.

That means industry can't just stand on the sidelines and point to the latest Tufts Center for the Study of Drug Development estimating the cost of developing a drug at $2.6 billion. "The problem we have as an industry is we have not educated over time the constituents of this drama" about what is involved in drug development, Cohen said.

Industry will have to start making its case, the panelists concluded.

The Amyloid Beta Debate and Advancements in AD

Last year's big win by Biogen Inc. with Alzheimer's disease candidate aducanumab, the first potentially disease-modifying drug to hit its pre-specified endpoint in a proof-of-concept study, restored optimism to a space that had been riddled with failure and reaffirmed faith in the amyloid beta (abeta) hypothesis – at least for some. (See BioWorld Today, March 23, 2015, and April 27, 2015.)

"We can argue if that's reproducible in phase III, but this is the first time it happened," noted Evercore ISI Analyst Mark Schoenebaum, during another BIO CEO therapeutic workshop. "In my mind, we're as close as you can get without a phase III trial to validating abeta as one of the targets."

He added that he believes one or more of the current abeta-targeting antibodies such as aducanumab will succeed in phase III and "that will be the beginning of a revolution."

But not everyone on the panel was swayed by the Biogen data, or even the abeta hypothesis for that matter.

Daniel Alkon, chief scientific officer at Neurotrope Bioscience Inc. and scientific director at the Rockefeller Neurosciences Institute, said he remains skeptical, pointing to the failures of multiple previous abeta approaches despite more than 20 years of research into the effects of amyloid beta on cognition.

"We know a number of patients with [Alzheimer's] don't have amyloid or have minimal amyloid," he said.

Alkon said to tackle Alzheimer's will involve approaches that can actually reverse or restore function, not just slow – or appear to slow – the cognitive decline. "The loss of synaptic connections is the elephant in the room," he said. He likened the brain of an Alzheimer's patient to a computer that has had its wiring removed, and said Neurotrope is working on a regenerative medicine approach aimed at inducing the growth of synaptic connections. "This is what has to be done with respect to a game-changer."

Untapped Opps in Ophthalmology

Despite the appeal of shorter development timelines – and the potential of a multibillion-dollar market – drug development in ophthalmology has lagged behind work in other disease areas in terms of new targets, biomarker development and even the number of players operating in the space.

"There's still an enormous amount of unmet need," said Nouhad Husseini, vice president of business development at Regeneron Pharmaceuticals Inc., during a BIO CEO panel focusing on the space. Compared to what's happening in cancer, for instance, "it's night and day. There are very few companies working in ophthalmology."

Even Regeneron came to the therapeutic area "almost by accident," Husseini added. The Tarrytown, N.Y.-based firm ended up developing bestselling wet-age-related-macular-degeneration (AMD) drug Eylea (aflibercept) from its platform technology – and another version of the VEGF inhibitor is approved for cancer.

While Eylea and other VEFG inhibitors Lucentis (ranibizumab, Roche) and Avastin (bevacizumab, Roche AG) have marked a huge change in the wet AMD space, other areas of ophthalmology such as uveitis and dry AMD offer no treatment options. And even dry-eye disease has limited therapies available. Eleven Biotherapeutics Inc. reported failure last year with EBI-005 in a phase III dry-eye trial. Meanwhile, Shire plc, has had better luck, disclosing positive phase III data late last year, which it included in its new drug application resubmission to the FDA for lifitegrast, which previously received a complete response letter. (See BioWorld Today, May 19, 2015, and Oct. 20, 2015.)

One impediment to ophthalmology development is simply a lack of adequate tools, an irony noted by Husseini. "One thing about the eye is you can visualize the eye; there aren't any other organs where you can take a device and see what your drug is doing to it. But we're at very crude techniques."

That makes it especially difficult to measure success in trials for diseases such as glaucoma. "You're not regrowing cells; you're just trying to get them to lose vision a little bit slower," Husseini said, adding that the space needs a "breakthrough" in imaging techniques that can be readily linked to regulatory requirements.

The space also needs to find ways to fully tap into the science. There are 220 unique genetic markers for eye diseases, said Tony Gibney, managing director of Leerink Partners, who moderated the ophthalmology panel. "We're really just scratching the surface of what we have."

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