November 28, 2016
By Mark Terry, BioSpace.com Breaking News Staff
News on November 23 that Eli Lilly and Company ’s Alzheimer’s drug, solanezumab (sola) failed a Phase III clinical trial cast shade on other companies working on Alzheimer’s, especially Biogen ’s similar drug, aducanumab. Now that everyone has had a chance to calm down and think about it, the results may not be as bad for Biogen as originally thought.
Lilly’s sola did not show a statistical slowing in cognitive decline compared to the placebo arm. That decline was measured by the ADAS-Cog14 (Alzheimer’s Disease Assessment Scale-Cognitive subscale). More in-depth data is expected to be released at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting on December 8.
For the most part, Alzheimer’s drugs focus on two mechanisms of action. Lilly, Roche and Biogen, for example, are focused on developing antibodies that attack beta-amyloid, the protein plaques that build up in the brain of Alzheimer’s patients and cause the brain damage that results in cognitive decline. It is the predominant theory of what causes Alzheimer’s disease.
AstraZeneca , Lilly and Merck are also focused on beta-amyloid, but rather than building antibodies that attack beta-amyloid after it exists, are working on BACE inhibitors, which work to prevent its development completely.
There are also companies that work on drugs that affect tau, which is a tangle of proteins that tends to occur later in the disease after beta-amyloid has done its damage.
Nonetheless, scientists are not 100 percent convinced that beta-amyloid is the sole cause of Alzheimer’s disease, although it is the predominant theory.
So when Lilly’s antibody for beta-amyloid failed, many investors immediately thought that meant the beta-amyloid theory was not the place to invest their money.
However, with some time to think, many analysts are pointing out that Lilly’s sola and Biogen’s aducanumab, although similar, are also very different. Andrew Fein, an analyst with H.C. Wainwright, wrote, “In contrast to solanezumab, aducanumab has both clear evidence of target engagement and clear clearance of Abeta from the CNS, and is additionally differentiated by a different patient population, prodromal rather than mild AD patients.”
Other analysts, such as Raymond James, agreed, noting that with the drop of Biogen shares by about 3.5 percent, it was likely a good time to buy.
Geoffrey Porges, an analyst with Leerink, however, cut Biogen’s chances of success from 65 percent to 35 percent, although what type of statistical model he’s relying on is a mystery. “While all antibodies are different and nuances can be picked apart in molecular structure, amyloid target subtypes, and clinical trial design, the simple fact that sola failed in such a large, heavily overpowered trial deals a significant but not fatal blow to the outlook for all drug development aimed at the beta amyloid cascade,” he wrote.
Despite that, Porges did note that Biogen’s drug is a “fundamentally different molecule,” and that those differences “justifies some continued confidence in a different clinical outcome for the two molecules.”
It’s worth noting that Lilly’s sola essentially failed a Phase II trial and rather than abandon the drug, chose to set different endpoints and patient populations and try again. Max Nisen, writing for Bloomberg, notes that this appears to be a trend in biopharma, saying, “Too rarely these days is a drug’s clinical-trial failure the end of the line. Drugmakers almost always find a ‘but’—‘But the drug appeared to work in a certain population of patients.’ ‘But the placebo effect was unexpectedly large.’ ‘But, but, but.’”
Which is true enough, and often worth evaluating, as pharmacogenomics testing provides more details about why certain drugs work or don’t work in certain patients. But it’s also probably true that in some cases, the drug just doesn’t work very well. Sola failed two previous Phase III trials. Nisen writes, “But in poring through those results, researchers came to believe the trials had failed the drug, not the other way around, and the latest trial selected patients more carefully. Sola was given every chance to succeed—Lilly even moved the goalposts of success—but it failed once again.”
Alzheimer’s is clearly a tricky area. Between 2002 and 2012, only a single drug out of 244 Alzheimer’s drug candidates was approved, a 99.6 percent failure rate.
Yet companies continue, not only because a modestly successful drug would likely be a blockbuster, but because it’s an area of unmet medical need.
Rita Balice-Gordon, recently appointed head of neuroscience at Paris-based Sanofi , ) told the Pittsburgh Post-Gazette, “This is such a devastating disease, and it’s so important for scientists to continue to push through this. I’m committed to beating the drum for doing well-reasoned and well-researched clinical experiments, which will help drive the field collectively forward.”
