Looking beyond intepirdine after the inevitable happened


As an analyst in DRG’s Market Assessment business, a core part of my job is to build the most rational drug forecasts I can with the latest information I have. But I cover Alzheimer’s disease (AD), which boasts a 99% pipeline failure rate, so there’s good reason not to forecast the launch of any emerging therapy. However, I don’t take that approach in my AD forecast for many reasons. But then every year like clockwork, once I hit the “publish” button, news breaks of another drug failure, and I’m reforecasting. Not this time.


As of last fall when Lundbeck’s idalopirdine data broke, I placed my bet against Axovant’s intepirdine, a 5HT-6 receptor antagonist in development as an adjunctive procognitive symptomatic therapy for the treatment of mild to moderate AD. Don’t misunderstand me: for the patients and their families, I hoped I would lose this one. No one wants to see another AD drug fail; with each trial readout, we find ourselves, maybe against our better judgment, thinking: could this finally be the one that offers benefits to patients in desperate need of new therapies? But given intepirdine’s history, it was too hard for me to imagine that this one would defy the odds.


We all know the story by now: the hedge fund wiz kid who bets big on a failed AD drug from GSK, and gets investors to bet big with him to the tune of a historic biotech IPO. They handwave at mixed data from four older Phase II trials citing signals of efficacy for the drug as an adjunct to current standard of care, and double down, initiating what they deem to be a “confirmatory” Phase III study enrolling over 1,300 patients with mild to moderate AD. In the meantime, Pfizer terminates its 5HT-6 receptor antagonist after an interim futility analysis and Lundbeck/Otsuka report data from three Phase III trials (enrolling over 2,500 patients) of their own 5HT-6 receptor antagonist idalopirdine, all of which failed to meet their primary endpoints. At that point, we all started to wonder if could this be a class issue, while the Axovant team claimed their drug was different, their dosing was better, and that we would all see at the end of September.


Fast forward to Tuesday morning (September 26, 2017) at 7am and there it was, the press release we’d all been waiting for and it pulls no punches: “Axovant Announces Negative Topline Results of Intepirdine Phase 3 MINDSET Trial in Alzheimer’s Disease.” There was no hidden signal unearthed, as the press release reports: “change from baseline in cognition was non-significantly improved in the intepirdine arm versus the placebo arm” and “there was essentially no difference between the intepirdine and placebo arms in change from baseline in activities of daily living.” Our latest failure in AD is an undisputable one. But… didn’t we see this one coming?


It’s becoming less common that developers in AD run Phase II programs (we can debate the merits of that, and have done so in past blog posts); they are expensive, long, hard to power, and not predictive of Phase III success. But, when there is extensive Phase II data and it is not overwhelmingly positive as in the case of intepirdine, should we be surprised when a Phase III trial doesn’t work? Maybe a fairer question is: should it have even been resurrected and advanced to Phase III?  And what is the cost of that gamble? Of course, there is a financial cost (estimates were about $1.8 billion in market cap lost at last check), but also a cost in time, energy, and emotional investment for the patients, families, and investigators who participated in new research evaluating a drug that already had a few strikes against it.


There will be tons of stories written about the implications of this failure for Vivek Ramaswamy and his family of companies, as there were before the data was released. As that spotlight fades, patients, families, and healthcare systems around the world will be left to wonder: Is there any hope? While the loss of intepirdine means little for the prospects of other compounds with fundamentally different MOAs, it’s natural to wonder if we will ever get a win. The answer to that question depends on who you talk to, and the drug you’re talking about.


For symptomatic drugs, the outlook is bleak. With intepirdine and idalopirdine gone, there are no procognitive symptomatic drugs left in Phase III development, and those that persist in the early-phase pipeline give us little reason to be even cautiously optimistic. Meanwhile, although the DMT pipeline is robust, there are no better guarantees of clinical success. Moreover, as DMTs are targeted at slowing disease progression in early-stage patients, they will mean little for millions of people with established disease. The best hope for a drug to help more advanced AD patients is in the realm of behavioral symptoms, particularly agitation and psychosis. There are quite a few molecules targeting these symptoms in both the late and early-phase pipeline, but Lundbeck/Otsuka’s Phase III trials of Rexulti for agitation in AD reported mixed results in May 2017 and there are no data to date for Otsuka/Avanir’s AVP-786. Suffice it to say, we have our doubts.


The largest segment of the pipeline comprises DMTs, most of them targeting amyloid. Of course, the rate of failure here is especially high, but developers continue to double down, reevaluating their strategy with each failed study and now—importantly—investing in bona fide prevention trials in preclinical AD patients. These trials may represent the real chance for DMT success. To the delight of many interviewed KOLs, developers have also finally advanced anti-tau therapies into clinical studies, including AbbVie and AC Immune.


With the inevitable but still disheartening intepirdine results behind us, we now look to CTAD in November where Merck is expected to report data from its terminated EPOCH trial of verubecestat in mild to moderate AD. This will be the first time we see clinical data from a BACE inhibitor, and those data will have huge implications for the future of class. Will there be a signal in the mild AD cohort that offers hope for other BACE inhibitors being tested in more-optimally designed trials in early AD, or will there be no sign of efficacy, possibly signaling the death knell for the class? This one, frankly, has bigger implications for us and our forecast model in AD than intepiridine—but, yet again, this news will break just after I hit that “publish” button.


Learn more about DRG’s complete pipeline assessment and latest pharmaceutical forecast in AD.

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