October 27, 2019

Rescinding the DNR order--for anti-amyloid drugs

The pharmaceutical firm Biogen issued a stunning press release this week: it would seek FDA approval for its anti-Alzheimer’s drug, Aducanumab—the very same drug the company had pronounced a failure just last March, after preliminary analyses indicated the drug was very unlikely to achieve its objectives. Dennis Selkoe, a prominent Alzheimer’s researcher at the Brigham and Women’s Hospital in Boston, wrote in STAT (a health-oriented news website owned by the Boston Globe) that he believed that “aducanumab is the breakthrough we have been waiting for.” But is it?

Aducanumab is by no means the first drug studied that targets beta amyloid, a protein widely believed to play an important role in the development of Alzheimer’s disease. An article in Nature Reviews (Drug Discovery), published shortly after the first analysis of the Aducanumab data, put the drug in perspective: a monoclonal antibody that binds to beta amyloid, it is the fourth such drug to make it to a Stage III clinical trial. And all three of its predecessors, as well as another five anti-amyloid drugs that have a different mechanism of action, were abysmal failures leading Nature Reviews to proclaim "Anti-Amyloid Failures Stack Up as Alzheimer's Antibody Flops." Maybe what this new analysis of the Aducanumab data has done is to reverse the Do-Not-Resuscitate label previously attached to monoclonal antibodies and instead put them on life support. So, what, exactly, does the new data analysis show? 

The details will be released to the FDA when Biogen files with the FDA to approve the drug. Thus far what we know is what Biogen has included in its press release. Biogen conducted two randomized, double blind, controlled studies, giving the monoclonal antibody (presumably by injection, like other monoclonal antibodies) or placebo to a total of 3285 patients and following them, some for 78 weeks. One study, sporting the acronym ENGAGE, produced negative results even upon re-analysis, although a subset of ENGAGE patients who received a high dose of the drug appeared to respond. The other study, named EMERGE, showed a reduction in the rate of clinical decline in treated patients compared to those receiving placebo. In other words, the study patients did not improve nor did they plateau; rather, they got worse more slowly. Unfortunately, the press release doesn’t report the absolute magnitude of the change, opting instead to say that the scores on the Mini-Mental State Examination (MMSE), a commonly used measure of cognition, fell 15 percent less with treatment than with placebo. Similarly, the rating on the ADAS-Cog13, another measure of cognitive function, declined 27 percent less in those on the drug. Finally, and perhaps most encouragingly, the decline in the ability to perform basic daily tasks (as measured by the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory) was 40 percent lower in those receiving Aducanumab than in their counterparts who received placebo. 

These are not spectacularly impressive results—the patients continued to worsen and the difference between treated individuals and untreated individuals, at least on measures such as the MMSE, was very small. But what we don’t know is whether the slowed rate of decline will persist over time or whether, as with drugs that are currently on the market such as donepezil (Aricept), there is a one-time effect. We don’t know whether the effect would be greater if the medication were used earlier in the progression of Alzheimer’s disease, perhaps in people with mild cognitive impairment. We don’t know whether the drug will prove to be more effective in those with “pure” Alzheimer’s disease, that is, without concurrent vascular changes. 

What we can predict is that if the drug is approved by the FDA, Biogen, whose stock price soared after the press release, will aggressively market the drug. An estimated 5.8 million Americans have Alzheimer’s disease, according to Alzheimer’s Association statistics released in 2019: since the time from diagnosis to death is 5-7 years, roughly one-fifth of the affected individuals or over a million people likely have early Alzheimer’s and are potential Aducanumab consumers. This could be a dream come true for the pharmaceutical company--a blockbuster specialty drug. (Blockbuster drugs are prescribed to at least one million people a year and specialty drugs are very expensive biologicals such as monoclonal antibodies). And if the sales price for the drug is anything like that of other newly marketed monoclonal antibodies, it may be upwards of $1000 per month (Dupilumab, brand name Dupixent, a new monoclonal antibody used in the treatment of asthma and/or nasal polyps, has a list price of $37,000 per year). 

Biogen stockholders will benefit enormously; how much people with Alzheimer’s disease will benefit is less clear. But on a more positive note, as Dennis Selkoe commented in STAT, for the first time we have evidence that it is possible both to design molecules that target amyloid and to administer them to real people with minimal toxicity and some evidence of benefit. That truly is good news.

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