OPINION: DON’T GIVE BIOGEN A “PASS” AT THE FDA

In October Biogen announced a sudden change in fortune for an Alzheimer’s drug previously declared dead. While any good news in the struggle against Alzheimer’s is welcome, the FDA should view Biogen’s claims with skepticism…

There is nothing like a good miracle to kick off the holiday season. Just as if they had turned water into wine, or walked on water, Biogen has pulled its own miracle trick, resurrecting a drug that was more dead than Lazarus. In October Biogen shocked the world by announcing that it’s experimental Alzheimer’s drug, Aducanumab, once left for dead as an abject failure, is in fact so efficacious that it intends to file for approval with the FDA. Biogen claims that a new analysis of the data from two large, stage three trials, indicate that the drug is effective at greatly slowing the deadly progression of Alzheimer’s.  They claim that earlier analysis gave too much consideration to a lack of efficacy at lower doses, while missing clear signs of efficacy at higher doses. 

The wholesale resurrection of a “dead” drug is unheard of in the world of biotech. If true, it represents an authentic  breakthrough in the quest to halt the tsunami of dementia that threatens Western Society. But the dramatic reversal of fortune seems suspicious on a lot of levels…..bold claims should require strong evidence. The FDA should require Biogen to perform another large, confirmatory phase three trial before approving  Aducanumab. 

The Back Story

Mainstream scientists have long suspected that protein plaques in the brain, a result of a complex and progressive pathology, were what caused the devastating memory loss and cognitive impairment associated with Alzheimer’s. Remove the plaques, the thinking went, and reduction or elimination of symptoms would follow.  

This theory was known as the Amyloid plaque theory. 

It made perfect logical sense to a host of pharmaceutical companies, both big and small, but there was just one problem….it didn’t work. Company after company created various versions of plaque removing agents; dozens of these agents failed to relieve the mental decline of Alzheimer’s.  Even when agents could be shown to have successfully removed amyloid plaques, cognitive function did not improve. 

In this atmosphere, American biotech Biogen, along with its Japanese partner Essai, boldy continued to forge ahead. After some promising initial results, Biogen launched two separate phase three trials for its anti-amyloid agent, Aducanumab. EMERGE (1,638 patients) and ENGAGE (1,647 patients) were phase 3 multicenter, randomized, double-blind, placebo-controlled, trials, meaning that Biogen invested serious time and money to produce data that the scientific community would consider to be the Gold Standard.  

Half way through the trials, the company’s statisticians conducted what is called a “futility analysis” which is a standard way of seeing if enough progress is being made that it’s worth the company’s time and money to continue. It wasn’t. The company’s own statisticians, PhD’s with years of biotech experience, decided that the drugs were a total failure. The company’s press release stated: 

“The decision to stop the trials is based on results of a futility analysis conducted by an independent data monitoring committee, which indicated the trials were unlikely to meet their primary endpoint upon completion. The recommendation to stop the studies was not based on safety concerns.” (Biogen Press Release, 3/21/19)

This announcement meant immediate catastrophe for Biogen. The shares fell 30% in one day; $18 Billion in shareholder value vanished within hours of the announcement. 

But, much like Lazarus rising from the grave, this drug’s story did not end at it’s death. Just six months later, Biogen electrified the biotech world with a new press release: 

“Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer’s disease (AD). The Phase 3 EMERGE Study met its primary endpoint showing a significant reduction in clinical decline…..The decision to file is based on a new analysis, conducted by Biogen in consultation with the FDA, of a larger dataset from the Phase 3 clinical studies that were discontinued in March 2019 following a futility analysis. This new analysis of a larger dataset that includes additional data that became available after the pre-specified futility analysis shows that aducanumab is pharmacologically and clinically active as determined by dose-dependent effects in reducing brain amyloid and in reducing clinical decline as assessed by the pre-specified primary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB).” (Biogen Press Release, 10/22/19)

Shazam!! Aducanumab is back, and now better than ever! In fact, so good that Biogen intends to go “all the way,” and submit to the FDA for approval; the first effective treatment for Alzheimer’s.  The greatest pharmaceutical comeback ever? Or just the greatest scam? 

Wait Just a Minute…

Of course this is exciting news for a variety of constituents. But the abrupt nature of these announcements raises a host of red flags. You could hardly have two more contradictory press releases in a six month time span. A number of disturbing questions cannot be avoided. 

The first question would be: who on earth have they hired to conduct their statistical analysis?  How does a team of highly experienced and respected PhD’s wind up looking like the Three Stooges? In the weeks leading up to the initial negative announcement, it must have been obvious that the bad news would unleash a chain of severe consequences for everyone involved …wouldn’t they have checked every single possibility for some hope of efficacy?  Wouldn’t the executives in charge have tried every angle to find a glimmer of favorable data? How on earth would a team of professionals miss this efficacy, and totally change their minds just six months later? If we aren’t talking about data manipulation or fraud, then we must be talking about naked incompetence. Neither seem too appealing. 

The second question is the data itself. Even though the new press release is, suddenly, the model of positivity, in fact, only one of the two trials showed drug efficacy if standard statistical methods are applied. As explained by the PharmaDeepDive Blog:

“In EMERGE, Biogen said treatment with high-dose aducanumab resulted in a 23% reduction in clinical decline versus placebo on a function and cognition test known as CDR-SB, the study’s primary endpoint.This both cleared the bar for statistical significance and surpassed the 20% mark executives argued is sufficient to be clinically meaningful to patients.But in ENGAGE, a supposedly identical trial, patients on high-dose aducanumab saw no benefit as measured by CDR-SB.For some analysts, that raised the question of whether EMERGE’s success represents a false positive.” 

The third question is: is a 23% “reduction in clinical decline” really such a breakthrough?  So this would mean that the Alzheimer’s patients were still spirling down the drain, they were just doing so at a 23% slower pace. Not great. And by the way, can we really measure if someone is 23% sharper today than they were last week, or the month before?  How do you really measure if someone is thinking 23% less clearly than they should be? 

Liberty Vrs. Regulation

Based on these gaping holes in Biogen’s story, why would they believe that they could gain FDA approval without needing to produce stronger data? 

One word: HOPE. 

Those  who have experienced first hand the decline of a loved one understand how desperate our current situation is regarding Alzheimer’s.  At times the disease seems impossibly cruel; cruelest of all seems to be our current inability to make any difference at all in the disease’s grim progression.  To helplessly watch a loved one slowly transformed into the living dead is to long for some way to make a difference. 

False hope is the danger of Aducanamab.  If hope overwhelms science, then the FDA may open up the door for one of the greatest pharmaceutical heists in history. 

Anyone who has read my work knows that I typically favor market based solutions as opposed to the heavy hand of government regulation. But this may be one case where market failure could result in a lot of broken hearts and depleted bank accounts. To put it simply, Aducanamab is a special case due to the deeply emotional nature of the disease in question. 

I generally favor a more permissive FDA approval, because regulatory approval is typically only the first hurdle a drug must clear. Even if a drug is approved by the FDA, many insurance companies will refuse to cover a drug if they feel that the data isn’t strong enough to warrant the price. Many hopes for outsize profit have been dashed upon these rocks.  

Even if drugs pass through the FDA, and then receive some level of insurance coverage, the medical community as a whole must accept the drug as safe and efficacious. If individual physicians do not believe in a drug’s data, the whole enterprise may die before it even leaves the doctor’s office.

These additional, market based protections are the reason why I typically recommend that the FDA approve drugs more leniently. As long as the new agent is proven safe, insurance companies and physicians generally know which drugs work, and which don’t, resulting in an extra filter against sham drugs. 

But these market based mechanism will not stand up against the sheer desperation that Alzheimer’s causes.  Millions upon millions of frantic families will effectively advocate for insurance coverage on the flimsiest of evidence; any sliver of hope is better than the grim reality that these families currently face. Physicians, bone tired of seeing dozens of patients per week that they can’t really help, will prescribe the drug in an attempt to calm desperate pleas for help that go unanswered. 

Which leaves us to the patients, and those unreliable measurements we discussed before. Cholesterol and blood sugar can be measured numerically; additionally, they are often measured by a third party lab, which lends itself to objective measurement. Searching for a   23% “reduction in clinical decline” can be highly subjective, especially since most of the measuring is likely to be done by the loved ones who are daily caregivers.  Different forms of denial are extremely common in families coping with Alzheimer’s…an understandable reaction to a situation that cannot really be helped. In short, millions of families would proudly spend their last pennies buying medication that doesn’t work anyhow, because anything is better than hopelessness. 

We could have a modern medical miracle on our hands. However, we must also guard against the possibility that a very cynical and shrewd Biogen team has realized that the bar for approval is very low, and the upside to bending the truth is measured with nine zeros.  

The FDA should demand new scientific data before allowing aducanumab on the market. As the saying goes, “Hope is not a strategy.”