The Food and Drug Administration’s decision to greenlight aducanumab (trade name Aduhelm) for Alzheimer’s disease has touched off an explosion of criticism and debate (see Part 1 of this series). Some researchers, however, consider the approval an overall positive development that the neurodegeneration field can build on as it seeks combination therapies that slow disease progression. For example, Ken Marek at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, believes the aducanumab decision heralds the beginning of a new era in neurodegenerative disease research, with a focus on therapies that move biomarkers in Alzheimer's and related diseases and slow the march of the underlying pathology (STAT news). Marek leads the Parkinson’s Progression Markers Initiative, which studies biomarkers of PD.
- Some Alzheimer’s researchers welcome aducanumab’s approval.
- Across the board, stakeholders slam the drug’s price tag.
- Will it cool interest in other therapeutic trials and observational studies?
Dawn of Disease Modification?
Some Alzheimer’s researchers, too, see the approval as a step toward disease-modifying therapies. They draw parallels with the history of drug development in other fields. “I think the FDA decision will benefit the AD field greatly, as did the approval of betaferon for the multiple sclerosis field in 1993. It will boost drug development and research in general,” Philip Scheltens at VU University, Amsterdam, wrote to Alzforum (full comment below). Bart De Strooper, who leads the U.K. Dementia Research Institute at UCL, compared the decision to the fast-tracking of the first drugs for AIDS, which had minimal clinical benefit. “This opened the way for further clinical experimentation and trials and brought the AIDS field in two decades to almost curative therapy,” De Strooper wrote.
Others drew a distinction between the messy approval process for aducanumab and its end result. “We all recognize the liabilities of the path to aducanumab approval, which I believe were more a function of trial execution than an intrinsic weakness of the agent or the biology behind it,” Dennis Selkoe at Brigham and Women’s Hospital wrote to Alzforum. “In my view, the strength of the biology and the clarity of aducanumab’s key biomarker endpoint overcame an imperfect clinical dataset,” Selkoe added (full comment below). Marwan Sabbagh, at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, went further. “It was a transformative moment in the field. It’s the first step toward taking Alzheimer’s from a terminal to a chronic disease,” Sabbagh said.
Other stakeholders hailed the decision, as well. In addition to positive reaction from advocacy groups such as the Alzheimer’s Association and Us Against Alzheimer’s, the Global Alzheimer’s Platform commended the FDA for its stance, and the National Institutes of Health called the approval a milestone achievement. “The hope is greater than it’s ever been before that we’re going to find increasingly effective interventions,” NIA director Richard Hodes told Alzforum.
The Price Isn’t Right
Even those who agree with the FDA’s decision, however, take issue with Biogen’s planned price of $56,000 per patient per year. In a poll of biopharma executives, 75 percent considered this too high, given the drug’s uncertain efficacy and known safety risks. They warned that given the large number of retirement-age people who might qualify for treatment, aducanumab's cost would blow an enormous hole into the taxpayer-funded budgets of Medicare and the Veteran's Health Administration. A recent analysis by the Kaiser Family Foundation estimated aducanumab could cost Medicare $57 billion per year, roughly the same amount as all other hospital outpatient services combined.
The approval could also deepen inequity in the U.S. health care system, where the well-off typically receive better care. “We know there will be disparities in access because our health care system is riddled with them,” Emily Largent, University of Pennsylvania, Philadelphia, wrote to Alzforum (full comment below). Others fear that hope and desperation may prompt patients whose disease is too advanced for them to benefit from this treatment to spend their life savings on out-of-pocket aducanumab.
“This price is simply unacceptable. … We call on Biogen to change this,” the Alzheimer’s Association wrote in a June 12 statement.
In a June 8 call with investors, Biogen CEO Michel Vounatsos defended the price, noting that aducanumab’s cost is about one-third that of cancer immunotherapies. He said the company is talking to private insurers such as Cigna about using value-based contracts, which set the price of a drug based on how well it performs, but gave no details on how that would work or what performance benchmarks might be used. He also promised not to raise the price for four years.
Meanwhile, Biogen’s chief financial officer Mike McDonnell estimated that U.S. sales of the antibody would ramp up over several years into the multibillion-dollar range. Mainstream and industry press likewise believe Biogen stands to rake in the cash (New York Times news; Endpoints news; STAT news).
Some predicted the antibody’s cost could spur renewed calls for drug pricing reform (Fierce Pharma news; STAT news). One senator has already called for Medicare to have the ability to negotiate cost, specifically citing aducanumab as an example of unjustifiable pricing (Endpoints news). A coalition representing employers and other health care purchasers is advocating for this as well.
Bane or Boon for Alzheimer’s Drug Research?
Many researchers fear the aducanumab approval will complicate their efforts to evaluate better Alzheimer’s drugs. One concern is that patients may prefer to take an approved medication rather than roll the dice on one still in development, especially given that they might end up on placebo. “Once aducanumab becomes commonly available, it’s going to become really hard to recruit for mild cognitive impairment trials,” Sabbagh predicted.
Some worry that participants in ongoing AD trials might drop out to go on aducanumab instead. Researchers at Eli Lilly, who are developing donanemab, among other investigational medicines for AD, did not respond to a request for comment. Roche scientists, meanwhile, expressed confidence in their program. “We are not changing our scientific approach for the pivotal trials of gantenerumab in AD,” Rachelle Doody of Roche wrote to Alzforum. “We're working closely with our investigator network to address any questions they or trial participants may have about continuing in our studies,” she added (full comment below).
Others think the field will adapt. “Finishing current trials will no doubt be more challenging with Aduhelm on the market, but other fields have faced this problem and moved on to add multiple new agents over time,” Selkoe wrote.
A related concern is that the aducanumab approval might lead funding agencies to favor anti-amyloid drugs at the expense of other approaches. The NIH, at least, has no plans to change course. “Right now, the large majority of Phase 1 and 2 [AD] trials are against non-amyloid targets, and this will certainly continue,” Hodes told Alzforum (see Alzforum Therapeutics listing of such trials). Hodes also sees no imperative to change trial designs to compare new drugs against aducanumab as a positive control, given that the antibody has not shown a definitive effect on symptoms.
De Strooper sees ample opportunity in aducanumab’s approval. It will open the door for studies that define the antibody’s benefit in different patient populations and test its efficacy in combination with other drugs. “Alzheimer’s disease and dementia are complicated disorders, and it is unlikely that one simple hypothesis and one golden bullet will explain and treat all,” he wrote.
Many believe this approval will encourage further investment in AD drug research. “History has shown us that approval of the first drug in a new category invigorates the field, increases investments in new treatments, and encourages greater innovation,” wrote Maria Carrillo of the Alzheimer’s Association in a statement. There are already signs of renewed investor interest, with pharma companies reporting a deluge of calls (Fierce Biotech news; related news). In part, investors are lured by the prospect of gaining approval more easily with amyloid reduction data alone.
Retired neurologist Daniel Gibbs of the Oregon Health and Science University, Portland, compared aducanumab to tacrine, the first acetylcholinesterase inhibitor to go on the market in 1993. Tacrine’s efficacy was controversial at the time (Relman, 1991). It was also toxic to the liver and was soon supplanted by other drugs in its class. “Aducanumab may be the tacrine of today: the first drug of its class with likely effectiveness, but it will almost certainly be joined and possibly replaced by other, more effective drugs in the future,” Gibbs suggested.
Selkoe summed up the situation this way: “We have taken a sizeable, albeit controversial, step in the direction of actual disease modification. There’s no going back.”—Madolyn Bowman Rogers
- Tacrine as a treatment for Alzheimer's dementia: editor's note. An interim report from the FDA. A response from Summers et al. N Engl J Med. 1991 Jan 31;324(5):349-52. PubMed.