Alzheimer's Drug Approval: FDA Decision & Future Implications

A Turning Point in Alzheimer’s Drug Development

A 17-year period without a new Alzheimer’s drug concluded on Monday with the FDA’s approval of Aduhelm (aducanumab) developed by Biogen. Despite substantial controversy surrounding the FDA’s decision, pharmaceutical companies are now focusing their efforts on tackling this debilitating brain disease.

The Controversial Approval of Aduhelm

The approval of Aduhelm followed clinical trials that yielded conflicting outcomes. An independent FDA advisory board, in November 2020, did not recommend agency endorsement of the drug. However, the agency proceeded with approval in June through the Accelerated Approval Program.

Aduhelm represents the first treatment designed to address a fundamental cause of Alzheimer’s – the accumulation of beta-amyloid plaques within the brain.

Support for the drug came from patient advocacy groups and the industry. The FDA also emphasized the “urgent need for treatment” in its statement explaining the approval. Nevertheless, concerns have been voiced by numerous physicians. A member of the expert committee that previously voted against recommending Aduhelm’s approval has since resigned.

Renewed Enthusiasm in the Pharmaceutical Industry

Despite the scientific inconsistencies and public debate surrounding Aduhelm’s approval, the pharmaceutical industry’s enthusiasm appears undiminished. This may herald a new wave of treatments in the coming years, building upon the precedent set by Aduhelm, regardless of the controversy.

“This is positive news for investors and companies developing novel drugs,” states Alison Ward, a research scientist at the USC Schaeffer Center for Health Policy and Economics.

Historical Challenges in Alzheimer’s Drug Development

Developing drugs for Alzheimer’s has historically presented significant obstacles.

One major factor is the 17-year track record of unsuccessful clinical trials. Even Biogen’s Aduhelm trials were paused in 2019 due to uncertainty about achieving clinical endpoints. Aduhelm’s approval was based on a “surrogate endpoint” – the reduction of beta-amyloid – rather than the primary endpoint of cognitive function.

Alzheimer’s drug trials have also been notably expensive. A 2018 study published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions estimated the cost of developing an Alzheimer’s drug to be approximately $5.6 billion. This contrasts with an average investment of $1.3 billion required to bring a new drug to market, based on SEC filings from companies seeking FDA approval between 2009 and 2018 (with a median cost of around $985 million). Earlier estimates placed the cost at $2.8 billion.

Shifting Funding Landscape

Traditionally, Phase 3 trials for Alzheimer’s drugs were primarily industry-sponsored. However, over the past five years, industry-solely sponsored trials have decreased. Government grants and public-private partnerships now constitute a growing portion of available funding.

Martin Tolar, founder and CEO of Alzheon, a company developing an oral Alzheimer’s treatment currently in a Phase 3 trial, explains that securing funding was previously a major challenge.

“Financing was impossible,” he says. “Wall Street showed no interest due to the consistent failures.”

He anticipates that Aduhelm’s recent approval will significantly alter this situation. Interest in companies already in Phase 3 trials has already increased; shares of Eli Lilly, also conducting a Phase 3 trial, surged by 10 percent following the FDA announcement.

“I’ve received hundreds of inquiries from bankers, investors, collaborators, and pharmaceutical companies,” Tolar states. “Alzheimer’s is now open for business.”

A Promising Future for Alzheimer’s Treatments

With renewed interest and a perceived pathway to FDA approval, the outlook for the next generation of Alzheimer’s drugs appears promising. Currently, around 130 Phase 3 clinical trials for Alzheimer’s drugs are either completed, active, or recruiting.

Tolar views the FDA’s decision, despite imperfect data, as a “signal of urgency” to approve forthcoming treatments.

As Ward highlighted in a white paper on in-class drug innovation, “follow-on” drugs often become industry leaders, particularly if they demonstrate improved safety or efficacy compared to the first-to-market drug. This suggests that drug approval may “pave the way” for more effective drugs in the future.

In the case of Alzheimer’s, she notes that a single dominant drug may not emerge. Instead, a combination of new, approved drugs may complement each other.

“The current understanding of Alzheimer’s Disease suggests that a combination of drugs, or a ‘cocktail,’ will be necessary to truly delay disease progression,” she explains.

“Historically, it’s individually approved drugs that come together to form these effective drug cocktails.”

Potential Challenges Ahead

Future drugs may face certain challenges. One concern is that the availability of an approved drug could make it more difficult to recruit participants for clinical trials, potentially slowing down drug discovery. However, Ward argues that this will be outweighed by the increased number of patients seeking a diagnosis now that a treatment option exists.

The high cost of Aduhelm ($56,000 per year) and the questionable data surrounding its efficacy may also drive patients towards other drugs, even those still in clinical trials. Medicare will bear the brunt of Aduhelm’s cost.

Furthermore, the effectiveness of Aduhelm in slowing cognitive decline and reducing beta-amyloid levels remains uncertain based on current data, and the FDA has mandated a critical follow-up study as a condition of approval.

However, Tolar believes the results of that study are less relevant, as the industry will have progressed by then. Biogen CEO Michel Vounatsos has indicated that the company may not share the trial results for up to nine years, although they aim to deliver data sooner.

“Better drugs will be available by then,” Tolar predicts.

Tolar’s Phase 3 clinical trial began dosing this week and is scheduled to conclude by 2024. Biogen and Esai are also expected to have another drug ready for evaluation by then, with Phase 3 trials for lecanemab, another beta-amyloid antibody treatment, scheduled for completion in 2024 and 2027.

Monday’s approval may represent a pathway for future drugs, rather than an end in itself. While the data is imperfect, the costs are high, and the controversy is considerable, a significant barrier has been removed.