What now? Alzheimer’s drugmakers ponder the path to approval

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Last week, Medicare rendered a fateful decision that’s become the latest flashpoint in Biogen’s ongoing saga with Aduhelm. As part of a new finalized policy, the Centers for Medicare and Medicaid Services (CMS) will limit coverage for the controversial drug — and other monoclonal antibodies that target amyloid plaques in with Alzheimer’s disease — to patients participating in approved clinical trials.

Notably, the CMS said it will cover this class of drugs if they receive a “traditional” FDA approval — a distinction that also restricts the use of Aduhelm, which won its FDA OK through an accelerated pathway.

The CMS’ whose coverage limit is the latest setback for Biogen, out of Aduhelm has been marred by unexpected hurdles and overall sales far below analysts’ original forecasts.

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But it also brings uncertainty for the whole industry, and possibly unintended consequences, says Alexander Scott, executive vice president of integrity at the Tokyo-based Eisai Co. Eisai, which is Biogen’s partner on the development of Aduhelm, has its own investigational drug in this category called lecanemab that’s in phase 3 trials, and appeared to be on a speedy path to FDA approval.

Given the latest ruling, Scott says that pharma companies may now need to consider separate standards when developing drugs — one for FDA approval and one for payment. When the FDA approves a drug, Medicare coverage typically follows, with commercial payers close behind. The Aduhelm decision shows that this may no longer be a given.

Questions raised about the process

The controversy surrounding Aduhelm arose when the FDA approved the treatment using its accelerated approval pathway. This allowed Biogen to get the drug approved based on a surrogate endpoint — the drug reduced amyloid protein in the brain — without having to show a direct clinical benefit, such as slowing cognitive decline.

Opponents argued that it was wrong to approve a high-cost drug without more substantial proof it will slow the progression of Alzheimer’s. The CMS seemed to acknowledge this controversy when it moved to limit broad coverage for Aduhelm and instead said it would only pay for the drugs approved using this pathway in specific, controlled circumstances. Alzheimer’s disease affects about six million older Americans — a number that’s expected to rise as high as 14 million by 2060, according to the CMS. With that many patients to cover, widespread use of Aduhelm could come with a hefty price tag.

“This disease state impacts so many people, of which the very vast majority are Medicare beneficiaries. So, certainly it’s understandable that they would want to think this through carefully given the impact potential,” Scott says.

Patient and pharma pushback

The Alzheimer’s Associationone of the loudest patient advocacy voices in the debates around Aduhelm, criticized the CMS for overstepping its bounds by rejecting the accelerated drug pathway, which was established by Congress to give patients rapid access to promising treatments to treat serious conditions with few, or no, other options. Under the final National Coverage Determination (NCD) amyloid-targeting drugs in this class can now only get broad coverage outside of a clinical trial if they can demonstrate a clinical benefit to patients and receive traditional approval from the FDA under coverage with evidence development (CED). ), Scott says.

“These coverage restrictions, including the distinction between accelerated approval and traditional approval, have never been applied to FDA-approved medicines for other disease areas,” according to Biogen officials, who called on the CMS to reconsider their decision.

Drug companies also pushed back against the proposed NCD. Eli Lilly, which also has an investigational drug in this category (donanemab) asked the CMS to reconsider its initial proposal and urged the CMS to permit coverage for treatments that demonstrate that they can slow cognitive decline. Eisai officials said they feared that the initial proposal ignored ongoing research, and would severely restrict access to all drugs in this class and exacerbate health inequities.

“We are further concerned that this action directly calls into question the US Food and Drug Administrations (FDA) role in determining safety and efficacy, as well as the agencys regulatory autonomy and scientific independence,” the company said in a January statement.

The final NCD did make some important concessions based on that feedback.

For one, the CMS revised its original proposal removing the requirement that clinical trial participation had to occur in a hospital-based clinic. Qualifying studies still must meet certain criteria, but it’s now much more flexible.

Even so, the Alzheimer’s Association expressed disappointment with the decision, calling it an “unnecessary and never before imposed barrier to access an FDA-approved treatment.”

The final determination also eliminated a provision that would have excluded certain groups, including people with Down Syndrome from coverage.

The path ahead

While the final NCD is less restrictive, fears still remain about the potential precedent this decision sets and the hurdles it may create.

“Neurodegenerative diseases, in particular, have very long development programs,” says Dr. Michael Irizarry, senior vice president of clinical research and chief clinical officer of Eisai’s neurology business group. It may take a decade to move a drug through the pipeline, and throughout that process, pharma companies interact with the FDA and other regulatory agencies to ensure that they are on track for approval. The CMS decision adds another set of uncertainties.

“I think it adds complications and risks for these already very risky development programs in terms of probability of success,” says Irizarry.

For Eisai, the focus has now shifted to identifying a path forward, Scott says.

“Eisai anticipates our anti-amyloid-beta (Aβ) protofibril antibody lecanemab’s rolling submission of a [BLA] to the FDA under the accelerated approval pathway in the first quarter of our fiscal year 2022, which began April 1,” Scott says. “Additionally, the readout of the phase 3 confirmatory Clarity AD clinical trial will occur in the fall of 2022.”

Lecanemab is being co-developed with Biogen.

He says the Clarity AD lecanemab trial could very well meet the high level of evidence criteria set for it by the CMS in the NCD. This could mean that the CMS might reconsider full coverage for the drug, if it gains FDA approval.

“We look forward to constructively with the CMS to ensure appropriate Medicare beneficiaries have access to this potential new therapy,” Scott says.

But while some drugs might find a way forward, the Alzheimer’s Association expressed fears that this decision will have a chilling effect on future research.

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