Biogen’s controversial Alzheimer’s drug Aduhelm will only be covered on Medicare for patients enrolled in approved clinical studies if a draft ruling by the Centers for Medicare & Medicaid Services becomes final guidance. The proposed restriction—and the complexity involved—has industry watchers worried about the therapy’s future.
The CMS proposal “could effectively spell the end for Aduhelm,” RBC Capital Markets analyst Brian Abrahams wrote in a Tuesday note to clients. That’s because older people covered by Medicare make up the bulk of the Alzheimer’s patient population, and restrictive access there would be a serious blow to Aduhelm’s market potential.
The requirement of a clinical trial as a condition for reimbursement—known as coverage with evidence development (CED)—would create “more logistical, administrative and other roadblocks” to getting Aduhelm, Jefferies analyst Michael Yee said in a separate note. It would limit access to no more than several thousands of patients, SVB Leerink analyst Marc Goodman pointed out in his note. By contrast, Biogen had estimated roughly 50,000 patients could start treatment this year if a Medicare reimbursement policy were in place.
Biogen has been advocating for coverage with restrictions that mirror the enrollment criteria for Aduhelm’s phase 3 clinical trials. During a Monday presentation at the annual J.P. Morgan Healthcare Conference, CEO Michel Vounatsos said that “anything that starts to provide access in this country … is very good news” as “it opens the door to access.” Now, though, Goodman argued the “disappointing” CMS ruling “barely opens door for access.”
Biogen is currently plotting a phase 4 postmarketing study as part of FDA’s accelerated approval. The study, dubbed EMBARK, is expected to enroll only 1,300 patients; not to mention, some of those participants will be assigned to the control arm and receive current standard of care rather than Aduhelm.
The company could expand the phase 4 trial or add other studies, but it may still take a year or more just to get CMS signoff on the study design. That would mean Wall Street’s current estimates of $311 million in Aduhelm 2022 sales would be unattainable by “orders of magnitude,” RBC’s Abrahams said.
A clinical trial as part of a commercial rollout could be challenging in itself. It would mean additional paperwork and patient follow-up, which would make treatment with Aduhelm even more onerous on top of the screening and monitoring for side effects and the intravenous administration, Abrahams noted. All of these barriers will “almost certainly keep uptake very slow for some time,” he added.
The CED pathway allows CMS to gather more clinical evidence of a drug to potentially one day lift the mandate. One critical question the agency wants addressed under CED is whether Aduhelm and other similar monoclonal antibodies directed against beta amyloid plaques in the brain offer statistically significant and clinically meaningful cognition and function benefit for Alzheimer’s patients. But CMS’ definition of that marker spells trouble for Aduhelm in the long run.
To explain what constitutes clinically meaningful improvement, CMS reviewers cited a widely used outcome measure called CDR-SB, which was also the primary endpoint for Aduhelm’s two phase 3 trials. Citing a 2019 study, the reviewers suggest a one- to two-point increase in CDR-SB would be indicative of a meaningful disease worsening. But in the one positive phase 3 study, Aduhelm only pared down CDR-SB increase by 0.39 points over placebo, Abrahams noted. Even in the best response group in which patients received full doses of the drug, the difference was about 0.75 points.
In opposing the CED proposal, a spokesperson with pharmaceutical industry group PhRMA criticized the CMS for “positioning itself and not FDA as the key arbiter of clinical evidence” and “erecting more barriers.”
Beyond all the negative aspects, RBC’s Abrahams figured CMS’ coverage of PET scans as part of the CED is “an incremental positive” for Aduhelm. For his part, Jefferies’ Yee noted CMS’ requirement that trials be conducted in a hospital-based outpatient setting might create a health equity problem.
CMS is seeking public comments before making a final decision by April 11. A final order could be different, but SVB Leerink’s Goodman said he wasn’t optimistic of a change without additional clinical data.