On January 11, the US Centers for Medicare and Medicaid Services (CMS) released a draft version of its highly anticipated reimbursement decision regarding Biogen and Eisai’s Aduhelm (aducanumab) and other future anti-amyloid monoclonal antibody (mAb) products in Alzheimer’s disease (AD): CMS proposed the reimbursement of Food and Drug Administration (FDA)-approved anti-amyloid mAb products under a coverage with evidence development (CED) policy. The CED requirement will limit Medicare reimbursement of Aduhelm to AD patients participating in randomised controlled trials (RCTs). Regarding enrollment in these RCTs, CMS stated that it would cover the cost of one beta-amyloid positron emission tomography scan per patient, but would limit study participation to patients with mild cognitive impairment (MCI) due to AD or mild AD dementia, which is in line with the FDA label for Aduhelm. Although this preliminary coverage decision signals some hope for the anti-amyloid mAb class in the long term, it will significantly delay and limit patient access to these products in the near term, with Aduhelm likely bearing the brunt of these troubles.
Aduhelm was approved in June 2021 through the FDA’s accelerated approval pathway, based on the surrogate endpoint of amyloid clearance. Although its approval was a major milestone for the AD community, the drug’s launch has been marred by controversy surrounding the FDA’s decision, which conflicted with its advisory board’s opinion, and ongoing disputes regarding the drug’s risk-benefit profile. As a result of this tumultuous market entry, as of Q3 2021, Aduhelm had only brought in $300,000 in revenue. Key opinion leaders interviewed by GlobalData in December 2021 projected that until a trial can prove the clinical benefit of amyloid reduction in AD, there will remain a large contingency of physicians, payers and patients who will not feel comfortable with Aduhelm’s risk-benefit profile and cost. This need for more data is exactly what spurred CMS’s decision for a CED requirement. At the end of 2021, Biogen and Eisai provided an update on their planned Phase IV confirmatory trial of Aduhelm, required by the FDA as part of the drug’s accelerated approval. With patient screening likely beginning in May 2022, Biogen and Eisai anticipate a primary completion date approximately four years after study start. A four or more year wait before gaining more widespread Medicare coverage could be disastrous for the product.
Furthermore, Aduhelm’s prospects may be improved or worsened by the successes and failures of the three anti-amyloid mAb products in pipeline development: Eisai and Biogen’s lecanemab, Roche /Genentech’s gantenerumab, and Eli Lilly’s donanemab. All three products are currently in Phase III trials, with expected readouts in H2 2022 and H1 2023, which will help to more definitively confirm or deny the clinical relevance of amyloid reduction in the treatment of AD. The first results will likely come from Roche/Genentech’s GRADUATE 1 (NCT03444870) study of gantenerumab, with a primary completion date of May 31, 2022. Further data from Roche/Genentech’s GRADUATE 2 (NCT03443973) study is expected towards the end of 2022. Around this time, data is also expected from the CLARITY AD (NCT03887455) study of lecanemab. Finally, Eli Lilly’s TRAILBLAZER-ALZ 2 (NCT04437511) study of donanemab is expected to reach its primary completion date in H1 2023.
Although positive competitor data supporting the clinical benefit of amyloid clearance could give Aduhelm sales a small boost, by the time this data is released, Aduhelm will no longer be the only anti-amyloid therapy on the market. Eisai and Biogen along with Eli Lilly are expected to pursue accelerated approval for lecanemab and donanemab, respectively, based on the surrogate endpoint of amyloid reduction, with both entering the AD market in Q3 2022. Another complicating factor is the uncertainty regarding how quickly positive clinical data from other anti-amyloid mAb products could persuade CMS to end the CED requirement on this class of products. In the draft guidance, CMS proposed that investigators may extend RCTs to prospective longitudinal studies once the RCT portion is completed and the drug has demonstrated a clinically meaningful benefit in cognition and function. This suggests CMS may want to see further long-term data on anti-amyloid mAb efficacy and safety before expanding access, which could spell trouble for all anti-amyloid mAbs, not just Aduhelm.
Despite Aduhelm’s first-to-market advantage, the months of controversy following the drug’s approval were a major setback. Although CMS’s guidance can still potentially change, with a final decision expected in April, this preliminary decision is yet another blow for the drug. GlobalData expects that continued delays in Aduhelm’s roll-out will likely allow competitors to enter the AD market before the drug can firmly set its roots. Based on Aduhelm’s delayed uptake trajectory, as well as its recently slashed price (nearly 50% of the original), GlobalData estimates that by 2028, the product will reach sales of $906.1m, only a quarter of the sales GlobalData had forecasted for the drug previously.