After the FDA rejected an accelerated approval bid in January, Eli Lilly has returned with topline data proving that donanemab may be an effective alternative to Eisai’s Leqembi (lecanemab) in treating Alzheimer’s disease.

On May 3, Eli Lilly announced that donanemab slowed Alzheimer’s progression by 35% in patients compared to placebo. However, as donanemab’s approval prospects increase, it is an open question whether the drug’s prospects for Centers for Medicare & Medicaid Services (CMS) coverage are better than those of previously approved amyloid-targeting therapies.

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In the Phase III TRAILBLAZER-ALZ 2 (NCT04437511) study, donanemab slowed disease progression in patients with high levels of tau by 29%. Tau is a small protein that builds up in the brains of patients with Alzheimer’s. These results will be considered in the FDA’s final approval decision for donanemab. If approved, the therapy will join a small cohort of marketed disease-modifying Alzheimer’s drugs.

Eli Lilly’s donanemab is a monoclonal antibody (mAb) therapy that causes the immune system to remove amyloid plaques that build up in patients with Alzheimer’s disease. Biogen’s Aduhelm and Leqembi target AD pathology in the same way.

The FDA approved Biogen’s Aduhelm (aducanumab) for treating Alzheimer’s disease in June 2021. Before this approval, no new drugs had been approved for Alzheimer’s in 18 years. In January 2023, the FDA followed this with an approval of Leqembi via the accelerated approval pathway. However, in February 2023, the CMS rejected an Alzheimer’s Association petition to reconsider the agency’s decision of the coverage of mAbs that target amyloid plaques, such as Leqembi. However, with more amyloid-targeting therapies for Alzheimer’s, including donanemab, approaching regulatory decisions, this issue is likely to come up again.

In an email to Pharmaceutical Technology, Philippa Salter, senior analyst at GlobalData, pointed out that this coverage stance has remained consistent for the two recent major Alzheimer’s approvals. However, she also said, “The CMS has already indicated that full approval of Leqembi could result in broader coverage, and the results from the donanemab Phase III trial add further weight that this class of drugs does have efficacy in Alzheimer’s. In a market where there is nothing else disease-modifying available, pressure will increase for reimbursement for Leqembi and donanemab as drugs that have demonstrated efficacy.”

Phase III donanemab data

Results from the Phase III TRAILBLAZER-ALZ 2 study showed that donanemab significantly slowed cognitive and functional decline in patients with early symptomatic Alzheimer’s disease. A cross-trial comparison suggests that donanemab gave a slightly higher efficacy compared to Leqembi with a 29% and 27% reduction in clinical decline, respectively. This was measured using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) as an endpoint to measure efficacy. Based on these results, and the FDA’s accelerated approval of Leqembi in January with full approval expected to follow in July 2023, Salter says it is likely that donanemab will also gain FDA approval having demonstrated comparable efficacy.

In a press release, Lilly’s chief scientific and medical officer Dr. Daniel Skovronsky said, “This is the first Phase III trial of any investigational medicine for Alzheimer’s disease to deliver 35% slowing of clinical and functional decline.”

Salter adds, “Donanemab requires only once-monthly dosing compared with Leqembi, which is administered every other week, therefore donanemab would provide a treatment option with less burden for patients.” She also said that an approval for donanemab could affirm the validity of the amyloid hypothesis for Alzheimer’s, which has been controversial in the field.

Coverage of Alzheimer’s therapies

In April 2022, a CMS National Coverage Determination (NCD) decision indicated the agency was interested in answers to three questions before providing widespread coverage for mAbs directed against amyloid. The CMS stated that it would need to determine whether the therapy meaningfully improved health outcomes for patients in broad community practice, whether the therapy was associated with harms such as brain hemorrhage and edema, and how harms and benefits change over time.

After the NCD decision, CMS released a national policy for coverage of Aduhelm and any other FDA-approved mAbs for treatment of Alzheimer’s disease. In a press release, CMS announced, “Medicare will cover mAbs that target amyloid (or plaque) for the treatment of Alzheimer’s that receive traditional approval from the FDA under coverage with evidence development.” However, CMS said drugs that have gone through an accelerated approval pathway or those that don’t have an established clinical benefit as per the FDA, will only receive coverage during FDA- or National Institutes of Health (NIH)-approved clinical trials. This significantly limits the accessibility of disease-modifying therapies to AD patients.

In January, Eisai launched Leqembi at a $26,500/year price, and calculated the weighted average out-of-pocket costs for Leqembi to be approximately $2 per day. Leqembi’s wholesale acquisition cost is $254.81 for the 200mg vial and $637.02 for the 500mg vial, as per GlobalData. Eisai. In December 2021, Biogen reduced Aduhelm’s wholesale acquisition cost from $56,000 per year to $28,200 at the 10mg/kg maintenance dose, after receiving negative feedback about the drug’s cost.

In a statement released after the CMS’s initial decision to not cover Alzheimer’s Association statement, the non-profit organisation said, “For CMS to treat those with Alzheimer’s differently than those with other diseases is unprecedented and unacceptable.” It added that this move from the CMS would likely “exacerbate and create further health inequities among those who are already disproportionately impacted by this fatal disease.”