Scan images of brains of Alzheimer’s Disease patients.
This week, Eli Lilly announced that its beta amyloid-directed monoclonal antibody named donanemab showed in a clinical trial that it can slow progress of Alzheimer’s Disease (AD). The trial included 1,736 patients. Use of donanemab led to a lessening of cognitive and functional decline of 36% compared with placebo. This was measured on the clinical dementia rating (CDR) scale, which is commonly used to diagnose dementia from AD. The sum of boxes of the CDR traces the progression of cognitive and functional impairment in the early stages of AD.
The topline numbers released by Lilly also reveal a risk of brain swelling and hemorrhaging, side effects that may be linked to three deaths in the clinical trial. Similarly, deaths occurred in the clinical trial of another beta amyloid-directed monoclonal antibody, Leqembi (lecanemab), which was granted an accelerated approval by the Food and Drug Administration (FDA) in January of this year.
In April 2022, the Centers for Medicare and Medicaid Services (CMS) issued a National Coverage Determination (NCD) that narrowly restricts reimbursement of biologics in the class of beta amyloid-directed antibodies to those enrolled in a post-marketing randomized controlled clinical trial. At the time of issuance of the NCD, the only approved biologic targeting AD was Aduhelm (aducanumab).
In the NCD’s decision memorandum, CMS indicated it would change course for regularly approved therapeutic agents if they can answer the following question in the affirmative:
“Does the anti-amyloid monoclonal antibody meaningfully improve health outcomes (that is, slow the decline of cognition and function) for patients in broad community practice?”
It’s certainly possible that once lecanemab and donanemab receive regular FDA approval, CMS will deem these two biologics worthy of meeting the reasonable and necessary standard for Medicare reimbursement.
But it’s not probable that the NCD itself will be voided in its entirety. Given that the late-stage clinical trials of each of four monoclonal antibodies have shown strikingly different results,* it’s more likely that a case-by-case approach for determining coverage and conditions of reimbursement for each antibody will be adopted.
With donanemab, 47% of patients remained stable in terms of their cognitive function and ability to perform daily activities during the subsequent year compared with 29% who took the placebo.
But at the same time findings from the trial show that 24% of patients had at least some brain swelling and bleeding, and 6% experienced symptoms like dizziness, headache or fainting.
And so, questions remain, including details on three deaths that may be related to the biologic, and which sub-group(s) of patients stand to benefit most. Lilly intends to present a comprehensive data analysis at a medical conference in Amsterdam this July, as well as in a forthcoming peer-reviewed publication.
Surely, the pharmaceutical industry and patient advocacy groups like the Alzheimer’s Association will push even harder for CMS to reverse its NCD and cover the class of drugs that target beta amyloid plaque. However, CMS is faced with a situation in which two drugs in the class appear to work and two don’t (gantenerumab and Aduhelm). A phase 3 clinical trial of gantenerumab was stopped early because of a lack efficacy, while Aduhelm, despite accelerated approval, didn’t yield statistically significant efficacy. The two that have shown promise provide relatively modest benefits with potentially serious side effects. While certain NCD restrictions could be lifted on a case-by-case basis, rescinding the NCD isn’t probable.
To illustrate how this might play out, let’s take the case of lecanemab. CMS has said it would broaden its coverage of lecanemab “on the same day” the FDA grants a regular approval of the biologic. The date for this decision is July 6th.
Though opinions from experts differ on the matter of how clinical meaningful the lecanemab trial data outcomes are, presumably lecanemab’s regular FDA approval will lead to a loosening of Medicare coverage restrictions. For example, should FDA give the nod to lecanemab in July, CMS will drop the randomized controlled trial precondition, though it could still require the establishment of a patient registry (or multiple registries) as a way to systematically collect post-marketing evidence on lecanemab’s safety and effectiveness in the real world. Furthermore, there would likely be a number of other coverage limitations, including at least some of the ones the Department of Veterans Affairs is imposing.
And what applies to lecanemab will likely apply to donanemab. The process for regular FDA approval of donanemab will be based on an evaluation of the full set of Phase 3 trial data. Submission for such approval won’t happen until this summer at the earliest.
Donanemab’s topline numbers drew immediate comparison to lecanemab, which slowed cognitive decline by 27% on the sum of boxes CDR. However, comparisons are hard to draw between donanemab and lecanemab owing to differences in the patient cohorts. But one difference that is independent of the qualitative discrepancies between the patient cohorts is the fact that lecanemab requires infusions every other week for an indefinite period of time, while donanemab is infused every four weeks, and only until a patient tests negative for amyloid plaque on brain scans. Fewer courses of treatment could make Lilly’s drug cheaper in the long term. But this would depend on donanemab’s pricing, which is unknown at this time.
Until lecanemab and donanemab are granted regular FDA approval it’s very unlikely there will be a change in Medicare’s current severely restrictive coverage policy. Once approved, however, Medicare will be inclined to relax coverage limits. This said, upon approval unfettered access will not be a plausible scenario.