In results posted today, Roche’s investigational Alzheimer’s Disease biologic, gantenerumab, did not reduce cognitive decline to a statistically significant degree compared to placebo. The cognitive functions measured were remembering, solving problems, orientation, and personal care in patients suffering from early stages of Alzheimer’s. Also, the level of removal of beta-amyloid plaque was lower than expected.
Gantenerumab’s flop in Phase 3 means that Eisai and Biogen’s lecanemab emerges as the preliminary favorite in the antibody class of biologics targeting beta-amyloid plaque in Alzheimer’s Disease patients.
As Dr. Howard Fillit, Co-Founder and Chief Science Officer at the Alzheimer’s Drug Discovery Foundation, said: “If you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy.” This class of monoclonal antibodies is exhibiting a tremendous amount of variation.
Indeed, the gantenerumab data come on the heels of positive top-line results reported just six weeks ago by Eisai and Biogen regarding their amyloid-clearing drug lecanemab; further proof that not all drugs or biologics that have the same target are identical. Eisai and Biogen are slated to present a comprehensive analysis of the data on lecanemab later this month at the Clinical Trials on Alzheimer’s Disease conference.
To round out the current set of late-stage amyloid-directed monoclonal antibodies there’s donanemab, which is apparently very good at amyloid plaque reduction. It also targets and decreases neurofibrillary tau deposits. But, the key question is whether this matters. In other words, do reductions in plaque and tau build-up caused by donanemab lead to statistically significant and clinically meaningful lessening of cognitive impairment compared to placebo? Furthermore, how does donanemab compare to other biologics with respect to safety issues, such as rates of brain swelling and bleeds? We’ll know more when fresh clinical trial data for donanemab are released in mid-2023.
For now, it looks increasingly likely that lecanemab will be the dominant player among these monoclonal antibodies. The hope for the product’s sponsors is that the data presented in November from the large Phase 3 trial will eventually convince the Food and Drug Administration (FDA) to give the nod to a full regular approval at some point next year.*
If approved, in some sense lecanemab would have a first-in-class advantage even though it would not be a first-in-class product (Aduhelm, or aducanumab, was). Presumably, there would at least be modest demand for the product. After all, there is a lot of unmet need in the Alzheimer’s Disease space, as no disease-modifying agents currently exist, other than the moribund Aduhelm.
But, in terms of lecanemab’s commercialization potential, and hence how much patient demand could actually be realized, there would still be several major coverage hurdles to overcome. The Centers for Medicare and Medicaid Services (CMS) constitute the biggest potential barrier to widespread patient access, given that at least 85% of eligible patients are Medicare beneficiaries.
Under the Coverage with Evidence Development (CED) protocols disseminated as part of a National Coverage Determination in April of this year, all amyloid-directed monoclonal antibodies approved under the accelerated approval program, including lecanemab, are subject to a mandatory randomized controlled clinical trial.
Furthermore, CMS concluded that such monoclonal antibodies, if granted regular FDA approval, must unequivocally demonstrate cognitive or functional benefits to be reimbursed outside of randomized trials. The question is whether lecanemab meets the somewhat ambiguous threshold CMS imposed for individual biologics, namely “does the anti-amyloid monoclonal antibody [lecanemab] meaningfully improve health outcomes (i.e., slow the decline of cognition and function) for patients in broad community practice?”
Here, clinical meaningfulness is subject to interpretation. According to the data released last month, patients who received lecanemab decline 27% (or 0.45 points) slower on the clinical dementia rating sum-of-boxes (CDR-SB) assessment than patients who were given a placebo. Neurologists have widely differing opinions on what 0.45 means. Nevertheless, surely there’s support for the idea that a modicum of statistically significant improvement is better than nothing and will have clinical meaning for some patients.
And with no real treatment alternatives available, the 0.45 score – if it holds up under further scrutiny – would in all likelihood meet CMS’s reasonable and necessary standard. Under the reasonable and necessary standard, CMS is only obliged to reimburse those items, technologies, and medical services the agency deems safe and effective; not experimental; and appropriate for Medicare patients.
Therefore, in the event of a regular FDA approval of lecanemab it’s very likely that CMS would drop the randomized trial requirement, removing the most onerous Medicare coverage restriction. However, it could and probably would still require the establishment of a patient registry, as way to systematically collect post-marketing evidence on lecanemab’s safety and effectiveness in the real world.
In addition, it would be expected that CMS imposes restrictions that follow the label that FDA would likely attach to lecanemab’s potential approval. For example, the product would only be reimbursed for early-stage and mild cases of Alzheimer’s Disease. Also, it is almost certain that diagnostic evidence of beta amyloid accretion – for example, in the form of a PET-scan or cerebrospinal fluid analysis – would be required prior to authorizing reimbursement. And finally, it may be assumed that certain patients predisposed to brain bleeds would be contraindicated.
So, while lecanemab appears to be the winning candidate thus far among amyloid-directed antibodies, several key market access challenges lie ahead for the Alzheimer’s Disease drug, should it get FDA approval in 2023.