Editor's Corner: Eisai and Biogen need to meet CMS halfway after lecanemab's Alzheimer's clinical trial win

Eisai and Biogen have their much-coveted—and surprisingly positive—lecanemab phase 3 win in Alzheimer’s disease. Eisai’s daily-limit-hitting stock price surge in Tokyo and Biogen’s 40% jump in New York reflect the overwhelming excitement among investors. An FDA approval now looks all but certain.

But before lecanemab can clear the name of the amyloid beta theory after the fallout from Biogen’s Aduhelm launch and before the drug can realize its megablockbuster sales potential down the road, there’s one major hurdle to cross—reimbursement.

Based on current clinical data, as well as Aduhelm's bad history and the existing reimbursement policy, Eisai and Biogen will need to meet the Centers for Medicare & Medicaid Services halfway to win proper coverage for lecanemab.

First, to convince CMS, lecanemab’s phase 3 data need to hold up when more detailed results are released at the Clinical Trials on Alzheimer’s Congress in November. At least at first glance, the Clarity AD trial was a clean win, hitting all primary and secondary endpoints. It found lecanemab could slow cognitive decline—not just clearing the amyloid beta plaques in the brain—in a statistically significant way among mild Alzheimer’s patients. Even the most critical of Aduhelm (*cough* Stat *cough*) has struck a relatively positive note on the outcomes.

But a statistically significant advantage that could support an FDA approval is not necessarily the same as what CMS views as clinically meaningful for full reimbursement. On Clarity AD’s primary endpoint, lecanemab was effective in slowing cognitive decline by 27% over placebo as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale. It represents an absolute difference in the score of 0.45.

Those CDR-SB numbers weren’t materially different from Aduhelm’s one successful phase 3. In the Emerge trial, Aduhelm reduced decline by 22% with a 0.39 difference from placebo on CDR-SB.

But lecanemab’s Clarity AD does bear high statistical significance, whereas Aduhelm’s Emerge was only successful in a post-hoc analysis. Besides, Aduhelm also failed a second trial dubbed Engage.

After Aduhelm’s controversial FDA approval, the CMS limited coverage for the drug—and other future anti-amyloid beta antibodies cleared under the accelerated approval pathway. The restriction meant that only patients who were enrolled in a randomized clinical trial would be eligible for CMS coverage.

In its original proposed coverage policy, the CMS reviewers pointed to an article published in The New England Journal of Medicine, which called Aduhelm’s improvement in the “partially successful” Emerge trial “very small.”

When discussing what constitutes a “clinically meaningful” improvement, the CMS in its draft policy pointed to a 2019 study funded by Eli Lilly, which is also working on an anti-amyloid antibody called donanemab. The study suggested that an average 1- to 2-point increase in the 18-point CDR-SB score was indicative of a meaningful decline in function. Plus, in a Tuesday note to clients, RBC Capital Markets analysts mentioned that the experts they interviewed suggested a benefit around 0.3 to 0.5 would have modest clinical meaningfulness.

So, lecanemab’s 0.45-point benefit is far from a homerun and is therefore still vulnerable to debate in the real world.

The good news is that the CMS removed that 1-2-point reference in its final decision for amyloid beta antibodies. But that doesn’t mean the agency won’t scrutinize lecanemab’s data against clinical meaningfulness.

But in another show of reservation, CMS’ final decision also noted that even if an FDA approval is granted based on the direct measure of clinical benefit rather than the amyloid beta biomarker, the rigorous nature of a randomized clinical trial means that the enrolled patients have fewer underlying health problems than the general Medicare population.

That’s why instead of a straightforward reimbursement process, CMS has erected an extra roadblock. To be blessed with CMS coverage, the agency is asking that any amyloid antibody that boasts full FDA approval should be included in a CMS-approved prospective comparative study such as a health registry until the drug proves itself in a broader population.

All these moves suggest CMS is willing to continue clamping down on anti-amyloid antibodies including those with full approval and positive clinical trial data.

Adding to the complication is the Biden administration’s focus on healthcare spending. Almost simultaneously as Eisai and Biogen released their lecanemab news, the U.S. President on Tuesday touted how Medicare premiums are slated to drop next year for the first time in over a decade, and that’s primarily because of the CMS’ tough decision to limit Aduhelm coverage.

However, unlike Aduhelm’s mixed trial results that triggered widespread pushback, resistance against lecanemab seems minimal at this point. That general positive notion could, of course, change when the full data are presented two months from now. But now, the overall sentiment is that lecanemab is indeed a drug that could slow Alzheimer’s progression.

The unequivocally positive Clarity AD trial will place a lot of public pressure on CMS to cover the drug. The lack of treatment options also means a drug with a 0.45-point improvement after 18 months of treatment might just have to do for now, although other anti-amyloid candidates like Lilly’s donanemab and Roche’s gantenerumab may—or may not—turn in better results down the road.

CMS will just have to live with the fact that a 1-point benefit in CDR-SB within a year and a half for a disease marked by chronic progression might simply be unrealistic for what the biopharma world can offer right now. And patients can’t wait until that 1-point drug emerges.

For Eisai and Biogen, the companies need to give CMS a bit of an extra nudge toward better coverage. And that is through pricing. After all, cost burden is a main concern for the CMS and the Biden administration overall. Aduhelm’s initial $56,000-per-year price drew wide condemnation. After that initial sticker shock, Biogen halved the price right before CMS’ draft coverage decision earlier this year, but the damage was already done.

Eisai is leading lecanemab this time. In an interview with Fierce Biotech earlier this year, Ivan Cheung, the company’s head of the neurology business group, said “gaining credibility and trust from the public is critically important” for lecanemab’s launch.

After releasing its phase 2b results and based on that data, the Japanese pharma floated a potential annual value-based price for lecanemab at $9,249 to $35,605. Despite a clean phase 3 win, a safe strategy for Eisai in its expected upcoming reimbursement discussion with CMS would be to remain humble and get that lecanemab list price around Aduhelm’s reduced cost and closer to the lower end of its cost-effectiveness calculation. That would give CMS one less reason to block lecanemab.