Breaking: FDA clears second Alzheimer's drug in 'foundational spark' for field
US regulators approved Eisai and Biogen’s Alzheimer’s drug lecanemab, a landmark moment for the disease and a second chance for the companies after their drug Aduhelm was a commercial flop in the face of cost and efficacy concerns.
The FDA cleared the monoclonal antibody under its accelerated approval pathway, for use in patients with mild cognitive impairment from Alzheimer’s who have confirmed presence of amyloid beta pathology prior to treatment, essentially the same population in clinical trials. Like Aduhelm, which the companies brought to market in June 2021, it claims to slow the progression of the neurodegenerative disease. Eisai will sell the drug as Leqembi.
The drug will be priced at $26,500 per year, Eisai said. Existing coverage limitations from Centers for Medicare & Medicaid Services mean many patients won’t have access. CMS said it’s looking at available information “may reconsider its current coverage based on this review.” Traditional approval could lead to broader coverage, CMS said in a statement.
“It’s not a cure, but I think any disease like oncology, HIV and all these areas, you always need that initial, foundational spark,” Eisai US leader and global Alzheimer’s chief Ivan Cheung told Endpoints News in an interview before the approval. “I think this could be that moment.”
Aduhelm at one time appeared to be that spark. But it quickly fizzled out. After the FDA cleared the drug, CMS, which insures the US’ 65-and-over population, refused to pay the $56,000 price except for use in patients in a clinical trial. The evidence that the drug actually made any difference in slowing Alzheimer’s was ambiguous, and even after the price was cut in half to $28,200, it failed to bring in any meaningful sales.
Under the companies’ partnership, Biogen was responsible for Aduhelm’s commercialization, which sparked an 18-month congressional investigation, while Eisai will take the lead with Leqembi.
Debate about efficacy
Leqembi is likely to face its own questions from doctors about whether patients will actually notice the drug’s impact. In September, Eisai announced that an 1,800-patient Phase III trial found the drug slowed the progression of Alzheimer’s disease by 27% over 18 months compared with a placebo, using a scale measuring cognition and function.
Researchers and clinicians have called the drug’s impact modest and said there’s still no definitive evidence of clinical meaningfulness, with the debate ongoing about how big an effect is needed. Yet the drug, which aims to clear toxic amyloid protein buildups in the brain, is a step in the right direction for a disease with few treatment options, doctors have said.
“The fact that it is even being discussed as potentially meaningful when you’re starting a trial where there are clinical symptoms on board, after a long degenerative process, is actually pretty stunning, especially when you align it with the movement of the biomarkers,” Barry Greenberg, an Alzheimer’s researcher since the 1980s and an associate professor of neurology at Johns Hopkins, said in an interview.
“We worked very, very hard with the FDA to narrowing the population to the one in the clinical trials,” Eisai’s Alzheimer’s leader said.
On an 18-point scale known as the Clinical Dementia Rating-Sum of Boxes, or CDR-SB, placebo patients had their scores worsen by 1.66, while Leqembi patients declined by 1.21 points. That amounts to a 0.45 point difference in Leqembi’s favor.
But experts have called a 1-point difference the minimum for clinical meaningfulness. Eisai and its investigators differ. When publishing the CLARITY AD Phase III results in the New England Journal of Medicine in late November, they claimed that such a definition “has not been established.”
What has been established is that there’s still plenty of debate.
“Eighteen months of treatment producing a difference of that minimal size is not the clinical effects that patients are hoping for,” Matthew Schrag, a Vanderbilt Alzheimer’s researcher unaffiliated with Leqembi, said in an interview with Endpoints. “This drug doesn’t give anyone their memory back.”
The debates about efficacy are certain to be paired with questions about safety. In the Phase III trial, Eisai reported cases of brain bleeding and swelling. Known as ARIA, the amyloid-related imaging abnormalities are detected by scans, and have been associated with other anti-amyloid drugs in clinical studies. The rates of ARIA-E, which can indicate swelling, were 12.6% for those on Leqembi and 1.7% for those on placebo. For ARIA-H, or signs of bleeding, the rates were 17.3% and 9.0%, respectively.
FDA placed a “warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur,” in the release.
In the label, FDA notes MRI monitoring for ARIA should be done prior to treatment and again before the fifth, seventh and 14th infusions. Under the warnings and precautions section, the FDA notes, based on the Phase II study, patients on Leqembi and anti-thrombotics, aspirin, other anti-platelets or anti-coagulants “did not have an increased risk of ARIA-H compared to patients who received placebo and anti-thrombotic medication.”
The label includes no boxed warning, no risk evaluation and mitigation strategy (REMS) and no contraindications, Cheung said.
“Having said that, we want to be proactive,” the Eisai executive said. Eisai will launch a sponsored program called “Understanding ARIA,” which he said will include self-directed educational modules for physicians, live interactive educational sessions for doctors and continuing medical education sponsorships.
Publications have reported cases of three deaths potentially linked to the drug, including one report that came out just weeks before the approval.
Schrag called Eisai and Biogen’s failure to disclose the death at a medical conference in late November disturbing, and said that “rushing this drug to market would be a mistake.” Michael Irizarry, Eisai’s deputy chief clinical officer for Alzheimer’s and brain health, told Endpoints the trial investigator hasn’t yet had access to the hospital records and scans that were reported.
“We do think that it does highlight that ARIA-E is an important adverse event with Leqembi and can be a serious adverse event,” Irizarry said.
Researchers like Schrag want more answers.
“As we as a field wrestle with the appropriate role of these drugs, we need to be working with all of the data. This episode undermines my trust in Eisai and Biogen and falls into the same pattern of frustrating behavior that we witnessed around the approval and post-approval marketing of” Aduhelm, Schrag said.
Leqembi’s accelerated approval means that the companies will still need to apply for full FDA approval, which will happen in mere days, Cheung told Endpoints.
The US-Japanese drugmaker has been in dialogue with CMS to open up payment for the medicine after the agency limited coverage of Alzheimer’s drugs in the wake of Aduhelm’s approval. Currently, to get covered by the program, most patients must be in a clinical trial. Conversations with the government thus far are “very productive,” Cheung said, and he noted many payers are in line with CMS’ decision, but that “doesn’t mean we’re not going to try our best to work with other payers.”
Eisai and other anti-amyloid drugmakers got the backing of the Alzheimer’s Association in mid-December, when the advocacy group called on CMS to reverse the coverage decision, calling it “not acceptable.”
Eisai said the company doesn’t expect CMS’ national coverage decision to be lifted or loosened ahead of a full approval. In the interview, Cheung acknowledged some hospital systems might not put any patients on Leqembi because of the CMS restriction, calling it a “mixed emotion of a launch,” but that other patients might have access, such as those under the age of 65, or those who are covered by Veterans Affairs or the Department of Defense. The VA did not cover Aduhelm.
“This initial phase, our goal at Eisai is not generating demand or generating sales. It’s really getting the ecosystem ready,” Cheung said. The “true launch” will come when changes are made to the NCD, he said.
Approval filings in Japan and the European Union are expected by the end of March. An application was initiated in China in December, and other countries on the horizon include Australia, Canada, UK and Switzerland, Cheung said. Lecanemab inventor BioArctic is also working with Eisai on preparing for filings in the Nordics, a spokesperson said. The European Medicines Agency could be more stringent, as the bloc’s drug regulator likely seeks confirmation of clinical relevance.
Price and data
Leqembi’s price is higher than the $9,000 to $21,000 per year “cost-effective” range calculated by the Institute for Clinical and Economic Review, the pricing watchdog which released a draft report on the drug in December. Once patients reach the maintenance phase, though, the annual price would be less than $15,000, Cheung said.
Eisai previously calculated an “annual value-based price” range of $9,200 to $35,600 based on Phase II results, and that price increased to $37,000 after factoring in the Phase III data as part of the “societal value of medicine,” the Eisai executive explained.
Inflation in the US and results from studies of a subcutaneous version of Leqembi will be taken into consideration in the future, as well, Cheung said, noting ICER’s draft and the Congressional report released in the last week of 2022 were not factored into the pricing analysis.
Cheung said Eisai is working on getting another paper published to include analyses of pre-specified areas that Sharon Cohen, a University of Toronto neurologist, presented at an Alzheimer’s conference the same day the NEJM paper went live.
“Our slope analysis [of CLARITY AD] suggests that placebo reaches a point after about 12 months that lecanemab doesn’t reach until 18 months and that kind of change increases over time,” Irizarry told Endpoints. “So we’re trying to put all this information together to support the clinical meaningfulness of the effect on the primary endpoint.”
Shortly after Eisai’s Phase III topline readout, a major setback came to the field as Roche’s anti-amyloid gantenerumab flunked a late-stage study. Another late-stage candidate is still in the works at Eli Lilly, whose donanemab is in multiple clinical trials, including one in which it proved better than Aduhelm. The FDA is expected to decide on that drug in the coming months.
A Lilly spokesperson told Endpoints in an emailed statement that the Big Pharma has “never been more excited about the promise of our Alzheimer’s disease portfolio and the difference that we believe donanemab could make for patients suffering from this disease.”
The go-ahead for Leqembi is a high point for the drug’s 17-year journey at Eisai. The Tokyo-based drugmaker initially inked arms with BioArctic in 2005 and then signed an exclusive license in December 2007 for an antibody at the time known as BAN2401.
The approval is a “recognition of the many scientists and doctors who have, over many years, patiently and persistently worked to find a treatment for this highly complex disease,” Chris Viehbacher, the recently installed Biogen CEO who took over for Michel Vounatsos, told Endpoints in a statement.
The drug’s name honors BioArctic founder Lars Lannfelt, representing the L; e for Eisai; and the moniker’s remainder roughly translates to healthy, elegant and beautiful in the biotech’s native language, Cheung said, noting Eisai wanted to incorporate “some positive meaning in the Japanese heritage.”
Biogen is responsible for manufacturing lecanemab at its Solothurn, Switzerland, facility, the partners said in March 2022, when they extended the supply agreement from five to 10 years.
Editor’s note: This story was updated to include information from Centers for Medicare & Medicaid and an Eli Lilly statement.