NEW YORK – Summer 2023 was a landmark for Alzheimer’s disease care, as Leqembi (lecanemab) became the first in a long line of beta-amyloid-targeting drug candidates to garner full regulatory approval in the US.
The US Food and Drug Administration had previously granted accelerated approval to Eisai and Biogen's drug based on its ability to clear beta-amyloid plaque, a surrogate endpoint that the agency felt was "reasonably likely" to predict clinical benefits. But once Leqembi achieved traditional approval, with the unanimous support of an FDA advisory committee no less, it gave the healthcare community, Alzheimer's patients, and their families added confidence that removing the protein buildup characteristic of Alzheimer's could actually slow the disease's progression. The new FDA approval also opened the door for broader insurance coverage.
In the year since that milestone approval, many neurologists have been telling patients they would take biweekly intravenous infusions of Leqembi for at least a year and a half based on data from the randomized, controlled Phase III CLARITY AD trial, which underpinned the FDA approval. Patients were monitored for 18 months in that study, but some doctors want more evidence on the benefits of giving the drug for longer.
Leqembi is indicated specifically for adult Alzheimer's patients with mild cognitive impairment or mild dementia who have evidence of beta-amyloid pathology. Patients receive an hour-long intravenous infusion of the drug every other week. The FDA-approved label for Leqembi doesn't specify at what point, if any, the treatment can be stopped.
That year-and-a-half mark is coming up for some patients who were the first to receive Leqembi after its accelerated approval, and their physicians are unsure what to do next and for how long to keep giving patients Leqembi infusions.
"That's still an open question," said Erik Musiek, a professor of neurology at Washington University School of Medicine in St. Louis. Musiek said he has been telling his patients at the university's Memory Diagnostic Center that they'll get the drug for at least 18 months, and "at that point, we're going to have to evaluate the data."
Musiek's patient who has taken Leqembi the longest has been on it for about 10 months, so hasn't yet hit the point where that ultimate decision must be made.
Leqembi, by targeting beta-amyloid, which many say is Alzheimer's root cause, is designed to slow the rate of cognitive decline for patients with early-stage disease but isn't designed to stop progression or restore cognitive function. After decades of failed attempts from Roche, Pfizer, Eli Lilly, and others to develop anti-amyloid drugs, Leqembi's approval has given new hope to the controversial "amyloid hypothesis," which posits that an accumulation of beta-amyloid proteins in the brain hinders communication between cells and causes a cascade of other issues that lead to the neurodegenerative disease. Since Leqembi's approval, one other anti-amyloid drug has reached the market, Eli Lilly's Kisunla (donanemab), which received regular FDA approval earlier this month.
Slow start
Leqembi's regular approval from the FDA not only re-energized the anti-amyloid drug space but also improved elderly patients' ability to access the drug with insurance coverage. Medicare, for example, had said it would not cover anti-amyloid monoclonal antibody Alzheimer's treatments unless they earned traditional approval from the FDA.
It's a game-changer to have a disease-modifying treatment available for Alzheimer's, said Lawrence Honig, a professor of neurology at Columbia University's Irving Medical Center, who was an investigator in the Clarity AD trial. He said it feels like all Alzheimer's patients want to know if Leqembi is an option for them but agreed that there's uncertainty at present around how long patients should keep taking it. "What we can tell patients is just what we know," he said, "which is that clinical trials showed benefit over an 18-month period."
Amid this uncertainty, Eisai is working to solidify Leqembi's long-term use. Eisai has submitted a supplemental biologics license application (BLA) seeking Leqembi's approval as a maintenance treatment in which patients would continue to receive a lower dose of the drug on a monthly basis after completing an initial regimen of biweekly infusions. The FDA expects to issue a decision on the application by Jan. 25, 2025. Eisai also has initiated a rolling submission of a BLA for a subcutaneous version of Leqembi that could be used as a weekly maintenance treatment after the biweekly infusion regimen.
The idea that Eisai hopes to advance is that continued administration of Leqembi will sustain removal of protofibrils, which the firm describes as a particularly toxic form of beta-amyloid that can cause neuronal injury and increase formation of beta-amyloid plaque.
If Eisai's gambit to make Leqembi into a chronic treatment for Alzheimer's is successful with regulators, it will be a boon for the company's Alzheimer's business, which has been growing slower than expected.
Eisai initially said it expected 10,000 US patients to be taking Leqembi by March 2024, the end of its last fiscal year. By then, the company had also projected Leqembi sales of around ¥10 billion ($63.3 million).
However, Eisai in May reported ¥4.26 billion in Leqembi sales during fiscal 2023. And as of late January — the company's most recently disclosed patient numbers — around 2,000 patients had received Leqembi, although Eisai claimed at the time that there were about 8,000 additional patients on waiting lists for the drug.
After that May disclosure, however, Eisai stopped reporting the number of patients on Leqembi. Such estimates can be complex to gauge, said Tom Fagan, VP of Eisai's US Alzheimer's disease commercial franchise. He maintained that the company has been "very pleased" with Leqembi's uptake so far.
"We all believed it was going to take some time for the system to evolve," he said, referring to care pathways that must be developed within healthcare organizations to diagnose, treat, and monitor these patients. "We continue to see, dating back to last summer, a very consistent and steady growth across the country."
To prescribe Leqembi, doctors first have to administer standard cognitive tests to determine whether they have Alzheimer's. But then, they also have to establish that patients have beta-amyloid pathology, testing for which isn't routinely done in neurology practices. Doctors also need to assess a patient's risk of certain side effects associated with the drug by performing genetic testing and imaging studies. And ultimately, they must establish whether the patient's insurance will cover the drug, which has a list price of $26,500 per year. While Medicare covers 80 percent of Leqembi's cost, private insurers vary in their coverage policies.
Fagan noted that Eisai is making investments to support Leqembi's adoption, including increasing marketing and adding physician education staff that provide information to neurologists and health systems.
Although Leqembi sales over the last fiscal year fell short of the ¥10 billion goal, revenue did steadily climb during that time. Leqembi sales were ¥70 million in FY Q1; ¥290 million in FY Q2, when the FDA converted the drug’s accelerated approval to full approval; ¥1.06 billion in FY Q3; and ¥2.83 billion in FY Q4 of 2023.
When Biogen reported its Q1 2024 financial results in April, company President and CEO Christopher Viehbacher also said in a statement that Leqembi's market adoption was building momentum "at a steady pace." During Q1, the number of patients on the drug increased almost 2.5-times compared to the end of calendar year 2023, according to Biogen, which comarkets the drug and splits product revenue and cost of sales with Eisai. In a note to investors about Biogen's Q1 earnings, market analysts from Leerink Partners estimated 4,500 patients were likely on Leqembi by the end of March.
Even if it is taking time for Leqembi sales to pick up steam, it's safe to say that Eisai and Biogen have big ambitions for the drug. Eisai expects Leqembi sales to "grow significantly" during fiscal 2024, reaching ¥56.5 billion, as diagnosis and treatment pathways are better established in the US and Japan and the drug is approved in other countries.
Leqembi's market success is critical for both Eisai and Biogen's Alzheimer's businesses, especially after Biogen opted to discontinue marketing the companies' previous codeveloped anti-amyloid product Aduhelm (aducanumab) due to slow sales. Aduhelm was the first anti-amyloid drug to reach the market after receiving accelerated approval from the FDA, but it wasn't able to overcome physicians' skepticism about the drug's mixed efficacy data from clinical trials. Furthermore, with only accelerated approval, Aduhelm wasn't covered by Medicare in most cases.
'Not an easy drug'
Neurologists interviewed for this article attest to the challenges of getting Leqembi to patients.
"We've been thinking a lot about it," said Musiek, the neurologist at the memory center at WashU, where he estimates neurologists have treated about 200 patients with Leqembi as of late spring. "It definitely is not an easy drug. There's a lot of cost, and time, and effort put into it."
Before prescribing Leqembi, Musiek said he has a long conversation with patients and their caregivers about the clinical trial data underpinning its approval, including efficacy and potential side effects. Patients have different priorities — some may be willing to try anything to slow progression of their disease, while others are put off by the burden of traveling for frequent infusions and MRI monitoring for a drug that isn't a cure.
That's especially tricky for patients who don't live near an academic medical center or well-resourced hospital system, since the typical community hospital may not employ dementia care specialists, perform beta-amyloid testing, or have an infusion center where patients would receive the treatment.
These resources are particularly absent in minority communities, as seen in research by Jose Soria, director of clinical research at the Neuron Clinic and an assistant professor of neurosciences at the University of California, San Diego School of Medicine. At the Alzheimer's Association's Latinos & Alzheimer's Symposium in April, Soria presented an abstract on the experience of community neurology clinics prescribing Leqembi in Southern California and said limited access to medical care for early Alzheimer's detection, inadequate insurance coverage, lack of caregiver availability, and transportation challenges are hindering Latino patients from getting the treatment.
Then, there are neurologists who, unconvinced of Leqembi's benefits, still aren't prescribing the drug. These neurologists worry that the degree to which Leqembi slowed cognitive decline in clinical trials may be too modest to make a noticeable difference in their patients' daily functioning.
That was a concern raised by Robert Friedland, a professor of neurology at the University of Louisville School of Medicine, ahead of Leqembi's approval, and as a naysayer of the amyloid hypothesis, he hasn't seen any data since that to change his opinion. For Friedland, the slew of failed anti-amyloid drug trials since the 1990s, plus the fact that there are people who have beta-amyloid deposits but don't have cognitive impairment, suggests that beta-amyloid plaque is not a primary driver of Alzheimer's. And he isn't impressed by Leqembi or Lilly's Kisunla. "The efficacy is poor," he said of both.
In the 18-month CLARITY AD trial, investigators reported that patients on Leqembi experienced a 27 percent slower rate of cognitive decline than those on placebo. That result was based on Leqembi-treated patients on average scoring just 0.45 points better than patients on placebo on the 18-point Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale. Kisunla demonstrated similar efficacy in the randomized, controlled Phase III TRAILBLAZER-ALZ 2 trial, in which patients who received Kisunla for up to 76 weeks had 29 percent slower disease progression compared to the placebo group. But again, when looking at CDR-SB scores between Kisunla-treated patients and the control arm, the average difference was less than 1 point, with patients on Kisunla scoring an average 0.7 points better.
Doctors must balance these efficacy data against the side effects these drugs can cause, such as infusion-related reactions and amyloid-related imaging abnormalities (ARIA), which can present as temporary swelling or bleeding in the brain. In their respective Phase III trials, Kisunla was associated with higher rates of ARIA than Leqembi. Patients with ARIA are typically asymptomatic, but in rare cases, it can be serious and fatal. Leqembi and Kisunla both carry boxed warnings on their labels about the risk of ARIA and recommendations for genetic testing to assess if patients carry two copies of the APOE4 allele. If they do, they are at higher risk of ARIA.
After considering the modest impact on cognitive and functional outcomes, and the high cost of the drugs and risk of adverse events, Friedland decided not to offer these drugs to his patients. "There are other things going on in the brain in this disease, which deserve more attention," he said.
The next big question
Neurologists are closely watching the FDA as it weighs whether to approve a new version of Leqembi for maintenance treatment. To some neurologists, like Honig, it makes sense that patients will need some type of continued maintenance treatment. "That's something that many of us are thinking about" and were wondering about even before Eisai submitted the applications for maintenance dosing to the FDA, he said. Based on the biology of the disease and what's known about beta-amyloid accumulation, "there's absolutely every reason" to believe patients will likely need ongoing treatment to "continually remove the amyloid that's continually being generated in patients with Alzheimer's disease," Honig added.
Maintenance dosing is likely needed to continue to treat the underlying biology of the disease, Soria agreed. But, even if the FDA approves Leqembi as a maintenance treatment, doctors' decisions to prescribe it long term are "going to still be very patient-specific," he said. Physicians will need to consider patient preferences and health, for example, as well as the current state of a patient's disease and whether continued treatment is accessible.
Other neurologists aren't convinced about Leqembi's use as a maintenance treatment and want to see more data.
Leqembi is expensive, Musiek said, and it can easily strain the healthcare system if a large proportion of eligible patients begin regularly receiving it at infusion centers for the rest of their lives. Already, the shortage of dementia care specialists and infusion centers is creating a bottleneck. Eisai hasn't shared the price for intravenous or subcutaneous maintenance dosing relative to the price of Leqembi's initial dosing regimen.
Musiek also hasn't bought Eisai's theory that it's necessary to continue to clear those toxic protofibrils with monthly maintenance dosing of Leqembi, after the initial beta-amyloid build-up is removed. "I haven't seen any data pro or con on that," Musiek said. "I'm not convinced it's true." Musiek said he would like to see additional research into the role that this form of beta-amyloid plays in Alzheimer's, and data on how long it takes beta-amyloid proteins to reaccumulate into plaques after a patient stops treatment with a monoclonal antibody targeting the protein clumps.
Moreover, it's tough to extrapolate long-term benefits from an 18-month trial, when for much of that time the drug is working to remove beta-amyloid plaque, he pointed out. He's curious to see what clinical outcomes look like long term after the beta-amyloid accumulation has been removed and the brain has been able to function without it for a few years.
Recognizing that an hour-long infusion every other week is burdensome for patients, caregivers, and health systems, Eisai, for its part, has highlighted the convenience of monthly maintenance dosing, compared to potentially ongoing biweekly treatment. "We've been working on strategies to ease those burdens," said Steven Hersh, VP of Eisai's clinical development in neurology. "What our data suggest is that those [maintenance dosing] strategies will sustain the benefits that we've seen with the initiation doses."
Eisai has evaluated an intravenous maintenance dosing regimen as part of an open-label expansion of a Phase II clinical trial, which it refers to as Study 201, in which investigators observed that continued Leqembi treatment beyond 18 months prolonged clinical benefit. Hersh also said that after the core Phase II trial, patients went off treatment for an average two years before entering the open-label extension study. During that gap period, beta-amyloid reaccumulated and other biomarkers of neurodegeneration increased.
Eisai has studied the subcutaneous formulation in a substudy of the CLARITY AD trial's open-label extension, as well as in Phase I studies assessing the pharmacologic characteristics in healthy volunteers. The subcutaneous version can be administered at home with an autoinjector within seconds, according to Hersh, and could save patients from having to travel to infusion centers.
Investigators from Eisai will present new data on Leqembi maintenance dosing at the Alzheimer's Association International Conference in Philadelphia next week.
Competition ahead
Eisai has made no secret of the fact that maintenance dosing will bolster its Alzheimer's business. In May 2023, during a call to discuss its fiscal 2022 financial results, Eisai executives characterized plans for an intravenous maintenance dosing regimen and a subcutaneous version of Leqembi as "value maximization programs" for Leqembi in fiscal 2023. The company also wants to expand Leqembi into a preclinical Alzheimer's treatment for patients who haven't displayed symptoms but have elevated levels of beta-amyloid. That indication, under testing in the Phase III AHEAD 3-45 trial, could significantly grow the market for the drug.
Lilly has taken a different strategy with Kisunla in that patients can cease treatment with the anti-amyloid drug after levels of beta-amyloid plaque drop. The firm proposed a limited-duration course for its intravenous treatment on the belief that beta-amyloid accumulation happens slowly. "Once plaque is considered 'cleared,' it will take an average of four years to reaccumulate to a level that would … meet a positive threshold," a company spokesperson said.
This raised new questions at an advisory committee meeting that the FDA convened before approving Kisunla. The agency asked its Peripheral and Central Nervous System Drugs Advisory Committee to weigh in on whether there was enough evidence to stop Kisunla, at what point, and whether patients would need to restart treatment in the future if beta-amyloid reaccumulates in the brain. Ultimately, committee members said that it would be beneficial to patients if they could stop treatment, but they wanted more information on how patients' beta-amyloid levels would be monitored.
In the TRAILBLAZER-ALZ 2 trial, investigators observed clinical improvements in patients treated with Kisunla, even among those who stopped treatment before the end of the study period. Nearly half of the patients who received Kisunla, 46.6 percent, were able to stop receiving the drug by week 52, and 17.1 percent by week 24, and continued to maintain improvements on the CDR-SB scale through the end of the study at week 76. Nearly 70 percent of patients were able to stop the drug by the end of the study period. However, the FDA in Kisunla's label cautions that beta-amyloid levels could increase after patients stop treatment, and that there isn't long-term data available to inform whether patients may need to restart dosing in the future.
In addition to considering the need for long-term maintenance dosing, neurologists trying to decide between Leqembi and Kisunla will have to also weigh their dosing regimens, safety, and cost. Compared to Leqembi's hour-long biweekly infusions, Kisunla requires a half-hour monthly infusion. On the other hand, Kisunla's list price is $32,000 per year, compared to Leqembi's $26,500 per year list price.
And the landscape for anti-amyloid drugs stands to only get more competitive and crowded. Lilly, for example, is also evaluating Kisunla for treating preclinical Alzheimer's in the Phase III TRAILBLAZER-ALZ 3 trial and is testing remternetug, another beta-amyloid-targeting drug with intravenous and subcutaneous formulations, in the Phase III TRAILRUNNER-ALZ 1 trial.
Aside from Lilly, Alzheon is testing valiltramiprosate, an oral medication designed to block beta-amyloid oligomers, in a Phase III trial, while Acumen Pharmaceuticals is testing intravenously infused sabirnetug, which also targets beta-amyloid oligomers, in a Phase II clinical trial and is also assessing a subcutaneous version. At the same time, Prothena is testing PRX012, a beta-amyloid-targeting antibody that's delivered subcutaneously, in a Phase I trial, and Takeda recently acquired an exclusive global license to AC Immune's beta-amyloid-targeting Alzheimer's drug candidates.
There may even be a future for Aduhelm. When Biogen discontinued commercialization of Aduhelm, it returned global rights to the drug's original developer, Neurimmune, which has said it plans to develop aducanumab-based therapeutics that could be administered subcutaneously as an early intervention against Alzheimer's.
Musiek stressed that he's optimistic about this class of anti-amyloid medications, despite the challenges of administering them. While Leqembi has been complicated to get to patients, "it's not impossible" — and there are cell therapies and radiopharmaceuticals in other specialties, such as cancer, that are just as difficult to deliver to patients.
Hospital systems will continue to build their capabilities to offer Leqembi and other drugs in this class over the course of next year, Musiek expects, and he believes that "the use of this drug and others like it will expand."