The approval of Leqembi in the U.S. last year was a breakthrough for the Alzheimer’s community, offering thousands a drug that would slow cognitive decline. But now, European regulators have refused to market the drug in the region. The European Medicines Agency (EMA) recommended against the drug developers Eisai and Biogen selling Leqembi in Europe citing the risk that the drug posed outweighed the benefit.
The claims were based on a clinical trial in which the drug was tested against a placebo in 1,795 people with early Alzheimer’s disease. Following 18 months of treatment, the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores of patients were measured. CDR-SB is a scale used to assess the severity of Alzheimer’s. For those who received the treatment, the score increased by 1.21, while the increase was by 1.66 in the placebo group. Although this suggested that Leqembi lowered CDR-SB scores, when compared to the placebo, the difference was small.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) stated that “the observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious adverse events associated with the medicine.”
Leqembi safety concerns threaten approval in Europe
The pressing safety concern with the drug is a side effect called amyloid-related imaging abnormalities (ARIA). These abnormalities observed during brain scans result in symptoms like headache, changes in mental state, confusion, vomiting, and issues with walking. This condition has been linked to anti-amyloid drugs – which Leqembi is.
Leqembi, which is a monoclonal antibody that contains the active substance lecanemab, works by binding to and getting rid of harmful proteins called amyloid beta – a hallmark of Alzheimer’s disease. These proteins form clumps in the brain, disrupting brain function. So, by eliminating these proteins, the drug is able to delay cognitive decline in patients.
Although most cases of ARIA were not serious during the clinical study of Leqembi and did not involve symptoms, “some patients had serious events, including large bleeds in the brain which required hospitalization,” according to the EMA review. “The seriousness of this side effect should be considered in the context of the small effect seen with the medicine.”
Moreover, people who have the ApoE4 gene have a higher risk of ARIA. The gene is not only associated with an increased chance of developing Alzheimer’s but also potentially, a worse form of the disease.
The drug makers have expressed disappointment with the EMA’s decision, and look to re-examine the review.
“We are extremely disappointed by the CHMP’s negative opinion and understand that this may also be disappointing for the wider Alzheimer’s disease community. Alzheimer’s disease is an irreversible, neurodegenerative disease that poses significant challenges to those living with Alzheimer’s disease, their care partners, and society,” said Lynn Kramer, chief clinical officer at Eisai in a press release. “There is a significant unmet need for new innovative treatment options that target an underlying cause of disease progression. We remain focused on making a meaningful difference to those living with early Alzheimer’s disease and those closest to them.”
Eisai and Biogen will have 60 days to give more information to support the request for re-examination of the negative opinion, and the CHMP will have 60 days to respond to that request, explained Meher Baba Kumar Nakka, Senior Healthcare Research & Data Analyst, at Clarivate, who overlooks the Alzheimer’s market.
“While Leqembi has had an impact on cognition and function in its pivotal study, the EMA’s CHMP opinion on the drug reflects a more cautious view toward the risk-benefit balance of anti-Aβ Mabs in the treatment of Alzheimer’s disease,” said Nakka.
U.S. Leqembi sales: not as initially projected
When the drug was greenlit by the U.S. Food and Drug Administration (FDA) in July last year, it was heralded as a breakthrough in neurodegenerative disease research as it is the first drug to slow disease progression. However, U.S. sales did not mirror the hype.
Sales were lagging as hospitals needed more time to set up their systems to deliver Leqembi, which is administered intravenously. On top of that, it takes a while to diagnose patients and ensure they’re eligible for the drug. Growing research in blood tests to detect amyloid plaques in the brain could speed things up.
While treatment access may improve, the $26,500 out-of-pocket cost per year along with paying for scans is a burden for many. In the U.S., Medicare covers up to 80% of the costs leaving patients to pay up to $5300 depending on the insurance plan. Moreover, only those above the age of 65 are eligible so younger patients with Alzheimer’s – although a small population – may miss out on insurance coverage of the drug.
Eisai expected 10,000 people to receive the drug by March this year, however, these projections were quashed since only around 2,000 patients received the drug as of January.
Will Leqembi wind up like ill-fated predecessor Aduhelm?
This is not the first time Leqembi developer Biogen has struggled with an Alzheimer’s drug in the market. Biogen pulled the plug on its controversial drug Aduhelm earlier this year after U.S. congressional committees faulted the FDA approval, which was “rife with irregularities.” The drug was rejected by the EMA in 2021 due to inadequate effectiveness and safety concerns as cases of brain swelling and bleeding were reported.
Besides, the drug was set at an “unjustifiably high price,” according to the congressional report. The company had priced the drug at $56,000 per year, despite insufficient evidence of the drug’s benefits.
Although the EMA has dropped Leqembi into the same pit as Aduhelm after its ruling, the drug makers hope to work with the regulators for clearance in the European Union. However, Nakka is unsure whether the drugmakers can address the CHMP’s concerns based on the existing results of the clinical trial.
“The CHMP’s move suggests a very uncertain path for the drug in the EU, as the success rate for appeals is generally low,” said Nakka. “If the CHMP’s decision is overturned after re-examination and the drug is ultimately approved, we expect health technology assessment (HTA) / reimbursement in Europe to remain the challenge. As another example, in France, anti-dementia drugs are approved but are not reimbursed nationally.”
Currently, in the U.K., regulators are reviewing Leqembi and a decision is expected to arrive soon, but “it will not be surprising should they go down the same path as EMA’s CHMP,” according to Nakka.
The drug has been approved by the U.S., Japan, China, South Korea, Hong Kong, and Israel, and is being marketed in the U.S., Japan, and China. An injectable version of Leqembi has been developed for ease of delivery as well, for which it seeks U.S. approval at present.
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