Lecanemab on the market or change? Less than half a year later, a second AD patient died

Alzheimer's disease (AD) was first reported in 1906 by the German neuropathologist Alzheimer's and has received attention for a century. Epidemiological studies have shown that there are 50 million AD patients worldwide, and the disease is still spreading due to the global aging problem.

According to data from the American Association for Drug Manufacturing and R&D, the global cumulative investment in Alzheimer's disease research and development has exceeded 600 billion US dollars, but the high investment has not brought back the same amount of return for AD treatment, and some brain swelling, cerebral hemorrhage and amyloid-related imaging abnormalities (ARIA) drug side effects have made the already dark AD development and treatment worse.

On November 28, the tragedy of Lecanemab's death was repeated again, and Biospace reported that after 5 months, Biogen/Eisai's anti-β amyloid (Aβ) monoclonal antibody Lecanemab had another clinical accident, and the second death occurred. Science also published a commentary on this.

This report is a 65-year-old woman who developed a stroke and acute swelling and bleeding of blood vessels after receiving Lecanemab. She then underwent a common intervention after a stroke, a powerful thrombo-damaging drug tissue plasminogen activator (tPA). But she had heavy bleeding in the outer layer of her brain and died a few days later.

This is similar to the situation in the first fatal case, also due to a brain hemorrhage. The patient is an 85-year-old male who participated in the open-label phase of the study in January 2022 after completing the double-blind phase of the Phase III clinical trial. Previously, the patient had said that he had fallen multiple times over several months during the injection, and then MRI images showed bleeding in the left back of his brain.

Considering the presence of falls, heart disease, anticoagulants, and other factors, Eisai judged that Lecanemab was not associated with the death. Rudolph Castellani, a neuropathologist at Northwestern University Medical Center in Chicago, agrees. As a participant in the fatal cases, she said that tPA in combination with Lecanemab or the real cause of death may have safety implications for AD patients.

Patients may have a pre-existing condition, extensive cerebral amyloid angiopathy (CAA), which makes blood vessels more vulnerable when Lecanemab clears amyloid from the brain, and tPA induces fragile blood vessel rupture, leading to severe ARIA and fatal intracerebral hemorrhage.

Unlike Aduhelm, which offers short-lived hope for AD, any negative news from Lecanemab, which holds hopes of a "milestone," will bring uncertainty to the progress of AD treatment.

In July, the FDA accepted Eisai's application for a biological product license (BLA) under the fast-track designation and granted priority review rights. The Action for the Prescription Drug User Fees Act (PDUFA) date is set for January 6, 2023.

While Eisai and academics say Lecanemab can't be blamed solely for the death, some researchers insist that its potential safety as a long-term chronic disease treatment needs to be carefully examined. As for whether this accident will affect the FDA's approval of the drug, it will take time to confirm.

Lecanemab's BLA approval will be based on a Phase III Clarity AD trial, with detailed data disclosure imminent. Earlier, on September 28, Biogen and Eisai jointly announced that the phase III clinical trial of Lecanemab for AD met the primary endpoint and all secondary endpoints. In nearly 1800 patients, according to the sum of clinical dementia scores (CDR-SB), the drug reduced the rate of cognitive decline by 27% after 18 months compared to placebo, a finding that was "highly statistically significant" and undoubtedly injected a shot in the arm into the Aβ hypothesis.

The hypothesis that amyloid causes Alzheimer's disease has dominated the AD space, with GlobalData predicting that spending on AD medicines in the EU's four largest markets will increase from $268.7 million this year to $717.5 million by 2027. In the face of a huge incremental market, even if AD drug research and development needs to face a failure rate of more than ninety percent, major pharmaceutical companies are still following - most Aβ antibodies have been broken in clinical research.

Roche's two drugs, Gantenerumab and Crenezumab, are losing ground. Pfizer, AstraZeneca and other multinational pharmaceutical companies have also been attracted by the big cake of the Alzheimer's disease market and competed for layout. However, in 2018, AstraZeneca announced the cessation of phase III clinical trials of oral inhibition of Lanabecesta, and then Pfizer announced its withdrawal from the AD research and development field, and the future of research and development is not clear.

Compared to leaving the market directly, many Biotech try to find a different way.

Acadia, which launched Nuplazid, the first FDA-approved drug to treat hallucinations and delusions associated with Parkinson's psychosis, announced in December that it would resubmit its BLAs for AD. But sadly, attempts to bring Nuplazid into the field of delirium-related hallucinations and delusions treatment in AD have failed. In June, the FDA expert committee voted 9-3 to reject the recommendation for approval for the new indication.

Also preparing to start with the peripheral markets is Axsome. On November 28, Axsome announced that its investigational therapy AXS-05 (dexromethorphan + bupropion) met its primary and secondary endpoints in a Phase III clinical trial. The results showed that AXS-05 statistically significantly delayed and avoided the recurrence of agitation symptoms in AD patients.

AXS-05 is a novel oral investigational N-methyl-D-aspartate (NMDA) receptor antagonist with multiple mechanisms of action for the treatment of major depressive disorder and other CNS disorders. At present, the drug has been approved by the FDA breakthrough therapy for the treatment of major depressive disorder and symptoms of agitation in Alzheimer's disease.

Herriot Tabuteau, CEO of Axsome, said the positive results of the ACCORD trial showed that AXS-05 showed good efficacy in treating AD agitation symptoms. In addition to the positive results shown in the double-blind phase compared to placebo, the results of the open-label trial demonstrated that AXS-05 can rapidly and strongly improve AD agitation symptoms. Axsome's next step is to discuss with the FDA the clinical development of AXS-05 for the treatment of this indication, providing more options for millions of AD patients.