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When an FDA advisory committee voted unanimously this week to recommend regulatory approval of Eli Lilly & Co.’s Alzheimer’s disease drug donanemab, the decision cemented another important milestone in a field that has been in serious stagnation for years.
From 1998 to 2017, the success rate of just 2.7% in Alzheimer’s drug development has been a major disappointment, with 146 treatment failures and four new therapies that only treat the symptoms of the disease. 2018 Report Since then, only two drugs have been approved in the United States to treat the suspected underlying cause of the disease: Aduhelm and Leqembi, from Biogen and Eisai, and only Leqembi is currently on the market.
But the two anti-amyloid drugs are just the tip of the iceberg when it comes to treating Alzheimer’s, according to Howard Fillitt, PhD, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation. Many of the voting members of donanemab’s advisory board are Donanemab is effective More clinical trials will help clarify the exact outcomes of anti-amyloid drugs, if the risk of side effects such as brain swelling, a condition called ARIA, is worth it.
“If approved, donanemab will expand the first class of disease-modifying therapies and serve as the foundation for the next generation of drugs,” Fillitt said. “While anti-amyloid drugs are not magic bullets, they offer patients the opportunity to alter the course of their disease as research advances toward developing newer therapies that target fundamental biology.”
Requenvi and donanemab have limited application in select patients: Both drugs are intended for people in the early stages of Alzheimer’s disease who also undergo PET scans to determine levels of amyloid plaques and tau tangles in the brain.
Moreover, the amyloid theory itself has come under criticism. Although two drugs have been shown to be capable of removing plaque, researchers Effects on cognitive function Less clear. Leqembi and donanemab improved cognitive function and clinical progression in clinical trials, but the linear progression was Questioned.
So, as anti-amyloid successes rumble in the Alzheimer’s field, many in the field are also looking to newer options and alternative targets for the next big win. Here, we introduce some of the leaders in the clinical anti-amyloid and anti-tau pipeline that may play a role in future treatments.
Anti-amyloid leads the way
Although some researchers believe amyloid is not the most effective target for treating the underlying causes of Alzheimer’s disease, many pharmaceutical companies are pursuing amyloid because of its long history of research and measurable indicators of clinical success. With nearly three approvals, the regulatory process is no longer an unknown factor.
Despite its market failure, Aduherm is the subject of two late-stage clinical trials by Biogen to further link amyloid clearance with reduced cognitive decline. The Phase 3 trials are designed around comparisons with placebo and long-term efficacy over a year. Despite these trials, Aduherm also competes with Lilly’s donanemab. Head-to-head trials The goal is to determine which one is better at removing amyloid plaques.
Eisai and Biogen are also seeking to further expand their drug, Lukembi, and are pursuing large-scale clinical trials to determine cognitive improvement, long-term outcomes and different mutations of the disease.
There are also several new molecules that have progressed to Phase 3 that haven’t gone through the regulatory process; Lilly has two of them. Retransmission and Solanezumab Both are monoclonal antibodies designed to remove amyloid plaques, and while Lilly tested solanezumab for preventative purposes, it found that the drug did not remove plaques or slow cognitive decline.
Other companies, including Alzeon and Cassava Sciences, are pursuing small molecule amyloid clearance. Late stage candidate in progress.
The Rise of the Tau
Big pharma is particularly interested in developing treatments that remove tangles of tau protein in the brain, another hallmark of Alzheimer’s disease and thought to be one of the causes. Roche, Biogen, Eisai, Johnson & Johnson and Eli Lilly are among the major pharmaceutical companies with anti-tau drug candidates in clinical trials.
Tau normally stabilizes the structure of brain cells, but in Alzheimer’s patients it grows out of control and the resulting tangles have been found to be potentially toxic to brain cells. As with amyloid clearance, these drug candidates aim to break down tau protein.
Roche is be plagued by late disappointment A potential anti-tau drug for Alzheimer’s disease is undergoing phase 2 clinical trials. Collaboration with UCBBiogen, Eisai, Johnson & Johnson and Lilly have also reached mid-stage trials with ongoing trials.
But the anti-tau theory faces similar challenges to the anti-amyloid camp. Some big pharma companies are trying to make anti-tau work, but a series of failures has given researchers pause. “It is time to rethink removing physiological levels of soluble (amyloid-β) and tau in patients and instead focus on understanding why (amyloid-β) and tau start to aggregate and form deposits in the brain in Alzheimer’s disease and tauopathies,” the researchers say. 2023 Papers.
