Acknowledging the limits of disease-modifying drugs like Leqembi and Kisunla, companies like Bristol Myers Squibb, Acadia, Otsuka and Lundbeck are renewing a decades-old search for symptomatic treatments, including in high-profile drugs like Cobenfy.
The 2023 and 2024 approvals of the first-ever disease-modifying treatments for Alzheimer’s disease—Biogen and Eisai’s Leqembi and Eli Lilly’s Kisunla, respectively—generated new momentum in the intractable space. M&A deal value ballooned from just $2 billion in 2022 to $18 billion last year. But the limitations of the anti-amyloid antibodies are driving much of that money toward biopharma’s long-standing effort to develop treatments that address Alzheimer’s devastating manifestations.
“I think we all understand that neurodegenerative diseases are just hard,” Catherine Owen Adams, CEO of Acadia Pharmaceuticals, which is developing a treatment for Alzheimer’s disease psychosis, told BioSpace. “With so many patients worldwide affected by Alzheimer’s, I think the time is now to start at least alleviating some of these symptoms.”
The cognitive and mood challenges associated with Alzheimer’s are a primary reason for patients being admitted to long-term care, she added. “Whilst memory loss is upsetting and difficult, the psychosis and other areas . . . including agitation, they’re really, really disturbing for families, and it means that caring for that patient becomes incredibly hard at home.”
Treating the psychosis and agitation associated with Alzheimer’s along with the cognitive impairment has long been a focus for drug developers. “Symptomatics have always been of interest,” Graig Suvannavejh, managing director at Mizuho Securities, told BioSpace. Cholinesterase inhibitors like Pfizer and Eisai’s Aricept, Novartis’ Exelon and Johnson & Johnson’s Razadyne have been on the market since the turn of the century, he pointed out.
These drugs do nothing to tackle beta amyloid. Instead, they act on acetylcholine, an enzyme that helps brain cells communicate with one another and that is made by neurons that are destroyed by Alzheimer’s disease. While these medicines don’t address the underlying cause of the disease, they have been shown to restore some cognitive capability.
Today, companies like Acadia, Bristol Myers Squibb, Otsuka Pharmaceutical and Lundbeck are taking myriad new approaches to best these old treatments in the fight against Alzheimer’s cognition and mood impairments. These companies point to the need for a “continuum of care” for patients with Alzheimer’s, focusing on both molecules that can prevent or slow the progression of the disease and therapies that can impact a patient’s experience.
Indeed, Leqembi and Kisunla have limited efficacy and have been plagued by concerns over amyloid-related imaging abnormalities (ARIA). Moreover, the drugs are approved only for patients with mild-to-moderate Alzheimer’s disease. Many patients have already progressed beyond the reach of such therapies, BMS’ Vice President of Neuroscience Research Ken Rhodes told BioSpace. In 2020, there were more than 55 million people living with dementia across the globe, according to Alzheimer’s Disease International. By 2030, this number is expected to hit 78 million.
“There are many patients who are in the mid stages or more advanced stages of their disease who are experiencing debilitating symptoms,” Rhodes said, “and those individuals need promising therapies as well.”
Symptomatic Trials To Watch
Most people know BMS’s Cobenfy as a schizophrenia drug, approved last October as the first novel treatment for the psychiatric disease in 35 years. But the combination of muscarinic M1/M4 agonist xanomeline and muscarinic antagonist trospium began its therapeutic journey as an Alzheimer’s hopeful at Eli Lilly.
“[Eli Lilly] noticed in the Phase I trial that patients with symptoms of psychosis were dramatically benefiting from xanomeline,” Rhodes said. Now, he continued, BMS is returning to Cobenfy’s roots. “We’re very hopeful that this molecule will address some of the debilitating psychiatric symptoms associated with advancing Alzheimer’s disease.”
The Phase III ADEPT-2 study comparing Cobenfy to placebo in approximately 400 patients with mild to severe Alzheimer’s who have moderate to severe psychosis attributed to the disease is expected to be complete July 31, with a readout slated to be released by the end of this year.
BMS is also developing an eIF2B activator to treat cognitive impairment associated with Alzheimer’s by targeting the integrated stress response (ISR), which in Alzheimer’s is triggered by misfolded proteins amyloid and tau. With this candidate, currently in Phase I, BMS is “looking to inhibit [the ISR] as a way to sort of reactivate protein synthesis in Alzheimer’s disease, with an eye towards preserving synaptic activity,” Rhodes said.
Still another program, an FAAH/MAGL dual inhibitor, is in Phase II development for both Alzheimer’s disease agitation and multiple sclerosis spasticity. This program targets the excitatory-inhibitory imbalance that may underlie subclinical seizure in Alzheimer’s, Rhodes explained.
Over at Acadia, an inverse agonist of the 5-HT2A receptor called ACP-204 is being tested in a Phase II trial for Alzheimer’s disease psychosis, with another Phase II study in Lewy body dementia with psychosis set to kick off this quarter. ACP-204 is a follow-on molecule to Nuplazid, approved by the FDA in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis. Data from the Alzheimer’s psychosis trial are expected in the summer of 2026, Owen Adams said.
Other active players in the symptomatic Alzheimer’s space include Otsuka and Lundbeck, which in 2023 won approval for Rexulti as the first FDA-approved treatment for agitation in Alzheimer’s disease. Like Cobenfy, Rexulti first hit the market as a treatment for schizophrenia, in addition to an adjunctive therapy for depression.
The drug is not without its challenges, however. Discussion at a pre-PDUFA advisory committee meeting centered partly around the boxed warning issued in 2005 for atypical antipsychotics—a class to which Rexulti belongs—after a meta-analysis that revealed a 70% increased risk of death among elderly patients. The adcomm members determined that the benefit of the drug in treating Alzheimer’s-related agitation outweighed this risk. Rexulti’s current label carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis.
Earlier in the industry’s pipeline, AbbVie is testing a treatment for Alzheimer’s disease psychosis. Emraclidine, acquired in the nearly $9 billion buyout of Cerevel Therapeutics, failed in schizophrenia last year, but AbbVie is now running a Phase I for the drug in the new indication. Neumora Therapeutics, meanwhile, has a Phase I ongoing for its a V1aR antagonist, NMRA-511, in agitation in Alzheimer’s disease.
Disease-Modifying Drugs Inch Forward
All of this is not to say that disease-modifying treatments are stalled—though their progress may seem painfully slow. While acknowledging that treatments like Leqembi and Kisunla have been “an incredible breakthrough for the field,” Rhodes said that “clearly there’s room for improvement on those therapies.”
To this end, BMS has a Phase II tau program targeting neurofibrillary tangle pathology, which Rhodes called “the other major pathology of Alzheimer’s disease” beyond amyloid beta. This, he said, is where “we think there’s tremendous hope for a different approach to disease-modifying therapy . . . without some of the risks that come with amyloid therapy.”
As for those risks, Eli Lilly just secured a label update for Kisunla that could mitigate some of the concerns around ARIA, which can present on brain scans as swelling (ARIA-E) or bleeding in the brain (ARIA-H). A gradually increasing dosing schedule for Kisunla was shown in a recently published clinical trial to decrease the incidence of ARIA-E.
Meanwhile, analysts are eagerly anticipating the results of Lilly’s Phase III TRAILBLAZER-ALZ 3 trial in presymptomatic Alzheimer’s. The study, which is testing the time to clinical disease progression, is expected to be complete in November 2027, according to Clinicaltrials.gov.
The field won’t have to wait quite as long to find out if GLP-1s—the current super drug—are effective against the memory-robbing disease as well. The EVOKE and EVOKE Plus trials, both testing Novo Nordisk’s semaglutide in people with early Alzheimer’s, are expected to be completed in September.
For Rhodes, the space is at an exciting and critical juncture. “I can confidently say that we’re really at a tipping point of bringing forward potentially transformational therapies in Alzheimer’s disease.”
