After decades of frustration and flops, the Alzheimer’s disease market is on the cusp of offering two disease-modifying treatments. Biogen and Eisai’s Leqembi earned full approval last July and an FDA stamp on Eli Lilly’s donanemab could come any day now—after the company advised to expect a decision before the end of 2023.
The anti-amyloid space endured a rocky start after Aduhelm’s history-making but controversial approval in 2021. Biogen has since made the decision to discontinue sales of the embattled therapy and terminate the post-approval study. Now, several other companies are looking to push their investigational drugs to market.
“We’re still in very early days of Alzheimer’s disease treatment,” said Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Many of the candidates currently in development target a specific piece of the Alzheimer’s puzzle, such as triggering receptor expressed on myeloid cells 2 (TREM2) and the hepatocyte growth factor (HGF) system. Suvannavejh told BioSpace that he believes a combination approach—like the ones seen in cancer treatment—is where the space is ultimately headed.
Here are five Alzheimer’s assets with data readouts Suvannavejh is excited about in 2024:
1. Alector/AbbVie’s AL002
Alector Therapeutics’ monoclonal antibody, AL002, has a novel target—TREM2. Impairments to this receptor’s functionality is believed to lead to Alzheimer’s disease and other forms of dementia, according to the company’s website. AL002 activates TREM2 signaling to improve cell survival and activity.
The infused antibody is currently in Phase II testing, with a data readout slated for the fourth quarter of 2024 that will determine the future of the program, Suvannavejh said. AbbVie has full opt-in rights to Phase III development if the results are sufficiently compelling.
2. Athira Pharma’s fosgonimeton
According to Athira, this potential first-in-class therapy is designed to modulate the HGF system to activate neuroprotective and anti-inflammatory pathways in the central nervous system. Fosgonimeton flopped in a Phase II trial in December for Parkinson’s disease dementia or dementia with Lewy bodies. However, once Athira shrunk the scope to five patients in the modified intent-to-treat population, it saw a statistically significant improvement in cognitive score.
Athira has now completed enrollment in a Phase II/III trial for mild-to-moderate Alzheimer’s, with a topline data readout expected in the second half of this year. Suvannavejh said he finds fosgonimeton “intriguing,” despite the controversial data so far collected, adding that HGF is a unique drug target that could potentially improve neuron function and be used in combination with an anti-amyloid or anti-tau therapy.
3. Alzheon’s ALZ-801
The first oral disease-modifying treatment for Alzheimer’s could come from the labs of Framingham, Mass.–based Alzheon. ALZ-801 is designed to prevent the formation of amyloid oligomers, the toxic amyloid species that eventually form plaques. It is being tested in patients with at least one copy of the APOE4 gene variant as these individuals tend to have a higher buildup of amyloid-beta in the brain. Topline results from an ongoing Phase II trial showed that after two years, ALZ-801 preserved the hippocampus without increasing the risk of ARIA, a side effect sometimes seen with anti-amyloid therapies like Leqembi and donanemab.
ALZ-801 is now in Phase III testing, with a readout expected around the middle of the year, Suvannavejh noted. While Alzheon is a private company at this point, Suvannavejh believes a positive data readout will lead to either a deal with a larger company or possibly an IPO.
4. Prothena’s PRX012
Holding the FDA’s Fast Track designation, Prothena’s next-generation anti-amyloid antibody carries best-in-class potential, Suvannavejh said. PRX012’s key differentiator: it’s delivered subcutaneously, as opposed to intravenously like Leqembi and donanemab.
Although the candidate is only in Phase I trials, Suvannavejh said investor interest was clear last year and resulted in a stock bump driven by the convenient formulation, efficacy and possibility of avoiding ARIA. But clinical readouts have been delayed, somewhat dampening excitement, Suvannavejh noted. In a January press release, Prothena reported that the ongoing Phase I trial “continues as planned,” with an update expected this year.
5. Axsome Therapeutics AXS-05
Unlike the other drugs on this list, this candidate is not a disease-modifying treatment but a symptom-treating one. Axsome has repurposed a drug currently on the market as an antidepressant and is testing it against Alzheimer’s disease-related agitation. According to Axsome’s website, agitation is reported in about 70% of people living with Alzheimer’s and is associated with decreased functioning, earlier nursing home placement and increased mortality.
Already riding high on positive Phase II and Phase III data, Axsome’s second pivotal Phase III study is expected to read out in the second quarter of 2024, Suvannavejh noted. While Otsuka and Lundbeck gained approval for Rexulti last year for Alzheimer’s agitation, the drug comes with a black box warning for elderly patients with dementia-related psychosis. Suvannavejh said that if Axsome is successful, it would be the only drug on the market indicated for AD agitation without such a warning.
As of January 2023, there were 187 trials assessing 141 drugs for Alzheimer’s disease. With these readouts and more anticipated in 2024, the stage is set for additional, compelling options for Alzheimer’s patients.
“This is, in my opinion, a really exciting place for innovation and Alzheimer’s disease,” Suvannavejh said.
https://www.biospace.com/article/five-alzheimer-s-data-readouts-to-watch-for-in-2024/
