Zagotenemab

UCB reported Thursday that a Phase 2 study for its anti-tau Alzheimer’s program bepranemab did not meet its primary endpoint. Neither the low dose nor high dose resulted in patients seeing a benefit, the company said, using a measurement called the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score to evaluate the drug’s effect on cognition and function after 80 weeks. The company is “evaluating next steps,” it said in a press release, while not disclosing specifics. UCB also highlighted two secondary endpoints it saw as positive, including a separate measurement of cognition known as the ADAS-Cog14. In this endpoint, both doses of bepranemab induced improvements in cognition compared to placebo. A UCB spokesperson described them to Endpoints News as “nominally significant.” Patients taking the low dose saw a 25.2% improvement over their baseline scores compared to placebo (p-value 0.0197; α=0.20), and those who received the high dose saw a 21.4% improvement compared to placebo (p-value 0.0485; α=0.20). UCB administered each of the doses once every four weeks through week 80. Additionally, both doses of the drug slowed the rate of tau accumulation in certain regions of the brain: by 58.3% and 50% in the low- and high-dose arms, respectively. It remains unclear which endpoint UCB might use if it decides to advance bepranemab to a pivotal study. Both Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla used CDR-SB as their primary endpoints, but also included different versions of the ADAS-Cog measurement as secondary endpoints. Both approved drugs saw statistically significant improvements across all endpoints. Researchers presented the data at the Clinical Trials on Alzheimer’s Disease annual meeting in Madrid. Additional data, including the amount by which each dose induced changes in the CDR-SB, will be presented in early 2025, UCB’s spokesperson said. Thursday’s results follow a decision earlier this month from Roche and Genentech to break off its partnership with UCB on this program. In 2020, Roche and Genentech spent $120 million upfront and committed up to $2 billion in milestones and royalties, but elected to return global rights to UCB on Oct. 22. While there have been two approvals for anti-amyloid antibodies, Leqembi and Kisunla, tau-targeting drugs have remained more difficult thus far. At least three other tau-targeting antibodies have failed in clinical trials, including Biogen’s gosuranemab, Lilly’s zagotenemab, and AC Immune’s semorinemab, which had mixed results in Phase 2 studies.

Biogen has two clinical-stage Alzheimer's disease assets behind Leqembi, both of which target tau proteins or their dysfunction. “What does it mean to be a leader in Alzheimer’s disease?” That’s the question Biogen is asking itself, and the question many of the company’s peers are working fervently to answer as the heated race to differentiate from the first batch of Alzheimer’s treatments turns to a simmer.  Adam Keeney, Ph.D., corporate development chief for the Leqembi co-maker, said in an interview with Fierce Biotech that Biogen is "not only just satisfied with [amyloid] beta" and instead "looking at the different pillars of disease." Keeney says the first stop on the portfolio-building circuit is tau. The company’s phase 2 antisense drug, BIIB-080, targets the protein buildup that accompanies amyloid beta in patients with Alzheimer’s. It’s an intrathecal injection—an injection into the spinal cord to bypass the blood-brain barrier— which Keeney described as “not ideal” though probably satisfactory for a first-generation option. But Biogen is planning for and think-tanking easier methods, like IV delivery and even oral compounds.  “We're thinking about degraders and molecular glues and different technologies that we can use,” Keeney said. Biogen already has one oral option in the clinic, the O-GlcNACase inhibitor BIIB-131, a small molecule that looks to block the enzyme research has tied to tau’s dysfunction in Alzheimer’s patients.  Keeney described oral delivery as a goal that’s on a “longer time horizon” routing the work back to the original question: What does it mean to be a leader in the space?  Biogen has experienced the ups and downs of Alzheimer's drug discovery more acutely than probably any company. Its well-documented Aduhelm failure came to a much-expected conclusion earlier this year, when Biogen wound down all work on the approved med. Not only was it made obsolete by Leqembi, but the therapy was a corporate representation of time wasted. Meanwhile, Eli Lilly pressed on from behind, raising up donanemab, which is expected to get an FDA ruling any day now.  The amyloid beta battle may not ultimately be an automatic reflection of tomorrow’s tau contest, or other options that may be discovered. Deeper into Biogen’s research work, the company is tinkering with novel anti-inflammatory targets, Keeney says. Targeting rogue tau buildup has proven difficult, just like amyloid. Lilly cut a phase 2 large-molecule zagotenemab in October 2021 after it failed to hit phase 2 endpoints. This followed phase 1 data showing four cases of brain bleeding (ARIA-H) across three patients, representing 19% of treated patients. Kenney says it remains to be seen whether that’s a genuine signal tied to tau-busting treatments—but it's certainly been an issue with Leqembi and donanemab.  “I think it's probably too early to say there's a signal or not in that,” he said. “We have no signal that is preventing us to move forward.”  Beyond drug development, critical advancements are happening in the Alzheimer’s diagnostic sector, with companies working to improve the tests that could detect amyloid buildup. There’s been such improvement in this area that a working group convened by the Alzheimer’s Association and the National Institute on Aging recently revised its criteria for diagnosing Alzheimer’s to include blood-based biomarkers. Keeney says those tests may not immediately be a primary diagnosis, but a negative result could preclude someone from an additional PET scan.  “So we're also investing and working with collaborators because there are blood-brain barrier biomarkers that are out there,” Keeney said, noting they aren’t yet 100% predictive. “We're helping also get the predictive validity improved.”  Despite the blood-based tests needing refinement, authors of the new testing criteria made clear that the future is now, and some tests provide “excellent diagnostic performance.” “The field is now in a transition phase during which plasma biomarkers are being integrated with traditional CSF and PET biomarkers,” the guidance states.