The week after seeing its partner Roche cut and run, UCB has reported the failure of its anti-tau antibody bepranemab to improve cognition and function in people with early Alzheimer’s disease. But UCB looked past the primary endpoint miss and focused on other results that left it “deeply encouraged” by the trial.
Roche licensed bepranemab for $120 million upfront in 2020 but opted against taking over development when UCB finished a proof-of-concept study in Alzheimer’s. UCB presented data from the phase 2a trial at the 2024 Clinical Trials on Alzheimer’s Disease meeting in Madrid this week, providing a snapshot of what Roche left behind—and why the Belgian drugmaker believes bepranemab may have a future.
Investigators randomized 466 patients to receive one of two doses of bepranemab or placebo. After 80 weeks, patients on the study drug did no better on the CDR-SB measure of cognition and function than their counterparts on placebo, causing the trial to miss its primary endpoint.
Yet, Alistair Henry, Ph.D., chief scientific officer at UCB, said in a statement that the team “is deeply encouraged by the proof-of-concept data for bepranemab,” adding that the findings strengthen his “belief in the value of targeting the mid-region of tau as an important strategy in altering the trajectory of the disease.” The targeting of the mid-region of tau sets bepranemab apart from failed antibodies that hit the N-terminus.
Henry’s positive take on the data is underpinned by secondary endpoints and subgroup analyses. UCB linked bepranemab to a placebo-adjusted 33% to 58% slowdown in the accumulation of tau in key brain regions, suggesting the molecule is acting on its target. The biotech also reported a 21% to 25% slowing of cognitive decline, as measured on ADAS-Cog14, compared to placebo.
William Blair analysts raised doubts about the ADAS-Cog14 data in a note to investors. While accepting the results “appear to show a nominally statistically significant” outcome, the analysts noted the “data is variable and used a high type-1 error rate assumption.” Those factors led the analysts to “caution the interpretability, especially when other efficacy metrics appear to show no benefit in our view.”
The analysts were similarly cautious about UCB’s analyses of predefined subgroup patients who had low tau burden at baseline or lacked the APOE4 gene linked to increased Alzheimer’s risk. About half of the participants fell into one of the two subgroups.
In those patients, UCB linked the high dose of bepranemab to a 29% slowdown on CDR-SB and a 41% to 54% slowdown on ADAS-Cog14. The investigators presenting the data argued the results show enhanced responses in the subgroup, the analysts said. That argument was met with skepticism.
“We caution on this conclusion given that 17% of the enrolled cohort had low tau at baseline, and it is difficult to assess if this finding is truly from these patients responding better to bepranemab, when the overall effects on tau burden are variable, in our view, or if this is an artifact of low-tau patients just being earlier in disease progression,” the analysts said.
UCB is now evaluating the next steps for the program, which is part of a broader, industrywide attempt to target tau. The analysts see “minimal read-through” from the bepranemab data to Biogen and Ionis’ BIIB080, an antisense oligonucleotide that targets tau expression. A phase 2 trial of BIIB080 could report data in 2026.