First Cognitive Signal that Tau Immunotherapy Works?

In a first for the field, there is now a hint that a tau immunotherapy may have slightly benefited people with Alzheimer’s disease. Semorinemab, a monoclonal antibody specific for tau’s N-terminus, stemmed cognitive decline by almost half among people with mild to moderate AD, according to topline results from the Phase 2 LAURIET trial. Co-sponsors Genentech of South San Francisco and AC Immune of Lausanne, Switzerland, announced on August 31 that the treatment slowed slippage on the ADAS-Cog11, but missed the mark on its other co-primary endpoint, functional decline.

The findings are a welcome reprieve after most tau immunotherapies thus far, including semorinemab itself, have come up short in trials. In a previous Phase 2 study, called TAURIEL, semorinemab brought no cognitive or functional benefit to people with prodromal AD or mild cognitive impairment (Mar 2021 news). Despite this negative result among people in earlier stages of the disease, the companies moved forward with LAURIET, which enrolled participants in the mild to moderate stages of AD.

LAURIET enrolled 272 participants whose MMSE scores were between 16 and 21 and who had brain amyloid at baseline. After receiving three doses spaced two weeks apart, participants received monthly intravenous infusions of semorinemab, or placebo, for the remainder of the trial. The study enrolled two cohorts, which received treatment for either 48 or 60 weeks. A third cohort, shich was to be treated for 72 weeks, was never enrolled. For both enrolled cohorts, between baseline and 49 weeks, those in the semorinemab groups declined 43.6 percent less on the ADAS-Cog11 than did those in the placebo groups, satisfying one primary outcome. AC Immune CEO Andrea Pfeifer told Alzforum that a difference between treatment and placebo groups became apparent by six months, and grew at nine and 12 months, when it was statistically significant. 

The same was not true for the other primary endpoint, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living. Both groups declined similarly on the ADCS-ADL, in which an appointed caregiver scores the participant on how they perform a variety of tasks. Pfeifer thinks the trial may have been too short to detect improvement in daily activities. There was also no difference between treatment and placebo groups on the CDR-SB or MMSE, which served as secondary endpoints.

An open-label extension is ongoing, and Pfeifer said most participants from the trial's placebo-controlled portion are enrolled. Particularly for participants who were well into the moderate stage of AD by the end of the placebo-controlled portion of the trial, any hint of a benefit in the OLE would be extraordinary, Pfeifer said. So far, no clinical trial for a disease-modifying treatment has proven efficacious in people with AD at this stage or beyond.

The topline results reported include no mention of tau PET, which was included in the trial. In TAURIEL, semorinemab did not slow tangle accumulation. Pfeifer noted that the antibody targets soluble, oligomeric forms of tau that spread from cell to cell, and therefore may not have an impact on existing tangles. “Tau PET may not be the right tool to detect the efficacy of our antibody,” she said. Pfeifer said that fluid biomarkers, including species of phospho-tau, are being measured in the study, and she expects them to more closely track with treatment. The current announcement included no biomarker results.

Why a possible efficacy signal in LAURIET, but not a peep in TAURIEL? Pfeifer thinks the difference could come down to which species of tau predominate in different stages of the disease. Perhaps specific hyperphosphorylated forms drive the earlier stages of disease, and semorinemab might not bind them. Some have interpreted the string of failures in N-terminally-trained tau antibodies as a call to target tau’s mid-region instead (Mar 2021 news). It houses the microtubule-binding domains that trigger aggregation. However, Pfeifer said that LAURIET’s hint at efficacy suggests that at least at this stage in the disease, N-terminal tau is a good species to target. She also noted that N-terminal forms of tau serve as fluid biomarkers for AD, suggesting they play an important role in the disease process.

To target these earlier versions of tau, AC Immune, with Janssen, is developing the anti-tau vaccine ACI-35. It evokes antibodies selective for phospho-tau over total tau (Apr 2020 conference news).

Complete results of the LAURIET study, as well as partial results from ongoing Phase 1b/2a trials of ACI-35, will be presented at the CTAD conference in November, Pfeifer said.

Plans for any Phase 3 trial of semorinemab, which would be sponsored by Genentech/Roche, have yet to be determined, Pfeifer said, and could be contingent on promising results from the ongoing OLE.—Jessica Shugart

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References

Therapeutics Citations

  1. Semorinemab
  2. ACI-35

News Citations

  1. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore
  2. Active Tau Vaccine: Hints of Slowing Neurodegeneration

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