Tau Agent Semorinemab Shows Significant Effect in Alzheimer Disease

Rachelle S. Doody, MD, PhD

The phase 2 LAURIET study (NCT03828747) of semorinemab, an investigational antitau antibody, has met 1 of its coprimary end points, change from baseline at week 49 in cognition on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11-Item Version (ADAS-Cog11), AC Immune and Genentech have announced. This marks the first positive result for a tau-targeting agent in a trial of Alzheimer disease (AD).¹

Semorinemab showed a statistically significant change in cognitive decline in people with mild-to-moderate AD (Mini-Mental State Examination (MMSE) scores of 16-21), based on ADAS-Cog11 scores, equaling a 43.6% reduction compared with placebo (P <.0025). Additionally, safety data suggested that treatment with semorinemab was well-tolerated without unexpected safety signals.

Although, the second coprimary end point, the change from baseline in activities of daily living as measured by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, was not achieved, nor were there significant changes on secondary efficacy end points of the MMSE and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. In total, LAURIET included 272 adult participants with mild-to-moderate AD across 43 study centers globally. Genentech noted that the open-label portion of the study will continue as planned, and that additional analyses of LAURIET are ongoing, with topline data expected to be presented at the upcoming Clinical Trials on Alzheimer's Disease (CTAD) conference in November 2021.

“The topline LAURIET results in people living with mild-to-moderate Alzheimer disease are another important step in our understanding of the role of tau and the potential for semorinemab to make a difference in the progress of this complex and difficult-to-treat disease,” Rachelle S. Doody, MD, PhD, global head, Neurodegeneration, Roche/Genentech, said in a statement obtained by NeurologyLive. “Although we are encouraged by the positive outcome for 1 coprimary end point measuring cognitive performance, we will continue our analyses of these data and continue the open-label portion of the study to better understand why semorinemab didn’t show an effect on the coprimary end point measuring functional decline in activities of daily living, or on the secondary end points.”

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“We are grateful to all of the patients, families, caregivers, and clinicians involved in the LAURIET study, and we remain committed to following the science and exploring multiple approaches and molecules that are designed to address key pathways of Alzheimer disease, including tau and ß-amyloid, as well as comprehensive approaches to AD care,” Doody added.

Semorinemab has been studied in another phase 2 study, TAURIEL (NCT03289143), in early (defined as prodromal-to-mild) AD, where the primary efficacy end point of the change from baseline to week 73 on the CDR-SB was not met. In conversations around biomarker data that Roche/Genentech presented at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30, Doody told NeurologyLive that the company was hoping to leverage those clinical trial data “to try and advance the field,” with these data specifically assessing the differences between cerebrospinal fluid (CSF) measures of tau and Aß, and PET measure.

“We did some correlations between GTP1 PET reflections of tau and CSF—and to some extent, plasma biomarkers of tau—in a small number of patients who participated in the semorinemab trial. What we found is that GTP1 does correlate with most of the tau biomarkers, even plasma, but the correlations are best with P-tau217,” Doody explained. “This is convergent with other data from other populations and other researchers, but it's important to get replicable results and perspectives. We found that there's really a very good, high level of correlation and sensitivity and specificity of P-tau217 for predicting elevated tau in the brain, in the 0.8+ range. This is important information because someday we would like to be using one or the other biomarker, and we might even get lucky and be able to use plasma biomarkers as those assays improve, and we and others are working on that.”

The TAURIEL study was a 73-week, double-blind, placebo-controlled trial that followed 457 participants across 97 study centers. Overall, the incidence of adverse events was similar between semorinemab and placebo arms. In addition to the failure to meet the primary end point, neither of the secondary end points—ADAS-Cog13 and ADCS-ADL—were met.²

“The topline results of the LAURIET phase 2 clinical trial of semorinemab are remarkable in that it is the first time we have seen a therapeutic effect by a monoclonal anti-Tau antibody therapy. We also are excited by the fact that this is the first time a monoclonal antibody has had a therapeutic impact on cognition in the mild-to-moderate AD patient population,” Andrea Pfeifer, PhD, CEO, AC Immune, said in a statement.¹ “Nevertheless, despite these interesting results, we are still cautious about what this may mean for patients as there was not an impact on the rate of functional decline or other efficacy end points. With that said, AD is a slow-moving chronic disease, and this small trial was relatively short, 49 weeks; so, the data from the open-label extension may be important in elucidating the potential of semorinemab in this patient population.”

Semorinemab targets the N-terminal portion of the tau protein, designed to bind to tau and slow its neuronal spread. This mechanism was designed based on the hypothesis that abnormal tau protein spreads between neurons and leads to clinical AD progression. The investigational antibody is being developed by Genentech after being identified in collaboration with AC Immune.

“Scientifically, these data are encouraging for the therapeutic strategies targeting Tau. We look forward to additional data from our other clinical-stage Tau programs: Tau vaccine ACI-35, partnered with Janssen; and the small molecule Morphomer® Tau aggregation inhibitor, partnered with Eli Lilly,” Pfeifer added to the statement.¹

In addition to her perspective on the biomarker insights from the TAURIEL study, Doody also shared her thoughts on another of the company’s ongoing developments: the NeuroToolKit. The toolkits assays contain several biomarkers, including amyloid-ß 1-42, amyloid-ß 1-40, α-synuclein, glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), neurogranin, neurofilament light chain, phosphotau, S100B, sTREM2, total tau, and YKL-40. In its analyses of the kit across 6 clinical trials, Roche/Genentech noted that all of these biomarkers, aside from IL-6, positively correlated with each other. The highest correlations were observed between total tau, phospho­­­tau, and neurogranin (Spearman’s rho >0.9). Additionally, NfL, GFAP, YKL-40, and sTREM2 biomarkers positively correlated with patient age.³

Check out the video below to hear more from Doody on the NeuroToolKit’s potential in AD and the company’s plans to continue to develop it for further use.

REFERENCES
1. AC Immune Announces First Positive Cognitive Results for a Tau-Targeting Monoclonal Antibody in Alzheimer’s Disease. News release. AC Immune. August 31, 2021. Accessed August 31, 2021. https://ir.acimmune.com/news-releases/news-release-details/ac-immune-announces-first-positive-cognitive-results-tau
2. AC Immune Reports Top Line Results from TAURIEL Phase 2 Trial Evaluating Semorinemab in Early Alzheimer’s Disease. News release. AC Immune. September 23, 2020. Accessed August 31, 2021. https://ir.acimmune.com/news-releases/news-release-details/ac-immune-reports-top-line-results-tauriel-phase-2-trial
3. Rabe C, Thorne N, Voyle N, et al. Evaluation of the Elecsys Neurotoolkit Panel in Early Alzheimer’s Disease Populations Across Six Clinical Trials. Presented at: AAIC; July 26-30, 2021; Virtual. Abstract 52033.