PMID- 38386949 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240505 IS - 1526-632X (Electronic) IS - 0028-3878 (Print) IS - 0028-3878 (Linking) VI - 102 IP - 5 DP - 2024 Mar 12 TI - Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease. PG - e208061 LID - 10.1212/WNL.0000000000208061 [doi] LID - e208061 AB - BACKGROUND AND OBJECTIVES: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD). METHODS: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology. RESULTS: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs. DISCUSSION: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03518073. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression. FAU - Fleisher, Adam S AU - Fleisher AS AUID- ORCID: 0000-0002-2556-0878 AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Munsie, Leanne M AU - Munsie LM AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Perahia, David G S AU - Perahia DGS AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Andersen, Scott W AU - Andersen SW AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Higgins, Ixavier A AU - Higgins IA AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Hauck, Paula M AU - Hauck PM AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Lo, Albert C AU - Lo AC AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Sims, John R AU - Sims JR AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Brys, Miroslaw AU - Brys M AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. FAU - Mintun, Mark AU - Mintun M AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. CN - PERISCOPE-ALZ Site Investigators AD - From Eli Lilly and Company, Indianapolis, IN. Dr. A.C. Lo is currently at Kisbee Therapeutics, Cambridge, MA. LA - eng SI - ClinicalTrials.gov/NCT03518073 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial DEP - 20240222 PL - United States TA - Neurology JT - Neurology JID - 0401060 RN - 0 (Antibodies, Monoclonal) SB - IM MH - Aged MH - Aged, 80 and over MH - Female MH - Humans MH - Middle Aged MH - *Alzheimer Disease/diagnostic imaging/drug therapy/psychology MH - Antibodies, Monoclonal/therapeutic use MH - Bayes Theorem MH - Disease Progression MH - Double-Blind Method MH - Treatment Outcome MH - Male PMC - PMC11067698 COIS- A.S. Fleisher is a full-time employee and minor stockholder of Eli Lilly and Company. L.M. Munsie is a full-time employee and minor stockholder of Eli Lilly and Company. D.G.S. Perahia is a full-time employee and minor stockholder of Eli Lilly and Company. S.W. Andersen is a full-time employee and minor stockholder of Eli Lilly and Company. I.A. Higgins is a full-time employee and minor stockholder of Eli Lilly and Company. P.M. Hauck is a full-time employee and minor stockholder of Eli Lilly and Company. A.C. Lo is a former full-time employee and minor stockholder of Eli Lilly and Company. J.R. Sims is a full-time employee and minor stockholder of Eli Lilly and Company. M. Brys is a full-time employee and minor stockholder of Eli Lilly and Company. M. Mintun is a full-time employee and minor stockholder of Eli Lilly and Company. Go to Neurology.org/N for full disclosures. EDAT- 2024/02/22 18:42 MHDA- 2024/02/26 06:44 PMCR- 2024/02/22 CRDT- 2024/02/22 16:03 PHST- 2024/02/26 06:44 [medline] PHST- 2024/02/22 18:42 [pubmed] PHST- 2024/02/22 16:03 [entrez] PHST- 2024/02/22 00:00 [pmc-release] AID - WNL-2023-001719 [pii] AID - 10.1212/WNL.0000000000208061 [doi] PST - ppublish SO - Neurology. 2024 Mar 12;102(5):e208061. doi: 10.1212/WNL.0000000000208061. Epub 2024 Feb 22.