Trial reportNature medicine2022
Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.
Trial report in Nature medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT02481674 (A Phase 2, Multi-center, Randomized, Double-blind, Placebo Controlled Study in Subjects With Late Prodromal and Early Manifest Huntington's Disease to Assess the Safety, Tolerability, pk, and Efficacy of Pepinemab), which is not on this map. Cited by 36 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 2, Multi-center, Randomized, Double-blind, Placebo Controlled Study in Subjects With Late Prodromal and Early Manifest Huntington's Disease to Assess the Safety, Tolerability, pk, and Efficacy of Pepinemab
Who cites it
36 citing papers in PubMed, 2 syntheses or guidelines pooled it, 58 citations in OpenAlex.
- Systematic Review of the Huntington's Disease Drug Development Pipeline, 2014 to 2025.Movement disorders : official journal of the Movement Disorder Society · 2026Pooled it
- A genome-wide association meta-analysis of all-cause and vascular dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Pooled it
- Phase II trial of intravenous human dental pulp stem cell therapy for Huntington's disease: a randomized, double-blind, placebo-controlled study.Stem cell research & therapy · 2025Trial
- Review
- Oligodendroglial Mutant Huntingtin Contributes to Neuroinflammation in Huntington's Disease Mice.Neuroscience bulletin · 2026Article
- An Open-Label Phase 1b Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ANX005 in Patients with Huntington's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Single-cell fixed RNA profiling uncovers SEMA4D and LMCD1 as therapeutic targets in a liver fibrosis model.JHEP reports : innovation in hepatology · 2026Article
- Alzheimer's disease: from molecular pathways to therapies.Molecular biomedicine · 2026Review
- Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review).Oncology letters · 2025Review
- Natural products proposed for the management of Huntington's disease (HD): a comprehensive review.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction.bioRxiv : the preprint server for biology · 2025Article
- Neuroinflammation in Huntington's disease: Causes, consequences, and treatment strategies.Journal of Huntington's disease · 2025Review
- Restoring brain barriers: an innovative approach for treating neurological disorders.Fluids and barriers of the CNS · 2025Review
- Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.Acta pharmacologica Sinica · 2025Review
- Research Advances in the Immunomodulatory Functions of CD100/SEMA4D and Their Roles in Viral Infectious Diseases.International journal of molecular sciences · 2025Review
- Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.Biochemistry · 2025Review
- Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes.Nature communications · 2025Article
- The Role of Genetic, Environmental, and Dietary Factors in Alzheimer's Disease: A Narrative Review.International journal of molecular sciences · 2025Review
- Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 20 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.