Synonyms: VX15, VX15/2503
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2), Huntington's Disease (Phase 2)
Company: Vaccinex, Inc.
Pepinemab is a humanized IgG4 monoclonal antibody to semaphorin 4D, a multifunctional membrane glycoprotein expressed by oligodendrocytes and astrocytes in the central nervous system. In response to stress or injury, neurons release soluble Sema4D, which binds to receptors on glia and activates inflammatory cytokine release. Sema4D inhibits axon extension and oligodendrocyte migration, and disrupts the blood-brain barrier (Smith et al., 2015). Pepinemab neutralizes Sema4D to prevent these actions (Fisher et al., 2016).
Semaphorins, a large family of signaling proteins, were first described in the nervous system. Sema4D, aka CD100, is expressed on macrophages and involved in monocyte migration, T cell activation, atherosclerosis, and other conditions (e.g. Hall et al., 1996; Elhabazi et al., 2003, Luque et al., 2018).
In preclinical work, pepinemab slowed brain atrophy and improved some behaviors in the YAC128 mouse model of Huntington’s disease (Southwell et al., 2015). According to data presented at the 2020 AAT-AD/PD conference, Sema4D expression rose as disease progressed in a second mouse model of HD, Q175 (Apr 2020 conference news).
At the same conference, the company reported that Sema4D was elevated in human postmortem HD brain, correlating with disease stage and neuronal death in several cortical regions. Where Sema4D expression was high, astrocytes pulled back their processes. On their web site, the company asserts that Sema4D has also been found to be upregulated in cortical neurons in people with AD [see pipeline].
In July 2015, the Phase 1/2 SIGNAL-HD trial began to test pepinemab in people with the CAG expansion that causes Huntington’s disease. The two-part study enrolled 301 patients. In part A, 36 people in the late prodromal or early manifest stage of disease received monthly infusions of 20 mg/kg pepinemab or placebo for six months. After that, all received drug for an additional six months. In part B, 265 participants were to be treated for 18 months with 20 mg/kg drug or placebo; the period was later extended to 36 months for some patients. The primary outcome of the trial is safety and tolerability. Secondary measures include MRI brain volumes, FDG-PET, and TSPO-PET, as well as immunogenicity of the antibody. Other secondary and exploratory endpoints comprise clinical measures of cognition, motor function, and behavior, as well as pharmacokinetic and pharmacodynamic assessments.
According to data presented at AD/PD 2020, pepinemab met its primary endpoint in part A. In a preliminary analysis of 11 people on drug and eight on placebo, the FDG-PET signal dropped over six months in untreated controls but rose in the treatment group. The increases occurred in every brain region and were largest in the frontal and parietal cortex. When the placebo group crossed over to drug treatment, their FDG signals rose (Apr 2020 conference news). As of the conference, part B was fully enrolled, with 179 people with early manifest HD and 86 with prodromal disease.
On September 22 2020, Vaccinex announced top-line efficacy results of 18 months treatment of the early manifest group (press release). The two endpoints, based on results of exploratory outcomes in group A, were a combination of two tests from the Huntington Disease Cognitive Assessment Battery, as well as the Clinical Global Impression of Change (CGIC). Neither endpoint was significantly changed by treatment, though the company reports trends toward cognitive improvement and clinical stabilization.
The FDA granted pepinemab both Orphan Drug and Fast Track designation for Huntington’s disease.
In May 2018, Vaccinex registered a Phase 1/2 trial in early AD. The plan was to enroll 60 people with PET or CSF evidence of amyloid positivity, and a CDR of 0.5 or 1 and randomize them to monthly infusions of 20 or 40 mg/kg pepinemab or placebo, up to a total of nine doses. The primary aim of the study is safety and tolerability. Secondary outcomes include changes in FDG-PET, standard measures of cognition, and immunogenicity of the drug. Exploratory measures are serum and CSF biomarkers of inflammation, amyloid and neurodegeneration, as well as MRI measures of brain volume. With support from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation, this trial started in September 2020, at 14 sites across the U.S.; it will run through 2021.
In other trials, single doses from 1 to 20 mg/kg were well tolerated in a Phase 1 study in people with multiple sclerosis (LaGanke et al., 2017). The antibody is also in trials for non-small-cell lung and other cancers, where Sema4D expression on tumors and immune cells modulates tumor growth and anti-tumor immune responses.
For details on pepinemab trials, see clinicaltrials.gov.
Last Updated: 22 Dec 2020
- LaGanke C, Samkoff L, Edwards K, Jung Henson L, Repovic P, Lynch S, Stone L, Mattson D, Galluzzi A, Fisher TL, Reilly C, Winter LA, Leonard JE, Zauderer M. Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial. Neurol Neuroimmunol Neuroinflamm. 2017 Jul;4(4):e367. Epub 2017 Jun 16 PubMed.
- Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, Klimatcheva E, Mallow C, Cornelius C, Leonard JE, Marchi N, Janigro D, Argaw AT, Pham T, Seils J, Bussler H, Torno S, Kirk R, Howell A, Evans EE, Paris M, Bowers WJ, John G, Zauderer M. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015 Jan;73:254-68. Epub 2014 Oct 18 PubMed.
- Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, Balch L, Bussler H, Torno S, Seils J, Mueller L, Huang H, Klimatcheva E, Howell A, Kirk R, Evans E, Paris M, Leonard JE, Smith ES, Zauderer M. Generation and preclinical characterization of an antibody specific for SEMA4D. MAbs. 2016;8(1):150-62. Epub 2015 Oct 2 PubMed.
- Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM, Freeman GJ. Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11780-5. PubMed.
- Elhabazi A, Marie-Cardine A, Chabbert-de Ponnat I, Bensussan A, Boumsell L. Structure and function of the immune semaphorin CD100/SEMA4D. Crit Rev Immunol. 2003;23(1-2):65-81. PubMed.
- Luque MC, Galuppo MK, Capelli-Peixoto J, Stolf BS. CD100 Effects in Macrophages and Its Roles in Atherosclerosis. Front Cardiovasc Med. 2018;5:136. Epub 2018 Sep 28 PubMed.
- Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015 Apr;76:46-56. Epub 2015 Feb 3 PubMed.
- Fisher TL, Seils J, Reilly C, Litwin V, Green L, Salkowitz-Bokal J, Walsh R, Harville S, Leonard JE, Smith E, Zauderer M. Saturation monitoring of VX15/2503, a novel semaphorin 4D-specific antibody, in clinical trials. Cytometry B Clin Cytom. 2016 Mar;90(2):199-208. Epub 2015 Dec 24 PubMed.
- Patnaik A, Weiss GJ, Leonard JE, Rasco DW, Sachdev JC, Fisher TL, Winter LA, Reilly C, Parker RB, Mutz D, Blaydorn L, Tolcher AW, Zauderer M, Ramanathan RK. Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors. Clin Cancer Res. 2016 Feb 15;22(4):827-36. Epub 2015 Oct 7 PubMed.
- Leonard JE, Fisher TL, Winter LA, Cornelius CA, Reilly C, Smith ES, Zauderer M. Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody. Mol Cancer Ther. 2015 Apr;14(4):964-72. Epub 2015 Feb 5 PubMed.