Vaccinex(US:VCNX)2025-04-15 21:12Drug Development and Clinical Trials - The company is focused on developing pepinemab, a humanized monoclonal antibody targeting SEMA4D, for Alzheimer's disease (AD) and other cancers, with over 650 patients treated in Phase 1 and 2 clinical trials as of December 31, 2024[24]. - The SIGNAL-AD study for pepinemab in AD reached its enrollment target in April 2023, with all 50 participants completing 12 months of treatment by June 30, 2024[28]. - The SIGNAL-AD Phase 1b/2 study for Alzheimer's disease reached its enrollment target in April 2023, with topline data reported on July 31, 2024[54]. - The SIGNAL Phase 2 clinical trial enrolled 265 subjects, with 179 in early manifest disease and 86 in late prodromal stages, randomized to receive either pepinemab or placebo for 18 months[99]. - The study did not meet pre-specified co-primary endpoints, but significant treatment effects were observed in cognitive assessments, particularly in patients with more advanced disease[100]. - The Phase 1 clinical trial of pepinemab in MS patients demonstrated no dose-limiting toxicity across doses ranging from 1 to 20 mg/kg, with an estimated half-life of approximately 20 days[72]. - Pepinemab was well-tolerated in a Phase 1/2 trial for children with recurrent solid tumors, although the frequency and duration of objective responses did not support further development as a single agent[49]. - The company has paused its cancer research efforts but previously studied pepinemab in advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC)[29]. - Clinical trials related to cancer have been paused, following the completion of a Phase 1 trial and the initiation of the CLASSICAL–Lung trial[118]. Mechanism of Action and Therapeutic Potential - Pepinemab demonstrated a 21.1% objective response rate (ORR) and a median progression-free survival (PFS) of 5.79 months in patients with low PD-L1 tumors, nearly double the historical response rates for immune checkpoint inhibitor monotherapy[33]. - Pepinemab's mechanisms of action include blocking SEMA4D signaling, which promotes immune cell infiltration and reduces immune suppression in tumors[26]. - Pepinemab is designed to block SEMA4D signaling, which regulates immune cell migration and activation, potentially enhancing immune responses in cancer and neurodegenerative diseases[41]. - The mechanism of action of pepinemab includes inhibiting the activation of inflammatory cells and promoting the repair of damaged tissues[53]. - SEMA4D is implicated in neuroinflammatory and neurodegenerative diseases, affecting the activation of microglia and astrocytes, which are critical in Alzheimer's disease pathology[55]. - SEMA4D impacts the pathology of Alzheimer's Disease through multiple mechanisms, making it a promising target for therapeutic development[78]. - Pepinemab treatment in preclinical studies showed substantial reductions in neuroinflammatory processes in a mouse model of multiple sclerosis[86]. - Pepinemab treatment in YAC128 mice resulted in a significant reduction in cortical and white matter volume loss, indicating potential neuroprotective effects[90]. - Behavioral assessments showed that pepinemab-treated YAC128 mice exhibited no significant difference in anxiety-like behavior compared to wild type control mice, suggesting a reduction in anxiety[91]. - In cognitive tests, pepinemab improved spatial memory in YAC128 mice, restoring memory performance to levels comparable to wild type controls[92]. Funding and Financial Support - The company received a funding grant of $750,000 from the Alzheimer's Association and up to $3 million from the Alzheimer's Drug Discovery Foundation to support the SIGNAL-AD study, with two-thirds of the funding received in 2020 and the remainder in Q3 2023[27]. Partnerships and Collaborations - The company has entered into antibody discovery agreements with third parties for the use of the ActivMAb platform, enhancing its partnership opportunities[23]. - The collaboration with Merck Sharp & Dohme for the KEYNOTE-B84 trial involves testing pepinemab in combination with pembrolizumab for R/M HNSCC patients[45]. - The company has entered into multiple investigator-sponsored trial agreements to further evaluate pepinemab in various cancer indications[50]. - The company has entered into collaborations for using ActivMAb to express complex antigens for antibody discovery under fee-for-service arrangements[187]. Intellectual Property and Competitive Advantage - The company believes it is the only entity targeting SEMA4D for potential treatments of neurodegenerative diseases, cancer, or autoimmune disorders, providing a competitive advantage[196]. - The intellectual property portfolio includes several issued U.S. and foreign patents for the SEMA4D antibody platform and pepinemab, with expiration dates projected between 2030 and 2038[204]. - The company wholly owns ten additional pepinemab-related patent families, with various projected expiration dates, including methods for treating cancer and neuroinflammatory disorders[205]. - The ActivMAb platform is protected by two patent families and a provisional patent application, along with granted U.S. and foreign patents licensed from the University of Rochester[212]. - The University of Rochester granted an exclusive, worldwide, sublicensable license to commercialize patents related to the ActivMAb antibody discovery platform, with low single-digit royalties on sales and milestone payments upon specific regulatory submissions[213]. Safety and Efficacy Observations - The company has observed no concerning safety signals with the combination of pepinemab and avelumab, with only one grade 3 pulmonary embolism reported[171]. - Pepinemab has shown potential as a single-agent therapy, with higher levels of circulating B and T cells correlating with longer progression-free survival in patients with solid tumors[133]. - Approximately 59% of subjects in the CLASSICAL-Lung trial experienced a halt or reversal of tumor progression after treatment with pepinemab plus avelumab[168]. - Among 21 evaluable immunotherapy naïve patients, the disease control rate (PR plus SD) was approximately 81%[169]. - The combination of pepinemab and KEYTRUDA™ resulted in an objective response rate (ORR) of 21.1% and a median progression-free survival (PFS) of 5.79 months in patients with PD-L1-low tumors[172]. Market Context and Disease Statistics - An estimated 6.9 million Americans aged 65 and older are living with Alzheimer's in 2024, projected to grow to 12.7 million by 2050 without medical breakthroughs[76]. - There are over 30,000 clinically diagnosed Huntington's Disease patients in the U.S., with an additional 250,000 at risk of inheriting the mutated allele[81]. - The American Cancer Society estimates that in 2024, approximately 2 million Americans will be diagnosed with cancer, with 611,720 expected to die from the disease[146]. Preclinical and Research Insights - Anti-SEMA4D treatment shifts the balance of cytokines and chemokines in the tumor microenvironment, enhancing secretion of tumoricidal cytokines (IFN γ, TNF α) while reducing immunosuppressive chemokines[136]. - In preclinical models, SEMA4D produced in tumors obstructs the activation of tumor-inhibiting immune cells, suggesting that targeting SEMA4D could enhance immune responses in various cancers[154]. - Pepinemab has demonstrated single-agent efficacy in PLXNB1 and ErbB-2 double positive tumors, indicating its potential as a therapeutic strategy for HER2+ cancers[156]. - The combination treatment with anti-CTLA-4 and anti-SEMA4D in colorectal tumor models demonstrated an average tumor regression of approximately 80%, with some cases achieving 100% regression[136].