お知らせ • Sep 27
Vaccinex Reports Groundbreaking Findings At Medical Conferences Supporting Development of Pepinemab for the Treatment of Neurodegenerative Diseases and Cancer
Vaccinex, Inc. will report on novel findings for its lead product, pepinemab, with implications for treatment of Alzheimer's and other slowly progressive neurodegenerative diseases and for cancer immunotherapy at two upcoming Medical Conferences. Results from phase 2 SIGNAL trial suggest pepinemab is the first therapeutic agent that appears to have the potential to prevent decline in brain metabolic activity and to slow or halt cognitive decline in Huntington’s disease (HD) [1], a slowly progressive, orphan neurodegenerative disease with many pathological similarities to the much more prevalent Alzheimer’s disease (AD). Encouraged by these findings, a separate, randomized, phase 1/2a study in AD is ongoing in which the last patient is anticipated to complete the planned 12-months of treatment in early June 2024. Pepinemab in combination with a checkpoint inhibitor is, to knowledge, the firsttreatment that has shown the potential to induce formation of lymphoid structures in tumors that promote efficient immune responses and are known to be associated with improved outcomes in head and neck cancer. Clinical results indicate an approximate doubling of objective responses (ORR) and progression free survival (PFS) relative to historical results with checkpoint monotherapy in patients with hard-to-treat tumors that express low levels of PD-L1 (CPS<20). Vaccinex completed enrollment in the randomized, double-blind SIGNAL-AD phase 1/2a study for early AD in May 2023. The last patient is anticipated to complete the planned 12 months of treatment by early June 2024 at which time the database will be locked and results analyzed. Key endpoints include brain metabolic activity along with measures of cognition specific to AD (CDR-SB, ADAS-Cog13) that have been recognized as clinically meaningful by the U.S. Food and Drug Administration (FDA). Investors will be aware of recent excitement surrounding full FDA approval of Eisai and Biogen’s drug Leqembi (lecanemab), the first anti-Aß amyloid antibody for treatment of AD. A second such drug from Eli Lilly, donanemab, has reported equivalent data and may be FDA approved before year end. Clinical consensus is that Leqembi and donanemab provide a modest but real benefit to patients at a very early stage of disease. Common side effects associated with these drugs, however, include an inflammatory and hemorrhagic response in brain denoted as ARIA. Although ARIA often resolves itself, it has proven to be life-threatening in a small percentage of patients. As a result, all patients treated with these drugs must be followed carefully with significant effort and expense to avoid complications. It is important to appreciate that pepinemab has a very different mechanism of action than Leqembi or donanemab and, in clinical studies conducted to date, has not been found to be associated with inflammatory responses in the brain. Believe that use of pepinemab to treat slowly progressive neurodegenerative diseases like AD has been substantially de-risked by results from completed phase 2 study in HD. Have had the opportunity to meet with several major pharmaceutical companies. Believe from their responses that they have prioritized improving treatments for AD. Believe that the prevalence of AD (6 million people diagnosed with AD in the US alone) and current concerns about the limitations of anti-Aß amyloid antibodies would make pepinemab attractive as a potential alternative to anti-Aß antibodies or possibly for use in combination with an anti-Aß for greater efficacy. The potential impact of the AD program on Vaccinex valuation and financial resources, therefore, make this Vaccinex’s most important near term catalyst. Highest priority in the coming months will be to complete the SIGNAL-AD trial, which believe may make substantial resources available for initiatives in cancer and other neurodegenerative diseases such as HD. The Phase 2 KEYNOTE-B84 study (NCT04815720) evaluated Vaccinex’s pepinemab antibody in combination with Merck’s anti-PD-1 therapy, KEYTRUDA® for immunotherapy of recurrent or metastatic head and neck squamous cell carcinoma. Results of a preplanned interim analysis of the first 36 patients treated in this study indicated that the Objective Response (ORR) for the PD-L1 low population, CPS <20 (N=19), was 21.1% (2 CR and 2 PR) and median progression free survival (PFS) was 5.79 months, which are approximately twice that of historical ORR and PFS for checkpoint monotherapy in this population [2]. In contrast, in the CPS =20 (N=17) subgroup, the ORR and PFS for combination therapy was similar to historical checkpoint monotherapy. The improvement in response to treatment is important for the 55% of HNSCC patients whose tumors are characterized as CPS <20. These data are also consistent with a prior study in which observed that the combination of pepinemab with PD-L1 inhibitor BAVENCIO® (avelumab) appeared to approximately double ORR in patients with PD-L1-low non-small cell lung cancer (NCT03268057). In view of these clinical findings, investigated the changes in the tumor immune environment that might correlate with response to pepinemab treatment by analyzing pre-treatment and on-treatment tumor biopsies collected during the KEYNOTE-B84 study. The results indicate that treatment with pepinemab in combination with KEYTRUDA appears to induce formation of highly organized lymphoid aggregates in the tumor of patients who demonstrate disease control (complete response plus partial response plus stable disease). Such aggregates are characterized by a high density of B cells, antigen-presenting dendritic cells and activated T cells; further, treatment-induced increase in the number of aggregates correlates with Disease Control and with Progression Free Survival. Representative images of 5-week on-treatment biopsies. Left: from a patient with stable disease, tumor biopsy contains highly organized immune aggregates consisting of high density antigen presenting cells as well as T lymphocytes. Right: from a patient with progressive disease, immune cells in the tumor biopsy are disorganized and include relatively high levels of inhibitory T regulatory (Treg) cells, but relatively few antigen presenting cells (B cells, DC). Patients who experience clinical benefit (Disease Control) during treatment with pepinemab and KEYTRUDA have a higher frequency of mature immune aggregates with a high density of B cells in their on-treatment biopsy compared to their pre-treatment biopsies, p<0.0001. This difference is not observed in on- and pre-treatment biopsies from patients whose cancer progresses rapidly. One-way ANOVA, <0.0001; ns = not significant, p=0.05. Immune Aggregates correlate with PFS. On-treatment patient biopsies with B cell aggregates positively correlate with longer progression-free survival. Log Rank survival analysis, p= 0.0056.