On November 12, 2021 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, reported updated results from its Phase 1/1b clinical trial of mupadolimab (formerly CPI-006), a humanized monoclonal antibody directed against CD73 with a proposed unique mechanism of activating B cells to generate immune responses to tumor antigens and viruses, and inhibiting the production of immunosuppressive adenosine in the tumor microenvironment (Press release, Corvus Pharmaceuticals, NOV 12, 2021, View Source [SID1234595334]). The clinical data, along with pre-clinical data, further strengthen mupadolimab’s mechanism of action and demonstrate its potential anti-tumor activity in cancer patients.
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The data were made available today in an on-demand, electronic poster format for registered participants of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, which is taking place from November 10 to 14, 2021. The poster is also being presented in-person at SITC (Free SITC Whitepaper) by Jason J. Luke, M.D., principal investigator of the trial and Director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center and Associate Professor of Medicine at the University of Pittsburgh School of Medicine.
"We continue to broaden our understanding of mupadolimab’s unique characteristics as an anti-CD73 antibody that exhibits potent blockade of adenosine production as well as powerful adenosine-independent effects on the immune system that result in enhanced B cell and T cell function," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "Recent research has demonstrated that B cells have a vital role in the immune response to tumors from non-small cell lung cancer (NSCLC) and head and neck squamous cell cancers (HNSCC) each frequently containing high numbers of B cells in the tumor and tumor microenvironment. In our Phase 1/1b clinical trial, treatment with mupadolimab in these cancers resulted in tumor regression in patients that failed to respond to, and progressed through prior treatment with anti-PD(L)-1 therapy. This suggests that, in some patients, mupadolimab’s novel mechanism of action may overcome resistance to anti-PD(L)1 therapies."
Dr. Miller added, "In addition, the results presented at SITC (Free SITC Whitepaper) provide important data on the immunologic effects of mupadolimab, as well as pharmacokinetic, pharmacodynamic and safety data for monotherapy and combination therapy. Looking forward, we are now enrolling additional patients with HNSCC and NSCLC in expansion cohorts. These patients will receive the combination of mupadolimab and pembrolizumab and we anticipate reporting results from these expansion cohorts in early 2022. We believe that the data presented at SITC (Free SITC Whitepaper) and data obtained from ongoing expansion cohorts may provide the rationale for a randomized controlled study of mupadolimab, which we expect could begin in 2022."
Mupadolimab Phase 1/1b Clinical Trial Key Results Presented at SITC (Free SITC Whitepaper) 2021
Mupadolimab is being studied in a Phase 1/1b clinical trial in patients with a variety of advanced, refractory cancers, including NSCLC and HNSCC that have failed previous treatment with anti-PD-1 therapy and chemotherapy. The study design included mupadolimab dose escalation from 1 mg/kg to 24 mg/kg intravenous infusion every 3 weeks until disease progression or dose limiting toxicities were reached. Cohorts of patients were treated with mupadolimab monotherapy; combination with ciforadenant, Corvus’ small molecule inhibitor of the A2A receptor; combination with pembrolizumab; or triplet combination with ciforadenant and pembrolizumab.
The data presented at SITC (Free SITC Whitepaper) showed that mupadolimab doses of 12mg/kg are optimal, resulting in complete occupancy of the CD73 target and maximal effects on B cell activation. In the assessment of anti- tumor activity in patients receiving optimal doses of mupadolimab, tumor regression (not meeting the threshold for partial response by RECIST) was seen in five patients who had progressive disease as best response to most recent therapy, which included anti-PD(L)1 therapy (see waterfall plot below). This indicates that tumor regression could occur in patients with tumors refractory to anti-PD(L)1 that are treated with mupadolimab.
A figure accompanying this announcement is available at View Source
"The findings of tumor regression with mupadolimab in patients who had grown through their most recent prior therapy with an anti-PD(L)1 is noteworthy. This supports the possibility that mupadolimab’s mechanism of action could serve to add to effectiveness or overcome limitations of current anti-PD(L)1 therapies. This activity would be expected to be more impactful in patients treated earlier in their disease, with less prior therapies," said Dr. Luke. "We look forward to expanding our experience with mupadolimab in combination with anti-PD(L)-1 in earlier lines of therapy."
Additional mupadolimab oncology program highlights from the SITC (Free SITC Whitepaper) poster presentation include:
Pharmacokinetic (PK) and pharmacodynamic (PD) results showed complete CD73 target occupancy with mupadolimab at doses of 12 mg/kg and higher. Doses up to 18 mg/kg were tolerated without dose limiting toxicities.
Within 30 minutes of mupadolimab intravenous infusion, a reduction in B cells in blood was seen, consistent with redistribution of B cells to lymphoid tissues.
Corvus presented updated preclinical data characterizing mupadolimab’s dual mechanism of action: Mupadolimab is an IgG1 humanized antibody that has been engineered to be Fc gamma receptor binding deficient. Lab data demonstrated that it completely blocks adenosine production from AMP without a hook effect, which is a reduction in binding with higher concentrations of antibody that may limit efficacy to a narrow range of concentrations. In vitro studies showed that binding of mupadolimab to B cells stimulates activation and differentiation into plasmablasts (antibody producing cells) in a mechanism that is independent of adenosine. In vitro studies showed that T cell functions are inhibited by adenosine monophosphate (AMP) and restored by the addition of mupadolimab.
Corvus analyzed CD73 expression in tumor biopsies, obtained from outside sources, using immunohistochemistry from 75 patients with NSCLC and 31 patients with HNSCC. High CD73 expression was seen in tumor cells and/or stroma in all patients. In HNSCC, CD73 expression is predominantly stromal.
Corvus is also developing mupadolimab as a therapeutic for infectious disease, starting with COVID-19. Preclinical data with humanized mice (mice with human immune system) inoculated with SARS-CoV-2 and influenza viral antigens showed that treatment with mupadolimab enhanced antibody responses that were viral specific, demonstrating its potential to be a universal therapy or adjuvant for viral diseases. In September, Corvus announced results from its Phase 3 clinical trial of mupadolimab for COVID-19, which have been published online at medRxiv.org. The results, which cover 40 patients that were enrolled in the trial prior to its voluntary discontinuation, suggest improvement in the primary and key secondary endpoints in patients treated with single doses of mupadolimab at 2mg/kg and 1mg/kg compared to placebo. Due to the small sample size, the results did not reach statistical significance. No drug related adverse events were reported in the trial.
Conference Call, Webcast and Presentation Slides
Corvus will host a conference call and webcast today, November 12, 2021, at 9:00 a.m. ET (6:00 a.m. PT), to discuss the update on mupadolimab and other topics. The conference call can be accessed by dialing 1-877-407-0784 (toll-free domestic) or 1-201-689-8560 (international) and using the conference ID 13724618. The live webcast, which will include presentation slides, may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus’ website for 90 days.