Molecular Templates provides update on clinical-stage programs

Eric Poma, PhD., Chief Executive and Chief Scientific Officer of MTEM, stated, “ETBs are a potentially powerful therapeutic approach to selectively depleting immunosuppressive cells in oncology or eliminating self-reacting immune cells in severe immune-mediated diseases. The monotherapy activity we see with MT-6402 in relapsed/refractory solid tumor patients, and the clinical and ex vivo depletion of CD38+ immune cells seen with MT-0169 at well-tolerated doses underscore the potential of this platform across multiple diseases.” Company Pipeline Highlights: MT-6402: Promising Single-Agent Activity: MT-6402 has shown monotherapy activity in heavily pre-treated patients who had previously progressed or were refractory to immuno-oncology therapy. Head and Neck Cancer Responses: MTEM had previously reported that nine patients with head and neck squamous cell carcinoma had been treated in the Phase 1 dose escalation. Two heavily pre-treated patients with low PD-L1 expressing squamous cell carcinoma of the head and neck had achieved partial responses with MT-6402 monotherapy. These patients remain in response and in good clinical condition, continuing treatment in cycles 21 and 12, respectively. In addition, four of the HNSCC patients treated with MT-6402 had stable disease with two showing tumor reduction. All patients with tumor responses or tumor reduction had low PD-L1 expression. New Lung Cancer Response: An unconfirmed partial response was observed in a non-small cell lung cancer patient with high PD-L1 expression in the Phase 1b monotherapy dose expansion study in solid tumor patients with high PD-L1 tumor expression. The patient achieved a partial response at the end of cycle 8 following sustained tumor reduction in prior assessments. A PET scan in cycle 8 showed no indications of active metastatic disease. This patient had previously progressed on chemotherapy, targeted therapy, and checkpoint therapy, including progression within six months on pembrolizumab + ramucirumab, before enrolling in the study. Three other NSCLC patients with high PD-L1 expression have been dosed in the Phase 1b expansion study. Two of these patients had progressive disease and one passed away from COVID and was not evaluable. Favorable Safety Profile: To date, MT-6402 appears to be generally well-tolerated, with no drug-related adverse events exceeding grade 3. Ongoing Enrollment: MTEM continues to enroll HNSCC patients with low PD-L1 expression and patients with solid tumors with high PD-L1 expression. MT-0169: Clinical proof-of-concept supports the elimination of CD38+ cells in immune-mediated disease. Recent clinical data with CD38 antibodies have demonstrated the therapeutic potential of CD38+ immune cell clearance in several immune-mediated diseases. Despite these promising early data, a more potent mechanism of CD38+ immune cell depletion may provide greater clinical benefit. Potent and unique mechanism of action. MT-0169 is designed to destroy CD38+ tumor or immune cells through internalization of CD38 and cell destruction via a novel mechanism of action. In ex vivo cell kill assays, MT-0169 shows potency against plasma cells with IC50 activity in the picomolar or femtomolar range. Plasma cells are exceptionally sensitive to ER stress, making them uniquely susceptible to the MT-0169 mechanism of action. MT-0169 also shows potent activity against T-cells that express low levels of CD38. HLA-DR CD38+ T-cells have been implicated in many immune-mediated diseases. Overcoming antibody resistance. The unique mechanism of action of MT-0169 and its lack of an Fc domain may avoid resistance mechanisms seen with CD38 antibodies like receptor downregulation or trogocytosis while allowing for combination approaches with FcRn-targeting therapies. Clinical proof-of-concept with MT-0169. MTEM’s Phase 1 study in patients with relapsed or refractory multiple myeloma dosed at 5, 10, or 15 mcg/kg showed potent depletion of CD38+ immune cells with no drug-related adverse events of grade 3 or higher noted in these patients. Planned clinical development with MT-0169. MTEM will continue to develop MT-0169 in hematology and is evaluating the potential of MT-0169 in severe immune-mediated diseases. MT-8421: Tumor microenvironment dismantling. MT-8421 is designed to potently destroy CTLA4+ Tregs, alleviating immunosuppression in the tumor microenvironment. Pharmacodynamic effects observed early Phase 1 dose escalation. Three patients were dosed in the first cohort of the Phase 1 study at 32 mcg/kg. No drug-related adverse events of grade 3 or higher were observed. One patient had disease progression at the end of cycle 2. Two patients have stable disease and remain on study at cycle 8 and cycle 7, respectively. The two patients in stable disease showed peripheral depletion of Tregs and significant elevations in IL-2 while on therapy. One of the patients has a notable decrease in ctDNA. Dose escalation continues. Enrollment is on-going in the second cohort of 48 mcg/kg for the Phase 1 study of MT-8421.