On November 10, 2022 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs), to create novel therapies with potent and differentiated mechanisms of action for cancer and other serious diseases, reported financial results and business updates for the third quarter of 2022 (Press release, Molecular Templates, NOV 10, 2022, View Source [SID1234623727]).

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"We are excited with the progress we continue to make across all our clinical and pre-clinical programs. We have now seen evidence of monotherapy clinical activity with MT-6402, MT-5111, and MT-0169 in heavily pretreated relapsed/refractory patients — in both solid and hematological cancer settings — demonstrating the broad potential utility of this novel scaffold," said Eric Poma, PhD., Chief Executive and Chief Scientific Officer of Molecular Templates. "We look forward to providing further updates on our MT-6402, MT-5111, and MT-0169 programs throughout 2023 and look forward to our anticipated IND submission for MT-8421 all while we continue to advance our development of additional ETB candidates targeting TROP2, TIGIT, and BCMA."

Company Highlights and Upcoming Milestones

Corporate

MTEM expects to provide periodic updates on MT-6402, MT-5111, MT-8421, and MT-0169 throughout 2023.
Dose escalation continues with MT-6402 with dose dependent pharmacodynamic (PD) effects observed. One patient in cohort 1 (16 mcg/kg) with non-small cell lung cancer (NSCLC) and osseous metastases demonstrated tumor regression. This patient is the only patient treated thus far with high tumor PD-L1 expression and HLA-A*02/ CMV+.
MT-5111 has declared Maximum Tolerated Dose (MTD) at 23 mcg/kg with a dose limiting toxicity (DLT) of grade 3 rash. The HER2-positive breast cancer (BC) dose expansion cohort (DEC) continues to enroll patients at a dose of 10 mcg/kg. Three of five evaluable BC patients treated at 10 mcg/kg have had prolonged Stable Disease for 40, 22, and 22 weeks, respectively. One of the patients treated for 22 weeks has experienced a 43% reduction in mediastinal lymphadenopathy and a halt in the growth of her pulmonary lesions. Overall, the patient has had a 14% reduction in index lesions. This patient has been previously treated with multiple HER2-targeting therapies including trastuzumab, pertuzumab, trastuzumab emtasine, lapatinib, trastuzumab deruxtecan, and tucatinib.
MT-0169 completed the 5 mcg/kg dose escalation cohort (N=4) without any cardiac adverse events (AEs) or DLTs and is enrolling at 10 mcg/kg. One patient with IgA myeloma treated at 5 mcg/kg has had a marked reduction in IgA serum protein, conversion from immunofixation positive to negative and marked improvement of hemoglobin to normal values, demonstrating at least a Partial Response. A PET scan is pending to determine if the patient is in a Complete Response.
Of the over 80 patients treated across MTEM’s three clinical programs to date, there has been no instance of capillary leak syndrome (CLS). One patient treated at 63 mcg/kg with MT-6402 showed a grade 2 decrease in albumin that may potentially represent a subclinical manifestation of CLS.
All toxicities seen to date appear to be target-mediated and unrelated to the underlying scaffold.
ETB Technology

ETBs represent a novel platform with unique biology for therapeutic development in oncology. ETBs have the target specificity of antibodies, can force their own internalization, even against non-internalizing receptors, and can induce tumor cell death through the novel mechanism of enzymatic and irreversible ribosomal destruction. Because of this unique biology, ETBs to targets like HER2 and CD38 have the potential to drive clinical benefit in patients that have progressed after all available therapeutics. ETBs also represent a unique approach to immuno-oncology. Unlike current approaches to PD-L1 that only block the steric interaction of PD-1 and PD-L1, MT-6402, MTEM’s ETB targeting PD-L1, is designed to directly kill PD-L1+ tumors cells, destroy immune cells that inhibit T-cell function and propagate tumor growth, and alter the immunophenotype of tumor cells.

MT-6402 (PD-L1 ETB with Antigen Seeding Technology)

The Phase 1 study of MT-6402 is a multi-center, open-label, dose escalation and dose expansion trial. Patients with confirmed PD-L1 expressing tumors or confirmed PD-L1 expression in the TME are eligible for enrollment, irrespective of HLA genotype or CMV status.
As of November 2022, 19 patients with relapsed/refractory tumors that express PD-L1 have been treated across four dose cohorts: 16 mcg/kg (n=6), 24 mcg/kg (n=6), 32 mcg/kg (n=4), and 42 mcg/kg (n=3). One DLT of grade 2 rash was observed in cohort 2 whereas no DLTs were reported in cohorts 1, 3 and 4. Enrollment continues in cohort 5 at 63 mcg/kg.
One patient in cohort 1 (16 mcg/kg) with NSCLC demonstrated tumor regression of osseous metastases. This patient is the only patient treated thus far with high tumor PD-L1 expression and who is also HLA-A*02/ CMV+.
MTEM continues to observe PD effects not seen with PD-L1 antibodies and consistent with the dismantling of the TME including PD-L1+ immune cell depletion and T cell activation, as well as cytokine changes in TNF-α, IL-2, and vascular endothelial growth factor (VEGF) in all dose escalation cohorts evaluated to date. The extent and timing of these PD effects appear dose-dependent with higher dose levels showing more rapid and profound PD effects, including MDSC depletion and T cell activation. These effects were seen across the majority of patients irrespective of HLA genotype or level of tumor or immune cell PD-L1 staining.
Treatment-related AEs including immune related AEs have been largely restricted to grade 1-2.
MT-5111 (HER2 ETB)

As of November 2022, the Phase 1 study of MT-5111 has enrolled 48 patients across 10 dose escalation cohorts ranging from 0.5 mcg/kg to 23 mcg/kg. One DLT of grade 3 acneiform rash was observed at 23 mcg/kg, which improved to grade 1 with topical steroids, and the patient continued treatment at the same dose. 23 mcg/kg has been declared the MTD.
Serum concentration of MT-5111 showed predictable and dose-proportional increasing exposure starting at 6.75 mcg/kg doses and higher.
The HER2-positive BC DEC continues to enroll patients at a dose of 10 mcg/kg. Six patients have been treated, three of whom for 40, 22, and 22 weeks, respectively, at 10 mcg/kg.
One of the patients treated for 22 weeks came on study with two nodal lesions and two non-nodal necrotic pulmonary lesions. The patient has seen a continued reduction in her nodal lesions while on therapy with a 43% reduction in mediastinal lymphadenopathy and a halt in the growth of her pulmonary lesions. Overall, the patient has had a 14% reduction in index lesions. This patient has been previously treated with multiple HER2-targeting therapies including trastuzumab, pertuzumab, trastuzumab emtasine, lapatinib, trastuzumab deruxtecan, and tucatinib. The next monotherapy cohort for BC patients is planned at 17 mcg/kg.
No clinically significant cardiac AEs have been observed at any dose; grade 1 hs-troponin elevations have been observed at various doses.
MT-0169 (CD38 ETB)

The Phase 1 study in patients with relapsed/refractory multiple myeloma (MM) or non-Hodgkin’s lymphoma explores MT-0169 at doses lower than the initial dose of 50 mcg/kg to reduce the risk of AEs and to enable patients to continue MT-0169 therapy for a longer duration that may drive tumor benefit.
The 5 mcg/kg cohort completed recruitment (N=4) and analysis with no related AEs higher than grade 1. CD38+ Natural Killer (NK) cell depletion was observed in cycle 1 and in cycle 2 for patients continuing therapy. Nadir levels of NK cells were delayed and lower in magnitude than observed at 50 mcg/kg. Enrollment at 10 mcg/kg has commenced.
One patient with IgA myeloma treated at 5 mcg/kg has had a marked reduction in IgA serum protein, conversion from immunofixation positive to negative and marked improvement of hemoglobin to normal values, demonstrating at least a Partial Response. A PET scan is pending to determine if the patient is in a Complete Response.
Research and Development

Preclinical data from MTEM’s MT-8421 program targeting CTLA-4 was featured in an abstract at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting held November 8-12, 2022, in Boston, Massachusetts. Clinical studies for MT-8421 are expected to commence in mid-2023.
MTEM continues to expand its unique approach to immuno-oncology targets with lead optimization ongoing for several targets.
Lead optimization continues on ETBs targeting TROP-2 incorporating Antigen Seeding Technology, a TIGIT-targeting ETB and BCMA.
Upcoming Conferences

MTEM will present four posters (736, 764, 817, and 1379) and provide an in-person R&D Day presentation at the SITC (Free SITC Whitepaper) annual meeting, Friday, November 11, 2022, 11:30am – 12:30pm ET. SITC (Free SITC Whitepaper) posters can be accessed via MTEM’s corporate website. The webcast can be accessed here.
MTEM will present a fireside chat at the virtual ISI HealthCONx Conference, Wednesday, November 30, 2022, at 9:15am ET. The webcast will be live-streamed and can be accessed here.
MTEM will present at the 2022 San Antonio Breast Cancer Symposium (SABCS) taking place December 6 – December 10, 2022, in San Antonio, Texas.
MTEM will participate at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s 64th annual meeting taking place December 10 – 13, 2022 in New Orleans, Louisiana. One-on-one meetings may be scheduled directly with MTEM.
Financial Results

The net loss attributable to common shareholders for the third quarter of 2022 was $24.6 million, or $0.44 per basic and diluted share. This compares with a net loss attributable to common shareholders of $30.4 million, or $0.54 per basic and diluted share, for the same period in 2021.

Revenues for the third quarter of 2022 were $4.2 million, compared to $2.4 million for the same period in 2021. Revenues for the third quarter of 2022 were comprised of revenues from collaborative research and development agreements with Bristol Myers Squibb.

Total research and development expenses for the third quarter of 2022 were $22.0 million, compared with $22.9 million for the same period in 2021. Total general and administrative expenses for the third quarter of 2022 were $5.9 million, compared with $9.0 million for the same period in 2021.

As of September 30, 2022, MTEM’s cash and investments totaled $79.4 million.

For more details on MTEM’s financial results for the third quarter 2022, refer to Form 10-Q filed with the SEC.