On November 6, 2024 Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, reported an update on its PRMT5 program (Press release, Tango Therapeutics, NOV 6, 2024, View Source [SID1234647866]). Based on positive data from the dose escalation and early dose expansion cohorts of the TNG462 phase 1/2 clinical trial, the Company has selected TNG462 to move forward into full development. TNG908, an MTA-cooperative brain penetrant PRMT5 inhibitor, is clinically active and well-tolerated in non-CNS solid tumors including NSCLC and pancreatic cancer. However, TNG908 did not meet the pharmacokinetic exposure threshold for clinical efficacy in glioblastoma (GBM) in the phase 1/2 trial. Thus, the Company is introducing TNG456, a next-generation brain penetrant MTA-cooperative PRMT5 inhibitor with enhanced potency and selectivity for the treatment of GBM, NSCLC and selected other solid tumors. TNG908 enrollment is being stopped in order to fully resource TNG462 and TNG456.
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"Early data from the TNG462 phase 1/2 clinical trial demonstrate activity, durability and tolerability, with the potential to be a best-in-class molecule. In this ongoing clinical trial, patients remain on treatment with a current median of 24 weeks and is still increasing," said Adam Crystal, M.D., Ph.D., President, Research and Development of Tango Therapeutics. "In addition, we are introducing TNG456, our next-generation brain-penetrant molecule, which is anticipated to enter the clinic in the first half of next year. Given the increased potency, selectivity and predicted brain penetrance of TNG456, we expect CNS exposure to be in the range needed for meaningful efficacy in glioblastoma and brain metastases. While it’s disappointing that, unlike in other solid tumors, TNG908 is not active in GBM, we believe this is due to lower-than-predicted central nervous system exposure. We remain steadfastly committed to bringing an effective treatment to people with glioblastoma and we are strongly positioned to achieve our goal of reaching as many patients as possible with MTAP-deleted cancers."
"Clinical data from the phase 1/2 trial demonstrate that TNG462 has potentially best-in-class characteristics including clinical activity across multiple tumor types included in the trial, substantive durability, and a good safety and tolerability profile, thus we are moving rapidly into the next phase of development. This includes clinical evaluation of TNG462 as a monotherapy and in multiple combinations of both targeted and standard of care agents to begin in 1H 2025, in preparation for registrational trials in NSCLC and pancreatic cancer. It also includes building key capabilities within Tango to bring TNG462 to a broad range of patients in the coming years. As part of this effort, we have entered into a clinical collaboration with Revolution Medicines under which we plan to conduct the first combination trials of an MTA-cooperative PRMT5 inhibitor with the exciting class of RAS(ON) tri-complex inhibitors. Given that nearly all MTAP-deleted pancreatic cancers have a co-occurring RAS mutation, we believe this could be a powerful approach to changing the treatment landscape for this challenging cancer," said Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics.
TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor
TNG462 dose escalation began in July 2023 and enrollment in the dose expansion cohorts began in June 2024. With a data cutoff of 20 October 2024, a total of 59 patients have been enrolled, 39 evaluable patients across 13 histologies at active doses (160-300 mg QD).
TNG462 is active and well-tolerated across multiple tumor types, including NSCLC and pancreatic cancer, with a current median time on treatment of 24 weeks, and is still increasing.
As has been reported with other MTA-cooperative PRMT5 inhibitors, tumors continue to shrink over time in multiple tumor types. Median time to response is 16 weeks (8-32 weeks) and ~60% of patients with partial responses were initially assessed with stable disease.
While there is not yet a sufficient number of evaluable patients and follow-up to accurately estimate ORR for most cancer types, we have enrolled seven cholangiocarcinoma patients and observed confirmed partial responses in 3/7 of these patients (ORR 43%). 4/7 cholangiocarcinoma patients are ongoing with a median time on study of 24 weeks, and is still increasing.
TNG462 has a good safety profile and is well-tolerated at active doses, with thrombocytopenia as the dose limiting toxicity. Other adverse events reported for the class, including nausea, vomiting, diarrhea, and fatigue, occurred in less than 20% of patients and were predominantly grade 1. Dysgeusia has not been reported with the doses being evaluated in expansion.
TNG462 efficacy and tolerability continue to be evaluated at 200 mg, 250 mg and 300 mg daily, predominantly in NSCLC and pancreatic cancer. The next clinical update is planned for 2025.
Development plans for TNG462 being implemented include targeted combinations with two RAS(ON) inhibitors – RAS(ON) multi-selective inhibitor, RMC-6236, and RAS(ON) G12D-selective inhibitor, RMC-9805 (Revolution Medicines) – osimertinib (AstraZeneca) and pembrolizumab (Merck), with enrollment planned to start in 1H 2025.
Combinations of TNG462 and standard of care chemotherapy for NSCLC and pancreatic cancer also are being planned as potential paths to approval in the first line setting and we are initiating conversations with the FDA in preparation for multiple registrational studies.
TNG908, a blood-brain barrier penetrant, MTA-cooperative PRMT5 inhibitor
TNG908 dose escalation began in August 2022 and enrollment in the dose expansion cohorts began in April 2024. With a data cutoff of 20 October 2024, a total of 103 patients have been enrolled, 70 non-CNS patients across 24 histologies and 33 glioblastoma patients.
TNG908 is active and well-tolerated across multiple non-CNS solid tumors, including NSCLC and pancreatic cancer, with a median time on study of 16 weeks.
Of the 70 patients with non-CNS solid tumors, 31 were treated at active doses (400-600 mg BID) and had at least one tumor assessment. Four partial responses were observed. Responses occurred in pancreatic cancer (2/9), NSCLC (1/4) and urothelial cancer (1/1).
Of note, there were a total of nine evaluable pancreatic cancer patients, two with partial responses (ORR 22%) and five with stable disease as best response to date. The five ongoing pancreatic cancer patients have been on study for an average of 24 weeks, the longest for 72 weeks.
Of the 33 patients with glioblastoma, 23 were treated at active doses (400-600 mg BID) and had at least one tumor assessment. No partial responses by RANO criteria were observed and median time on study was less than 8 weeks.
In preclinical primate studies of TNG908, cerebral spinal fluid (CSF) exposure was 50-70% of plasma exposure. In CSF samples from three glioblastoma patients on study, exposure was ~30% of plasma exposure and below the threshold required for efficacy.
Dose-limiting toxicities were elevated creatine kinase and aspartate aminotransferase in one patient and altered mental status in a second patient, both at 900 mg BID. Nausea and fatigue were reported in ~40% of patients at 600 mg BID, the expansion dose.
While TNG908 is an active and well-tolerated MTA-cooperative PRMT5 inhibitor in non-CNS solid tumors, enrollment is being stopped to allow full resourcing of TNG462 as a potential best-in-class molecule. In particular, the notably longer time on treatment observed – 24 weeks and still increasing for TNG462 versus 16 weeks for TNG908 – the superior target coverage and the safety and tolerability profile all support selection of TNG462 for further development.
TNG456, a next-generation, brain penetrant MTA-cooperative PRMT5 inhibitor
TNG456 is a novel, brain-penetrant MTA-cooperative PRMT5 inhibitor that is 55X selective for MTAP deletion with 20 nM potency (GI50) in preclinical studies.
Based on primate CSF exposure that is 50%-110% of plasma levels and the markedly increased potency and selectivity of TNG456 compared to TNG908 (GI50 120 nM, 15X MTAP-deleted selectivity), TNG456 CNS exposure is predicted to be in the range needed for efficacy in glioblastoma and brain metastases.
TNG456 will be evaluated in glioblastoma, NSCLC and select other solid tumors as a monotherapy and in combination with the brain-penetrant CDK4/6 inhibitor abemaciclib (Lilly). The combination with abemaciclib is based on the co-deletion of CDKN2A and MTAP in essentially all MTAP-deleted cancers and on strong synergy observed in preclinical models.
The Company plans to begin enrolling patients in the TNG456 phase 1/2 study in 1H 2025.