Tango Therapeutics (TNGX) 2024 Wells Fargo Healthcare Conference summary

Competitive landscape and clinical validation

• PRMT5 is emerging as a clinically validated target, with data from Mirati, Amgen, and IDEAYA showing sensitivity across tumor types and hints of durable responses.

• IDEAYA's MAT2A inhibitor, which indirectly inhibits PRMT5, has shown responses in sensitive tumor types.

• Amgen, Mirati, and Tango are leading with second-generation, MTA-cooperative PRMT5 inhibitors, which offer improved selectivity and efficacy in MTAP-deleted tumors.

• The competitive environment is intense, with major players at similar development stages, prompting consideration of development partnerships for global reach.

• PRMT5 inhibitors are expected to be most effective in combination therapies, though they show promising single-agent activity.

Clinical programs and trial design

• Two PRMT5 inhibitors, 908 (brain-penetrant) and 462 (more selective, not brain-penetrant), are in phase I trials with dose escalation and expansion cohorts.

• Both trials focus on solid tumors with MTAP deletion; 908 includes lung, glioblastoma, and pancreatic cancer, while 462 includes lung, pancreatic, and rare histologies.

• Dose expansion for both trials began in 2023, with updates in the second half of 2024 to include efficacy, pharmacokinetics, durability, and future development plans.

• 908's dose escalation included about 65 patients, with 462 having a shorter escalation due to regulatory allowances.

Safety, efficacy, and resistance

• 462 shows good tolerability with expected hematologic toxicity at higher doses; 908 and competitors have not reached this level of target inhibition.

• 908's dose-limiting toxicities included mental status changes and rhabdomyolysis; GI side effects are present but manageable.

• Resistance to PRMT5 inhibitors is less likely to arise from enzymatic pocket mutations due to the essential nature of PRMT5 and its complex binding requirements.

• Durability of response may be greater than with tyrosine kinase inhibitors, with resistance mechanisms expected to be more diverse.