Tango Therapeutics (TNGX) 2024 Cantor Fitzgerald Global Healthcare Conference summary

Strategic focus and scientific rationale

• Targeting tumor suppressor genes, specifically those with MTAP deletions, to address a significant unmet need in oncology beyond traditional oncogene targeting.

• PRMT5 inhibitors exploit synthetic lethality in MTAP-deleted cancers, aiming to selectively kill cancer cells while sparing normal cells.

• MTAP deletions are prevalent in 10–15% of all solid tumors, with higher rates in glioblastoma (40%) and lung cancer (15–20%).

• First-generation PRMT5 inhibitors failed due to lack of selectivity, causing toxicity in normal cells.

• Next-generation MTA-cooperative PRMT5 inhibitors, including TNG908 (brain penetrant) and TNG462 (more potent, not brain penetrant), are in clinical development.

Competitive landscape and validation

• Multiple companies are developing MTA-cooperative PRMT5 inhibitors, with Amgen and BMS/Mirati as key competitors.

• PRMT5 inhibition is considered a validated clinical target, though response rates are lower than for some oncogenic driver inhibitors.

• Durability of response is seen as a differentiator for this class, with recent Amgen data supporting activity in lung and pancreatic cancers.

• Some tumor types, such as cholangiocarcinoma and mesothelioma, appear particularly sensitive to PRMT5 inhibition.

• Sensitivity differences among tumor types remain empirically observed, with no clear genetic explanation yet.

Clinical development and combination strategies

• TNG462 and TNG908 are advancing in clinical trials, with TNG462 showing good safety up to 600 mg and on-target hematologic toxicity at higher doses.

• Combination strategies are being explored, with CDK4/6 inhibitors highlighted due to frequent co-deletion of CDKN2A in MTAP-deleted tumors.

• MAT2A inhibitor combinations are deprioritized, as full PRMT5 inhibition with a single agent is considered sufficient.

• RAS inhibitor combinations, especially in pancreatic cancer, are a future focus.

• TNG908 is positioned for CNS tumor indications due to its brain penetrance, with ongoing evaluation in GBM.