Tango Therapeutics has shuffled TNG908 off the dance floor, halting enrollment in a study of the cancer drug candidate to focus its resources on two other molecules that hit the same target. Shares in Tango fell 26% to $3.81 in premarket trading.
TNG908 is a MTA-cooperative PRMT5 inhibitor. In cells with MTAP deletion, a mutation found in 10% to 15% of solid tumors, the metabolite MTA accumulates and partially inhibits PRMT5. By selectively targeting the PRMT5-MTA complex, Tango and a clutch of other companies are aiming to leverage the synthetic lethality of PRMT5 without causing intolerable harm to healthy cells.
Tango provided an update on its efforts to realize that potential on Wednesday. The news for TNG908, the first PRMT5 inhibitor that Tango took into the clinic, is bad. The molecule is designed to penetrate the brain but Tango saw no partial responses in the 23 glioblastoma patients who received active doses.
Tumors outside the central nervous system (CNS) did respond but the failure to shrink brain tumors took away TNG908’s raison d'etre. Tango has another MTA-cooperative PRMT5 inhibitor, TNG462, for treating tumors outside the CNS.
The biotech has identified lower-than-predicted CNS exposure as the potential cause of the lackluster efficacy against brain tumors. In preclinical primate studies, cerebral spinal fluid (CSF) exposure to the drug candidate was 50% to 70% of plasma exposure. Tango’s analysis of three glioblastoma patients found CSF exposure was 30% of plasma exposure and below the threshold required for efficacy.
Adam Crystal, M.D., Ph.D., president, research and development at Tango, said in a statement that it is “disappointing” that TNG908 is inactive in glioblastoma but made the case that the follow-up candidate TNG456 will be more effective. Crystal said TNG456’s increased potency, selectivity and predicted brain penetrance should increase exposure to the level needed for “meaningful” efficacy in the CNS.
Primate CSF exposure to TNG456 is 50% to 110% of plasma levels. Tango is aiming to move the candidate into the clinic in the first half of next year. The biotech plans to study the molecule as a monotherapy and in combination with Eli Lilly’s CDK4/6 inhibitor Verzenio in glioblastoma, non-small cell lung cancer and other solid tumors. Tango said it has seen a strong synergy with Verzenio in preclinical models.
The biotech will advance TNG456 while continuing to move its peripheral candidate TNG462 deeper into the clinic. Tango shared clinical data on TNG462 as part of its update, revealing three responses in seven cholangiocarcinoma patients while saying it is too early to accurately estimate the response rate in other tumors. The company said tumors continue to shrink over time, with responses taking 8 to 32 weeks.
Tango is pushing ahead with development of TNG462. Combination studies with AstraZeneca’s Tagrisso and Merck & Co.’s Keytruda are forecast to start enrolling in the first half of next year. However, the lack of clinical data provided to date make it hard to gauge Tango’s claims that TNG462 could be best in class.
Amgen set the bar in the class in September, when it published data from a first-in-human study of AMG 193. Bristol Myers Squibb entered the space through its acquisition of Mirati Therapeutics and recently shared clinical data. AstraZeneca moved its challenger into the clinic early this year.