Tango faces a fresh PRMT5 competitor

Disappointing first data with Amgen’s PRMT5 inhibitor AMG 193 shook confidence in this mechanism of action, to which Tango Therapeutics is especially exposed, and now Tango faces a fresh challenge: AstraZeneca is taking its own PRMT5 inhibitor, AZD3470, into the clinic.

The phase 1 study details emerged in the latest new listings on the clinicaltrials.gov registry, and this development can also be seen as an endorsement of PRMT5 inhibition. Other first-in-human studies being initiated include those of Caribou’s CB-012, the first fruit of a Sanofi/Seagen discovery tie-up, and what could be a MAb derived from Amgen’s $1.9bn takeover of Five Prime in 2021.

In PRMT5 inhibition the focus is on Tango, which is promising first clinical data on TNG908 next year. In a similar timeframe it could also reveal human data on TNG462, a non-brain penetrant PRMT5 inhibitor, its chief executive, Barbara Weber, told this week’s Jefferies London healthcare conference.

Astra presented preclinical results for AZD3470 at AACR this year, showing reduced toxicity versus first-generation PRMT5 inhibitors, and its phase 1 trial in MTAP-deleted tumours started this month. The field, buoyed by first data with Mirati’s MRTX1719, recently saw the entry of Schrödinger.

Car-T, bispecific and ADC

Meanwhile, Caribou is primarily focused on the Antler study of its allogeneic anti-CD19 Car CB-010, but next month it will start the phase 1 Amplify trial of a CLL1-directed Car – its third clinical-stage allogeneic asset.

A separate antigen in which interest has been growing recently is B7-H4, with GSK’s licensing of Hansoh Pharma’s HS-20089 setting up a battle against Seagen’s soon-to-be Pfizer-owned SGN-B7H4V. Now South Korea’s ABL Bio is entering the fray, taking ABL103, a CD137-agonist MAb against B7-H4, into a phase 1 solid tumour study.

And Seagen itself remains active in first-in-human initiations, with a phase 1 trial of its Sanofi-partnered anti-CEACAM5 ADC due to start at the end of December. This is the result of a March 2022 tie-up, and comes after Sanofi’s earlier collaboration with Immunogen yielded a CEACAM5-targeting ADC called tusamitamab ravtansine, which is now in phase 3.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 13 and 15 Nov 2023.

Yesterday the FDA approved Bristol Myers Squibb’s repotrectinib, a result of the $4.1bn acquisition of Turning Point, for ROS1-mutated NSCLC. The nod came 12 days before the agency’s Pdufa date, and the new drug, trademarked Augtyro, joins Roche’s Ignyta-derived Rozlytrek in this setting. 

The latest clinicaltrials.gov listings include the first phase 1 trial of a rival ROS1 inhibitor, Joyo Pharma’s JYP0322. However, this study has been ongoing for some time, and has featured on Chinese clinical trial registries and in OncologyPipeline for over a year.

A year before Bristol bought Turning Point Amgen handed across $1.9bn for Five Prime Therapeutics; though that deal was focused on bemarituzumab Five Prime’s preclinical portfolio included an anti-CCR8 MAb coded FPA157. Now clinicaltrials.gov reveals the first phase 1 study for AMG 355, which might be the new code for FPA157.

The idea behind FPA157 was that CCR8 is expressed on T regulatory cells, and by targeting it these immunosuppressive cells can be depleted. However, the only clue to AMG 355’s identity lies in its trial’s secondary endpoints: one of these measures change in CCR8 expression.