Nuvation takes the battle to Nuvalent

Nuvation Bio, a group led by the former chief exec of Medivation, has dabbled in numerous approaches but it now has a brand new focus. Its all-stock takeover of AnHeart Therapeutics, a private biotech, brings with it the ALK/ROS1/NTRK inhibitor taletrectinib, which Nuvation reckons could be approved by the end of next year.

There are several questions about taletrectinib, however, such as why it was cut loose by its originator, Daiichi Sankyo, and how it might perform in a crowded niche that has seen the emergence of the US biotech Nuvalent as new force in targeted NSCLC therapeutics. The fact the AnHeart takeover hasn’t actually cost Nuvation any cash appears to mitigate these sorts of concerns.

ROS1-mutated NSCLC, the niche where taletrectinib is being positioned, features the marketed drugs Xalkori (Pfizer), Rozlytrek (Roche) and Augtyro (Bristol Myers Squibb). Nuvalent is relevant because its lead, the ROS1 inhibitor NVL-520, has impressed, with activity even in patients who have failed two prior ROS1 tyrosine kinase inhibitors.

Nuvalent has made a name for itself as a group able to design molecules that are highly specific and brain penetrant, and can hit mutations that develop in response to earlier-generation inhibitors – with a market cap to match. What Nuvation/AnHeart can do in the face of such competition is a relevant question.

A common theme here is the difficulty of designing a molecule that hits only ROS1 and avoids the related ALK and especially NTRK, which brings added toxicity. It’s notable that Nuvation is describing taletrectinib as a “ROS1 inhibitor”, when in fact the molecule has documented activity against NTRK, and possibly hits ALK too.

Takeover

The AnHeart deal has a somewhat complex structure, involving Nuvation common stock, non-voting shares and warrants. But after completion the current Nuvation holders will own 67% of the combined entity, and as Nuvation is capitalised at just under $500m the implied value of AnHeart is around $250m.

Nuvation trades well below its $600m cash balance. The group listed in 2021 via a SPAC largely on the back of the pedigree of its founding chief executive, David Hung, who had sold Medivation to Pfizer for $14bn; since then Nuvation has lost 75% of its value, as a clinical-stage CDK2/4/6 inhibitor, and preclinical projects targeting Wee1 and A2AR, all fell by the wayside.

Until the AnHeart takeover Nuvation’s lead was NUV-868, a BET inhibitor relevant because of Novartis’s takeover of MorphoSys, developer of the industry’s most advanced BET asset, pelabresib. Now, with taletrectinib overtaking NUV-868 in Nuvation’s pipeline, the focus changes again.

Taletrectinib is in two phase 2 trials, of which the global one, Truist-II, yielded initial data in ROS1-positive NSCLC at last year’s ESMO; these showed ORRs of 92% in ROS1 inhibitor-naive, and 57% in ROS1 pretreated patients, with evidence of intracranial activity.

Nuvation calls this a registrational study, and China’s NMPA is already reviewing taletrectinib filings in second and first-line NSCLC. A US filing strategy has yet to be revealed, but the project does carry FDA breakthrough therapy designation.

Taletrectinib was originated by Daiichi, but after showing early activity in ROS1-positive NSCLC, along with dose-limiting toxicities above 800mg daily, it was licensed to AnHeart for an undisclosed amount. AnHeart later gained rights to Daiichi’s IDH1 inhibitor safusidenib/DS-1001 and AXL inhibitor DS-1205/AB-329.

The last no longer appears in the pipeline, and AnHeart’s inability to make much of the first two assets likely justifies Daiichi’s limited faith in them.

The combined Nuvation/AnHeart pipeline

Source: OncologyPipeline.