AACR 2023 – Hippo makes a splash

If one purpose of AACR meetings is to bring before a wide audience novel oncology mechanisms that have hitherto sailed under the radar then this year might have seen the Hippo/Yap/Tead pathway emerge from obscurity.

At least a dozen projects with this mechanism were presented over the weekend, most importantly VT3989, a Tead palmitoylation inhibitor from the private group Vivace Therapeutics that yielded clinical data. The pipeline includes projects from Novartis and Sanofi, and investors in Ikena Oncology, which went public two years ago, should also pay close attention.

This is because Ikena’s investment case is centred on the lead project IK-930, which is also a Tead inhibitor. Analysts reckon Vivace’s clinical data – the first for a Tead inhibitor – validate Ikena’s approach, showing that the Hippo pathway might be druggable. That said, toxicity looms large, and Ikena is doing things differently.

Getting around tox

VT3989 treatment caused proteinuria, as well as liver enzyme elevations and cardiomyopathy in some patients. Proteinuria is an on-target effect, and “when we designed IK-930 ... that is the tox we were looking at”, Ikena’s chief executive, Mark Manfredi, tells Evaluate Vantage.

The big difference is that Vivace, in line with most early approaches, is working on pan-Tead inhibition, whereas Ikena’s IK-930 is a Tead1-specific molecule, it was revealed at AACR yesterday. Ikena has seen no proteinuria in monkey trials, and Manfredi reckons others are now following his company in developing subtype-selective Tead inhibitors to get around toxicity; Sporos’s Tead1/4 inhibitor SPRI-0117 appears to be one of these.

Another thing Vivace did over the weekend was to validate mesothelioma as a target for Hippo pathway blockade, Manfredi says. The VT3989 study has so far enrolled 67 patients, and six of 42 refractory mesothelioma subjects experienced partial responses.

The Hippo pathway controls cell proliferation and renewal, and its dysregulation is thought to drive the growth of some cancers. Tead is a family of four transcription factors that modulate gene expression in response to Hippo signalling, and transcription is regulated by co-activators called Yap and Taz.

The pathway can be activated by NF2 gene loss of function, and 40% of mesotheliomas are driven by such mutations, Manfredi says. Separately, Yap or Taz fusions are wholly responsible for a rare type of sarcoma called epithelioid hemangioendothelioma (EHE).

Assuming that toxicity can be circumvented this provides two obvious cancer indications to go after, though Manfredi says even in mesothelioma screening would be required to enrich the population for the NF2 mutation. EHE, meanwhile, is already diagnosed not by histology but by Yap/Taz gene fusion screening.

Percolating

Targeting the Hippo pathway is an idea that “has been percolating for a few years now”, with much preclinical and translational data published, says Manfredi, but he sees this year’s AACR as the first big meeting where it has made a splash.

Why has it taken so long? Apart from toxicity it has proved difficult to design drugs that target Tead, Yap or Taz effectively. Interestingly, verteporfin, the active ingredient in Novartis’s photodynamic therapy Visudyne, is thought to inhibit the interaction of Yap with Tead, though this seems to have arisen serendipitously rather than by design.

More focused development has now yielded a pipeline that includes three clinical-stage projects. IK-930 is in phase 1 dose escalation, with data expected in the second half of this year; behind Vivace’s VT3989 the third asset is Novartis’s IAG933, which was profiled for the first time at AACR and, like verteporfin, was revealed to be a Yap-Tead interaction inhibitor.

Manfredi reckons IK-930 is more targeted and thus better than both. Whether this is the case will not emerge until all three generate data in patients.