Erasca doubles down on RAS

Erasca’s development pipeline never seems to stand still, and yesterday it underwent another transformation. The company has acquired two preclinical assets from China’s Joyo Pharmatec on the one hand, and discontinued work on three pipeline assets on the other, alongside a $160m equity offering.

The moves see Erasca doubling down on the RAF/RAS pathway – its lead remains the Novartis-derived pan-RAF inhibitor naporafenib, which recently entered phase 3 – and away from other targeted small-molecule approaches. Remarkably, the Joyo deal is at least the eighth transaction Erasca has struck to bring in R&D assets since it was founded in 2018, but most have now fallen by the wayside.

This now includes the clinical-stage ERK1/2 inhibitor ERAS-007 and EGFR inhibitor ERAS-801, both licensed in 2020, from Asana BioSciences for $20m up front and from Katmai Pharmaceuticals for $6m respectively. Erasca is cutting 18% of its staff, and says ERAS-007’s Herkules-3 trial efficacy data underwhelmed; ERAS-801 was in the Thunderbbolt-1 study, but any development will now be investigator-sponsored.

Pan-KRAS in and out

The company previously had a preclinical internal pan-KRAS programme, coded ERAS-4, but this is now being discontinued and replaced by Joyo’s ERAS-4001, another pan-KRAS approach. Pan-KRAS inhibition is becoming a hot theme, and competing assets include Revolution’s RM-6236 and BridgeBio’s BBO-11818.

The terms of Erasca’s Joyo deal call for a $12.5m up-front payment, which is in line with the company’s other deals and reflects the preclinical status of the two assets involved. An IND filing for ERAS-4001’s first-in-human Borealis-1 trial, in patients with KRAS-mutated solid tumours, is expected in the first quarter of next year.

Meanwhile, the other Joyo project now in Erasca’s hands is ERAS-0015, described as as pan-RAS molecular glue. This type of mechanism involves the bringing together of two proteins that normally wouldn’t interact, and Monte Rosa Therapeutics, for instance, is using it to cause protein degradation.

Next year Erasca also plans an IND filing to start ERAS-0015’s Auroras-1 study in RAS-mutant solid tumours. Interestingly, the company earlier used Auroras-1 as the name of a first-in-human trial of the KRAS G12C inhibitor ERAS-3490/ERAS-1, but this never got under way as the project was discontinued last June, with Erasca citing an “increasingly competitive landscape”.

At the same time the company axed three preclinical assets, including the internally discovered SOS1 inhibitor ERAS-9, and highlighted ERAS-7 as key pipeline project, along with naporafenib.

A third cull

Five months later brought another R&D cull, as three projects were discontinued, including the SHP2 inhibitor ERAS-601, which in its phase 1 Flagship-1 study was said to have achieved confirmed responses with and without Erbitux, but these were deemed insufficient to justify development.

Erasca’s Nasdaq float raised $345m in mid-2021, on the back of a focus on RAS/MAPK pathway-driven cancers – and that was before the Novartis deal brought in naporafenib. While yesterday’s deal sees Erasca doubling down on RAS inhibition, the SHP2 and SOS1 discontinuations show that the company won’t pursue this at all cost.

This is especially relevant given how crowded a space KRAS inhibition has become, something that sets a high bar for the Joyo assets to meet to warrant their continued development. But with Erasca now trading nearly 90% off its IPO price it might not have many more chances at transformation.

How Erasca has grown and shrunk its R&D pipeline

Source: OncologyPipeline.