Who will follow Curis’s clinical validation?

When Curis recently dribbled out preliminary case reports from an uncontrolled study of CA-4948 its resulting fourfold share price surge looked like an overreaction. Then again, the human data supported something the company had proposed preclinically years earlier: that inhibiting Irak-4 could be an anticancer strategy.

There are other industry projects targeting this protein kinase in clinical development, some more advanced than Curis’s, but crucially CA-4948 is the only one being tested in cancer. The question for biopharma now is whether any of the other players targeting this mechanism pick up Curis’s theme.

The typical setting for Irak-4 inhibition is autoimmune diseases like rheumatoid arthritis (RA). This is due to the kinase’s activating effects on cytokine production, and the fact that pro-inflammatory cytokines play a role in driving RA.

And the industry’s most advanced Irak-4 inhibitor, Pfizer’s PF-06650833, has yielded positive early data in RA; its lead indication in phase II is the skin disorder hidradenitis suppurativa. The other four clinical assets, from Rigel, Bayer and Gilead, are being studied in disorders including psoriasis and inflammatory bowel disease.

Oncogenic?

However, back in 2017 Curis presented preclinical data at AACR suggesting potential for CA-4948 in acute myelogenous leukaemia and myelodysplastic syndromes. This, it was later claimed, was because an Irak-4 variant, driven by various mutations, is oncogenic and preferentially expressed in AML and MDS.

Two weeks ago the company put clinical evidence behind the scientific hypothesis, reporting that a monotherapy trial that dosed its first patient in October had yielded marrow complete remissions in two subjects, one with MDS and the other with AML.

The other four subjects had also shown reductions in marrow blasts. Additional phase I data are to be reported in the second half of 2021, presumably at a meeting like Ash.

So who will follow suit? Surprisingly, none of the leading Irak-4 players has picked up the theme of Curis’s 2017 AACR presentation.

In 2019 Kymera Therapeutics announced preclinical data for an oral Irak-4 degrader, KYM-001, in MYD88-mutated lymphoma. But this project has not progressed into the clinic, and when a year later it was licensed to Sanofi for $150m up front the deal was limited to immune-inflammatory diseases, with Kymera retaining rights to oncology indications.

Another preclinical project, the subject of a 2014 tie-up between TG Therapeutics and Ligand Pharmaceuticals, targets oncology as well as autoimmune use, and at the 2015 AACR meeting the companies presented evidence of monotherapy and combinatorial activity in lymphoma.

However, this too has yet to progress into human trials. What is worse, Ligand originally gained rights to the Irak-4 programme via its 2008 acquisition of Pharmacopeia; not only is 12 years a rather long time to spend in preclinical development, the timeline raises questions about the project’s patent exclusivity.

It would seem that for now Curis has a head start. The pressure is on for it to show that the first case reports were not a fluke.