EHA 2021 – Curis’s renaissance continues

Results in a handful of patients raise hopes again for Curis's blood cancer project CA-4948, but it is still early days.

In December, six patients’ worth of data boosted Curis’s stock more than fivefold. Yesterday, results in another three patients added 66% to the company’s market cap and raised hopes that the group could have a viable project in the oral Irak-4 inhibitor CA-4948.

But it is early days for the asset and Curis still has a lot to do. The data, detailed in a EHA abstract, come from a phase 1/2 study in patients with acute myelogenous leukaemia or myelodysplastic syndrome: in nine evaluable subjects, there were two complete responses and two bone marrow complete responses.

The patients in question received CA-4948 monotherapy dosed at 200mg, 300mg or 400mg twice daily. Curis is backing away from a 500mg twice-daily dose following two grade three adverse events, of rhabdomyolysis and syncope, in the trial.

Curis executives said during a conference call yesterday that they had been on the lookout for rhabdomyolysis after seeing it previously in a study in non-Hodgkin lymphoma, at a 400mg twice-daily dose. They do not appear to believe that this is a problem with the lower doses in AML/MDS.

The company now has to figure out which dose to take into phase 2, with the execs saying that all three “look therapeutic”. When asked, they would not give details on which dose or doses led to the CRs, saying this information would be presented at EHA.

Spliceosome mutants

As for which patients to target, Curis believes it might have found a suitable population for monotherapy: those with spliceosome mutations. There were three such patients in the dataset and all achieved a marrow CR or better.

The company also plans to evaluate CA-4948 combinations, which it believes could be appropriate for all comers in AMS/MDL.

To this end, Curis is expanding its phase 1/2 trial to include combos of CA-4948 and either azacitidine or Venclexta; the study will also feature four new monotherapy cohorts, focusing on patients with and without spliceosome and Flt3 mutations.

In NHL, combinations are apparently the way forward, with Curis's phase 1/2 trial here now focused on CA-4948 plus Imbruvica; initial combo data are due in the fourth quarter. And an investigator-sponsored trial is also evaluating CA-4948 in low-risk MDS patients.

Curis, whose market cap now sits at nearly $1.5bn, has a lot riding on CA-4948. Its next most advanced asset is the anti-Vista monoclonal antibody CI-8993, on which phase 1 data is due in the second half of the year. Two further clinical-stage assets are on ice after earlier disappointments.

Still, the group is way ahead in the Irak-4 space in oncology. Plenty of others are looking at the mechanism, but in autoimmune diseases.

Curis's pipeline
Project Description Setting Status
CA-4948* Irak-4 inhibitor AML/high-risk MDS, +/- azacitidine or venetoclax Ph1/2, monotherapy data reported
NHL + Imbruvica Ph1/2, monotherapy data reported
Low-risk MDS Ph2 Lucas trial started Feb 2021^
CI-8993** Anti-Vista antibody Solid tumours Ph1 to report initial data in H2'21
Fimepinostat HDAC/PI3K inhibitor TBD Ph1 trial + venetoclax in DLBCL discontinued Mar 2020; group "evaluating future studies"
CA-170* PD-L1/vista inhibitor TBD Data disappointed in mesothelioma; group "evaluating future studies"
CA-327* PD-L1/Tim3 inhibitor PDL1/TIM3-expressing cancers Preclinical
*IP licensed from Aurigene; **Exclusive option to license IP from Immunext; ^Sponsored by Universität Leipzig. Source: Evaluate Pharma, clinicaltrials.gov, company presentation.

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