EHA 2024 – Shattuck reassurances fall on deaf ears

Shattuck Labs spooked investors last month with the EHA abstract on its anti-CD47 asset SL-172154; full data presented at the conference were designed to reassure, with efficacy looking good and more details on the cardiovascular adverse events that caused consternation.

A fatal cardiac arrest and grade 4 myocardial infarction were deemed by Shattuck as unlikely related to therapy. Still, the company’s stock sank 10% on Friday, with investors clearly still cautious about the prospects for this project, and perhaps about CD47 targeting in general. 

While other efforts here, notably Gilead’s magrolimab, have imploded, Shattuck reckons SL-172154 could be differentiated, helped by the inclusion of a CD40L domain, which the company says activates macrophages and helps spur a T-cell response. Another important feature, shared with ALX’s evorpacept, is use of an inactive Fc domain, designed to reduce the risk of cytopenias, which have been seen with magrolimab, for example. 

Efficacy bars cleared

Evercore ISI analysts, for one, believe that the latest data have set Shattuck’s asset apart, both in terms of efficacy and safety.

The results, published in a poster at EHA on Friday, came from a phase 1 study, from cohorts testing SL-172154 plus azacitidine in first-line TP53-mutant acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS).

Ahead of the readout, Shattuck set out the response rate thresholds that it wanted to clear to justify further development in these indications – something it has now comfortably done.

Expectation vs reality: data on Shattuck’s SL-172154 in AML & MDS

Note: median duration of response and overall survival not reached by any cutoff date. Source: EHA.

The company also noted that, in TP53m AML, a 29% complete response rate exceeded the 11% or less seen historically with azacitidine monotherapy. In HR-MDS, the complete response rate was 42%, versus 22% with azacitidine alone in Aprea’s failed phase 3 trial of eprenetapopt.

Shattuck has also previously highlighted the importance of durability of effect, and here there is little to go on yet, with median duration of response not yet met for either cohort. The company plans to present durability data later this year.

Cardiovascular concerns calmed?

Evercore analysts said they were now “much more comfortable” on cardiovascular safety. They noted that the patient who died, in the AML cohort, should “never have been treated on study”; the subject had significant coronary artery disease including worsening arrhythmia. Although the death was deemed “possibly related” by investigators, Shattuck deemed it unlikely related.

It was a similar story for the patient with grade 4 myocardial infarction, who was in the HR-MDS group, and also had a history of heart disease. In addition, the heart attack was “secondary to sepsis driven by disease”, Evercore wrote.

The analysts added that there were no low-grade cardiac signals that might point to toxicity linked with SL-172154’s mechanism.

Still, investors will no doubt be keeping an eye on adverse events as Shattuck moves the project into more patients: the company has already begun a randomised, controlled dose-optimisation and expansion cohort in HR-MDS (part D), and is planning a randomised, controlled expansion cohort in TP53m AML (part E).

These could support accelerated approval, Evercore believes, but added that this hadn’t been confirmed with regulators. Shattuck has yet to disclose phase 3 plans.