Shattuck gears up for go/no go year

So far, efforts to inhibit CD47 have disappointed, despite billions of dollars being spent on acquisitions in this space. Shattuck Labs reckons its lead project, SL-172154, could succeed where others have stumbled, thanks to differences in design – and several readouts due this year should give an idea whether the company is on the right track. 

Shattuck’s stock has more than quadrupled since it reported early data in December with SL-154 in first-line acute myeloid leukaemia and high-risk myelodysplastic syndrome. However, the company still has a market cap of under $500m, suggesting that investors remain wary about the group and CD47 inhibition more broadly.

The ghost of magrolimab

A cautionary tale in CD47 is Gilead’s magrolimab, gained through the $4.9bn acquisition of Forty Seven, and now effectively on the scrapheap. That project is a straightforward monoclonal antibody, as is I-Mab’s lemzoparlimab, which AbbVie walked away from last year.

Amazingly, there is still plenty of activity here, however, with several companies, including Shattuck, ALX Oncology and Pfizer (via its purchase of Trillium), developing SIRPα fusion proteins designed to block CD47.

A key difference with Shattuck’s is 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. 

Shattuck now needs to prove that these differences have an impact in the clinic. SL-154 is in two phase 1 trials, one in platinum-resistant ovarian cancer, alongside liposomal doxorubicin or Immunogen’s Elahere, and the other in AML with TP53 mutations and high-risk MDS.

For all four cohorts Shattuck has been clear about what it wants to see to justify pressing ahead – and durability will be particularly important, its chief executive, Taylor Schreiber, tells ApexOnco ahead of the readouts.

Expectations for upcoming readouts with Shattuck’s SL-172154

Note: PROC=platinum-resistant ovarian cancer. Source: company communications & JP Morgan 2024 presentation.

In platinum-resistant ovarian cancer Shattuck cites the 4% ORR seen with pegylated liposomal doxorubicin alone in Pfizer’s failed Javelin Ovarian 200 trial of Bavencio. But durability targets will also have to be met to spur a go decision, Schreiber emphasises.

Meanwhile, investors have yet to see results with an SL-154/Elahere combo. Here, Shattuck is looking to exceed benchmarks set by the ImmunoGen drug, “probably more importantly on duration of response”. With Elahere soon to be in AbbVie’s hands, it is unclear where those data might be presented.

AML and MDS

In first-line TP53m AML, a disease subtype with particularly poor prognosis, there are two existing benchmarks: azacitidine alone, which historically has produced complete response rates of less than 10%, and Venclexta plus azacitidine, which is linked with around a 30% CR rate. Both regimens lead to overall survival of around six months – a number Shattuck must exceed to progress.

Meanwhile, in high-risk MDS, Schreiber points to the 22% complete response rate seen with azacitidine alone in Aprea’s failed phase 3 trial of eprenetapopt in patients with TP53 mutations. Shattuck believes that this is an appropriate benchmark because all but one of the 14 evaluable MDS patients in its trial also had this genetic subtype.

Shattuck has already disclosed plans for a phase 3 trial in TP53m AML and high-risk MDS, expected to start in early 2025. 

First, though, the group is planning a dose-optimisation trial in high-risk MDS, testing two doses of SL-154 plus azacitidine versus azacitidine – which will be the first time Shattuck’s project has gone up against an internal control.

This might give a better idea of the project’s chances than historical benchmarks. But if, in the meantime, Shattuck hits the targets it has set, it could help spur renewed interest in CD47.