Elritercept, an inhibitor of activin A and other select TGF-β superfamily ligands, appears to be useful in improving haematopoiesis and reducing symptoms and transfusion requirements in patients with myelofibrosis and a high disease burden.
Results from the phase two RESTORE trial were presented at ASH 2024 meeting in San Diego, which recruited 73 patients into either an elritercept monotherapy arm for those who were JAK inhibitor relapsed, refractory, intolerant or ineligible or to combination therapy with elritercept as an add-on therapy to ruxolitinib.
Patients included those who were transfusion dependent and those who were non-transfusion dependent, anaemic and with a platelet count ≥25 x109/L.
Median age was 72 years, patients were mostly male (64.4%) and most were at intermediate risk (76.7%) according to their DIPSS score. A JAK2 mutation was common (58.9%) and 75.3% of patients had prior use of a JAK inhibitor.
The study found elritercept – a modified activin receptor type IIA ligand trap – was generally well tolerated with the most frequently reported TEAEs including thrombocytopenia (20.5%) and diarrhoea (19.2%).
“Unfortunately, six participants have had treatment-emergent adverse events leading to death. None of these were deemed related to study treatment and reflect the patient population being recruited,” said study investigator Professor Claire Harrison, from Guy’s and St Thomas’ NHS Foundation Trust in the UK.
Regarding efficacy, the study found elritercept, both as monotherapy and as add-on therapy, increased haemoglobin levels “supporting potential to address both ruxolitinib-associated anaemia and anaemia due to underlying myelofibrosis”.
Similarly, elritercept reduced the transfusion burden in both treatment arms.
“Concerning the entire dosing cohort, 16 of 41 patients had a reduction of at least 50% and 10 of those patients achieved transfusion independence,” Professor Harrison said.
She said platelet counts were generally maintained or improved in participants in both arms including in those with thrombocytopenia at baseline.
Elritercept therapy reduced spleen volume, particularly in combination with ruxolitinib.
Treatment also reduced the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and individual MPN-SAF TSS symptoms in both arms of the study.
Pipeline
Professor Harrison told the limbic after her presentation at ASH 2024 that patients with myelofibrosis were heterogeneous but all had unmet needs.
“So some patients have an unmet need in terms of a big symptom burden. Some patients have an unmet need in terms of needing a lot of transfusions. All patients have the unmet need that we need to do better with treatments, and we want to be able to modify their disease a bit better.”
She said myelofibrosis was a very complex disease with a lot of different biological targets.
“So at this meeting, we’ve seen the pim inhibitor, we’ve seen TGF-beta family inhibitors, we’ve seen the lysyl oxidase inhibitor… [and] we saw MDM2 inhibitors and we’ve seen T-regs infusions. So we’re trying lots of different techniques. I just think we’re waiting for the break, and I don’t think we saw it at ASH this year, but there are lots of therapies under development that are potentially super exciting.”
“I’m really looking forward to, for example, seeing in the next year the outcome with mutation-specific therapies, particularly therapies targeting calreticulin (CALR) mutations.”
“So this afternoon, we saw some data from an investigator in the UK who’s developed a CAR T-cell targeting calreticulin but we’ve also got ongoing studies with antibodies and bispecific antibodies targeting calreticulin. We’ve got more specific JAK inhibitors as well targeting the V617F mutation etcetera, so all of those things are coming in the pipeline.”
The RESTORE study was funded by Keros Therapeutics. Australian co-investigators included Dr Lynette Chee from the Royal Melbourne Hospital, Dr David Ross from the Royal Adelaide Hospital and Dr Shuh Ying Tan from St Vincent’s Hospital Melbourne.
Very encouraging data on a multifaceted drug, elritercept, from the RESTORE trial in MF (n=73) expertly presented by @harrisoncn1 at #ASH24. Hgb responses, TI, spleen and symptom responses all seen. Eagerly await US trials of this promising agent! #MPNSM
— Prithviraj Bose (@bose_prithviraj) December 10, 2024