Background Myelofibrosis (MF) is associated with elevated expression of lysyl oxidases, a family of enzymes responsible for maturation of the most abundant extracellular matrix (ECM) proteins, collagen and elastin. Amsulostat (PXS-5505) is a novel pan-lysyl oxidase inhibitor that works to improve the bone marrow microenvironment via a multifaceted mode of action. In addition to mediating extracellular structural effects, amsulostat also reduces intracellular proto-oncogene growth factor signaling.

PXS5505-MF-101 (NCT04676529) is a multi-center Phase 1/2a study of amsulostat in MF patients (pts). In the Add-On Phase (AOP) of this study, amsulostat 200 mg BID was given in addition to ruxolitinib (RUX) over 52 weeks to assess safety and tolerability and determine the impact of amsulostat on disease-related parameters. As previously reported, 16 pts were recruited into this phase of the study. At 24 weeks, 11 pts remained on amsulostat treatment and all had improvements in symptom score, with 4 pts achieving a 50% reduction (TSS50). Early interim data suggested that longer duration of therapy may lead to additional improvements in symptoms and spleen volume reduction (SVR) (Watson, EHA 2025).

Methods Pts ≥ 18 yrs with intermediate-2/high risk PMF or post-ET/PV MF disease by DIPSS (including those with severe thrombocytopenia) treated with RUX for at least 12 weeks prior to first administration of amsulostat were eligible for enrollment. Pts must have been on a stable dose of RUX for ≥ 8 weeks prior to study treatment (but with no limitations on RUX dose); must not have achieved complete remission by IWG criteria and must have been symptomatic (MFSAF v4.0 score of ≥ 10). Amsulostat 200 mg BID was to be administered for up to 52 weeks. The RUX dose could be varied as clinically indicated during the study; additionally, if RUX was discontinued then the patient could continue treatment with amsulostat at the Investigator's discretion. The primary objectives during the AOP were safety and tolerability, with changes in symptom scores (MFSAF v4.0), spleen volume and bone marrow fibrosis also being assessed.

Results A total of 16 pts was enrolled into the AOP. The median duration of previous RUX treatment was 38 months (range 5–89)and the median total symptom score (TSS) score at baseline was 23 (range 10-52). Full baseline patient characteristics were previously reported (Watson, EHA 2025).

At 38 weeks, 8 pts were ongoing on amsulostat therapy; all 8 pts had improvements in symptoms relative to baseline, with a mean absolute reduction in TSS of 13. The mean % reduction was 56%, with 6 pts (75%) achieving TSS50. Two pts maintained the reduction seen at Week 24, while a further 5 pts experienced additional reductions beyond Week 24.

At 38 weeks, 1 pt who stopped ruxolitinib at Week 21 had a similar spleen volume (SV) to baseline. Reductions in SV were seen in the remaining 7 pts who were continuing on RUX in addition to amsulostat. Four of the 8 pts (50%) achieved an SV reduction of 25% (SVR25) at Week 38, with 3 pts (38%) achieving a 35% reduction (SVR35). Hemoglobin and platelet levels were generally stable during treatment. 1/2 transfusion dependent pts had > 50% transfusion reduction in > 1 rolling 12-week period (Minor anemia response) and 1/7 transfusion independent pts had > 10 g/L increase in Hb (Minor anemia response).

Amsulostat was well tolerated with no treatment related serious adverse events. The majority of treatment emergent AEs were mild, 63/84 (75%) ≤ Grade 2 (data cut-off 5th May 2025).

Efficacy and safety from the completed 52-week study will be presented at the conference.

Conclusion The complete data from the AOP will provide insight into the safety profile of amsulostat in combination with RUX and also whether longer durations of amsulostat provide additional efficacy benefits. This evidence will be used to plan a randomized controlled confirmatory trial of amsulostat in the treatment of MF.

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2025
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