PXS5505-MF-101: A Phase 1/2a Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Pxs-5505 in Patients with Primary, Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis

Background: Myelofibrosis (MF) is characterized by a progressive increase in extracellular matrix in the bone marrow (BM) associated with decreased production of hematopoietic cells. Though Janus kinase (JAK) inhibitors provide clinical benefit in patients (pts) with MF, they have no direct effect on BM fibrosis (BMF) and thereby limited disease modifying effects. MF is associated with elevated expression of most lysyl oxidase (LOX) isoforms which cross link collagen and elastin. PXS-5505 is a pan-LOX inhibitor that prevents the cross-linking of collagen and elastin and exhibits anti-fibrotic effects in murine models of MF. PXS5505-MF-101 is an ongoing multi-center phase 1/2a study of PXS-5505 in pts with primary, post-polycythemia vera (PV) or post-essential thrombocythemia (ET) MF. (NCT04676529) The study started with two phases: Dose Escalation (DEP) and Cohort Expansion (CEP). The DEP has been completed, establishing a dose of 200mg BID to carry forward into the CEP. During the CEP, up to 24 pts are to be treated for 6 months. Preliminary data from the CEP is presented here. Methods: Study objectives are to determine PXS-5505 safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), BMF changes, spleen volume and MF symptoms (MFSAF). Eligible pts must have primary or post-ET/PV MF of Int-2/high risk; relapsed/refractory or intolerant/ineligible to available JAK inhibitors and have symptomatic disease. Results: At data cutoff (30/Jun/2023), 21 pts have enrolled in the CEP (7 F and 14 M); age 60-86 yrs (median 72 yrs); of these, 10 have completed 24 weeks of Rx and 20 pts have completed ≥1-month Rx. 8 pts had post-ET MF, 5 post-PV MF and 8 PMF; 9 pts have withdrawn from the CEP. Total drug exposure in the CEP is 372 weeks, median 162 days (min 25, max 191). Preliminary CEP PK data are consistent with the DEP with steady state reached by Day 28 with no accumulation observed past this point. The PD data from the DEP demonstrated excellent inhibition of LOX as measured by LOX and LOXL2 target engagement (data previously presented) and this level of inhibition continues to be observed in CEP. [Figure 1] All 9 pts completing 24 weeks PXS-5505 with baseline (BL) biopsies available showed stable reticulin fibrosis at each visit; collagen fibrosis was reduced in 5/9 pts. [Figure 2] Hematological parameters were stable; 7/10 pts had stable/improved hemoglobin and 8/10 had stable/improved platelets over 24 weeks including 3 pts with Grade 4 thrombocytopenia at BL. 4/10 pts had improvements in MF-SAF TSS of ≥20% with 2/10 pts of ≥40% at 24 weeks. No SVR35 responses were seen. There has been 1 fatal AE (febrile neutropenia) on Rx, and 2 post-Rx discontinuation/completion (sepsis, acute myocardial infarction), all unrelated. There have been 6 Rx related adverse events (TRAEs); 2 Grade 1 (vomiting, urticaria), 2 Grade 2 (purpura, hypomagnesaemia), 1 Grade 3 (platelet count decreased), 1 Grade 4 (anemia, noted as leading to drug withdrawal). There have been no serious TRAEs reported. Enrolment into the CEP continues and an additional cohort is planned using PXS-5505 as an add-on to Ruxolitinib Rx. Conclusion: PXS-5505 has been well tolerated with no dose limiting toxicity or serious TRAEs. PD results indicate excellent LOX inhibition at the 200mg BID level. Further, there are preliminary indications of disease modification characterized by stable/improved blood counts and an improvement in collagen fibrosis. These results are encouraging given the poor prognosis seen after Ruxolitinib discontinuation in pts with MF and warrant continued investigation in an earlier Rx setting.