Multicenter, Open-Label Phase 1/2a Study of Pxs-5505 and Ruxolitinib in Patients with Primary, Post-Polycythemia Vera (PV) or Post-Essential Thrombocythemia (ET) Myelofibrosis
Authors: Tan Peter , Baker Ross , Lee Sung-Eun , Watson Anne Marie , Cheung Stanley , Wu Shang-Ju , Chen Chih-Cheng , Tan Shuhying , Vachhani Pankit , Chen Tsai-Yun , Lee Jae Hoon , Hsiao Hui-Hua , Lee Ji Yun , Lee Won Sik , Masarova Lucia , Baskar Jana , Jarolimek Wolfgang , Leadbetter Joanna 
Published: December 2024

Background:
PXS-5505 is a pan-lysyl oxidase (LOX) inhibitor that prevents the cross-linking of collagen and elastin and exhibits anti-fibrotic effects in murine models of myelofibrosis (MF). While JAK2 inhibition has become a standard treatment for MF, it has no direct effect on BM fibrosis nor on lysyl oxidase mediated cell signaling or gene expression changes. Thus, a pan-LOX inhibitor such as PXS-5505 combined with a JAK inhibitor may help to modify the MF disease trajectory by reversing BM fibrosis, normalizing blood counts and reducing mutational burden. PXS5505-MF-101 is an ongoing phase 1/2a study in patients (pts) with intermediate or high-risk MF (NCT04676529).
The study consists of 3 phases: Dose Escalation (DEP), Cohort Expansion (CEP) and an Add-on (AOP). The DEP and CEP are complete, establishing a monotherapy dose of 200mg BID with strong target engagement over a 24-week treatment period that was well tolerated and with no dose limiting toxicity or adverse events of concern.
Herein, we present the AOP study design and preliminary data where PXS-5505 is given in addition to ruxolitinib (RUX) over 52 weeks to determine safety and tolerability and assess the impact of PXS-5505 on RUX dosing and disease-related parameters.
Methods:
Eligible pts must have PMF or post-ET/PV MF, intermediate-2/high risk disease by DIPSS (including those with severe thrombocytopenia) and have been treated with RUX for at least 12 weeks prior to first administration of PXS-5505. The pts must be on a stable dose of RUX for ≥ 8 weeks prior to study treatment, have not achieved complete remission by IWG criteria and be symptomatic (MFSAF v4.0 score of ≥10).
Pts participating in the AOP are required to have a BM biopsy within 3 months prior to Day 1 treatment. Pts will receive PXS-5505 200mg BID for up to 52 weeks or until progressive disease, unacceptable toxicity, dose limiting toxicity or withdrawal of consent. Fifteen pts are planned to be enrolled in this phase of the study.
Patients are allowed to vary RUX dose during the study, and any pt that discontinues RUX will be allowed to continue treatment with PXS-5505 at the Investigator's discretion.
Results:
As of 31 of July 2024, AOP completed planned enrollment with 15 pts enrolled and treated (median age 72 years [range 46-82]). Of the treated patients, 47% were male; 2 had post-ET MF, 7 post-PV MF, 6 PMF, 3 were high risk and the remainder were Int-2 risk. The median time since MF diagnosis was 58 months (range 6.5-&gt;120), with median MPN-SAF TSS of 22.5 (range, 10-52). Median duration of previous RUX therapy was 26 months (range, 3.5-74) and the median daily dose of RUX at study entry was 20mg (range 5 -40 mg) with 13 pts having a best response of stable disease as per IWG on RUX at BL. BL median spleen volume was 1353 cm3 (n=14). Median BL hemoglobin was 94 g/dL (range, 66 - 132 g/dL) and 11/15 had hemoglobin &lt;100 g/dL at BL. Two pts were transfusion-dependent at enrollment; 40% of pts had platelet levels below 100x109/L. Of the 11 patients with available BL mutation profile, 7 had a JAK2 V617F mutation and 6 had ≥1 high risk mutation (ASXL1, EZH2, SRSF2, IDH1/2, U2AF1).
Updated efficacy and safety data will be presented at the conference including 12-week data from all pts.
Conclusion:
The results from this trial using a novel combination of PXS-5505 and RUX will add to the existing safety profile of PXS-5505 and provide preliminary indicators of efficacy to help inform future investigations of PXS-5505 in pts with MF.