MASP-3 Inhibitor Demonstrates Clinical Efficacy in Paroxysmal Nocturnal Hemoglobinuria

Jens Panse, MD

OMS906, a MASP-3 inhibitor, normalized hemoglobin (Hgb), lactate dehydrogenase (LDH), and reticulocytes levels in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to interim analysis findings from a proof-of-concept study (NCT05889299) that were presented at the 2023 EHA Congress.

OMS906 led to transfusion independence in the majority of patients with PNH enrolled so far on the trial (n = 10).

PNH, a rare and life-threatening blood disorder, is characterized by the absence of surface proteins CD55 and CD59 resulting in hemolytic anemia. This can cause debilitating anemia, increased mortality, fatigue, and thrombosis, if left untreated.

Previously, complement component 3 (C3), complement factor B (CFB), and complement factor D (CFD) inhibitors have shown prevention of extravascular hemolysis. Pro-CFD is exclusively activated by MASP-3, which then continuously generates mature CFD. MASP-3 inhibition blocks the alternative pathways CFD, CFB, and C3.

“MASP-3 is a key activator of the alternative pathway and a novel target for PNH treatment,” Jens Panse, MD, from University Hospital RWTH Aachen, Aachen, Germany, explained in his presentation.

OMS906, a highly selective humanized IgG4 monoclonal antibody, is being investigated in patients with PNH because it binds to and inhibits MASP-3. This was seen in a phase 1 study of healthy patients at 5 mg/kg subcutaneously (SC), where it was well tolerated and provided substantial MASP-3 inhibition through day 42. OMS906 can be given as SC or intravenous treatment.

In this phase 1b proof-of-concept trial, after a screening period, OMS906 was given as 13 SC treatments of 5 mg/kg every 4 weeks. The treatment period would be up to 48 weeks and the follow-up period and end-of-study visit would be 8 weeks after the last dose of OMS906. The interim data cutoff was May 29, 2023. Primary and key secondary end points, respectively, were safety and tolerability, and preliminary efficacy by effect on hemolysis and anemia.

Patients on the trial had to be 18 years or older with a confirmed PNH diagnosis through flow cytometry—meaning red blood count clone size of more than 10%—be naïve to complement inhibitor treatment, have Hgb of less than 10.5 g/dL, LDH of more than 1.5 the upper limit of normal, and have received vaccination for Neisseria meningitidis.

At the interim analysis, patients on this trial without myelodysplastic syndrome (n = 8) reached gender-normal Hgb levels. All 10 patients had an increase in Hgb of 2 g/dL or more, and the 8 patients without myelodysplastic syndrome achieved Hgb of 12 g/dL or more. No patients required transfusions following the initiation of OMS906 treatment.

Normalization of LDH was seen in 7 of the 10 patients. There were 2 patients who had increases in LDH, 1 of which was due to COVID-19 infection near the beginning of enrollment, but their LDH level went back down again after, according to Panse. These increases in LDH for the 2 patients could suggest initiation of hemolysis at the end of a dosing period, but Hgb was not reduced in either patient. To achieve once-quarterly dosing, the pharmacokinetics and pharmacodynamics from the patients investigated so far will help inform planned dose escalation.

At all timepoints, mean absolute reticulocyte counts were reduced from baseline by 90 to 133 × 10⁹/L. Nine patients achieved normalization of reticulocyte counts.

OMS906 was well tolerated, with no safety signals of concern. There were no instances of clinical breakthrough hemolysis, major adverse vascular events, or serious adverse events. Those with reported cytopenia had evidence of underlying bone marrow failure. There was 1 grade and 1 grade 4 event of increased thrombocytopenia. Two patients had grade 3 transient neutropenia, and 1 patient had a grade 3 reduction in neutrophils. All other events were grade 1 or 2.

Current enrollment for this study occurred between December 20, 2022, and April 3, 2023. Out of the 10 patients who received OMS906, all received at least 1 dose, 9 received 2 or more doses, 8 received 3 or more doses, 4 received 4 or more doses, and 3 received 6 doses.

“Importantly, the study provided treatment access for patients with PNH who had no other options available,” Panse said.

Investigation of OMS906 in patients with PNH will continue by exploring treatment in those with GPI-deficient disease with suboptimal response to C5 inhibitors or who are naïve to complement inhibition. C5-switchover trials and C3G trial are currently underway, as well as evaluations of additional alternative pathway-mediated indications.

Reference

Kamabeda O, Gavriilaki E, Nangia N, Whitaker S, Panse. OMS906, a mannan-binding lectin-associated serine protease-3 (MASP-3) inhibitor, normalizes hemoglobin levels in treatment-naïve PNH patients: interim data from a proof-of-concept clinical trial. HemaSphere. 2023;7(S3):LBA2714