OMS906, A NOVEL ALTERNATIVE PATHWAY MASP-3 INHIBITOR, IMPROVED HEMATOLOGIC PARAMETERS in PNH PATIENTS with SUBOPTIMAL RESPONSE to RAVULIZUMAB TREATMENT: PHASE 2 DOSE-FINDING STUDY INTERIM RESULTS.
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All Authors
Griffin, M.
Kelly, R.J.
Gavillet, M.
Muus, P.
Hochsmann, B.
Cummings, W.J.
Humphreys, J.
Philpot, E.
Efthimiou, J.
Pullman, W.
LTHT Author
Griffin, Morag
Kelly, Richard
Muus, Petra
Kelly, Richard
Muus, Petra
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , ANAEMIA , ANAEMIA, APLASTIC , BACK PAIN , CLINICAL TRIALS AS TOPIC , COVID-19 , DIAGNOSIS , DRUG DOSAGE CALCULATIONS , DRUG THERAPY , FATIGUE , WOMEN , HEADACHE , ANAEMIA, HAEMOLYTIC , MEN , NOSE DISEASES , OROPHARYNX , BLOOD CELL COUNT , COMMON COLD , THROMBOCYTOPOENIA , BILIRUBIN , HAEMOGLOBINS , ANTIBODIES, MONOCLONAL
Subject Headings
Abstract
Background: PNH is a life-threatening hemolytic disorder driven by dysregulation of the complement system. C5 inhibition attenuates intravascular hemolysis (IVH) but often induces extravascular hemolysis (EVH). Proximal inhibitors targeting complement's alternative pathway (AP) block IVH and prevent EVH, as shown with C3, Factor B and Factor D inhibitors. Mannanbinding lectin-associated serine protease-3 (MASP-3) is an upstream activator of Factor D. OMS906, a highly selective humanized mAb that binds to and inhibits MASP-3, has been shown to normalize hemoglobin (Hb), lactate dehydrogenase (LDH), and absolute reticulocyte counts (ARC) in anti-complement treatment-naive pts with PNH. Aim(s): Evaluate safety and efficacy of repeat-dose OMS906 in adult PNH pts with persistent anemia on ravulizumab (ravu). Method(s): This is an ongoing single-arm, open-label, Phase 2 proof-of-concept clinical trial (NCT05972967); primary endpoints are safety and tolerability. Key secondary endpoints are change from baseline in Hb, LDH, ARC, and number of transfusions. Eligibility criteria include confirmed PNH diagnosis by flow cytometry (RBC clone size >10%) and suboptimal response to ravu (baseline Hb <10.5 g/dL despite >=2 doses [4 mo] of ravu). Pts continued ravu at wks 0, 8, and 16 with concurrent therapy of 3 or 5 mg/kg IV OMS906. Clinical responders (increase in Hb levels >=2.0 g/dL) at wk 24 are eligible to receive 5 mg/kg IV OMS906 as monotherapy or continue with concurrent therapy. We report preliminary results through wk 24. Result(s): As of Feb 7, 2024, 13 pts were enrolled and included in this pre-specified interim analysis (53.8% female; mean age 53.2 yr [range 23-80]); 1 pt discontinued due to a treatment-emergent serious adverse event (SAE, elevated ALT and bilirubin with prior elevated values). Six pts had prior history of aplastic anemia and 6 pts received RBC transfusions prior to OMS906 treatment. The initial cohort of 7 pts received >=2 doses of 3 mg/kg OMS906 before escalating to 5mg/kg; the next 6 pts started at 5 mg/kg OMS906. Five of 7 pts (71%) transitioned to monotherapy. OMS906 was well tolerated. Treatmentrelated AEs, observed in 38.5% of pts, were mostly mild-moderate grade. Most common treatment-emergent adverse events (TEAEs) in >=10% of pts were headache (46.2%), oropharyngeal pain (30.8%), thrombocytopenia (23.1%), EVH, back pain, COVID-19, fatigue, nasal congestion and nasopharyngitis (15.4% each). No pts met criteria for clinical breakthrough hemolysis. There were no other SAEs (1 case with abnormal LFTs), no MAVEs, meningococcal infections, or deaths. Following OMS906, mean Hb increased from baseline by 3.39 g/dL (N=13, P<0.001) at wk 4 and 3.27 g/dL (N=7, P<0.001) at wk 24. By wk 4, 12/13 pts (92.3%) achieved clinical response, including 6/6 (100%) of those treated with 5 mg/kg. Mean ARC decreased from baseline (230 x109/L) by-150 x109/L at wk 4 (N=13, P<0.001) and was sustained to wk 24 (-110 x109/L, N=6, p=0.01). All pts were free from transfusion following OMS906 treatment. The 3 mg/kg dose did not demonstrate sufficient durability, while 5mg/kg showed greater magnitude of response at wk 4 post dose and greater durability to the next dose (wk 8), consistent with the expected PK/PD profile of OMS906. Summary/Conclusion: MASP-3 inhibitor OMS906 added to ravu was well tolerated with no safety signals of concern in PNH pts who were experiencing substantial EVH on ravu monotherapy. Rapid improvement in Hb and reduced ARC demonstrate OMS906 prevents EVH. Dose range and frequency of OMS906 are being further explored, including the potential of OMS906 as monotherapy for PNH.
Journal
HemaSphere