Session: 508. Bone Marrow Failure: Acquired: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Bone Marrow Failure Syndromes, Clinical Research, Paroxysmal Nocturnal Hemoglobinuria, Diseases
Methods: This is an ongoing, single-arm, open-label, Phase 2 proof-of-concept clinical trial (NCT05972967) evaluating safety, PK/PD, and preliminary efficacy of zaltenibart in adult pts with PNH experiencing persistent anemia on ravu. Primary endpoints are safety and tolerability; secondary endpoints include change from baseline in Hb and ARC, number of transfusions, and PK/PD measures. Eligibility criteria include confirmed PNH diagnosis by flow cytometry (RBC and/or granulocyte clone size >10%) and suboptimal response to ravu (baseline Hb <10.5 g/dL despite 4 months of ravu). Pts continued ravu at weeks 0, 8, and 16 with concurrent zaltenibart dosing. Clinical responders (Hb increase ≥2.0 g/dL) to the combination at week 24 (study day d169) continued on 5 mg/kg IV Q8W zaltenibart monotherapy or treatment with both ravu and zaltenibart 5mg/kg. Here we report interim results for pts receiving ≥1 dose of zaltenibart monotherapy.
Results: Thirteen pts were initially enrolled (7 female, mean age 53.2 yr [range 23-80]); 1 discontinued due to a treatment-emergent serious adverse event (SAE) (elevated ALT and bilirubin). Six pts received RBC transfusions prior to treatment with zaltenibart. As of the interim data cut-off (July 8, 2024), 10/12 pts (83%) are on zaltenibart monotherapy. During the adjunctive phase, pts experienced rapid and sustained responses to zaltenibart with marked improvements in Hb from baseline (mean baseline=9.26 g/dL, mean increase=3.39 g/dL at d29 and 3.27 g/dL at d169; N=13). This response was sustained following initiation of zaltenibart monotherapy on d169 (mono dose #1): mean Hb was 13.31 g/dL at d197 (4 weeks post-mono dose #1; N=10) and 12.72 g/dL at d225 (pre-mono dose #2; N=10). Hb was 12.36 g/dL at d281 (pre-mono dose #3; N=7) and 12.77 g/dL at d309 (4 weeks post-mono dose #3; N=6), a 3.85 g/dL increase from initial study baseline (P=0.003). Five of these 6 pts (83.3%) achieved Hb >12 g/dL and >2 g/dL improvement. At d309, mean ARC decreased and normalized from baseline by -114 ×109/L to mean=112 ×109/L (N=6; P=0.003); all but 1 pt remained transfusion-free. Overall, zaltenibart was well tolerated. Treatment-related adverse events (AEs) were observed in 46.2% of pts and were mostly mild-moderate grade. Treatment-emergent AEs occurring in >10% of pts were headache (53.9%), oropharyngeal pain (30.8%), fatigue, cough, and thrombocytopenia (all 23.1%), followed by COVID-19, nasopharyngitis, nasal congestion, cystitis, arthralgia, abdominal discomfort, and EVH (all 15.4%). There was one case of breakthrough hemolysis secondary to ear infection (SAE not related to treatment), which required a blood transfusion. No MAVEs, meningococcal infections, or deaths were reported.
Conclusion: MASP-3 inhibitor zaltenibart 5mg/kg IV Q8W monotherapy was well tolerated with no safety signals of concern in pts with PNH experiencing substantial EVH with ravu. Zaltenibart monotherapy resulted in sustained clinically meaningful improvements in Hb and ARC and prevented both IVH and EVH. Data from this interim analysis support the potential for zaltenibart as monotherapy for treating PNH in pts with suboptimal response to C5 inhibitors.
Disclosures: Griffin: Regeneron Pharmaceuticals: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees. Kelly: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Florio: Consultancy, Honoraria, Speakers Bureau; Otsuka: Consultancy, Honoraria, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biologix: Speakers Bureau; Astellas: Speakers Bureau. Muus: Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis Global: Membership on an entity's Board of Directors or advisory committees; Novartis UK: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sobi Middle East: Speakers Bureau. Hoechsmann: Novartis: Honoraria; Sobi: Honoraria; Roche: Honoraria; Omeros: Honoraria; Pfizer: Honoraria; Alexion: Honoraria. Cummings: Omeros Corporation: Current Employment. Efthimiou: Omeros Corporation: Current Employment. Pullman: Omeros Corporation: Current Employment. Schrezenmeier: Apellis: Other: Fees; F. Hoffmann-La Roche: Other: Fees; Omeros: Other: Fees; Sobi: Other: Fees and travel support, Research Funding; Sanofi: Other: Fees; Novartis: Other: Fees and travel support, Research Funding; Alexion, AstraZeneca Rare Disease: Other: Fees and travel support, Research Funding; Amgen: Other: Fees. Panse: Swiss Biopharma: Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Current equity holder in publicly-traded company, Honoraria; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Consultancy, Current equity holder in publicly-traded company, Honoraria; MSD: Consultancy, Current equity holder in publicly-traded company, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland., Speakers Bureau; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Current equity holder in publicly-traded company; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.