A Phase 2 Dose-Finding Trial of MY008211A in Complement Inhibitor–Naive Patients with Paroxysmal Nocturnal Hemoglobinuria and Signs of Active Hemolysis

Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease characterized by red blood cell (RBC) destruction, blood clots, and impaired bone marrow function. We evaluated the efficacy and safety of 3 dosages of MY008211A, a complement factor B inhibitor, for treating PNH.

Methods: This was a multicenter, open-label, phase 2 dose-finding study of MY008211A conducted in China among men and women aged ≥18 years with complement inhibitor–naive PNH and signs of active hemolysis. Over an 8-week period, patients were initially screened for hemoglobin (Hb) concentration and other criteria; those who qualified received meningococcal and S. pneumoniae vaccinations if they had not been so vaccinated within 3 and 5 years, respectively. Patients with Hb <100 g/L were assigned to receive oral MY008211A 400 mg twice daily (bid), 600 mg bid, or 800 mg once daily (qd) for 12 weeks; patients could then enter a 32-week extension (not reported here). The primary endpoint (EP) was the proportion of patients who achieved an increase in Hb concentration of ≥20 g/L on day (D)84 compared to baseline, without RBC transfusions after the first 4 weeks of dosing. Secondary EPs included proportions of patients with Hb ≥120 g/L (without RBC transfusions), proportions of patients with hemolysis control (lactate dehydrogenase [LDH] levels <1.5 × upper limit of normal), and mean changes from baseline (CFBs) in Hb, LDH, reticulocyte count, indirect bilirubin, Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-F score), and PNH RBC clone levels. Safety assessments included incidence and severity of adverse events (AEs).

Results: Fifteen patients were assigned to MY008211A 400 mg bid, 9 to 600 mg bid, and 10 to 800 mg qd. Patient characteristics were similar across groups; overall, 19 of 34 patients were female, and mean age was 39.5 years. On D84, all 34 patients treated with MY008211A had achieved the primary EP of an increase in Hb concentration of ≥20 g/L from baseline. Six of 15 patients treated with 400 mg bid, 4 of 9 with 600 mg, and 2 of 10 with 800 mg achieved Hb ≥120 g/L. All 15 patients in the 400-mg, all 9 in the 600-mg, and 9 of 10 in the 800-mg groups achieved hemolysis control. Mean (standard deviation [SD]) CFBs in Hb were +44.7 (13.0) g/L with 400 mg, +43.6 (13.2) g/L with 600 mg, and +42.4 (14.4) g/L with 800 mg. Mean (SD) CFBs in LDH were −1672.3 (811.5) U/L with 400 mg, −1527.4 (418.8) U/L with 600 mg, and −1333.0 (392.2) U/L with 800 mg, and mean (SD) CFBs in reticulocyte count were −118.3 (67.0) × 10⁹/L, −84.3 (67.4) × 10⁹/L, and −90.9 (67.9) × 10⁹/L in the respective groups. Mean (SD) indirect bilirubin was reduced from baseline by 15.0 (9.5) µmol/L in the 400-mg, 14.5 (7.0) µmol/L in the 600-mg, and 11.8 (14.1) µmol/L in the 800-mg groups. The FACIT-F score improved from baseline by a mean (SD) 9.7 (11.8) points with 400 mg, 3.2 (6.1) points with 600 mg, and 8.7 (7.6) points with 800 mg. Mean (SD) CFBs in PNH RBC clone levels were 33.4% (15.7) with 400 mg, 29.6% (18.3) with 600 mg, and 35.7% (16.1) with 800 mg. There were no deaths, no drug-related serious AEs, and no treatment discontinuations. The most frequent AEs across dosages were headache (n=15 of 34 patients) and upper respiratory infections (n=10); overall, AEs were mild to moderate in intensity.

Conclusions: In this multicenter, open-label study of 3 dosages of MY008211A administered over 12 weeks to 34 patients with PNH and signs of active hemolysis, all patients achieved increases in Hb ≥20 g/L from baseline by end of treatment without RBC transfusions. Improvements in secondary EPs, including fatigue, were of similar magnitude across dosage groups. This, together with the evidenced safety profile, supports the continued development of MY008211A.