Apply-PNH: Analysis of complement pathway biomarkers provides evidence for pharmacodynamic response in PNH patients who receive oral iptacopan monotherapy versus continuing anti-C5 therapy Free

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder characterized by complement-mediated intravascular hemolysis (IVH), bone marrow failure, and severe thrombophilia. Anti-C5 therapies like eculizumab help control IVH but do not impact C3 fragment deposition on PNH erythrocytes, leaving them susceptible to extravascular hemolysis (EVH). Iptacopan, an oral Factor B (FB) inhibitor targeting the alternative pathway (AP) of the complement system, provides comprehensive control of hemolysis through inhibition of IVH and prevention of the emergence of EVH. Biomarkers of activation of the AP such as soluble C5b-9 (sC5b-9) and Factor Bb can help evaluate the inhibitory effect of iptacopan on AP-mediated complement activation.

The Phase 3 APPLY-PNH trial (NCT04558918) evaluated iptacopan in adults with PNH and residual anemia (Hb <10 g/dL) despite ≥6 months of stable anti-C5 therapy (either eculizumab or ravulizumab), which showed superior efficacy of receiving iptacopan monotherapy over continuing anti-C5 therapy. Here, we report the pharmacodynamic response of the complement pathway in patients who received iptacopan following previous anti-C5 therapy in the APPLY-PNH study.

Methods: In this biomarker analysis, a set of complement pathway biomarkers (sC5b-9, FB, and Factor Bb) were measured using validated immunoassays. Data from APPLY-PNH was preprocessed and inspected. Measurements below the lower limit of quantification (LLoQ) were imputed as half the LLoQ value, whereas measurements exceeding the upper limit of quantification were imputed as the maximum observed value. Unmeasured values were excluded from the dataset for the relevant analysis, and concentration values were log₁₀ transformed. Geometric mean baseline and end of treatment levels (Day 168), with 95% confidence intervals (CIs) are reported. Geometric mean ratios (GMRs) to baseline (95% CI) are reported for the change in biomarker levels for each treatment arm from baseline to end of treatment; a statistically significant difference is based on 95% CIs.

Results: In APPLY-PNH, 97 patients were randomized to receive iptacopan (n=62) or continue anti-C5 therapy (n=35). Overall, 75 patients had complete data for sC5b-9 (iptacopan, n=46; anti-C5, n=29) and 87 patients had complete data for FB and Factor Bb (iptacopan, n=56; anti-C5, n=31). In patients who received iptacopan, geometric mean (95% CI) sC5b-9 decreased from baseline to end of treatment (540 ng/mL [410, 790] vs 230 ng/mL [190, 300]; GMR = 0.4 [0.26, 0.66]). In contrast, patients who continued anti-C5 therapy showed no significant change from baseline (420 ng/mL [300, 620] vs 330 ng/mL [240, 510]; GMR = 0.81 [0.50, 1.30]). In patients who received iptacopan, geometric mean (95% CI) FB increased from baseline to end of treatment (200 µg/mL [190, 210] vs 300 µg/mL [260, 400]; GMR = 1.5 [1.3, 2.1]). In patients who continued anti-C5 therapy, FB showed no significant change (210 µg/mL [180, 300] vs 190 µg/mL [170, 210]; GMR = 0.89 [0.59, 1.00]). Factor Bb decreased from baseline for both iptacopan (1600 ng/mL [1400, 1700] vs 1300 ng/mL [1200, 1400]; GMR = 0.86 [0.80, 0.92]) and anti-C5 (1700 ng/mL [1500, 2300] vs 1500 ng/mL [1300, 1700]; GMR = 0.87 [0.63, 1.00]). However, while a statistically significant reduction from baseline in Factor Bb was observed in the iptacopan treatment arm, the similarity of the geometric mean point estimates and overlapping 95% CIs suggests no difference between the two treatment arms.

Conclusions: Analysis of complement pathway biomarkers provides evidence for pharmacodynamic response and supports the clinical benefits of switching from anti-C5 therapy to iptacopan. sC5b-9 decreased after receiving iptacopan, consistent with the observed clinical efficacy of iptacopan treatment in the study through inhibition of the terminal complex activation of the complement pathway. FB increase in the setting of iptacopan could be due to decreased consumption and/or increased production of FB. Despite a significant reduction of Factor Bb in the iptacopan treatment arm, the lack of a statistical difference compared to continued anti-C5 therapy suggests a similar effect between the two treatment arms. There was no statistically significant change in all three complement biomarkers in patients who continued anti-C5 therapy.