Dose-Exposure-Response Relationships of Biomarkers and Efficacy Measures with Iptacopan, a Complement Factor B Inhibitor, in Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) with or without Concomitant Anti-C5 Therapy

Background: Standard of care treatment for pts with PNH targets C5 in the complement pathway; however, residual intravascular hemolysis (IVH) and emerging C3-mediated extravascular hemolysis (EVH) can still occur. In two Phase II trials (X2201 [NCT03439839] and X2204 [NCT03896152]), the oral, selective, reversible complement factor B inhibitor iptacopan provided hematologic benefit in pts with PNH who had active hemolysis, both as add-on therapy in anti-C5-treated pts and monotherapy in anti-C5-naïve pts (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022). Using data from these two studies, this integrated analysis aimed to evaluate dose-exposure-response relationships of biomarkers and efficacy measures to support dose selection for iptacopan.

Methods: X2201 and X2204 were open-label studies that enrolled pts with PNH who had active hemolysis, despite treatment with anti-C5 therapy, or in the absence of prior anti-C5 therapy, respectively. In X2201, pts with lactate dehydrogenase (LDH) ≥1.5 x upper limit of normal (ULN) received iptacopan 200 mg twice daily (bid; Cohort 1) and pts with LDH ≥1.25 x ULN and hemoglobin (Hb) <10.5 g/dL received iptacopan 50 mg bid (Cohort 2). Pts in Cohort 2 could have their dose increased to 200 mg bid if hemolysis persisted. Both cohorts received iptacopan as add-on therapy to eculizumab; eculizumab treatment could be adjusted or withdrawn after 26 weeks (wks) at the investigator's discretion. In X2204, pts with LDH ≥1.5 x ULN and Hb <10.5 g/dL who were naïve to anti-C5 treatment were randomized to receive iptacopan 25 mg bid for 4 wks followed by iptacopan 100 mg bid for 8 wks (Cohort 1), or iptacopan 50 mg bid for 4 wks followed by iptacopan 200 mg bid for 8 wks (Cohort 2). To quantify the exposure-response relationship, trough concentrations of iptacopan (C_trough) were correlated with LDH, Hb, factor Bb fragments, Wieslab® alternative complement pathway activity assay data, C3 fragment deposition on red blood cells (RBCs) and PNH RBC clone size using sigmoid maximum effect (E_max) models. Analyses were performed after pts had received iptacopan at the same dose for 4 wks.

Results: A total of 29 pts with PNH were enrolled (X2201, N=16; X2204, N=13). The pharmacokinetic parameters of iptacopan were in line with previous reports in these two studies (Risitano et al. Lancet Haematol 2021; Jang et al.Blood Adv 2022) and were similar between the two study populations. In the dose range 25-200 mg bid, increases in dose resulted in a less than proportional increase in exposure, probably because of on-target binding to the highly abundant plasma factor B. Age and sex did not significantly impact exposure; the impact of ethnicity was not assessed because it was confounded by the study populations (15/16 pts in X2201 were Caucasian; all pts in X2204 were Asian). When assessing LDH, Hb, factor Bb fragments and Wieslab® assay data, 95% of the maximum response was reached with C_trough >700 ng/mL, >650 ng/mL, >500 ng/mL and >750 ng/mL (EC₉₅), respectively. C3 deposition was only informative in X2201; in X2204, C3 deposition was negligible at baseline and throughout the study because the pts were anti-C5-naïve. Complete abrogation of C3 deposition was reached at all dose levels in X2201 (C_trough >600 ng/mL). PNH RBC cell clone size increased in both studies, but no clear dose-dependent relationship was observed. Accounting for interpatient variability in exposure, iptacopan 200 mg bid was identified as the optimum regimen to achieve C_trough >750 ng/mL in most pts.

Conclusions: Results from this pooled dose-exposure-response analysis of the X2201 and X2204 studies indicate that iptacopan 200 mg bid is the optimum dose to achieve C_trough >750 ng/mL and consequently to provide maximal disease control via alternative complement pathway inhibition. The dose-exposure-response relationship was similar between pts regardless of whether they had a partial response to C5 inhibition (X2201) or were anti-C5-naïve (X2204), supporting the use of iptacopan 200 mg bid in both populations. Based on clinical efficacy and safety data from these two studies (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022) and supported by data from this integrated dose-exposure-response analysis, two ongoing Phase III trials are investigating iptacopan monotherapy at a dose of 200 mg bid in anti-C5 treated (APPLY-PNH; NCT04558918) and anti-C5-naïve (APPOINT-PNH; NCT04820530) pts with PNH.

Risitano:Roche: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Ra Pharma: Research Funding; Samsung: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Yoon:Chugai Pharmaceutical: Consultancy; Takeda: Consultancy; Janssen Pharmaceutical: Consultancy; Astellas Pharma: Consultancy; Yuhan Pharmaceutical: Research Funding; Roche-Genetech: Research Funding; Amgen: Consultancy; Tikaros: Consultancy; Celgene: Consultancy; Kyowa Kirin: Research Funding; Novartis: Consultancy. Roeth:Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding. Baltcheva:Novartis Pharma AG: Current Employment. Milojevic:Novartis AG: Current Employment. Fagan:Novartis: Current Employment. Kulmatycki:Novartis: Current Employment, Current equity holder in publicly-traded company. Nidamarthy:Novartis Healthcare Pvt. Ltd.: Current Employment. Junge:Novartis Pharma AG: Current Employment.