IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare, progressive and life-threatening form of thrombotic microangiopathy (TMA) caused by dysregulation of the alternative complement pathway (AP); inhibiting AP is therefore an attractive therapeutic strategy to slow aHUS disease progression. Iptacopan (LNP023) is an oral, first-in-class, highly potent, selective inhibitor of factor B, a key regulator of the AP. In Phase 2 studies in patients with IgA nephropathy (IgAN), paroxysmal nocturnal hemoglobinuria (PNH) and in those with C3 glomerulopathy (C3G), iptacopan inhibited the AP, showed clinically relevant benefits and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with a convenient oral administration. The efficacy and safety of iptacopan observed in Phase 2 studies in IgAN, C3G and PNH, coupled with the established efficacy of complement inhibitor therapies in aHUS, provide a strong rationale to directly evaluate its benefits in aHUS patients in a Phase 3 trial to support iptacopan registration.MethodsThe APPELHUS (Alternative Pathway Phase III to Evaluate LNP023 in aHUS) study (NCT04889430) is a global, multicenter, single-arm, open-label, Phase 3 study evaluating the efficacy and safety of iptacopan 200 mg twice daily in 50 adult aHUS patients naïve to complement inhibitor therapy. The study comprises a 26-week core treatment period followed by a 26-week extension treatment period. At the end of the study, patients will have the option to rollover into an open-label extension study. In the absence of Phase 2 data with iptacopan in aHUS patients, an interim analysis will be performed when approximately 8 participants complete 12 weeks of treatment. Eligible patients must have evidence of TMA (platelet count <150×109/L, LDH ≥1.5×ULN, hemoglobin ≤LLN, serum creatinine ≥ULN). Key exclusion criteria include treatment with complement inhibitors, ADAMTS13 deficiency (<5% activity), Shiga toxin-related HUS, positive Coombs test and other secondary or non-complement mediated TMA. The primary endpoint is the proportion of patients achieving complete TMA response without the use of plasma exchange/plasma infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. TMA response in iptacopan treated patients will be evaluated in the context of benefits reported for eculizumab and ravulizumab. The TMA response rate and its 95% confidence interval (CI) will be calculated for the APPELHUS study based on asymptotic Gaussian approximation with continuity correction, and this will be compared with a pre-determined threshold based on the two historical trials of eculizumab and ravulizumab in patients with aHUS. A lower bound of the CI greater than the pre-determined threshold would suggest that iptacopan preserves a significant proportion of the treatment effect relative to current standard of care. Secondary endpoints include time to complete TMA response; change from baseline in hemoglobin (≥2 g/dL), eGFR, chronic kidney disease stage, hematologic parameters (platelets, LDH and hemoglobin), dialysis requirement status, and patient-reported fatigue scores; safety; and tolerability. Long-term efficacy, safety and tolerability of iptacopan will be evaluated during the extension period.ResultsRecruitment ongoing.ConclusionsAPPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.Conflict of interest Corporate sponsored research or other substantive relationships:The study is funded by Novartis Pharma AG.DGK reports grant support from Medical Research Council Wellcome Trust Kidney Research UK Complement UK Fight For Sight, Macular Society, consultant for Silence Therapeutics, Alexion Pharmaceuticals, Novartis, Apellis and Sarepta, Founder and Scientific Advisor, Gyroscope Therapeutics. LAG is a consultant for Novartis. FF has received consultancy and/or speaker honoraria from Roche, Alexion, Apellis, Achillion, Novartis and Alnylam. C-W, RK, SV, and MD are employees of Novartis. IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare, progressive and life-threatening form of thrombotic microangiopathy (TMA) caused by dysregulation of the alternative complement pathway (AP); inhibiting AP is therefore an attractive therapeutic strategy to slow aHUS disease progression. Iptacopan (LNP023) is an oral, first-in-class, highly potent, selective inhibitor of factor B, a key regulator of the AP. In Phase 2 studies in patients with IgA nephropathy (IgAN), paroxysmal nocturnal hemoglobinuria (PNH) and in those with C3 glomerulopathy (C3G), iptacopan inhibited the AP, showed clinically relevant benefits and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with a convenient oral administration. The efficacy and safety of iptacopan observed in Phase 2 studies in IgAN, C3G and PNH, coupled with the established efficacy of complement inhibitor therapies in aHUS, provide a strong rationale to directly evaluate its benefits in aHUS patients in a Phase 3 trial to support iptacopan registration. Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive and life-threatening form of thrombotic microangiopathy (TMA) caused by dysregulation of the alternative complement pathway (AP); inhibiting AP is therefore an attractive therapeutic strategy to slow aHUS disease progression. Iptacopan (LNP023) is an oral, first-in-class, highly potent, selective inhibitor of factor B, a key regulator of the AP. In Phase 2 studies in patients with IgA nephropathy (IgAN), paroxysmal nocturnal hemoglobinuria (PNH) and in those with C3 glomerulopathy (C3G), iptacopan inhibited the AP, showed clinically relevant benefits and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with a convenient oral administration. The efficacy and safety of iptacopan observed in Phase 2 studies in IgAN, C3G and PNH, coupled with the established efficacy of complement inhibitor therapies in aHUS, provide a strong rationale to directly evaluate its benefits in aHUS patients in a Phase 3 trial to support iptacopan registration. MethodsThe APPELHUS (Alternative Pathway Phase III to Evaluate LNP023 in aHUS) study (NCT04889430) is a global, multicenter, single-arm, open-label, Phase 3 study evaluating the efficacy and safety of iptacopan 200 mg twice daily in 50 adult aHUS patients naïve to complement inhibitor therapy. The study comprises a 26-week core treatment period followed by a 26-week extension treatment period. At the end of the study, patients will have the option to rollover into an open-label extension study. In the absence of Phase 2 data with iptacopan in aHUS patients, an interim analysis will be performed when approximately 8 participants complete 12 weeks of treatment. Eligible patients must have evidence of TMA (platelet count <150×109/L, LDH ≥1.5×ULN, hemoglobin ≤LLN, serum creatinine ≥ULN). Key exclusion criteria include treatment with complement inhibitors, ADAMTS13 deficiency (<5% activity), Shiga toxin-related HUS, positive Coombs test and other secondary or non-complement mediated TMA. The primary endpoint is the proportion of patients achieving complete TMA response without the use of plasma exchange/plasma infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. TMA response in iptacopan treated patients will be evaluated in the context of benefits reported for eculizumab and ravulizumab. The TMA response rate and its 95% confidence interval (CI) will be calculated for the APPELHUS study based on asymptotic Gaussian approximation with continuity correction, and this will be compared with a pre-determined threshold based on the two historical trials of eculizumab and ravulizumab in patients with aHUS. A lower bound of the CI greater than the pre-determined threshold would suggest that iptacopan preserves a significant proportion of the treatment effect relative to current standard of care. Secondary endpoints include time to complete TMA response; change from baseline in hemoglobin (≥2 g/dL), eGFR, chronic kidney disease stage, hematologic parameters (platelets, LDH and hemoglobin), dialysis requirement status, and patient-reported fatigue scores; safety; and tolerability. Long-term efficacy, safety and tolerability of iptacopan will be evaluated during the extension period. The APPELHUS (Alternative Pathway Phase III to Evaluate LNP023 in aHUS) study (NCT04889430) is a global, multicenter, single-arm, open-label, Phase 3 study evaluating the efficacy and safety of iptacopan 200 mg twice daily in 50 adult aHUS patients naïve to complement inhibitor therapy. The study comprises a 26-week core treatment period followed by a 26-week extension treatment period. At the end of the study, patients will have the option to rollover into an open-label extension study. In the absence of Phase 2 data with iptacopan in aHUS patients, an interim analysis will be performed when approximately 8 participants complete 12 weeks of treatment. Eligible patients must have evidence of TMA (platelet count <150×109/L, LDH ≥1.5×ULN, hemoglobin ≤LLN, serum creatinine ≥ULN). Key exclusion criteria include treatment with complement inhibitors, ADAMTS13 deficiency (<5% activity), Shiga toxin-related HUS, positive Coombs test and other secondary or non-complement mediated TMA. The primary endpoint is the proportion of patients achieving complete TMA response without the use of plasma exchange/plasma infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. TMA response in iptacopan treated patients will be evaluated in the context of benefits reported for eculizumab and ravulizumab. The TMA response rate and its 95% confidence interval (CI) will be calculated for the APPELHUS study based on asymptotic Gaussian approximation with continuity correction, and this will be compared with a pre-determined threshold based on the two historical trials of eculizumab and ravulizumab in patients with aHUS. A lower bound of the CI greater than the pre-determined threshold would suggest that iptacopan preserves a significant proportion of the treatment effect relative to current standard of care. Secondary endpoints include time to complete TMA response; change from baseline in hemoglobin (≥2 g/dL), eGFR, chronic kidney disease stage, hematologic parameters (platelets, LDH and hemoglobin), dialysis requirement status, and patient-reported fatigue scores; safety; and tolerability. Long-term efficacy, safety and tolerability of iptacopan will be evaluated during the extension period. ResultsRecruitment ongoing. Recruitment ongoing. ConclusionsAPPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.Conflict of interest Corporate sponsored research or other substantive relationships:The study is funded by Novartis Pharma AG.DGK reports grant support from Medical Research Council Wellcome Trust Kidney Research UK Complement UK Fight For Sight, Macular Society, consultant for Silence Therapeutics, Alexion Pharmaceuticals, Novartis, Apellis and Sarepta, Founder and Scientific Advisor, Gyroscope Therapeutics. LAG is a consultant for Novartis. FF has received consultancy and/or speaker honoraria from Roche, Alexion, Apellis, Achillion, Novartis and Alnylam. C-W, RK, SV, and MD are employees of Novartis. APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.