Comparative Efficacy of Iptacopan Monotherapy vs. Danicopan Add-on to C5i in Paroxysmal Nocturnal Hemoglobinuria (PNH) Results From an Indirect Treatment Comparison (ITC)
Author(s)
Phillip Scheinberg, MD1, Austin Kulasekararaj, MD2, Maria-Magdalena Balp, MASc, MD3, Anggie Wiyani, MSc4, Jason Steenkamp, BS5, Becky Hooper, MS5, Pearl Wang, MS5, Régis Peffault de Latour, PhD6.
1Hospital A Beneficência Portuguesa, São Paulo, Brazil, 2King’s College Hospital NHS Foundation Trust, London, United Kingdom, 3Novartis Pharma AG, Basel, Switzerland, 4Novartis Pharmaceuticals UK Ltd, London, United Kingdom, 5EVERSANA, Burlington, ON, Canada, 6French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France.
1Hospital A Beneficência Portuguesa, São Paulo, Brazil, 2King’s College Hospital NHS Foundation Trust, London, United Kingdom, 3Novartis Pharma AG, Basel, Switzerland, 4Novartis Pharmaceuticals UK Ltd, London, United Kingdom, 5EVERSANA, Burlington, ON, Canada, 6French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France.
OBJECTIVES: PNH is a rare disorder characterized by hemolysis, anemia, and thrombosis. Current newly approved oral treatments are: iptacopan, factor B inhibitor; monotherapy, and danicopan, factor D inhibitor; add-on to complement 5 inhibitors (C5i). Iptacopan and danicopan were individually assessed in clinical trials in patients with residual anemia despite C5i. In the absence of head-to-head data, this study aimed to conduct an ITC of iptacopan vs danicopan in this target population.
METHODS: A systematic literature review identified two trials: APPLY-PNH (Phase III, open label active-comparator controlled; iptacopan vs eculizumab/ravulizumab (hereafter C5i; [NCT04558918]) with individual patient data (N=97), and ALPHA (Phase III, active-controlled; danicopan+C5i vs. placebo+C5i [NCT04469465]) with published aggregated data (N=73). Feasibility assessment concluded that anchored matching-adjusted indirect comparisons were suitable. Patients from APPLY-PNH (full analysis set) were matched to the ALPHA cohort (prespecified interim analysis set) by excluding patients with baseline hemoglobin (Hb; g/dL) >9.5, reticulocyte count <120x109/L, and no transfusions ≤6 months prior to randomization. Patients were re-weighted based on identified treatment effect modifiers (baseline Hb and sex). Outcomes assessed were change from baseline (CFB) in Hb, lactate dehydrogenase (LDH), FACIT-Fatigue, and transfusion avoidance, reported as point estimates (95% confidence interval [CI]).
RESULTS: After matching and adjusting, the baseline characteristics between the trials were similar with an effective sample size of 9 for APPLY-PNH. Iptacopan showed a significantly greater improvement in Hb vs. danicopan+C5i with a mean difference (MD) (95% CI): 1.41 (0.28-2.55), and higher odds of transfusion avoidance (odds ratio [95% CI]: 58.56 [2.82-1214.72]). Results for CFB in LDH indicates both treatments were comparable: -22.08 (-74.32-30.28). FACIT-Fatigue scores were significantly higher for iptacopan with a MD of 8.271 (0.837-15.705).
CONCLUSIONS: The results from this ITC suggest that iptacopan monotherapy may provide significantly improved clinical outcomes and decreased fatigue versus danicopan+C5i and should be interpreted in the context of ITCs.
METHODS: A systematic literature review identified two trials: APPLY-PNH (Phase III, open label active-comparator controlled; iptacopan vs eculizumab/ravulizumab (hereafter C5i; [NCT04558918]) with individual patient data (N=97), and ALPHA (Phase III, active-controlled; danicopan+C5i vs. placebo+C5i [NCT04469465]) with published aggregated data (N=73). Feasibility assessment concluded that anchored matching-adjusted indirect comparisons were suitable. Patients from APPLY-PNH (full analysis set) were matched to the ALPHA cohort (prespecified interim analysis set) by excluding patients with baseline hemoglobin (Hb; g/dL) >9.5, reticulocyte count <120x109/L, and no transfusions ≤6 months prior to randomization. Patients were re-weighted based on identified treatment effect modifiers (baseline Hb and sex). Outcomes assessed were change from baseline (CFB) in Hb, lactate dehydrogenase (LDH), FACIT-Fatigue, and transfusion avoidance, reported as point estimates (95% confidence interval [CI]).
RESULTS: After matching and adjusting, the baseline characteristics between the trials were similar with an effective sample size of 9 for APPLY-PNH. Iptacopan showed a significantly greater improvement in Hb vs. danicopan+C5i with a mean difference (MD) (95% CI): 1.41 (0.28-2.55), and higher odds of transfusion avoidance (odds ratio [95% CI]: 58.56 [2.82-1214.72]). Results for CFB in LDH indicates both treatments were comparable: -22.08 (-74.32-30.28). FACIT-Fatigue scores were significantly higher for iptacopan with a MD of 8.271 (0.837-15.705).
CONCLUSIONS: The results from this ITC suggest that iptacopan monotherapy may provide significantly improved clinical outcomes and decreased fatigue versus danicopan+C5i and should be interpreted in the context of ITCs.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO58
Topic
Clinical Outcomes, Study Approaches
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Rare & Orphan Diseases, Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)