By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration has approved the first oral drug to treat paroxysmal nocturnal hemoglobinuria (PNH). Iptacopan is a first-in-class oral selective inhibitor of complement factor B (C3 pathway). Pegcetacoplan, a parenterally administered anti-C3 inhibitor, previously was approved for this same indication. Iptacopan was given a priority review and Breakthrough Therapy and Orphan Drug designations. It is distributed by Novartis Pharmaceutical Corporation as Fabhalta and is available only through a restrictive program under a Risk Evaluation and Mitigation Strategy (REMS) called FABHALTA REMS.
INDICATIONS
Iptacopan is indicated for the treatment of adults with PNH.1
DOSAGE
The recommended dose is 200 mg orally twice daily with or without food.1 Iptacopan is available as 200 mg capsules.
POTENTIAL ADVANTAGES
Iptacopan provides the first oral drug for the treatment of PNH. Current standards of care are anti-C5 monoclonal antibodies, eculizumab, or ravulizumab. Anti-C5 experienced patients who switched to iptacopan demonstrated superiority in terms of increase of hemoglobin and avoidance of transfusion compared to those who remained on anti-C5 treatment.1 It is an option to the parenterally administered anti-C3 inhibitor, pegcetacoplan. Anti-C3 treatment controls both intravascular and extra-vascular hemolysis
POTENTIAL DISADVANTAGES
As with anti-complement inhibitors, iptacopan increases the risk of serious and life-threatening infections caused by encapsulated bacteria (e.g., Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type B).1 Patients receiving a complement inhibitor should follow current Advisory Committee on Immunization Practices recommendations. Iptacopan increases total cholesterol, low-density lipoprotein cholesterol, and serum triglycerides.1 Some patients may require cholesterol-lowering medications.1 Other adverse events (> 10%) include headache, nasopharyngitis, viral infections, rash, and thrombocytopenia.1 Iptacopan primarily is metabolized by CYP2C8; therefore, use with a strong CYP2C8 inhibitor is not recommended.1 Use with a CYP2C8 inducer may reduce the effectiveness of iptacopan.
COMMENTS
The efficacy of iptacopan in PNH was evaluated in two clinical trials, one in anti-C5 treatment experienced subjects (APPLY-PNH) and a single-arm study in subjects who were treatment-naïve (APPOINT-PNH).1-3 Subjects in APPLY-PNH had residual anemia (hemoglobin < 10 g/dL) despite treatment with a stable regimen of an anti-C5 monoclonal antibody (eculizumab or ravulizumab) for at least six months.1,2 The mean age was about 50 years, 69% were female, about 75% were white, and the baseline hemoglobin was 8.9 (± 0.7) g/dL. They were randomized to iptacopan (n = 62) or continued anti-C5 treatment (n = 35) for 24-weeks. Primary efficacy endpoints were increase of hemoglobin ≥ 2 g/dL at 24-week from baseline (three out of four measurements taken between days 126 and 168) in the absence of red blood cell (RBC) transfusion (between day 14 and day 168) and sustained hemoglobin levels ≥ 12 g/dL in the absence of transfusion. The secondary endpoint was transfusion avoidance rate. Response rates were 82.3% vs. 0% and 67.7% vs. 0% for iptacopan vs. continued anti-C5 treatment. Transfusion avoidance rates were 95.2% vs. 45.7%, respectively. Results demonstrated superiority of switching to iptacopan compared to continuing anti-C5 therapy. In the single-arm study, APPOINT-PNH, treatment-naïve subjects (n = 40) were administered iptacopan for 24 weeks.1,3 A total of 77.5% of subjects achieved a sustained increase in hemoglobin levels between weeks 18 and 24 from baseline of ≥ 2 g/dL in the absence of RBC transfusions.
CLINICAL IMPLICATIONS
PNH is a rare, acquired, debilitating condition.4 It is caused by a somatic mutation of the phosphatidylinositol glycan class A gene of the X-chromosome. This results in loss of two protector proteins, CD55 and CD59, and deregulation of the complement pathway and manifestation of intravascular hemolysis and potential serious thrombotic events (major cause of death).4 Allogeneic hematopoietic stem cell transplantation is the only curative treatment. Current standard of care is one of the anti-C5 monoclonal antibodies (eculizumab or ravulizumab).5 Ravalizumab is modified from eculizumab and is noninferior to eculizumab but with less frequent dosing (e.g., every four to eight weeks vs. every two weeks) and is associated with less breakthrough hemolysis.4 A limitation of anti-C5 treatment is C3 mediated extravascular hemolysis and some patients still need tranfusions.4 Some patients develop eculizumab refractory PNH.6 Both pegcetacoplan and iptacopan have been shown to be superior to eculizumab in controlling both intravascular and extravascular hemolysis.1,4,7 Iptacopan has the advantage of oral administration. The cost is $45,208 for 60 days, or $550,000 for one year of therapy. A cost-effectiveness analysis using Markov modeling suggests that a monthly cost of $61,000 can be a cost-effective option for transfusion-dependent, treatment-experienced patients.8 A formal review by the Institute for Clinical and Economic Review is expected in February 2024.9
REFERENCES
- Fabhalta prescribing information. Novartis Pharmaceutical Corporation. December 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/218276s000lbl.pdf
- ClinicalTrials.gov. Study of efficacy and safety of twice daily oral LNP023 in adult PNH patients with residual anemia despite anti-C5 antibody treatment (APPLY-PNH). https://clinicaltrials.gov/study/NCT04558918?intr=nct04558918&rank=1&tab=results#results-overview
- ClinicalTrials.gov. Study of efficacy and safety of twice daily oral iptacopan (LNP023) in adult PNH patients who are naïve to complement inhibitor therapy (APPOINT-PNH). https://clinicaltrials.gov/study/NCT04820530?intr=nct04820530&rank=1&tab=results
- Bravo-Perez C, Guarnera L, Williams ND, Visconte V. Paroxysmal nocturnal hemoglobinuria: Biology and treatment. Medicina (Kaunas) 2023;59:1612.
- Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK562292/
- Syed S, Khan R, Khurram F, et al. Treatment of eculizumab refractory paroxysmal nocturnal hemoglobinuria: A systematic review about current treatment options and future direction. SAGE Open Medicine 2023;11:1-7.
- Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2021;384:1028-1037.
- Ito S, Chetlapalli K, Potnis KC, et al. Setting cost-effective price thresholds before FDA approval: Cost-effectiveness of iptacopan monotherapy versus standard-of-care anti-C5 therapy in transfusion-dependent, treatment-experienced adult patients with parolxysmal nocturnal hemoglobinuria in the United States. Blood 2023;142(Suppl 1):5042.
- Institute for Clinical and Economic Review. ICER to assess treatments for paroxysmal nocturnal hemoglobinuria. https://icer.org/news-insights/press-releases/icer-to-assess-treatment-for-paroxysmal-nocturnal-hemoglobinuria/
