Paroxysmal Nocturnal Hemoglobinuria (PNH) is a genetic disorder caused by a somatic mutation in the PIGA gene, which affects the functions of (GPI)-anchored proteins and impacts the regulation of complement activity. However, the current standard of treatment, including eculizumab, has limitations, as many patients continue to suffer from anemia due to persistent activation of proximal complement pathways. Consequently, a novel oral medication called iptacopan was developed, seeking to address the limitations of current anti-C5 therapies by selectively acting against factor B. This therapy offers a promising alternative for treating and rescuing PNH. Therefore, we conducted a systematic review aiming to consolidate and summarize current knowledge on the efficacy and safety of this new treatment.

We performed a systematic literature review and a meta-analysis adhering to PRISMA guidelines. Our search strategy encompassed 5 databases, utilizing the key terms ’PNH’ and ’iptacopan’. Efficacy outcomes included markers of hemolysis such as LDH, Hemoglobin, Bilirubin, Reticulocyte count. Safety outcomes comprised most common adverse events (AEs). Data were summarized using pooled mean for continuous outcomes and pooled proportion for dichotomous outcomes, with 95% confidence intervals. I2 was used to assess heterogeneity. Statistical analyses were performed using R Studio 4.3.3.

Out of 160 initially identified studies, 3 were included in the final analysis, encompassing 5 clinical trials with 122 patients with PNH, showing a female sex predominance of 56%. The LDH levels decreased from 938 to 259 U/L (95% CI 251.04; 267.22; I2 = 0%). Hemoglobin levels increased from 8.7 to 12.5 g/dL (95% CI 12.27; 12.79; I2 = 29%). Bilirubin levels decreased from 31.35 to 11.47 μmol/L (95% CI 10.29; 12.66; I2 = 0%). Reticulocyte count decreased from 182.26 to 82.53 ×10/L (95% CI 69.05; 96.01; I2 = 56%). Furthermore, the transfusion-free status was observed in 96.7% of the patients (95% CI 94.36; 100.00; I2 = 0%) and the necessity for transfusions decreased. Regarding adverse events, headache occurred in 18.8% of patients, diarrhea in 9.8%, coronavirus disease in 9%, and upper respiratory tract infections in 7.4%.

This meta-analysis suggests iptacopan is a promising option for PNH patients, both as first-line monotherapy and rescue therapy. Significant reductions in LDH and bilirubin levels, increased hemoglobin, and decreased reticulocyte count indicate improved hemolysis control. The high rate of transfusion-free status (96.7%) is particularly encouraging. As a first-line treatment, iptacopan offers an effective oral alternative to anti-C5 therapies. For eculizumab non-responders, it shows potential by targeting factor B. This novel mechanism of action may provide a more comprehensive approach to managing PNH by addressing the limitations of current treatments. Iptacopan's safety profile appears favorable, with mild adverse events.

This meta-analysis underscores the considerable potential of Iptacopan in treating PNH, whether as monotherapy or rescue therapy for refractory patients. It demonstrates efficacy in reducing hemolysis and boasts an excellent safety profile. Additional prospective studies are necessary to bolster the evidence and provide a comprehensive assessment.