Iptacopan (Fabhalta) Hits Primary Endpoint in Phase 3 APPULSE-PNH Trial

On June 12, 2025, Novartis announced positive results from APPULSE-PNH, a phase 3B trial investigating the safety and efficacy of the twice-daily oral monotherapy iptacopan (Fabhalta) in adults with paroxysmal nocturnal hemoglobinuria (PNH) with hemoglobin (Hb) levels ≥10 g/dL who switched from the anti-C5 therapies eculizumab or ravulizumab.1

“Today, some patients living with PNH have unmet needs not addressed by eculizumab or ravulizumab,” said Austin Kulasekararaj, MBBS, MD, consultant hematologist at the Kings College Hospital and Kings College London. “The positive results from APPULSE-PNH reinforce that iptacopan can provide clinically meaningful improvements in hemoglobin among patients with higher baseline hemoglobin levels than those enrolled in previous trials, while offering an oral monotherapy for patients.”1

APPULSE-PNH was a multicenter, single-arm, open-label trial, divided into 2 periods. The first component was an 8-week screening period, followed by a 24-week treatment period. At the end of treatment, Hb level improved across the board by an average of 2.01 g/dL (95% CI, 1.74-2.29), with most patients achieving normal or near-normal levels. Patients who continue to benefit from the treatment will be able to join the roll-over extension study.3

A total of 52 patients were included in the trial. Inclusion criteria included patients ≥18 years of age, with a stable regimen of anti-C5 antibody treatment, mean hemoglobin ≥10 g/dL, and vaccination against Neisseria meningitidis, S. pneumoniae, and Hemophilus influenzae. Patients were excluded if they required red blood cell transfusion up to 6 months prior, had a stem cell or organ transplantation, had a history of recurrent invasive infections caused by encapsulated organisms, history of cancer, unstable medical conditions including myocardial ischemia and active gastrointestinal bleeding, or any other medical condition deemed likely to interfere in the study.2

The vast majority of patients (92.7%) achieved Hb ≥12 g/dL, and none required transfusion during the study. Additionally, many patients treated with iptacopan also reported clinically meaningful improvements in fatigue. Novartis also noted maintenance of intravascular hemolysis control and resolved extravascular hemolysis control, demonstrated by lactate dehydrogenase levels and a reduction in absolute reticulocyte count. Iptacopan was well-tolerated and exhibited no new safety signals.1

“Novartis is dedicated to advancing research and innovation that can transform care and significantly improve the lives of people living with PNH and those who support them,” said Shreeram Aradhye, MD, president, development and chief medical officer of Novartis. “New data from APPULSE-PNH, combined with findings from the Phase III roll-over extension of the APPLY-PNH and APPOINT-PNH studies, reinforce the efficacy and safety profile of Fabhalta in delivering real benefits to patients. Fabhalta is the first and only oral monotherapy currently available for the treatment of adults with PNH, regardless of previous treatment experience.”1

Results from APPULSE-PNH, as well as longer-term data from patients included in the APPLY-PNH and APPOINT-PNH phase 3 studies, will be presented at the European Hematology Association Congress 2025.1

References

1. Novartis. Novartis Fabhalta shows statistically significant and clinically meaningful improvements in hemoglobin in new population of patients with PNH. June 12, 2025. Accessed June 12, 2025. https://www.novartis.com/news/media-releases/novartis-fabhalta-shows-statistically-significant-and-clinically-meaningful-improvements-hemoglobin-new-population-patients-pnh

2. Holt M, Kelly RJ, Fermont JM, et al. Effectiveness of Iptacopan Versus C5 Inhibitors in Complement Inhibitor-Naive Patients With Paroxysmal Nocturnal Haemoglobinuria. EJHaem. 2025;6(3):e270055. Published 2025 May 20. doi:10.1002/jha2.70055

3. Clinicaltrials.gov. NCT05630001. Single Arm, Open Label Trial with Iptacopan Treatment for 24 Weeks, in Patients on Stable Regimen of Anti-C5 Who Switch to Iptacopan. (APPULSE). November 25, 2024. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT05630001