Iptacopan Meets Primary End Point of APPOINT-PNH Trial in Paroxysmal Nocturnal Hemoglobinuria

Iptacopan elicited improved hemoglobin levels measuring at least 2 g/dL higher vs baseline, leading to transfusion independence after 24 weeks in approximately 92.2% of patients with complement inhibitor–naïve paroxysmal nocturnal hemoglobinuria.

Antonio Risitano, MD, PhD

Antonio Risitano, MD, PhD

Treatment with iptacopan resulted in improved hemoglobin levels measuring at least 2 g/dL higher vs baseline, leading to transfusion independence after 24 weeks in approximately 92.2% (95% CI, 82.5%-100%) of patients with complement inhibitor–naïve paroxysmal nocturnal hemoglobinuria (PNH), meeting the primary end point of the phase 3 APPOINT-PNH trial (NCT04820530).

The data, which were presented at the 2023 EBMT Meeting, also demonstrated clinically meaningful improvements in key secondary end points, including achieving hemoglobin levels of at least 12 g/dL without the need for red blood cell (RBC) transfusions in 62.8% (95% CI, 47.5%-77.5%) of patients.

Additionally, approximately 97.6% (95% CI, 92.5%-100%) of patients achieved RBC transfusion independence at 24 weeks––the same population in which 70% of patients received blood transfusions in the 6 months prior to treatment with iptacopan. No clinical breakthrough hemolysis events or major adverse vascular effects occurred during the 24-week trial period.

At 24 weeks, lactate dehydrogenase (LDH) levels had decreased by 83.55% (95% CI, −84.90% to −82.08%) from baseline, with reductions seen as early as day 7. At week 24, 95% of patients had LDH levels at or below 1.5 times the upper limit of normal.

Patients also experienced clinically meaningful improvements in fatigue, with an adjusted average increase of 10.75 points (95% CI, 8.66-12.84) from baseline in Functional Assessment of Chronic Illness Therapy – Fatigue score, with comparable absolute levels to those reported in the general population.

“In addition to improvement of hemolysis and fatigue seen on currently available treatments, [patients with] hemolytic PNH treated with iptacopan achieve improvement of anemia never seen before with anti-C5s; these data underscore the potential of iptacopan to be a practice-changing oral medicine for this devastating disease,” Antonio Risitano, MD, PhD, trial coinvestigator, president of the International PNH Interest Group, and head of the Hematology and Hematopoietic Transplant Unit, Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati in Avellino, Italy, said in a news release.

PNH is a rare, chronic, and serious complement-mediated blood disorder. Despite treatment with anti-C5 therapy, patients remain anemic, fatigued, and dependent on blood transfusions.

The multinational, multicenter, open-label, single-arm study assessed the efficacy and safety of 200 mg of oral iptacopan twice daily in 40 patients with PNH who were naïve to complement inhibitor therapy, including the anti-C5 therapies eculizumab (Soliris) and ravulizumab-cwvz (Ultomiris).

The primary end point was the proportion of patients achieving an increase in hemoglobin levels from baseline of 2 g/dL or more in the absence of RBC transfusions at 24 weeks. Secondary end points included the proportion of patients achieving sustained hemoglobin levels of 12 g/dL or more in the absence of RBC transfusions, transfusion independence, average change in hemoglobin levels, average percent change in LDH levels, rate of breakthrough hemolysis, average change in absolute reticulocyte counts, change in fatigue, and rates of major adverse vascular effects.

Additionally, iptacopan was well tolerated and did not demonstrate new safety signals. The most common adverse effects (AEs) were infections (40.0%)—mainly COVID-19 (15.0%) and upper respiratory tract infection (12.5%)—headache (27.5%), and diarrhea (7.5%). Four serious AEs occurred, but no patients discontinued iptacopan in the 24-week treatment period.

Updated data from the phase 3 APPLY-PNH trial (NCT04558918), which were also presented at this year’s EBMT meeting, demonstrated improved efficacy with iptacopan vs anti-C5 therapy in patients with PNH with residual anemia despite prior exposure to anti-C5 therapy. The safety profile of iptacopan was also consistent with data from the APPOINT-PNH trial.

“The APPOINT-PNH results are consistent with the tolerability and safety profiles seen in APPLY-PNH and show oral iptacopan controls hemolysis while nearly eliminating the need for blood transfusions,” principal coinvestigator Régis Peffault de Latour, MD, PhD, of Saint-Louis Hospital, Greater Paris University Hospital, added.

Data from both APPOINT-PNH and APPLY-PNH will be included in global regulatory submissions in the first half of 2023.

“We continue to be impressed by the totality of evidence from APPLY-PNH and APPOINT-PNH, which confirm the practice-changing potential of iptacopan in the treatment of PNH,” David Soergel, MD, global head, Cardiovascular, Renal and Metabolism Development Unit, Novartis, said. “We look forward to our first submissions to regulatory authorities for PNH in the first half of this year, and are continuing to progress our iptacopan studies for a range of other complement-mediated diseases, with phase 3 results in C3 glomerulopathy and IgA nephropathy anticipated later in the year.”


Novartis Phase III APPOINT-PNH trial shows investigational oral monotherapy iptacopan improves hemoglobin to near-normal levels, leading to transfusion independence in all treatment-naïve PNH patients. News release. Novartis. April 26, 2023. Accessed April 26, 2023.

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