FDA Approves Iptacopan for Paroxysmal Nocturnal Hemoglobinuria

The FDA has approved iptacopan (Fabhalta) for use in adult patients with paroxysmal nocturnal hemoglobinuria (PNH).¹

The regulatory decision was supported by data from the phase 3 APPLY-PNH trial (NCT04558918) and the phase 3 APPOINT-PNH trial (NCT04820530).

Data from the 24-week core treatment periods in both trials showed that patients experienced a sustained increase of hemoglobin levels of at least 2 g/dL from baseline without red blood cell (RBC) transfusions. Specifically, 82.3% of patients who had prior exposure to anti-C5 agents and received iptacopan responded vs 0% of those who continued on anti-C5 agents (difference, 81.5%; P < .0001). Moreover, 77.5% of patients who were naive to complement inhibitors achieved this outcome; on sensitivity analysis, this rate was 87.5%.

Moreover, 67.7% of patients who had prior exposure to an anti-C5 agent and received iptacopan responded compared with 0% of those on continued treatment with anti-C5 agents (difference, 66.6%; P < .0001). Those with prior exposure to anti-C5 agents who received iptacopan achieved an RBC transfusion avoidance rate of 95.2% vs 45.7% for those on continued treatment with anti-C5 agents (difference, 49.5%; P < .0001).

“An efficacious oral treatment with a demonstrated safety profile could be practice-changing for physicians and help relieve burdens experienced by people with PNH,” Vinod Pullarkat, MD, MRCP, clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, stated in a press release. “In clinical studies, iptacopan was superior to anti-C5s in hemoglobin improvement in the absence of RBC transfusion and transfusion avoidance rate, and also effective in complement inhibitor-naïve individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions.”

APPLY-PNH

The multinational, multicenter, open-label trial enrolled patients with PNH who had received a stable regimen of anti-C5 antibody treatment with either eculizumab (Soliris) or ravulizumab-cwvz (Ultomiris) for at least 6 months before randomization.² Patients needed to be at least 18 years of age, have a mean hemoglobin level of less than 10 g/dL, and have been vaccinated against Neisseria meningitidis infection before the initiation of study treatment.

If they had known or suspected hereditary complement deficiency at the time of screening, a history of hematopoietic stem cell transplantation, evidence of bone marrow failure, or active bacterial, viral, or fungal infection within 2 weeks of the start of study treatment, they were excluded. Those on a stable dose of eculizumab but who had an 11-day or less dosing interval or those on a stable dose of ravulizumab but with a dosing interval of less than 8 weeks were also excluded.

A total of 97 patients were randomly assigned 8:5 to receive oral iptacopan at 200 mg twice daily or intravenous anti-C5 therapies in that they continued on the same regimen that they were on before randomization.¹

Primary outcome measures included the marginal proportion of patients with a sustained increase in hemoglobin levels from a baseline of 2 g/dL or higher in the absence of RBC transfusions and the marginal proportion of patients with sustained hemoglobin levels of 12 g/dL or more in the absence of RBC transfusions.

Secondary outcome measures included the marginal proportion of patients who remain transfusion free, change from baseline in hemoglobin in the randomized treatment period, change from baseline in FACIT-Fatigue Questionnaire, change from baseline in absolute reticulocyte count in the randomized period, ratio to baseline in log-transformed lactate dehydrogenase (LDH), adjusted annualized clinical breakthrough hemolysis rate, and adjusted annualized major adverse vascular events rate—all in the in the randomized treatment period.

In October 2022, it was announced that the trial met its 2 primary end points.³ Topline data showed a significant increase in the proportion of patients who received iptacopan experiencing hemoglobin level increases of at least 2 g/dL more from baseline without requiring blood transfusions at 24 weeks vs anti-C5 therapies. A significant increase in the proportion of patients who received iptacopan achieving hemoglobin levels of at least 12 g/dL without requiring blood transfusions at 24 weeks vs anti-C5 therapies.

APPOINT-PNH

The multinational, multicenter, active-comparator controlled, open-label trial enrolled patients with adult PNH who are naive complement inhibitor therapy.⁴ Patients needed to be at least 18 years of age, have a mean hemoglobin level of less than 10 g/dL, an LDH greater than 1.5 x the upper limit of normal, and be vaccinated against Neisseria meningitidis infection before receiving study treatment.

They could not have known or suspected hereditary complement deficiency, a history of hematopoietic stem cell transplantation, evidence of bone marrow failure, a history of recurrent invasive infections resulting from encapsulated organisms, or active systemic bacterial, viral, or fungal infection within 2 weeks before the start of study treatment.

A total of 40 patients received iptacopan at a twice-daily dose of 200 mg.^1,4

The primary outcome measure was the marginal proportion of patients with a sustained increased in hemoglobin levels from a baseline of 2 g/dL or higher in the absence of RBC transfusions. Secondary measures included the marginal proportion of patients with sustained hemoglobin levels of 12 g/dL or higher without RBC transfusions, the marginal proportion of patients who continued to be transfusion free, change from baseline in hemoglobin levels, and percent change from baseline in LDH, among others.

“The US approval of Fabhalta is an extraordinary moment for people living with PNH, their loved ones, and the healthcare providers who care for them,” Victor Bultó, president of US, Novartis, added in the press release.¹ “This new, effective oral medicine may mean that patients can reset their expectations of living with PNH, a chronic and life-altering blood disease. As Novartis continues to focus on conditions with unmet patient need, we are exploring the potential of Fabhalta in other complement-mediated diseases – with an ultimate goal to drive meaningful change for patients.”

References

1. Novartis receives FDA approval for Fabhalta (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH. News release. Novartis. December 6, 2023. Accessed December 5, 2023. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-fabhalta-iptacopan-offering-superior-hemoglobin-improvement-absence-transfusions-first-oral-monotherapy-adults-pnh
2. Study of efficacy and safety of twice daily oral LNP023 in adult PNH patients with residual anemia despite anti-C5 antibody treatment (APPLY-PNH). ClinicalTrials.gov. Updated November 28, 2023. Accessed December 5, 2023. https://clinicaltrials.gov/study/NCT04558918
3. Novartis investigational oral monotherapy iptacopan demonstrates clinically meaningful superiority over anti-C5 treatment in Phase III APPLY-PNH study. News release. Novartis. October 24, 2022. Accessed December 5, 2023. https://www.novartis.com/news/media-releases/novartis-investigational-oral-monotherapy-iptacopan-demonstrates-clinically-meaningful-superiority-over-anti-c5-treatment-phase-iii-apply-pnh-study
4. Study of efficacy and safety of twice daily oral iptacopan (LNP023) in adult PNH patients who are naive to complement inhibitor therapy (APPOINT-PNH). ClinicalTrials.gov. Updated November 15, 2023. Accessed December 5, 2023. https://clinicaltrials.gov/study/NCT04820530