Switching to Fabhalta boosts hemoglobin, eases fatigue in PNH
Trial results also show adult patients remained free from blood transfusions
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Most adults with paroxysmal nocturnal hemoglobinuria (PNH) who switched from standard C5 inhibitors to Fabhalta (iptacopan) saw their hemoglobin levels rise, remained free from blood transfusions, and reported less fatigue after six months of treatment, according to Phase 3 trial results.
The open-label Phase 3b APPULSE-PNH study (NCT05630001) was designed to evaluate the efficacy and safety of twice-daily oral Fabhalta in adults with PNH who had been receiving stable treatment with intravenous, or into-the-vein, Soliris (eculizumab) or Ultomiris (ravulizumab) for at least six months.
“Evidence from the APPULSE‐PNH study and previous clinical trials continues to establish oral [Fabhalta] as a potentially practice‐changing treatment for PNH,” researchers wrote.
The study, “Iptacopan monotherapy resulted in increased hemoglobin level in patients with PNH and hemoglobin ≥10 g/dL after anti-C5 therapy,” was published in HemaSphere.
Fabhalta aims to control intravascular and extravascular hemolysis
PNH occurs when red blood cells lack protective proteins that normally shield them from attacks by the complement cascade, a group of immune proteins that are part of a person’s immune system. As a result, red blood cells are destroyed prematurely, leading to anemia (a shortage of red blood cells), fatigue, and other symptoms.
Soliris and Ultomiris work by blocking a complement protein called C5. While these therapies are highly effective at preventing the destruction of red blood cells within blood vessels, known as intravascular hemolysis, some patients continue to experience red blood cell destruction outside blood vessels, a process called extravascular hemolysis.
Fabhalta, an oral therapy approved in the U.S. for adults with PNH, blocks factor B, a protein involved earlier in the complement cascade. By acting further upstream, the therapy is designed to control both intravascular hemolysis and extravascular hemolysis.
Its approval was based on data from two Phase 3 clinical trials: APPLY-PNH (NCT04558918), which enrolled patients with anemia despite treatment with a C5 inhibitor, and APPOINT-PNH (NCT04820530), which enrolled patients who had never received a complement inhibitor.
In both studies, one year of treatment with Fabhalta significantly increased hemoglobin levels, with good control of both intravascular and extravascular hemolysis, eliminated the need for blood transfusions, and eased fatigue in most participants. In APPLY-PNH, Fabhalta also outperformed C5 inhibitors, helping more patients achieve meaningful improvements in hemoglobin levels and better control of hemolysis.
Treatment met trial’s primary goal
In this study, researchers report on results from APPULSE‐PNH. The trial enrolled 52 adults with PNH who had hemoglobin levels of at least 10 g/dL, indicating they did not have moderate or severe anemia, and were on stable treatment with a C5 inhibitor. Participants also had not required blood transfusions during the previous six months. All switched to 200 mg twice daily of Fabhalta for about six months.
Before switching to Fabhalta, participants had been treated with a C5 inhibitor for a median of 2.6 years, with most (88.5%) transitioning from Ultomiris. At the start of the study, nearly two-thirds of participants (61.5%) had hemoglobin levels below 12 g/dL. Compared with those whose hemoglobin levels were 12 g/dL or higher, these patients generally reported more fatigue and showed higher levels of laboratory markers associated with ongoing hemolysis.
In line with previous results, hemoglobin levels increased by a mean of 2 g/dL after participants switched to Fabhalta. Statistical analyses showed that switching to Fabhalta maintained the benefits of prior C5 inhibitor treatment while providing additional improvements in hemoglobin levels, meeting both the trial’s primary goal and key secondary outcome.
The increase was particularly pronounced among patients whose hemoglobin levels were below 12 g/dL at the start of the study, with mean gains of 2.4 g/dL, compared with 1.4 g/dL among those who had hemoglobin levels of 12 g/dL or higher. Overall, 48 of 51 evaluable participants (92.7%) maintained or reached hemoglobin levels of at least 12 g/dL between about four and six months.
By conveniently delivering comprehensive hemolysis control as an oral monotherapy, [Fabhalta] may emerge as an excellent outpatient option for patients with PNH.
Fabhalta also significantly reduced markers of ongoing hemolysis. Indicators of extravascular hemolysis declined rapidly after the switch from C5 inhibitors, while markers of intravascular hemolysis remained well controlled, indicating that the benefits of C5 inhibition were maintained after the transition to Fabhalta.
No patients required blood transfusions, experienced breakthrough hemolysis, or had major adverse vascular events during the study.
Participants also reported less fatigue during treatment. Scores on the FACIT-Fatigue questionnaire, a measure of fatigue and its impact on daily life, improved by 4.3 points after six months of treatment. The benefit was greatest among participants whose hemoglobin levels were below 12 g/dL at the start of the study, whose scores improved by 6.4 points, compared with 1.5 points among those with higher hemoglobin levels.
Fabhalta was generally well tolerated, with no deaths reported during the study. The most common side effects were headache (17.3%), diarrhea, nausea, and nasopharyngitis, commonly known as the common cold (11.5% each). Two participants experienced serious adverse events that were considered unrelated to treatment with Fabhalta, and one patient discontinued Fabhalta due to nonserious heart palpitations suspected to be related to treatment.
“By conveniently delivering comprehensive hemolysis control as an oral monotherapy, [Fabhalta] may emerge as an excellent outpatient option for patients with PNH,” the researchers concluded.
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