Fabhalta boosts hemoglobin in PNH, eliminates need for transfusions
Clinical trial data suggest start of new treatment era for disease: Researchers
One year of treatment with Fabhalta (iptacopan) boosts hemoglobin levels, eliminates the need for blood transfusions, and eases fatigue in most adults with paroxysmal nocturnal hemoglobinuria (PNH).
That’s according to final data from two global Phase 3 clinical trials: APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530), which evaluated the efficacy and safety of Fabhalta in PNH patients who had and had not been previously treated with standard anti-C5 medications.
Data from both clinical trials were reported in the study, “Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors,” published in The Lancet Haematology.
“We believe that these data support [Fabhalta] as a potential therapy option, suggesting that we are in a new treatment era for [PNH],” the researchers wrote.
Fabhalta patients reported less fatigue, better quality of life
PNH is caused by the abnormal activation of the complement cascade, a group of immune proteins that normally help the immune system eliminate infectious agents. This leads to the destruction of red blood cells (hemolysis) and symptoms of anemia.
Soliris (eculizumab) or Ultomiris (ravulizumab-cwvz) are approved PNH therapies designed to suppress complement activation by targeting a protein called C5. Administered directly into the bloodstream, they can effectively prevent red blood cell destruction occurring inside blood vessels, but in some patients, red blood cell destruction continues to occur outside blood vessels.
Novartis’ Fabhalta is an oral therapy approved in the U.S. and other countries for adults with PNH that’s designed to stop hemolysis from occurring both inside and outside blood vessels. It works by inhibiting factor B, a protein that acts upstream of C5 in the cascade of complement activation.
Fabhalta’s approvals were supported by data from the APPLY-PNH and APPOINT-PNH clinical trials.
APPLY-PNH enrolled 97 patients who continued to experience anemia despite being on a stable regimen of Soliris or Ultomiris for at least six months. Participants were randomly assigned to continue treatment with standard therapies or to switch to Fabhalta for 24 weeks, or about six months. APPOINT-PNH enrolled 40 PNH patients who hadn’t been previously treated with a complement inhibitor.
Early data from both trials indicated Fabhalta could boost hemoglobin levels in PNH adults, regardless of whether or not they had been treated with a C5 inhibitor. Fabhalta-treated patients also reported less fatigue and improved quality of life. Hemoglobin is the protein that carries oxygen in red blood cells.
Nearly all participants avoided blood transfusions after week 2
The second half of APPLY-PNH and APPOINT-PNH was an extension study, in which all participants received Fabhalta for an additional period of 24 weeks, for a total of 48 weeks.
According to final data encompassing all 48 weeks of treatment, Fabhalta boosted hemoglobin levels by at least 2 grams per deciliter of blood (g/dL) in most patients. In APPLY-PNH, this was seen in 86% of the patients who were always on Fabhalta and in 72% of those who switched to Fabhalta in the extension study. In APPOINT-PNH, it was seen in 97% of the patients.
The proportion of patients in APPLY-PNH whose hemoglobin reached at least 12 g/dL at week 48 was 68% in those always on Fabhalta and 59% among those who switched to Fabhalta. In APPOINT-PNH, 79% of Fabhalta-treated patients achieved this outcome.
Nearly all Fabhalta-treated patients in APPLY-PNH (92%) and APPOINT-PNH (98%) avoided blood transfusions between weeks two and 48. Similarly, almost all (94%) of those who switched from standard therapies to Fabhalta in the APPLY-PNH extension avoided transfusions between weeks 26 and 48.
Reductions in fatigue seen at week 24 were sustained through to week 48 for patients in APPLY-PNH and APPOINT-PNH treated with Fabhalta, as indicated by higher scores on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue tool. Similar improvements in mean fatigue scores were observed for patients who switched to Fabhalta in the APPLY-PNH extension.
We believe that the 48-week APPLY-PNH and APPOINT-PNH data support [Fabhalta] as a potentially practice-changing therapy.
Breakthrough hemolysis occurred in seven (7%) Fabhalta-treated patients in APPLY-PNH and two (5%) in APPOINT-PNH. Still, it was generally mild or moderate, and did not lead to treatment discontinuation. Three major adverse vascular events occurred in APPLY-PNH, but all were considered unrelated to Fabhalta.
The most common treatment-emergent adverse event was COVID-19 in APPLY-PNH (24% to 29%) and headache in APPOINT-PNH (30%). The most common serious treatment-emergent adverse event was COVID-19, occurring in one (2%) of the patients in the APPLY-PNH Fabhalta group and two (5%) in APPOINT-PNH. There were no treatment discontinuations due to adverse events or deaths, and no severe treatment-emergent adverse events occurred in more than one patient.
“We believe that the 48-week APPLY-PNH and APPOINT-PNH data support [Fabhalta] as a potentially practice-changing therapy,” the researchers wrote.
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