Fabhalta more effective than Empaveli for anemia in PNH, data suggest
Indirect study compared 2 approved therapies in reducing blood transfusions
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Fabhalta (iptacopan) appears to outperform Empaveli (pegcetacoplan) in raising hemoglobin levels and reducing the need for blood transfusions in adults with paroxysmal nocturnal hemoglobinuria (PNH) who continue to have symptoms despite previous treatment.
Those are the findings of a new study that indirectly compared the two approved therapies using data from two separate but similar clinical trials. The data showed that Fabhalta may work better than Empaveli to increase levels of hemoglobin, the protein responsible for carrying oxygen in red blood cells.
No differences were found between the two treatments in patient-reported fatigue, red blood cell destruction, or side effects in the analysis.
“While these findings suggest [Fabhalta] may be more effective at raising hemoglobin levels and reducing transfusion dependency, they are associated with limitations because they are based on a small number of patients and should be confirmed with future direct comparisons,” the researchers wrote.
The study detailing the findings, titled “Indirect treatment comparison of iptacopan versus pegcetacoplan for patients with paroxysmal nocturnal hemoglobinuria and residual anemia despite C5 inhibitor treatment,” was published in the Journal of Comparative Effectiveness Research. It was funded by Novartis, the developer of Fabhalta. Five of the study’s 10 researchers work for Novartis.
A rare acquired blood disorder, PNH is caused by the abnormal activation of the complement cascade — a part of the body’s immune system — that ultimately destroys red blood cells in a process called hemolysis.
This results in decreased hemoglobin, which ensures oxygen is transported through the body, leading in turn to symptoms of anemia, such as fatigue, pale skin, and shortness of breath.
The condition is primarily treated with medications that block complement activation. These include the approved PNH therapies Soliris (eculizumab) and Ultomiris (ravulizumab), which help to prevent hemolysis, ease symptoms, and reduce the risk of life-threatening complications.
Many PNH patients remain anemic despite regular treatment
While both medications, which specifically suppress the C5 complement protein, can reduce hemolysis within blood vessels, they are less effective against hemolysis outside blood vessels. As a result, many patients remain anemic despite regular treatment.
Two newer medications have been developed to address this gap: Fabhalta, an oral pill, and Empaveli, a self-administered injection under the skin. Both are designed to block complement proteins upstream of C5 and prevent hemolysis, both inside and outside blood vessels.
No clinical trial to date has directly compared Fabhalta and Empaveli in PNH patients. Now, an international team of researchers used an indirect treatment comparison — a statistical method for estimating the relative effectiveness of two therapies using matched patient data — with the findings from two separate but similar studies.
A database search yielded two PNH trials for the indirect treatment comparison: APPLY-PNH (NCT04558918), which tested Fabhalta against Soliris or Ultomiris, and PEGASUS (NCT03500549), which compared Empaveli with Soliris.
Both were Phase 3 trials conducted at multiple sites across North America and Europe. Participants knew which treatment they were receiving, and all were adults with PNH who continued to have anemia despite treatment with C5-blocking medications.
To increase the reliability of the results, the researchers used two adjustment methods. Scenario A accounted for pretreatment differences in sex, blood hemoglobin levels, and the need for a blood transfusion in the previous year. Scenario B accounted for those three factors plus age and blood levels of two hemolysis markers.
Fabhalta appeared to work better to increase hemoglobin
According to the analysis, the individuals treated with Fabhalta saw their hemoglobin rise by an average of 3.71 g/dL, compared with 2.66 g/dL for those on Empaveli. The difference between the two treatment groups was statistically significant — meaning it was unlikely to have occurred by chance — in both scenario A and scenario B. These results remained consistent even when blood transfusion data were removed from the analysis, the researchers noted.
Between days 29 and 140 of treatment (one to 4.5 months), more than 98% of Fabhalta-treated patients remained transfusion-free in both scenarios, compared with 85% of those given Empaveli. Here, the odds of avoiding a blood transfusion with Fabhalta were about nine times greater than with Empaveli in scenario A. In scenario B, those odds were nearly 13 times higher, the data showed.
Before treatment, the patients’ mean blood levels of lactate dehydrogenase (LDH), a marker of hemolysis, were slightly above the upper limit of normal in both treatment groups. By day 140, LDH levels had changed minimally, with no significant differences between the Fabhalta and Empaveli groups.
The results suggest that [Fabhalta] may be more effective than [Empaveli] in improving clinically relevant outcomes for managing PNH, such as increasing [hemoglobin] levels and allowing patients to be transfusion-free.
In both scenarios, no significant group differences were found in terms of changes in fatigue and its impact on daily life, as indicated by self-reported FACIT-Fatigue scores.
In the original trials, the rate of serious adverse events was higher in patients treated with Empaveli than in those given Fabhalta (17% vs. 9.7%). However, after matching and adjusting, the odds of experiencing such events were comparable in two treatment groups, according to the researchers.
“The results suggest that [Fabhalta] may be more effective than [Empaveli] in improving clinically relevant outcomes for managing PNH, such as increasing [hemoglobin] levels and allowing patients to be transfusion-free,” the scientists concluded.
Still, more work is needed to directly compare the effects of the two treatments, the team noted.
“Ultimately, the potential therapeutic advantages of [Fabhalta single therapy] should be confirmed in head-to-head clinical trials or real-world studies,” the researchers wrote.
