Empaveli most effective in newly treated PNH patients in study

Therapy found to work better than Ultomiris or Soliris

Marisa Wexler MS avatar

by Marisa Wexler MS |

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People with paroxysmal nocturnal hemoglobinuria (PNH) newly treated with Empaveli (pegcetacoplan) are more likely to see their hemoglobin levels rise and less likely to experience breakthrough disease attacks than those started on Soliris (eculizumab) or Ultomiris (ravulizumab-cwvz).

That’s according to a new study reporting the findings from an indirect comparison of clinical trial data.

“Treatment with [Empaveli] was associated with favorable outcomes and a suggestion of improvement in all measured laboratory parameters compared with [Ultomiris and Soliris],” the researchers wrote.

Empaveli also showed a stronger positive effect on life quality, though the three therapies showed comparable efficacy in measures of patient-reported fatigue and physical function.

The study, “Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab and Eculizumab in Complement Inhibitor-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria: A Matching-Adjusted Indirect Comparison,” was published in the journal Advances in Therapy. The work was funded by Apellis, which codeveloped Empaveli along with Sobi. AstraZeneca, which markets both Soliris and Ultomiris, was not involved.

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Soliris effective in PNH when properly prescribed: Study

Empaveli outperforms other approved therapies on key measures

Empaveli, Soliris, and Ultomiris are the three approved therapies to treat PNH in the U.S. All three medications work by blocking the activation of a group of immune proteins that are part of the complement cascade.

In PNH, activation of the complement cascade leads to the destruction of blood cells, which ultimately gives rise to disease symptoms. The advent of complement-blocking therapies has revolutionized PNH treatment and substantially improved clinical outcomes for people with the disease.

Soliris and Ultomiris specifically target a complement protein called C5. These two medications have a virtually identical mechanism of action, but Ultomiris is designed to last longer in the body, allowing for less frequent dosing compared with Soliris. Empaveli targets another complement protein called C3, which is activated slightly earlier in the complement cascade.

A Phase 3 trial called PEGASUS (NCT03500549) enrolled 80 people with PNH who had not adequately responded to Soliris. Its results showed that Empaveli outperformed Soliris at boosting patient levels of hemoglobin, the protein in red blood cells that is responsible for oxygen transport.

However, there has never been a clinical trial directly comparing Empaveli against either of the C5-targeting medications in patients who are starting treatment and have not previously been on a complement-blocking therapy.

Now, scientists used data from two clinical trials to perform an indirect comparison of these medications in PNH patients starting for the first time on such therapies.

Their study included data from the Phase 3 ALXN1210-PNH-301 trial (NCT02946463), which tested Soliris against Ultomiris in previously untreated PNH patients, as well as the open-label Phase 3 PRINCE trial (NCT04085601) that tested Empaveli in a similar population.

In total, the analysis included data for 34 patients treated with Empaveli, 121 given Soliris, and 125 treated with Ultomiris. Upon entering the respective studies, patients on Empaveli showed some significant differences from those on the other therapies in terms of ethnic background and clinical measures.

To account for these differences, researchers used a statistical analysis called a matching-adjusted indirect comparison. In simple terms, this involved statistical adjustments that aim to minimize the effect of baseline differences between the treatment groups — those found at a study’s start.

A notable limitation of this approach, the researchers highlighted, is that they could only minimize differences that were clear in the available data.

“Although matching was applied to observed cross-trial differences in patient characteristics to the extent possible, there may have been unobserved differences that influenced the results,” the team wrote.

The analysis’ findings showed that Empaveli “was associated with statistically significant improvements in most clinical and hematologic [blood-related] endpoints” compared with the other two treatments, the researchers wrote.

For example, patients given Empaveli tended to experience a more pronounced decline in the levels of the cell damage marker lactate dehydrogenase (LDH), implying that these patients were experiencing less blood cell destruction than those on Soliris or Ultomiris. More patients on Empaveli had LDH levels within the normal range while on treatment compared with the other two medications.

“The results of the present study show that patients receiving [Empaveli] had significantly greater reductions in LDH level than those receiving [Ultomiris or Soliris]; they were also more likely to achieve LDH normalization, and achieved it more rapidly,” the researchers wrote.

Quality of life scores improved more with Empaveli

Hemoglobin levels also rose significantly more in patients treated with Empaveli. Additionally, more patients on Empaveli had stable hemoglobin levels, and fewer of them required blood transfusions.

Breakthrough attacks of hemolysis, or red blood cell destruction, were not recorded in any of the patients treated with Empaveli, but were rarely noted among those on the other two treatments.

Overall quality of life scores, measured with the EORTC QLQ-C30, improved significantly more with Empaveli than with Soliris or Ultomiris. However, the three treatments showed similar effects on measures of fatigue and physical functioning.

Although the team did not study safety outcomes in detail, they noted that certain side effects, particularly diarrhea and injection site reactions, appeared to be more common in patients given Empaveli, while headache has been more frequently reported as a side effect in patients treated with Soliris or Ultomiris.

“Patients treated with [Empaveli] had greater improvements in clinical, hematologic, and [quality of life] outcomes than those treated with either [Soliris or Ultomiris] in this analysis,” the researchers wrote. “These findings can potentially guide clinical decision-making for optimized treatment of patients with PNH.”