Study Demonstrates Potential of Composite End Point in Assessing Treatment for PNH

A study published in the European Journal of Haematology found that a composite end point developed by the researchers was effective in assessing the impact of treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder caused by uncontrolled activation of the terminal complement pathway.

The composite end point was applied to analyze the clinical benefits of 2 approved drugs for PNH that were evaluated in Study 301. Study 301 was a phase 3, open-label, interventional study that evaluated the effects of ravulizumab vs eculizumab in complement inhibitor–naïve patients with PNH.

Components of the composite end point were chosen based on relevance to PNH. Each component of the composite end point would be a binary indicator and each component must be present for patients to meet the overall end point indicator.

The final variables that were selected for the composite end point were lactate dehydrogenase (LDH) levels as a measure of intravascular hemolysis (IVH); complete terminal complement inhibition; absence of major adverse vascular events (MAVEs); absence of any adverse events (AEs) leading to death or discontinuation of study treatment; and transfusion avoidance.

There were 246 adult patients with PNH who were treated with ravulizumab (n = 125) or eculizumab (n = 121) during a 26-week period.

Reducing LDH levels below 1.5 times the upper limit of normal (ULN) is a primary goal for patients on complement inhibitors. There were 68.0% of patients in the ravulizumab arm and 57.0% of patients in the eculizumab arm who had all LDH values below 1.5 × ULN, with a treatment-effect difference of 11.0% (95% CI, –1.2% to 22.6%)

All patients in the ravulizumab arm and most patients in the eculizumab arm (87.6%) had all serum free C5 levels less than 0.5 mcg/mL from after the first infusion to week 26, with a treatment effect difference of 12.4% (95% CI, 7.1%-19.6%).

Almost all patients reached the MAVE threshold and demonstrated absence of MAVEs at 26 weeks. The ravulizumab arm (98.4%) and eculizumab arm (99.2%) both demonstrated a vast majority of MAVE absence, with a treatment-effect difference of –0.8% (95% CI, –6.1% to 5.7%).

Many patients demonstrated an absence of AEs leading to death or discontinuation of study in the ravulizumab arm (100%) and the eculizumab arm (99.2%); there was a treatment-effect difference of 0.8% (95% CI, –2.3% to 4.6%). There were 73.6% of patients in the ravulizumab arm and 66.1% in the eculizumab arm who avoided transfusion.

The composite end point was defined as the patients meeting all 5 selected individual component thresholds. There were 51.2% of patients in the ravulizumab arm and 41.3% of patients in the eculizumab arm that met the composite end point, with an adjusted treatment difference of 9.4% (95% CI, –3.0% to 21.5%).

The researchers found that the numbers of patients with high baseline LDH values and of those who received more transfusions were higher in patients who did not meet the composite end point. The age of patients at their PNH diagnosis and the first infusion was lower in patients who met the end point criteria compared with patients who did not.

There were several limitations to this study. The definition of a composite end point compared with an isolated end point has risks and limitations. The composite end point was exploratory in nature and used data from 1 trial, which means the results should be taken with caution. Discontinuations due to MAVEs and AEs were evaluated in 26 weeks, which may be too short to evaluate. It is a challenge to compare lifetime history of MAVEs with a reduction in a short period of time.

The researchers concluded that their composite end point allowed for an integrated and simultaneous assessment of the clinical benefits of the 2 approved drugs for PNH.

“The composite end point provides a holistic goal offering a single measurement of therapeutic benefit…This composite end point is recommended for use in future PNH research to explore clinical benefit,” the authors wrote.

Reference

Kulasekararaj A, Glasmacher A, Liu P, et al. Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria. Eur J Haematol. Published online January 31, 2022. doi:10.1111/ejh.13746