Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder that leads to hemolysis. Patients with PNH have episodes where red blood cells are prematurely destroyed, which may be triggered by stresses on the body. During these occurrences, severe anemia, profound fatigue, shortness of breath, intermittent episodes of dark-colored urine, kidney disease, or recurrent pain may occur. 

The treatment landscape for PNH is rapidly evolving. Clinicians have more effective and convenient treatment options for patients that have helped control the disease and improve survival. The first agent for patients with PNH was eculizumab (Soliris), a humanized monoclonal antibody targeting the terminal complement of C5, which the FDA approved in 2007. Updated data presented at the 63rd American Society of Hematology Annual Meeting and Exposition in 2021 showed that treatment with eculizumab for patients with PNH led to an improvement in survival in addition to controlling hemolysis.

The next agent approved by the FDA for patients with PNH was ravulizumab (Ultomiris) in 2018. The approval of ravulizumab, a long-acting C5 complement inhibitor given every 8 weeks, was based on findings from 2 studies. In the open-label phase 3 ALXN1210PNH-301 study (NCT02946463), investigators compared the safety and efficacy of ravulizumab with that of eculizumab in complement inhibitor– naïve adult patients with PNH.

 In the phase 3 ALXN1210-PNH-302 study (NCT03056040), investigators compared treatment with ravulizumab vs eculizumab in patients with PNH previously treated with eculizumab.

 Both trials showed that ravulizumab given every 8 weeks was noninferior to standard therapy in terms of clinical end points, including transfusion avoidance, lactate dehydrogenase (LDH) normalization, change in FACIT-Fatigue score, breakthrough hemolysis, and stabilized hemoglobin. 

The most recent agent for patients with PNH to receive FDA approval was pegcetacoplan (Empaveli) in 2021. Pegcetacoplan is a C3 inhibitor with the potential to inhibit both intra- and extravascular hemolysis. The approval was based on data from the phase 3 PRINCE trial (NCT04085601) that were presented during the European Society for Blood and Marrow Transplantation’s annual meeting.

Findings from PRINCE showed that patients with PNH who were naïve to complement inhibitor treatment displayed meaningful hematologic and clinical improvements through 26 weeks of pegcetacoplan treatment as demonstrated by improved hemoglobin levels. Avoidance of greater than 1-g/dL decrease from baseline was 85.7% with pegcetacoplan vs 0% in the standard-of-care control arm (P < .0001). Additionally, hemoglobin levels that were at least sex-specific lower limit of normal were 45.7% vs 0%, respectively (P = .0010), and change from baseline in LDH levels at week 26 were –1870.5 U/L vs –400.1 /LU, respectively (P < .0001).

There are currently trials involving iptacopan, an oral complement factor B inhibitor, and pozelimab, another monoclonal antibody targeting C5, both of which are displaying efficacy and a tolerable safety profiles in phase 2 trials.

Overall, we have come a long way in addressing this rare and serious condition and are still making inroads in treatments to better help patients with PNH.

Terriou L, Patriquin CJ, Griffin M, et al. Longterm survival benefit of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria: data from the international PNH registry. Blood. 2021;138(suppl 1):2188. doi:10.1182/ blood-2021-153560

Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540-549. doi:10.1182/blood-2018-09-876805 

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133(6):530-539. doi:10.1182/blood-2018-09-876136 

Wong RS, Navarro JR, Comia NS, et al. Efficacy and safety of pegcetacoplan treatment in complement- inhibitor naïve patients with paroxysmal nocturnal hemoglobinuria: results from the phase 3 prince study. Blood. 2021;138(suppl 1):606. doi:10.1182/ blood-2021-147493

Jang JH, Wong L, Ko BS, et al. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-ofconcept study. Blood Adv. 2022;6(15):4450-4460. doi:10.1182/bloodadvances.2022006960

Jung JH, Weyne J, Chaudhari U, et. al. Pozelimab, a human monoclonal antibody against complement factor C5, provided inhibition of intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2021;138(suppl 1):1128. doi:10.1182/blood-2021-146178

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The treatment landscape for PNH is rapidly evolving, and clinicians have more effective and convenient treatment options for patients that have helped control the disease and improve survival. T

Muthu Veeraputhiran, MD

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The Evolving Treatment Landscape in Paroxysmal Nocturnal Hemoglobinuria