Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the pathological activation of the terminal complement pathway, which causes intravascular hemolysis and thrombosis. Untreated, it is associated with a poor health-related quality of life, increased hospitalizations, and a greater risk of early death.
The mainstay PNH treatment is eculizumab (Soliris®), a complement inhibitor that targets the terminal complement. In 2007, the introduction of this drug created a sea change in the way patients with PNH were treated and their prognosis. It is a monoclonal antibody that works by blocking terminal complement at C5.
It is difficult to overemphasize the impact of eculizumab on the treatment of PNH. For the first time in history, patients with PNH treated with this drug could expect a similar life expectancy to that of the general population. This drug “changed the natural history of PNH,” Brodsky wrote in a paper published in Blood.
Another drug, ravulizumab (Ultomiris®), was approved by the US Food and Drug Administration (FDA) the following year. Ravulizumab is a long-acting C5 inhibitor; its main advantage over eculizumab is that it requires a lower number of infusions per year, reducing treatment burden. Ravulizumab is typically administered via intravenous (IV) dosing once every 8 weeks, whereas eculizumab needs to be given more frequently.
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In 2022, a subcutaneous formulation of ravulizumab was introduced; this formulation requires only once-weekly self-administration: a prefilled cartridge is applied onto the body and the drug can be self-administered via the push of a button. This formulation of ravulizumab was designed to be quick, convenient, and painless.
This means that ravulizumab can now be administered either intravenously once every 8 weeks, or subcutaneously once weekly. Although the frequency of injections is higher via the subcutaneous route, many patients prefer it over IV injections, since it does not require a venous puncture.
“A recent modeling analysis estimated that [subcutaneous] ravulizumab may reduce time spent receiving therapy and costs associated with productivity losses compared with IV administration, with benefits to both patients and caregivers,” Yenerel and colleagues wrote in Advances in Therapy.
However, this begs the question: is the subcutaneous formulation of ravulizumab at least equal in efficacy to its IV form? A drug that can be self-administered may be more convenient, but not all drugs can be administered subcutaneously without losing some of its potency.
Achieving Terminal Complement Inhibition
Yenerel and colleagues hence conducted a study to evaluate the pharmacokinetics of subcutaneous ravulizumab compared to intravenous ravulizumab. They recruited patients with PNH who previously received IV eculizumab treatment for a minimum period of 3 months prior to study enrollment.
To maximize the pool of participants, this study was conducted at 51 centers in 14 countries. The screening period was up to 30 days long, after which a 10-week randomized treatment period commenced. This study had an initial extension period of 42 weeks, which was extended up to 172 weeks.
To be considered for this study, patients had to be aged 18 or more years with a diagnosis of PNH confirmed by high-sensitivity flow cytometry. They had to weigh between 40 and 100 kg and have been vaccinated against meningococcal infection. Patients had to have lactate dehydrogenase levels no greater than 1.5 times the upper limit of normal.
Selected participants were randomized in a 2:1 ratio to receive either subcutaneous or IV ravulizumab. Participants receiving subcutaneous ravulizumab (n=70) received a weight-based loading dose of IV ravulizumab on the first day of the trial, followed by maintenance doses of subcutaneous ravulizumab administered once weekly (490 mg) on day 15 until the end of the randomized treatment period.
Participants on IV ravulizumab (n=35) similarly received a weight-based loading dose of IV ravulizumab on day 1 and a maintenance dose on day 15 (ranging from 3000 mg to 3300 mg depending on the weight of the patient). After the randomized treatment period on day 71, all patients regardless of their initially assigned group received weekly subcutaneous ravulizumab maintenance doses.
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The results demonstrated that subcutaneous ravulizumab achieved pharmacokinetic (PK) noninferiority compared with intravenous ravulizumab for the primary endpoint, which was day 71 serum ravulizumab trough concentration. This was true across a number of sensitivity analyses performed.
The results also revealed that all participants, regardless of their assigned treatment group, had individual serum ravulizumab concentrations greater than 175 μg/mL, which is the threshold for achieving and sustaining complete terminal complement inhibition. In addition, all participants had individual serum free C5 concentration levels less than 0.5 μg/mL, the threshold for complete terminal complete inhibition. Adverse events were similar across the treatment groups.
“With the demonstration of PK noninferiority of [subcutaneous] ravulizumab to IV ravulizumab in this study, the established efficacy data from IV ravulizumab can be bridged to [subcutaneous] ravulizumab,” the research team concluded.
The option of receiving ravulizumab via self-administered subcutaenous injection is a continuation in the story of how science is tackling the mortality and morbidity associated with PNH. With every new innovation, patients with PNH have a greater chance of living free, independent lives, equal to their peers.
Yenerel MN, Sicre de Fontbrune F, Piatek C, et al. Phase 3 study of subcutaneous versus intravenous ravulizumab in eculizumab-experienced adult patients with PNH: primary analysis and 1-year follow-up. Adv Ther. 2022;1-22. doi:10.1007/s12325-022-02339-3
Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812