Piasky (crovalimab)

A C5 inhibitor like eculizumab (Soliris) and ravulizumab (Ultomiris), given as an injection under the skin every 4 weeks after the loading phase. Because it binds a different spot on C5, switching between it and those drugs carries a risk of Type III hypersensitivity reactions.

In PNH, red blood cells lack protective proteins on their surface, so the complement system, part of the immune defenses, attacks them. The final step of that attack depends on a protein called C5 being split into C5a and C5b, which builds a pore called the membrane attack complex that bursts red cells inside blood vessels (intravascular hemolysis). Crovalimab is a humanized antibody that binds tightly to C5 and stops it from being split, so the pore cannot form^[1]. Chugai Pharmaceutical created it using its antibody recycling technology^[4]. Hemolysis can return after treatment stops, so the label calls for close monitoring for at least 20 weeks if Piasky is stopped without a switch to another PNH treatment^[1].

Piasky carries a boxed warning for serious meningococcal infections. Like other complement inhibitors, it raises the risk of life-threatening or fatal infections caused by Neisseria meningitidis, a cause of meningitis and bloodstream infection, even in people who have been vaccinated. Meningococcal vaccines for serogroups A, C, W, Y and B must be completed or updated at least 2 weeks before the first dose; if treatment cannot wait, antibiotics are given and the vaccines are given as soon as possible. Because of this risk, Piasky is available only through a restricted program called the PIASKY REMS: prescribers must enroll, and patients carry a Patient Safety Card during treatment and for 11 months after the last dose. People switching from eculizumab or ravulizumab to Piasky, or the other way, can develop Type III hypersensitivity reactions, an immune reaction to clumps of C5 bound to both drugs that can cause joint pain, rash, fever, muscle aches or headache. These occurred in 39 of 201 patients (19%) who switched to Piasky in trials, so the label calls for watching for symptoms for 30 days after a switch. In the main trial in people new to complement inhibitors, the most common side effects on Piasky vs eculizumab were infusion-related reactions (16% vs 13%), respiratory tract infections (13% vs 20%), viral infections (11% vs 7%), headache (8% vs 6%) and diarrhea (7% vs 1%). It can also raise the risk of other infections from encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae^[1].

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Approved for adults and children 13 and older with PNH who weigh at least 40 kg (88 pounds). Safety and effectiveness have not been established under age 13 or under 40 kg. It cannot be started during an unresolved serious meningococcal infection. Breastfeeding is not recommended during treatment and for 9 months after the last dose.

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COMMODORE 2 (NCT04434092) randomized 204 people with PNH who had never taken a complement inhibitor to Piasky or eculizumab (2:1) for 24 weeks. Hemolysis control, meaning LDH (a blood marker of red cell destruction) at or below 1.5 times the upper limit of normal, averaged 79.3% on Piasky and 79.0% on eculizumab, and 65.7% vs 68.1% avoided transfusions, meeting the goal of showing Piasky was not worse (non-inferior). Breakthrough hemolysis occurred in 10.4% vs 14.5% and hemoglobin stayed stable in 63.4% vs 60.9%^[1][3]. COMMODORE 1 studied people switching from eculizumab, and COMMODORE 3 (NCT04654468) was a single-arm trial. Across these trials, 12 teenagers aged 13 to 17 were treated, with results consistent with adults^[1].

Chugai Pharmaceutical discovered crovalimab and described it in 2018 as an anti-C5 recycling antibody under the code SKY59^[4][5]. Roche develops it as RG6107 in collaboration with Chugai^[6]. Genentech, a member of the Roche Group, submitted the application to the FDA on June 19, 2023, and the FDA approved Piasky on June 20, 2024 for people 13 and older with PNH who weigh at least 40 kg^[2]. The approval letter lists a postmarketing commitment to complete the COMPOSER study, which refers to the drug by the code RO7112689^[2].

PNH is treated with complement inhibitors. The C5 inhibitors eculizumab (Soliris), ravulizumab (Ultomiris) and crovalimab (Piasky, approved June 2024) block red cell destruction inside blood vessels. Pegcetacoplan (Empaveli), which binds C3, and iptacopan (Fabhalta, approved December 2023), a factor B inhibitor pill, act earlier in the complement cascade and target red cell destruction both inside and outside blood vessels. Danicopan (Voydeya, approved March 2024) is an add-on pill for extravascular hemolysis in people who stay on eculizumab or ravulizumab.