Introduction of new PNH drugs…expanding competition landscape

Roche's C5 inhibitor joins the competition…changes brought to the market structure, previously dominated by Soliris·Ultomiris

Treatment options have been expanded, including C3, Factor B, and Factor D…administration method is a determinant for competitiveness

The competition landscape for Paroxysmal Nocturnal Hemoglobinuria (PNH) treatment market in South Korea has intensified with the introduction of a new C5 complement inhibitor.

The market, which was dominated by AstraZeneca's C5 inhibitors 'Soliris (eculizumab)·Ultomiris (ravulizumab)', is expected to see full-scale competition from new mechanism treatments, including C3·Factor B·Factor D inhibitors. Industry observers anticipate that the key criteria for selecting PNH treatments will shift from mechanism alone to factors such as administration convenience, including dosing intervals and formulations.

Roche's PNH treatment 'Piasky (crovalimab)'

According to industry sources on December 27, the Ministry of Food and Drug Safety (MFDS) approved Roche's PNH treatment, 'Piasky (crovalimab)', on December 24. Piasky is a C5 complement inhibitor developed by Roche. This drug works by administering a low dose subcutaneously (SC) every 4 weeks, which then recirculates in the blood to inhibit complement activity continuously.

Piasky obtained U.S. FDA approval in June last year and was commercialized in Europe in August of the same year. In South Korea, it was designated as an orphan drug in February of last year.

The basis of approval is the results of the Phase 3 COMMODORE 2 study. COMMODORE 2 was a randomized, open-label, active-controlled non-inferiority trial comparing Piasky directly with the current standard of care, AstraZeneca's Soliris, in PNH patients aged 13 and older weighing at least 40 kg.

The primary endpoints of the trial were transfusion avoidance and hemolysis control rates. The secondary endpoints included breakthrough hemolysis, hemoglobin stabilization, changes in fatigue, and safety.

In the studies, the hemolysis control rate from week 5 to week 25 was 79.3% in the Piasky group and 79.0% in the Soliris group, successfully meeting the criteria for non-inferiority.

The proportion of patients who avoided red blood cell transfusions from baseline to week 25 was also similar, at 65.7% and 68.1%, respectively. The incidence of breakthrough hemolysis tended to be lower in the Piasky group (10.4%) than in the control group (14.5%), and there was no significant difference between the two groups in the proportion of patients maintaining stable hemoglobin levels.

In terms of safety, the Piasky group had an approximately 6% incidence of serious adverse events, with epistaxis, pneumonia, and infusion-related reactions as the primary reports. The overall adverse event profile was similar to that of existing C5 inhibitors.

C3 and Factor B...Competition over 'Mechanism + Convenience' begins in full-scale

Following the domestic approval of Piasky, the PNH treatment market is expected to shift from the existing C5-inhibitor-dominated structure into a phase of competitive diversification in mechanisms.

PNH is a rare disease caused by acquired genetic mutations. While multiple mutations in hematopoietic stem cells can lead to blood cancers, PNH occurs when a mutation develops in the X-linked PIGA gene.

PNH is reportedly a disease without a fundamental cure. However, with scientific advances, the development of treatments that inhibit complement activation is changing the therapeutic approach. The complement system is a core element of innate immunity, a robust defense that directly attacks and destroys pathogens. This system consists of various pathways, such as C3 and C5, and ultimately forms the membrane attack complex (MAC) to destroy red blood cells.

Until now, treatments inhibiting C5, located at the terminal pathway of the complement system, have been primarily used. The treatment environment improved with the introduction of Soliris, an injectable administered every two weeks, followed by Ultomiris, which can be administered every eight weeks. Many patients still manage the disease based on these treatments.

Recently, the competitive axis has widened with the addition of Handok's C3 inhibitor 'Empaveli (pegcetacoplan)', Novartis's Factor B inhibitor 'Fabhalta (iptacopan)', and AstraZeneca's Factor D inhibitor 'Voydeya (danicopan)'. Each drug targets a different stage in the complement system. They have been designed to employ strategies to address unmet needs, such as extravascular hemolysis (EVH), may persist even after C5 inhibition.

From left, PNH treatments 'Empaveli (pegcetacoplan)', 'Fabhalta (iptacopan)', 'Voydeya (danicopan)'

Analysts suggest that the future market landscape will likely be driven more by administration convenience than by differences in efficacy.

The dosing structure of Voydeya is complex requiring co-administration with a C5 inhibitor. However, it offers the advantage of potentially easier compliance management.

For Fabhalta, its oral formulation is a strength, offering greater dosing convenience than injectables. This treatment is particularly effective for treating anemia and EVH.

Empaveli poses burden of twice-weekly subcutaneous injections, but it remains an option for patients who can expect clinical effects from direct inhibition at the C3 stage. Experts evaluate it as a sufficiently effective option for patients who do not have a strong aversion to injections.

Empaveli was developed by the U.S. company Apellis Pharmaceuticals, while Swedish Orphan Biovitrum (Sobi) holds the rights outside the United States. Handok signed a strategic partnership agreement with Sobi in 2023 to introduce Empaveli into the Korean market.