Paroxysmal nocturnal hemoglobinuria (PNH), historically termed nocturnal hemoglobinuria, is a rare but potentially life-threatening hematologic disorder characterized by uncontrolled intravascular and extravascular hemolysis, bone marrow failure, and a high risk of thrombotic events.

Recent therapeutic milestones have transformed this landscape, offering patients oral medications, biosimilars, and innovative complement inhibitors designed to enhance convenience and reduce treatment burden.

Established Complement Inhibitors

The complement system plays a central role in PNH pathophysiology. Terminal complement (C5) inhibitors brought dramatic survival improvements:

• Eculizumab (Soliris) was approved in 2007 and remains a frontline therapy for controlling intravascular hemolysis and reducing thrombotic risk 


• Ravulizumab (Ultomiris) launched in 2018 as a long-acting C5 inhibitor with an every‑8‑week dosing schedule and similar efficacy to Soliris, with improved convenience and fewer breakthrough events


• Pegcetacoplan (Empaveli) targets complement protein C3 to address both intra‑ and extravascular hemolysis. Administered subcutaneously twice a week, it gained approval in 2021 and proved effective for patients who remain transfusion-dependent despite C5 inhibition 

First Oral Monotherapy: Fabhalta (Iptacopan)

Fabhalta, approved in December 2023, is the first oral monotherapy for PNH. It works by inhibiting factor B, acting upstream in the complement cascade, and significantly reducing both intravascular and extravascular hemolysis.

In Phase III clinical trials (APPOINT‑PNH and others), adult patients treated with Fabhalta experienced higher hemoglobin levels and transfusion independence compared to those on Soliris or Ultomiris 

Add‑On Oral Therapy: Voydeya (Danicopan)

Voydeya (danicopan), approved in early 2024, is an oral factor D inhibitor intended as an adjunct to C5 inhibitors in patients with clinically significant extravascular hemolysis. Trials showed that when combined with Soliris or

Ultomiris, it raised hemoglobin levels and increased transfusion avoidance rates to nearly 80% by Week 12 

CMA (cost‑effectiveness) analyses suggest value if priced between $12,300 to $13,100 annually

Biosimilar Options: Bkemv

Bkemv, Amgen’s eculizumab biosimilar, received FDA approval in May 2024 as an interchangeable alternative to Soliris at a lower cost

This provides payers and providers with a more affordable option while preserving clinical efficacy and safety, though it carries the same boxed warning for meningococcal infection risk

Next‑Generation Complement Inhibitors

New C5 inhibitors and advanced modalities offer improved patient convenience and sustained complement blockade:

• Crovalimab (PiaSky), approved by FDA in June 2024, is a subcutaneous/intravenous C5‑recycling antibody requiring monthly dosing. In trials, it maintained hemolysis control comparable to Soliris with high tolerability


• PiaSky approvals in China, Japan, EU, and US make it broadly accessible 


• Additional advanced candidates in development include KP104 (dual-pathway biologic), LN‑CC5 plus Veopoz (combination C5 suppression), RG6107 (subcutaneous C5), and NM5072 (anti‑Bb antibody). These pipeline agents aim to deliver broader complement pathway control with better side‑effect profiles

Conclusion

Innovations in nocturnal hemoglobinuria medicine are rapidly redefining patient care. From long‑established C5 inhibitors to pioneering oral therapies like Fabhalta and Voydeya, and biosimilars such as Bkemv, the therapeutic spectrum now offers tailored options balancing efficacy, safety, and patient preferences. Next‑generation agents like crovalimab further expand delivery flexibility and complement blockade precision. As treatments evolve, informed, individualized decisions based on clinical profile, cost, route of administration, and patient lifestyle will be essential. Multidisciplinary coordination, risk mitigation, and real‑world data will guide the next frontier in optimizing outcomes for patients living with PNH.