Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease caused by somatic mutations in the PIGA (phosphatidylinositol glycan A) gene in hematopoietic stem cells.1 The mutations result in a deficiency of glycosylphosphatidylinositol-anchored proteins, which render red blood cells susceptible to hemolysis. Patients who have PNH typically present with hemolytic anemia, bone marrow dysfunction, and thrombosis.1

The current standard of care in PNH involves treatment with complement inhibitor monoclonal antibodies. Despite the positive effects of these drugs on the clinical course of PNH, many patients still experience anemia and fatigue and remain dependent on blood transfusions, mainly because of persistent C3-mediated extravascular hemolysis.1,2

Currently, several experimental drugs for the treatment of PNH are in clinical development; some of these intend to address problems that anti-C5 therapies do not solve.


Iptacopan, an investigational small molecule developed by Novartis, is an oral selective inhibitor of factor B.1 It acts upstream of the C5 terminal pathway, preventing both intravascular and extravascular hemolysis in patients with PNH.2 Iptacopan received US Food and Drug Administration (FDA) breakthrough therapy designation in PNH on the basis of disease prevalence and data from phase 2 clinical studies in which both intra- and extravascular hemolysis were reduced in patients who had PNH with persistent hemolysis.1,2

Recently, Novartis announced that the pivotal phase 3 trial APPLY-PNH (NCT04558918) has met its 2 primary endpoints, demonstrating that iptacopan is superior to both Soliris® (eculizumab) and Ultomiris® (ravulizumab) in adult patients with PNH who still have anemia after treatment with anti-C5 therapy.2

Read more about PNH prognosis


Crovalimab is an anti-C5 sequential monoclonal antibody recycling technology (SMART) that combines isoelectric point, neonatal Fc receptor, and pH-dependent affinity engineering.3 Crovalimab binds to an epitope on the C5 ꞵ chain distinct from that of the Soliris and Ultomiris binding site.4 In addition, crovalimab is highly soluble; therefore, subcutaneous administration of a reduced amount of the drug may be possible.3

A phase 3 clinical trial (COMMODORE 1; NCT04432584) sponsored by Hoffmann-La Roche is currently recruiting participants. The study will evaluate whether crovalimab is non-inferior to Soliris in patients with PNH who are currently being treated with complement inhibitors. It is expected that approximately 250 participants will be enrolled.5

Read more about PNH clinical trials

Pozelimab and Cemdisiran

Pozelimab and cemdisiran are subcutaneously administered C5 inhibitors currently in development for the treatment of PNH and other diseases in which terminal complement pathway activity is involved.6 Pozelimab is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody against C5; cemdisiran is a synthetic small interfering RNA (siRNA) that targets C5 mRNA.6 Previous data obtained from healthy volunteers showed that combining the 2 drugs may make it possible to reduce doses and increase intervals between doses of pozelimab (NCT03115996, NCT02352493).6

A currently ongoing phase 2 clinical trial sponsored by Regeneron Pharmaceuticals is evaluating the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy (NCT04811716).7

Read more about PNH pathophysiology


BCX9930 is an oral factor D inhibitor being developed by BioCryst Pharmaceuticals for the treatment of complement-mediated diseases.8 Factor D is a complement system protein involved in amplifying the complement system response.9 Inhibiting this factor may control intravascular hemolysis and prevent C3-mediated extravascular hemolysis.10 

Two phase 2 clinical trials to determine the safety and efficacy of BCX9930 in patients with PNH are currently recruiting (REDEEM-1, NCT05116774; REDEEM-2, NCT05116787).8,11,12

REDEEM-1 is a randomized, open-label, active comparator-controlled study of the safety and efficacy of BCX9930 in patients with PNH who have an inadequate response to a C5 inhibitor. REDEEM-2 is a randomized, placebo-controlled trial that will compare the safety and efficacy of BCX9930 as monotherapy vs placebo in patients with PNH who are not receiving complement inhibitor therapy.8

Read more about PNH therapies


Danicopan is an investigational complement alternative pathway factor D inhibitor10 developed by Alexion, AstraZeneca Rare Disease, which is a group within AstraZeneca focused on the treatment of rare diseases.9 The drug is being studied as an add-on to the C5 inhibitors Ultomiris and Soliris in patients with PNH who have clinically significant extravascular hemolysis.9

Recently, a prespecified interim analysis of the phase 3 ALPHA clinical trial (NCT04469465) reported that the primary endpoint of change in the hemoglobin level from baseline to 12 weeks was met, in addition to key secondary endpoints, including transfusion avoidance and change in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score.9 The ALPHA trial is currently evaluating danicopan as an add-on treatment with Ultomiris and Soliris. Danicopan plus either Ultomiris or Soliris demonstrated superiority in comparison with placebo plus anti-C5 therapy.9

Read more about Ultomiris

ABP 959

ABP 959 is an investigational drug developed by Amgen that is a biosimilar candidate to Soliris for the treatment of PNH. ABP 959 is a monoclonal antibody with the same amino acid sequence as Soliris and the same pharmaceutical form, dosage, route of administration, and dose regimen as Soliris. It binds to complement protein C5, blocking the classical and alternative complement pathways.13

Recently, Amgen announced that the randomized, double-blind, active-controlled, 2-period crossover phase 3 clinical trial DAHLIA had met its primary endpoints and reported no clinically meaningful differences between the investigational drug and Soliris for the control of intravascular hemolysis. The study also demonstrated a safety and immunogenicity profile for ABP 959 comparable with that of Soliris.13

Read more about Soliris


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

2. Novartis investigational oral monotherapy iptacopan demonstrates clinically meaningful superiority over anti-C5 treatment in Phase III APPLY-PNH study. News Release. Novartis; October 24, 2022.

3. Röth A, Nishimura JI, Nagy Z, et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135(12):912-920. doi:10.1182/blood.2019003399

4. Nishimura JI, Usuki K, Ramos J, et al. Crovalimab for treatment of patients with paroxysmal nocturnal haemoglobinuria and complement C5 polymorphism: subanalysis of the phase 1/2 COMPOSER study. Br J Haematol. 2022;198(3):e46-e50. doi:10.1111/bjh.18274

5. A study evaluating the efficacy and safety of crovalimab versus eculizumab in participants with paroxysmal nocturnal hemoglobinuria (PNH) currently treated with complement inhibitors. (COMMODORE 1). June 16, 2020. Updated September 26, 2022. Accessed November 27, 2022.

6. van Zyl T, Weyne J, Chaudhari U, et al. Interim analysis of an open-label, ascending-dose, phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of the subcutaneously administered human monoclonal antibody pozelimab in combination with single doses of the subcutaneously administered human monoclonal antibody pozelimab in combination with single doses of the subcutaneously administered siRNA cemdisiran in healthy volunteers. Blood 2021;138 (Suppl 1):1998. doi:10.1182/blood-2021-146205 

7. Pozelimab and cemdisiran combination treatment in adult participants with paroxysmal nocturnal hemoglobinuria who have received pozelimab monotherapy. March 23, 2021. Updated November 9, 2022. Accessed November 27, 2022.

8. BioCryst resumes enrollment in BCX9930 clinical program. Press Release. BioCryst; August 4, 2022.

9. Danicopan (ALXN2040) add-on to Ultomiris or Soliris met primary endpoint in ALPHA phase III trial for patients with paroxysmal nocturnal haemoglobinuria who experience clinically significant extravascular haemolysis. News Release. AstraZeneca; September 16, 2022. 

10. Risitano AM, Kulasekararaj AG, Lee JW, et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(12):3188-3197. doi:10.3324/haematol.2020.261826

11. BCX9930 for treatment of PNH in subjects with inadequate response to C5 inhibitor therapy (REDEEM-1). November 11, 2021. Updated November 7, 2022. Accessed November 27, 2022.

12. BCX9930 for the treatment of PNH in subjects not receiving other complement inhibitor therapy (REDEEM-2). November 11, 2021. Updated November 4, 2022. Accessed November 27, 2022.

13. AMGEN announces positive top-line results from phase 3 study of ABP 959, biosimilar candidate to Soliris® (eculizumab). Press Release. Amgen; August 23, 2022.

Reviewed by Kyle Habet, MD, on 11/29/2022.