Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell (HSC) disease, characterized by complement-mediated hemolytic anemia, thrombophilia, and bone marrow failure. PNH is caused by mutations in the PIG-A gene, which is essential for the first step in the biosynthesis of glycosylphosphatidyl-inositol (GPI) anchors, resulting in the absence or marked deficiency of all GPI anchored proteins (e.g. complement regulatory proteins, CD55 and CD59).
The absence of CD55 and CD59 leads to uncontrolled complement activation on the surface of PNH cells. Deficiency of CD59 increases MAC formation and induces intravascular hemolysis (IVH), which is central to the pathophysiology of PNH. Deficiency of CD55 leads to increased C3 convertase activity and C3d-associated extravascular hemolysis (EVH).
Figure 1. The complement cascade, PNH, source: reference 
Approved Drugs for PNH
As a complement-mediated disease, PNH was an appropriate medical condition to develop and to investigate therapeutical complement inhibitors. Complement C5 inhibition is the standard of care (SoC) for patients with PNH. Currently, three PNH drugs have been approved, Soliris (eculizumab, AstraZeneca/Alexion), Ultomiris (ravulizumab, AstraZeneca/Alexion) and Empaveli (pegcetacoplan, Apellis).
▶ Soliris (eculizumab) is a first-in-class C5 complement inhibitor. The drug works by inhibiting the C5 protein in the terminal complement cascade, which is a component of the body's immune system. When activated in an uncontrolled manner, the terminal complement cascade overreacts, causing the body to attack its own healthy cells. Soliris is administered intravenously every two weeks after the introductory dosing period. Soliris is approved in the U.S., EU, Japan and China for the treatment of patients with PNH, aHUS and certain adult gMG. In addition, Soliris is approved in the U.S., EU and Japan for the treatment of NMOSD in certain adults.
▶ ULTOMIRIS™ (ravulizumab-cwvz), an upgraded version of Soliris, is the first and only long-acting C5 inhibitor administered every eight weeks. It was approved by the FDA in December 2018 for the treatment of PNH and subsequently approved for the treatment of aHUS, gMG and NMOSD.
▶ Empaveli is the first complement C3-targeted therapy approved by the FDA for the treatment of PNH. It is a synthetic cyclic peptide that is coupled to a polyethylene glycol polymer and specifically binds to C3 and C3b. In May 2021, Empaveli was approved by the FDA for the treatment of patients with PNH who are treatment naïve and those who are switching from the C5 inhibitors eculizumab (Soliris) and ravulizumab (Ultomiris).
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Investigating Drugs for PNH
In addition, there are a number of new PNH drugs under investigation worldwide, as detailed in the table below. Crovalimab from Roche and Iptacopan from Novartis are progressing faster.
|CAN-106||C5||CANbridge Pharmaceuticals||Phase 2|
Table 1. Investigating Drugs for PNH
Crovalimab is a recyclable monoclonal antibody targeting complement protein C5. Roche recently announced positive results from its global Phase 3 clinical COMMODORE 2 study. The analysis showed that crovalimab met the co-primary efficacy endpoints of transfusion avoidance and hemolysis control in patients with PNH not previously treated with complement inhibitors. Crovalimab achieved disease control with subcutaneous injections every 4 weeks and was not inferior to the current standard-of-care drug. Results from the Phase 3 COMMODORE 3 trial in China showed that patients achieved lactate dehydrogenase (LDH) ≤1.5 (upper limit of normal) by week 3 and maintained it through week 25 of the trial.
Figure 2. Crovalimab: Positive Ph III results in PNH, source: reference 
Crovalimab has obtained Breakthrough Therapy Designation and Priority Review in China for the treatment of PNH. In addition to the development of PNH treatment, clinical phase 3 and phase 2 trials of crovalimab for the treatment of atypical hemolytic uremic syndrome (aHUS) and sickle cell disease (SCD) are underway.
Compared to approved C5 inhibitors, Crovalimab is highly soluble, provides sustained and complete inhibition of the terminal complement pathway, allows for small subcutaneous doses (1-4 mL), and can be administered once a month. As a subcutaneous agent, patients can self-administer the drug at home, greatly improving adherence. And with its specific targeting epitopes, Crovalimab reaches a wider range of PNH patients in clinical situations and has demonstrated good tolerability and an acceptable safety profile.
Iptacopan is the first oral inhibitor developed by Novartis to target factor B of the alternative complement pathway. It acts upstream of the C5 terminal pathway of the complement system to control both intravascular and extravascular hemolysis, bridging the gap between anti-C5 antibodies while providing patients with an oral monotherapy option.
In April 2023, Novartis announced positive results from phase III APPOINT-PNH trial of iptacopan at the 2023 Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT). APPOINT-PNH is a Phase III, multinational, multicenter, open-label, single-arm study to evaluate the efficacy and safety of oral iptacopan monotherapy (200 mg) in adult PNH patients who are naïve to complement inhibitor therapy, including anti-C5 therapies (Soliris or Ultomiris).
Data at EBMT show that the primary endpoint met an estimated 92.2% of patients achieved a 2 g/dL or more hemoglobin-level increase from baseline without the need for red blood cell transfusions after the 24-week core treatment period. For important secondary endpoints, an estimated 97.6% of patients avoided red blood cell transfusion and an estimated 62.8% achieved a sustained hemoglobin level of ≥12 g/dl without red blood cell transfusions.
Figure 3. Summary of efficacy and quality of life endpoints after the 24-week core treatment period of APPOINT-PNH, source: reference 
Compared head-to-head with the already marketed C5 antibody, the efficacy of Iptacopan significantly exceeds that of the former.
Figure 4. Iptacopan head-to-head comparison with other C5 antibody
 DeZern AE, Brodsky RA. Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. Hematol Oncol Clin North Am. 2015 Jun;29(3):479-94. doi: 10.1016/j.hoc.2015.01.005. Epub 2015 Mar 7. PMID: 26043387; PMCID: PMC4695989.
 Roche Q1 2023 sales. Retrieved April 26, 2023 https://assets.cwp.roche.com/f/126832/x/469b6bc1c5/irp230426-a.pdf
 Risitano AM, Han B, Ueda Y, et al. Oral Complement Factor B Inhibitor Iptacopan Monotherapy Improves Hemoglobin to Normal/Near-Normal Levels in Paroxysmal Nocturnal Hemoglobinuria Patients Naïve to Complement Inhibitors: Phase III APPOINT-PNH Trial. Presented at: 49th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); April 23-36, 2023; Paris, France.
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