Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disorder primarily managed through complement inhibition. At an industry-sponsored meeting organized by the Hong Kong Society of Haematology, experts discussed challenges in PNH management and the role of terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, as current standard-of-care (SoC) therapies. They also explored recent data on emerging treatments, particularly the first-in-class oral complement factor D inhibitor, danicopan, as an add-on therapy to C5 inhibitors for optimizing patient outcomes.
Epidemiology and challenges in PNH management
PNH is a rare haematological disorder characterized by intravascular and extravascular haemolysis (IVH and EVH) due to uncontrolled complement activation. [Blood 2013;121:4985-4996; Am J Hematol 2016;91:366-370; Ther Adv Hematol 2019;10:2040620719873321] Its prevalence is about 10–38 per million people. [Eur J Haematol 2021;107:211- 218; Clin Epidemiol 2020;12:497-508]
“If left untreated, PNH may be life-threatening,” said Professor Jun-Ho Jang of the Samsung Medical Center in Seoul, South Korea. [Eur J Haematol 2023;111:796-804] “A retrospective study reported a 10-year mortality rate of about 24 percent in patients with PNH.” [Blood 2008;112:3099- 3106] Chronic haemolysis contributes to morbidity and premature mortality in patients with PNH, which is often complicated by thrombosis, chronic kidney disease, and pulmonary hypertension. [Blood 2013;121:4985-4996; Blood 1981:57:83-89; Am J Hematol 2010;85:553-559; Br J Haematol 2012;158:409-414; Br J Haematol 2007;137:181-192]
“Complement inhibition, particularly targeting the terminal complement C5, has been the cornerstone of treatment,” said Dr Raymond Wong of the Chinese University of Hong Kong. [Blood 2014;124:2804-2811; J Manag Care Spec Pharm 2020;26:S14-S20] “However, access to these life-saving treatments is limited due to stringent reimbursement criteria, posing challenges for clinicians and patients.”
C5 inhibitors as SoC
In patients with PNH, the presence of IVH, indicated by elevated lactate dehydrogenase (LDH) levels of >1.5 times the upper limit of normal (ULN), is associated with a 4.8-fold higher mortality rate vs age- and sex-matched general population (p<0.001). [J Korean Med Sci 2016;31:214-221] “In particular, IVH contributes to the development of thrombosis, which is the most common cause of death in patients with PNH, accounting for up to 67 percent of fatalities with known causes,” said Jang. [Blood 2013;121:4985-4996]
“LDH levels are a critical marker for IVH,” Jang continued. “LDH ≥1.5 x ULN is a strong predictor of thromboembolic events [TE], which are major predictors of PNH mortality. Meanwhile, haemoglobin [Hb] level <8 g/dL has not been shown as a significant predictor of TE, renal impairment or even mortality. Therefore, controlling IVH by maintaining LDH <1.5 x ULN is the primary goal in PNH management.” [J Korean Med Sci 2024;39:e81]
Eculizumab and ravulizumab are the current SoC therapies for PNH, inhibiting terminal complement activation to prevent IVH and its complications. [J Manag Care Spec Pharm 2020; 26:S14-S20] Eculizumab has established long-term efficacy and safety data. It has been associated with rapid and sustained decrease in serum LDH over a 3-year treatment period (relative reduction from baseline, 86.9 percent), with no evidence of cumulative toxicity. [Br J Haematol 2013;162:62-73]
“However, eculizumab requires biweekly dosing and may incompletely inhibit C5, leading to breakthrough haemolysis [BTH] in up to 29 percent of patients,” Jang commented. [Soliris Hong Kong Prescribing Information; Biol Pharm Bull 2016;39:285-288; Hematology Am Soc Hematol Educ Program 2011;2011:21-29]
“Ravulizumab was developed to address some of the unmet needs of eculizumab, offering an improved half-life and enhanced C5 clearance, helping limit complement-mediated damage,” noted Jang. [PLoS One 2018;13:e0195909] “This allows less frequent dosing, typically every 8 weeks, improving patients’ convenience and potentially adherence.” [Ultomiris Hong Kong Prescribing Information]
6-year data of ravulizumab
Ravulizumab has established long-term safety data with up to 6 years of follow-up from the phase III studies 301 and 302, showing sustained control of IVH and improved patient outcomes. Study 301 involved C5 inhibitor–naive patients, while study 302 involved patients switching from eculizumab to ravulizumab. Both studies demonstrated ravulizumab's noninferiority to eculizumab after a primary evaluation period of 26 weeks. [Blood 2019;133:530- 539; Blood 2019;133:540-549; Ann Hematol 2025;104:81-94]
These results were sustained after a 6-year follow-up. Ravulizumab provided durable control of terminal complement activity and IVH, with low incidence of major adverse vascular events, including thrombotic events (rate, 0.7– 1.4/100 patient-years). Compared with 414 untreated patients from the International PNH Registry, ravulizumab treatment in C5 inhibitor–naïve patients was significantly associated with an improved unadjusted survival probability of 86.0 percent at 4 years (p<0.001). When adjusted for age at PNH diagnosis, gender and transfusion history, the survival probability increased to 97.7 percent at 4 years. These results support the long-term use of ravulizumab as a first-line treatment for patients with PNH. [Ann Hematol 2025;104:81-94]
Risks of BTH and EVH
Although terminal complement inhibition largely prevents IVH and its complications, IVH may still occur in the form of BTH, characterized by sudden reappearance of IVH signs and symptoms associated with marked LDH increase and sharp decrease in Hb levels. BTH may be due to pharmacokinetic (eg, low levels of C5 inhibitors) or pharmacodynamic (eg, during an infection or inflammation) factors, impacting therapy considerations. [N Engl J Med 2022;387:160-166]
Terminal complement inhibition may also lead to increased C3 opsonization of surviving PNH red blood cells, potentially resulting in chronic EVH. (Figure 1) [N Engl J Med 2022;387:160- 166] According to real-world data from the Korean Health Insurance Review and Assessment Service, EVH occurred in up to 29 percent of PNH patients with high disease burden who received eculizumab. However, only about 11 percent were considered clinically significant (ie, requiring intervention). [J Korean Med Sci 2023;38:e328]
In general, EVH is less severe than IVH and is not considered life-threatening. [Blood 2013;121:4985- 4996; Blood 2021;137:1304-1309] Nevertheless, patients may experience persistent signs and symptoms of anaemia (eg, fatigue) and require intervention, which has led to the development of proximal complement pathway inhibitors. [Blood 2021;137:1304-1309; N Engl J Med 2022;387:160-166]
Proximal inhibitors target early components of the complement cascade to address EVH. The inhibitors, such as danicopan (oral factor D inhibitor) and iptacopan (oral factor B inhibitor), offer a new approach by blocking an alternative molecular pathway, thereby potentially reducing the risk of EVH. “Despite their effectiveness, the incidence and management of massive BTH in patients on proximal inhibitors remain poorly understood, highlighting the need for robust long-term safety data to guide clinical decision-making,” opined Jang. (Figure 1)
Dual complement inhibition in PNH: Factor D inhibitor plus C5 inhibitor
Of note, combining proximal and terminal inhibition may be a safer approach. Even if inhibition of each complement is incomplete, C3 and C5 convertases escaping inhibition find only a few uninhibited C5 molecules. Thus, any BTH is likely to be limited. (Figure 1) [N Engl J Med 2022;387:160-166]
Dual inhibition by suppressing IVH with a terminal complement inhibitor and clinically significant EVH with a proximal complement inhibitor has emerged as a valid alternative to terminal or proximal complement inhibitor monotherapy in PNH management. [Lancet Haematol 2023;10:e955-e965]
Danicopan as add-on therapy: 72-week data
“ALPHA is an ongoing, international, phase III, randomized, double-blind, placebo-controlled trial that evaluates the efficacy and safety of the first-in-class, oral, proximal complement factor D inhibitor, danicopan 150 mg TID, as add-on therapy to ravulizumab or eculizumab in adult patients with PNH and clinically significant EVH [ie, Hb ≤9.5 g/dL; absolute reticulocyte count (ARC) ≥120 x 109/L] for ≥6 months,” shared Professor Jong Wook Lee of the Hanyang University Medical Hospital in Seoul, South Korea. [Blood 2025;145:811-822]
Protocol-prespecified interim efficacy analysis (n=63) showed that the study met its primary endpoint in favour of the danicopan group, achieving significantly improved Hb levels vs the placebo group as early as week 2 through week 12 (Hb least squares mean [LSM] change from baseline to week 12: danicopan, 2.9 g/ dL; placebo, 0.5 g/dL; LSM difference, 2.4 g/dL; p<0.0001. [Lancet Haematol 2023;10:e955-e965]
“These results were sustained during the subsequent 12-week treatment period 2, where patients receiving placebo switched to danicopan, and during the 2-year long-term extension period,” noted Lee. “Patients who switched from placebo to danicopan at week 12 demonstrated improved mean Hb levels at week 24 and maintained levels at week 72.” (Figure 2) [Blood 2025;145:811-822]
No new safety signals were observed, demonstrating the sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, IVH and clinically significant EVH in patients with PNH.
“In ALPHA, the mean study drug adherence rate of all patients receiving danicopan based on dose was 97.1 percent, reflecting the practicality and tolerability of this regimen and its potential for sustained disease control to improve patient outcomes,” noted Lee. [Blood 2025;145:811-822] “These results show that dual inhibition with danicopan and C5 inhibitors [ie, ravulizumab or eculizumab] may provide effective disease management even if occasional oral doses are missed, offering patients an added layer of safety.” [Blood 2025;145:811-822; N Engl J Med 2022;387:160-166]
Conclusions
Complement inhibition has revolutionized PNH treatment, improving patients’ survival and quality of life. Dual complement inhibition with danicopan and SoC terminal inhibitors (ie, eculizumab and ravulizumab) offer new opportunities to address persistent challenges, such as EVH and residual anaemia. Continued research on long-term safety and personalized strategies is crucial for optimizing patient outcomes.
