Summary
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life‐threatening disorder characterized by complement‐mediated haemolysis, leading to anaemia and thrombosis. HRS‐5965 is a novel, oral, selective complement factor B inhibitor targeting the alternative pathway, potentially reducing both intra‐ and extravascular haemolysis. In this randomized, open‐label phase II study, we evaluated the efficacy and safety of HRS‐5965 monotherapy in complement inhibitor–naïve adult PNH patients. Twenty‐six patients were randomized 1:1 to receive HRS‐5965 50 mg orally twice daily (BID) (with potential up‐titration to 100 mg BID) or 75 mg BID for 12 weeks. The primary end‐point was the change in haemoglobin (Hb) from baseline to Week 12. Both groups showed marked Hb increases, with least squares mean increases of 37.6 and 37.7 g/L for the 50 and 75 mg BID groups respectively. Lactate dehydrogenase levels declined by 87% and 85% from baseline. The most common treatment‐related adverse events were mild lab abnormalities, including increased alkaline phosphatase and alanine aminotransferase. In conclusion, HRS‐5965 monotherapy at either 50 or 75 mg BID resulted in substantial Hb improvements and reduced haemolysis with an acceptable safety profile, suggesting its potential as a promising oral therapy for complement inhibitor–naïve PNH patients.
Keywords: haemoglobin, HRS‐5965, lactate dehydrogenase, paroxysmal nocturnal haemoglobinuria
INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem‐cell disorder characterized by complement‐mediated intravascular haemolysis, marrow failure and high thrombosis risk. 1 , 2 Its global incidence is approximately 1–5 per million. 3 PNH results from somatic mutations in the phosphatidylinositol glycan class A gene, causing deficiency of glycosylphosphatidylinositol‐anchored proteins. 4 The absence of key complement regulators CD55 and CD59 renders erythrocytes susceptible to uncontrolled activation of the alternative complement pathway, leading to chronic intravascular haemolysis and clinical manifestations. 4 , 5
Anti‐C5 monoclonal antibodies, notably eculizumab introduced in 2007, significantly reduced haemolysis, improved haemoglobin (Hb) stabilization, lowered thromboembolic risk and enhanced survival. 6 , 7 Ravulizumab, a longer acting C5 inhibitor administered every 8 weeks, showed comparable efficacy. 8 However, many patients continue to experience anaemia and require red blood cell transfusions. 6 This residual anaemia is largely attributed to extravascular haemolysis, driven by ongoing proximal complement activation, which results in opsonization of red blood cells with C3 fragments and their subsequent removal by macrophages in the spleen and liver. 8 , 9
To overcome the limitations of terminal complement inhibition, proximal complement inhibitors have been developed. 10 Pegcetacoplan, a C3 inhibitor, provides broader complement control by mitigating both intravascular and extravascular haemolysis, although complete C3 blockade may increase the risk of infections. 11 , 12 Oral agents like iptacopan, which targets complement factor B to block the formation of the alternative pathway C3 convertase, have shown promising improvements in Hb levels, reductions in lactate dehydrogenase (LDH) and decreased transfusion requirements. 9 , 13 , 14 Danicopan, a proximal complement inhibitor targeting factor D, has demonstrated efficacy as an add‐on treatment to ravulizumab or eculizumab in patients with PNH who experience clinically significant extravascular haemolysis. 15 , 16
HRS‐5965 is a novel oral small‐molecule inhibitor that selectively targets complement factor B. By inhibiting the enzymatic activity of factor B, HRS‐5965 disrupts the formation of C3 convertases within the alternative pathway, thereby halting C3 cleavage and downstream complement activation. 17 In addition to inhibiting the alternative pathway, HRS‐5965 dampens the amplification loops that link the alternative, classical and lectin pathways, contributing to more comprehensive modulation of complement dysregulation. 17 Preclinical studies have demonstrated potent inhibition of factor B enzymatic activity (data on file, Hengrui). In this phase II study, we evaluated the efficacy and safety of HRS‐5965 monotherapy in adult PNH patients naïve to complement inhibitor.
MATERIALS AND METHODS
Study design
This open‐label, randomized phase II proof‐of‐concept trial (NCT06051357), conducted at two centres in China, investigated HRS‐5965 monotherapy in adult PNH patients naïve to complement inhibitor therapy. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the institutional review boards and independent ethics committees at each centre, and all patients provided written informed consent.
Patients
Eligible patients were adults (≥18 years) with a confirmed diagnosis of active PNH who had not previously received complement inhibitor therapy. They were required to meet the following criteria: a documented clone size of ≥10% in monocytes or granulocytes (by flow cytometry); LDH levels exceeding 1.5 times the upper limit of normal (ULN); and Hb levels below 10 g/dL at both screening and baseline. In addition, all patients had to be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae ≥2 weeks prior to receiving the first dose of study treatment. Patients who initiated treatment within 2 weeks of vaccination were mandated to receive prophylactic antibiotics. Additional details regarding the key exclusion criteria are provided in the Supporting Information.
Treatment interventions
Following screening, patients were randomized in a 1:1 ratio to two treatment arms using a computer‐generated code via an interactive web response system. The titration group received 50 mg HRS‐5965 orally twice daily (BID) for the first 2 weeks; on Day 15, if a patient's serum LDH level had decreased by less than 40% from baseline, the dose was escalated to 100 mg BID for the remainder of the 12‐week period. The fixed‐dosage group received 75 mg BID throughout the 12 weeks. At the end of treatment, investigators assessed efficacy and safety outcomes. Patients without safety concerns could enrol in an independent extension study, while those who did not demonstrate a treatment benefit (e.g. an Hb increase of less than 10 g/L from baseline after receiving 100 mg BID) underwent a 1‐week taper‐down followed by a 3‐week safety follow‐up. Dose interruptions up to 14 days were permitted, and dose down‐titration (from 100 to 75 mg BID or from 75 to 50 mg BID) was allowed at the investigator's discretion for safety or tolerability reasons (Figure S1). This report focuses on the initial 12‐week treatment results.
Efficacy end‐points and assessments
The primary efficacy end‐point was the change in Hb from baseline to Week 12. Secondary end‐points included changes from baseline to Week 12 in LDH, haptoglobin, total and unconjugated bilirubin, reticulocyte count and PNH red‐cell clone size, as well as the proportion of patients achieving transfusion avoidance from 2 weeks after treatment initiation until Week 12. Prespecified exploratory end‐points evaluated the percentages of patients achieving an Hb increase of ≥20 g/L from baseline and of those attaining Hb levels of ≥120 g/L at Week 12. The study protocol required a total of 10 visits during the screening and 12‐week treatment periods, with weekly assessments until Week 4 and biweekly assessments thereafter.
Safety was evaluated by monitoring adverse events (AEs), thromboembolic events, vital signs, physical examinations, electrocardiograms and changes in clinical laboratory parameters. Additional methodological details, including pharmacokinetic (PK) and pharmacodynamic (PD) analyses, are provided in the Supporting Information.
Statistical analyses
Based on prior studies of other oral selective complement factor B inhibitors in PNH, it was hypothesized that the mean Hb increase from baseline to Week 12 would be ~25 g/L in each treatment group, with an assumed standard deviation of 15 g/L. A sample size of 12 patients per group was estimated to provide 85% power to detect a mean Hb increase greater than 20 g/L at Week 12. A total of 26 patients were ultimately enrolled in this phase II study.
Efficacy was assessed in the full analysis set, comprising all randomized patients who received at least one dose of the assigned treatment. The safety set included all enrolled patients who received at least one dose of the study drug. Data collected after intercurrent events (such as early withdrawal, red‐cell transfusions within 30 days or use of prohibited treatments during the treatment period) were excluded from the efficacy analysis based on the hypothetical strategy.
The primary and continuous secondary end‐points at Week 12 were analysed using a mixed‐effects model for repeated measures (MMRM) with restricted maximum likelihood estimation. Baseline values were included as covariates, and treatment group, visit and the treatment‐by‐visit interaction were modelled as fixed effects, with patients as random effects using an unstructured covariance matrix to account for within‐patient variability. Missing data were imputed via the last observation carried forward (LOCF) method, and least squares (LS) mean changes from baseline with 95% confidence intervals (CIs) were calculated for each treatment group. The proportions of patients achieving an Hb increase of at least 20 g/L from baseline or reaching Hb levels of ≥120 g/L at Week 12 were presented as numbers and percentages, with non‐response imputation applied for missing data or intercurrent events. All statistical analyses were performed using SAS version 9.4.
RESULTS
Patient baseline characteristics
Between 7 October 2023 and 4 December 2023, 34 patients were screened for eligibility; 26 were enrolled and randomized in a 1:1 ratio to either the HRS‐5965 50/100 mg BID group (n = 13) or the HRS‐5965 75 mg BID group (n = 13). All randomized patients received at least one dose of study treatment and completed the 12‐week treatment period per protocol (Figure 1). No patient in the 50/100 mg BID group required dose up‐titration on Day 15. The median age was 39.5 years (range, 19–70 years), and 61.5% were male. At baseline, all patients exhibited laboratory evidence of intravascular haemolysis (mean LDH: 2080.0 U/L, corresponding to 8.3× ULN; ULN = 250 U/L) and clinically significant anaemia (mean Hb: 74.0 g/L). In addition, 15 patients (57.7%) were transfusion‐dependent, having received red‐cell transfusions in the 12 months prior to study entry (Table 1).
FIGURE 1.
Trial profile. *Six patients were ineligible for the following reasons: Use of prohibited medications (n = 2); laboratory evidence of bone marrow failure at screening (reticulocyte count <100 × 109/L, platelet count <30 × 109/L or neutrophil count <0.5 × 109/L; n = 2); laboratory evidence of bone marrow failure plus Hb >10 g/dL at screening and baseline (n = 1); and suspected concomitant haemolytic anaemia (n = 1). #No patient in the HRS‐5965 50/100 mg BID group required dose up‐titration on Day 15; therefore, all patients in this group received HRS‐5965 at 50 mg BID throughout the 12‐week treatment period. †One patient in the HRS‐5965 50 mg BID group (diagnosed with aplastic anaemia) and one in the HRS‐5965 75 mg BID group (diagnosed with myelodysplastic syndrome) were excluded from the Hb and LDH analyses (confirmed via bone marrow biopsy). BID, twice daily; Hb, haemoglobin; LDH, lactate dehydrogenase.
TABLE 1.
Demographics and baseline characteristics.
| Parameter | HRS‐5965 | HRS‐5965 |
|---|---|---|
| 50 mg BID | 75 mg BID | |
| (n = 13) | (n = 13) | |
| Age, mean ± SD, years | 37.2 ± 15.1 | 45.5 ± 10.4 |
| Sex, n (%) | ||
| Male | 9 (69.2) | 7 (53.8) |
| Female | 4 (30.8) | 6 (46.2) |
| BMI, mean ± SD, kg/m2 | 24.7 ± 4.0 | 25.0 ± 3.5 |
| No. of patients who received transfusion, a n (%) | 7 (53.8) | 8 (61.5) |
| Mean units of RBC transfused a | 4.4 ± 6.3 | 5.7 ± 7.9 |
| Median no. of transfusions (range) a | 1.0 (0–11) | 1.0 (0–9) |
| Hb, g/L | ||
| Mean | 72.3 ± 14.8 | 75.6 ± 10.6 |
| Median (range) | 77.0 (47.0–91.0) | 77.0 (54.0–90.0) |
| Free haemoglobin level, mg/L | ||
| Mean | 414.7 ± 282.0 | 475.2 ± 356.8 |
| Median (range) | 354.6 (77.4, 1240.0) | 294.0 (58.6, 1263.0) |
| Red cell count, ×1012/L | ||
| Mean | 2.4 ± 0.6 | 2.4 ± 0.6 |
| Median (range) | 2.4 (1.5–3.5) | 2.2 (1.6–3.3) |
| Reticulocyte count, ×109/L | ||
| Mean | 208.3 ± 72.3 | 263.4 ± 134.0 |
| Median (range) | 197.1 (101.4–314.0) | 242.8 (129.7–633.8) |
| LDH, U/L | ||
| Mean | 1845.0 ± 518.5 | 2315.0 ± 1329.5 |
| Median (range) | 1834.2 (871.0–2627.0) | 2175.0 (1194.0–6387.6) |
| Total bilirubin, μmol/L | ||
| Mean | 32.4 ± 7.7 | 40.8 ± 20.7 |
| Median (range) | 29.7 (20.4–45.7) | 34.7 (16.2–84.3) |
| Unconjugated bilirubin, μmol/L | ||
| Mean | 25.6 ± 7.3 | 33.2 ± 18.1 |
| Median (range) | 22.8 (16.3–40.1) | 28.6 (10.0–68.0) |
| Total PNH red‐cell clone size, % | ||
| Mean | 54.1 ± 14.2 | 62.6 ± 20.7 |
| Median (range) | 51.0 (25.0–82.0) | 60.8 (27.0–99.8) |
| Haptoglobin, g/L | ||
| Mean | 0.15 ± 0.09 | 0.14 ± 0.09 |
| Median (range) | 0.07 (0.07–0.25) | 0.07 (0.07–0.25) |
| D‐dimer, mg/L FEU | ||
| Mean | 0.49 ± 0.23 | 1.11 ± 0.87 |
| Median (range) | 0.51 (0.15–1.05) | 0.74 (0.15–2.91) |
| Medical history, n (%) | ||
| Aplastic anaemia | 5 (38.5) | 4 (30.8) |
| Myocardial infarction | 1 (7.7) | 0 |
| Deep vein thrombosis | 2 (15.4) | 0 |
| Venous thrombosis limb | 0 | 1 (7.7) |
| Blood creatinine increased | 0 | 1 (7.7) |
Abbreviations: BID, twice daily; BMI, body mass index; FEU, fibrinogen equivalent units; Hb, haemoglobin; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal haemoglobinuria; RBC, red blood cell; SD, standard deviation.
Within the prior 12 months.
Efficacy
During the treatment period, one patient in the 50 mg BID group was diagnosed with aplastic anaemia (AA) and one in the 75 mg BID group with myelodysplastic syndrome (MDS) (confirmed by bone marrow biopsy); these patients were excluded from the Hb and LDH efficacy analyses. At Week 12, mean Hb levels increased to 111.6 g/L in the 50 mg BID group and to 112.6 g/L in the 75 mg BID group, with LS mean changes from baseline of 37.6 g/L (95% CI: 31.5–43.6) and 37.7 g/L (95% CI: 31.6–43.7) respectively (Figure 2A,B; Table 2).
FIGURE 2.
Effect of HRS‐5965 on Hb and LDH levels during the 12‐week treatment period. (A) Mean Hb levels. (B) Change from baseline in Hb levels. (C) Mean LDH levels. (D) Percentage change from baseline in LDH levels. Data are presented as follows: (A, C) mean ± SE, (B) LS mean ± SE and (D) the LS mean with 95% CIs. BID, twice daily; CI, confidence interval; Hb, haemoglobin; LDH, lactate dehydrogenase; LS, least squares; SE, standard error; ULN, upper limit of normal (LDH ULN = 250 U/L).
TABLE 2.
Efficacy endpoints at Week 12.
| Endpoints | HRS‐5965 | HRS‐5965 |
|---|---|---|
| 50 mg BID | 75 mg BID | |
| (n = 13) | (n = 13) | |
| Hb, g/L a | ||
| Absolute value | ||
| Mean ± SD | 111.6 ± 8.3 | 112.6 ± 6.9 |
| Median (range) | 112.0 (99.0, 122.0) | 110.5 (103.0, 124.0) |
| Change from baseline, LS mean (95% CI) | 37.6 (31.5, 43.6) | 37.7 (31.6, 43.7) |
| LDH a | ||
| Absolute value, U/L | ||
| Mean ± SD | 255.8 ± 78.9 | 300.9 ± 70.2 |
| Median (range) | 242.0 (156.0, 458.0) | 276.2 (219.7, 441.8) |
| Percentage change from baseline, LS mean (95% CI), % | 87 (85, 89) | 85 (83, 87) |
| Haptoglobin, g/L | ||
| Absolute value | ||
| Mean ± SD | 0.42 ± 0.92 | 0.30 ± 0.46 |
| Median (range) | 0.22 (0.06, 3.48) | 0.25 (0.06, 1.79) |
| Change from baseline, LS mean (95% CI) | 0.25 (−0.14, 0.64) | 0.18 (−0.21, 0.57) |
| Total bilirubin, μmol/L | ||
| Absolute value | ||
| Mean ± SD | 15.2 ± 4.8 | 16.8 ± 7.1 |
| Median (range) | 15.6 (6.6, 23.2) | 14.7 (8.4, 36.7) |
| Change from baseline, LS mean (95% CI) | −20.4 (−23.0, −17.8) | −20.8 (−23.4, −18.2) |
| Unconjugated bilirubin, μmol/L | ||
| Absolute value | ||
| Mean ± SD | 10.9 ± 3.4 | 12.3 ± 5.5 |
| Median (range) | 10.6 (4.5, 15.8) | 11.9 (5.4, 26.1) |
| Change from baseline, LS mean (95% CI) | −17.7 (−19.8, −15.6) | −17.8 (−19.8, −15.7) |
| Reticulocyte count, ×109/L | ||
| Absolute value | ||
| Mean ± SD | 104.7 ± 30.1 | 103.8 ± 31.2 |
| Median (range) | 100.0 (62.3, 159.6) | 103.3 (64.3, 164.3) |
| Change from baseline, LS mean (95% CI) | −131.0 (−149.1, −112.8) | −132.3 (−150.5, −114.1) |
| Total PNH red‐cell clone size, % | ||
| Absolute value | ||
| Mean ± SD | 88.0 ± 8.8 | 91.4 ± 6.7 |
| Median (range) | 90.5 (62.0, 95.0) | 93.0 (80.0, 99.9) |
| Change from baseline, LS mean (95% CI) | 30.4 (26.4, 34.4) | 32.2 (28.2, 36.2) |
| Free haemoglobin level, mg/L | ||
| Absolute value | ||
| Mean (SD) | 43.8 ± 24.3 | 48.3 ± 23.6 |
| Median (range) | 45.0 (10.4, 94.0) | 42.6 (20.7, 108.5) |
| Change from baseline, LS mean (95% CI) | −399.7 (−413.9, −385.6) | −398.0 (−412.2, −383.8) |
| Patients who achieved Hb levels that increased by ≥20 g/L from baseline, a n (%) | 12 (100.0) | 10 (83.3) |
| Patients who achieved Hb levels ≥120 g/L, a n (%) | 3 (25.0) | 3 (25.0) |
Abbreviations: BID, twice daily; CI, confidence interval; Hb, haemoglobin; LDH, lactate dehydrogenase; LS, least squares; PNH, paroxysmal nocturnal haemoglobinuria; SD, standard deviation.
One patient in the HRS‐5965 50 mg BID group (diagnosed with aplastic anaemia) and one in the HRS‐5965 75 mg BID group (diagnosed with myelodysplastic syndrome) were excluded from the Hb and LDH analyses (confirmed via bone marrow biopsy).
Concurrent with Hb improvements, LDH levels dropped markedly. At Week 12, mean LDH decreased to 255.80 U/L in the 50 mg BID group and to 300.86 U/L in the 75 mg BID group (Figure 2C). The mean percentage reductions in LDH were 87% and 85% for the 50 and 75 mg BID groups, respectively (Figure 2D; Table 2), highlighting the potent inhibition of complement‐mediated intravascular haemolysis by HRS‐5965.
Additional haematological improvements corroborated reduced haemolysis. By Week 12, transfusion independence, defined as an Hb increase of ≥20 g/L from baseline, was achieved in all evaluable patients in the 50 mg BID group (12/12, 100%) and in 10 of 12 patients (83.3%) in the 75 mg BID group. Moreover, 25% of patients in both groups reached Hb levels ≥120 g/L without requiring transfusions. Except for one patient in the 50 mg BID group, who received two units of red cells when Hb fell to 55 g/L due to AA, no transfusions were required from 2 weeks after treatment initiation through Week 12 (Figure 3; Table 2).
FIGURE 3.
Proportion of patients achieving prespecified Hb levels and transfusion avoidance. Left: Proportion of patients with an Hb increase of ≥20 g/L from baseline. Middle: Proportion of patients with Hb levels ≥120 g/L at Week 12. Right: Proportion of patients achieving transfusion avoidance during the 12‐week treatment period. *One patient in the HRS‐5965 50 mg BID group (diagnosed with aplastic anaemia) and one in the HRS‐5965 75 mg BID group (diagnosed with myelodysplastic syndrome) were excluded from the Hb and LDH analyses (confirmed via bone marrow biopsy). #Only red blood cell transfusion records collected from 2 weeks after treatment initiation through the end of the 12‐week treatment period were included. BID, twice daily; Hb, haemoglobin; LDH, lactate dehydrogenase.
Other haemolysis markers also improved: Reticulocyte counts fell to means of 104.7 × 109/L (LS mean change −131.0 × 109/L) in the 50 mg BID group and 103.8 × 109/L (−132.3 × 109/L) in the 75 mg BID group (Figure S2; Table 2). Free Hb likewise declined to means of 43.8 mg/L (LS mean change −399.7 mg/L) and 48.3 mg/L (−398.0 mg/L) respectively (Figure S3; Table 2).
HRS‐5965 increased circulating PNH red cells and improved biochemical markers of haemolysis. By Week 12, mean PNH red‐cell clone size rose to 88.0% in the 50 mg BID group (LS mean change +30.4%) and 91.4% in the 75 mg BID group (+32.2%) (Figure S4; Table 2). Total bilirubin also decreased, reaching mean values of 15.2 μmol/L in the 50 mg BID group (LS mean change: –20.4 μmol/L) and 16.8 μmol/L in the 75 mg BID group (LS mean change: −20.8 μmol/L). Unconjugated bilirubin declined similarly, to 10.9 μmol/L in the 50 mg BID group (LS mean change: −17.7 μmol/L) and 12.3 μmol/L in the 75 mg BID group (LS mean change: −17.8 μmol/L) (Figure S5; Table 2). Haptoglobin, an indicator of red‐cell protection, rose to a mean of 0.42 g/L in the 50 mg BID group (LS mean change: +0.25 g/L) and 0.30 g/L in the 75 mg BID group (LS mean change: +0.18 g/L) (Figure S6; Table 2).
Safety
Treatment compliance was nearly 100% in both dosing groups, with all 26 randomized patients completing the study treatment. One patient in the 50 mg BID group was diagnosed with AA, and one in the 75 mg BID group progressed to MDS; both entered a tapering phase after treatment. Only the patient who progressed to MDS discontinued treatment during the subsequent taper‐down period owing to an AE (decreased platelet [PLT] count).
Overall, AEs of any grade occurred in 69.2% of patients in the 50 mg BID group and 92.3% in the 75 mg BID group (Table 3). In the 50 mg BID group, common AEs (≥10%) were upper respiratory tract infections (23.1%) and increased blood alkaline phosphatase (ALP, 15.4%); in the 75 mg BID group, they were increased blood ALP (69.2%), increased C‐reactive protein (38.5%), increased alanine aminotransferase (ALT, 15.4%) and hypertriglyceridaemia (15.4%). All treatment‐related AEs (TRAEs) were mild; the most common were increased blood ALP (15.4% in the 50 mg group; 69.2% in the 75 mg group) and elevated ALT (7.7% and 15.4% respectively). Serious AEs occurred in 7.7% of patients in the 50 mg group (n = 1, gastroenteritis) and 15.4% of patients in the 75 mg group (n = 2, one with deep vein thrombosis [DVT] and one who progressed to MDS with decreased PLT and breakthrough haemolysis); none were attributed to HRS5965. No deaths were reported (Table S1). Two patients in the 75 mg BID group experienced thromboembolic events (one with pre‐existing DVT symptoms and one with new limb DVT at Week 12); both were deemed possibly unrelated to treatment. Mean changes from baseline in PLT (Figure S7) and in lipid parameters (serum total cholesterol and triglycerides; Figure S8) exhibited no clinically meaningful variation over 12 weeks. One patient in the 50 mg BID group with a long‐standing history of AA showed no Hb improvement, and one in the 75 mg BID group experienced thrombocytopenia and was diagnosed with MDS; both events were considered possibly unrelated to HRS‐5965.
TABLE 3.
Adverse events in the safety set.
| AEs, n (%) | HRS‐5965 | HRS‐5965 |
|---|---|---|
| 50 mg BID | 75 mg BID | |
| (n = 13) | (n = 13) | |
| Any AEs | 9 (69.2) | 12 (92.3) |
| Mild | 8 (61.5) | 9 (69.2) |
| Moderate | 1 (7.7) | 2 (15.4) |
| Severe | 0 | 1 (7.7) |
| Any TRAEs a | 4 (30.8) | 10 (76.9) |
| AEs leading to dose interruption | 0 | 0 |
| AEs leading to dose discontinuation | 0 | 1 (7.7) |
| Serious AEs | 1 (7.7) | 2 (15.4) |
| AEs leading to death | 0 | 0 |
| Prespecified AESI b | 0 | 0 |
| AEs by preferred term | ||
| Blood alkaline phosphatase increased | 2 (15.4) | 9 (69.2) |
| C‐reactive protein increased | 0 | 5 (38.5) |
| Hypertriglyceridaemia | 0 | 2 (15.4) |
| Alanine aminotransferase increased | 1 (7.7) | 2 (15.4) |
| Upper respiratory tract infection | 3 (23.1) | 1 (7.7) |
| Hyperglycaemia | 1 (7.7) | 1 (7.7) |
| Pyrexia | 1 (7.7) | 1 (7.7) |
| Hypoalbuminaemia | 0 | 1 (7.7) |
| Hypokalaemia | 0 | 1 (7.7) |
| Oedema peripheral | 0 | 1 (7.7) |
| Arthralgia | 0 | 1 (7.7) |
| Gamma‐glutamyltransferase increased | 0 | 1 (7.7) |
| Neutrophil count decreased | 0 | 1 (7.7) |
| White blood cell count decreased | 0 | 1 (7.7) |
| Blood pressure increased | 0 | 1 (7.7) |
| Platelet count decreased | 0 | 1 (7.7) |
| Headache | 0 | 1 (7.7) |
| Throat irritation | 0 | 1 (7.7) |
| Conjunctival haemorrhage | 0 | 1 (7.7) |
| Hepatic function abnormal | 0 | 1 (7.7) |
| Myelodysplastic syndrome | 0 | 1 (7.7) |
| Breakthrough haemolysis c | 0 | 1 (7.7) |
| Venous thrombosis limb | 0 | 1 (7.7) |
| Deep vein thrombosis | 0 | 1 (7.7) |
| Decreased appetite | 1 (7.7) | 0 |
| Asthenia | 1 (7.7) | 0 |
| Eosinophil count increased | 1 (7.7) | 0 |
| Blood triglycerides increased | 1 (7.7) | 0 |
| Cough | 1 (7.7) | 0 |
| Nasal obstruction | 1 (7.7) | 0 |
| Gastroenteritis | 1 (7.7) | 0 |
| Diarrhoea | 1 (7.7) | 0 |
| Aplastic anaemia | 1 (7.7) | 0 |
Abbreviations: AE, adverse event; AESI, adverse events of special interest; ALT, alanine aminotransferase; AST, aspartate transaminase; BID, twice daily; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal haemoglobinuria; TRAE, treatment‐related adverse event; ULN, upper limit of normal.
TRAEs were defined as AEs for which causality to treatment was definitely related, possibly related, or not assessable.
Predefined AESIs included liver function abnormalities and infections. Liver function abnormality was identified when: (1) ALT or AST levels were ≥3× ULN if baseline values were normal, or 2× baseline and >3× ULN, or >8× ULN (whichever is lower) if abnormal at baseline; (2) Total bilirubin was >2× ULN if normal at baseline, or increased by >1× ULN or >3× ULN (whichever is lower) if abnormal; and (3) alkaline phosphatase was <2× ULN in the absence of haemolysis. Infections were defined as those requiring intravenous antimicrobial treatment following study treatment administration.
A breakthrough haemolysis event is defined as either a haemoglobin (Hb) decrease of ≥2 g/dL from the most recent assessment (or within 15 days) or the occurrence of severe haemoglobinuria, fatigue, abdominal pain or other significant PNH‐related symptoms, provided that any one of these clinical criteria is accompanied by an LDH increase to >1.5× ULN compared with the two preceding assessments.
Pharmacokinetics and pharmacodynamics
At steady state (Weeks 2, 4, 8 and 12), geometric mean trough concentrations (C trough,ss) were 783, 826, 802 and 787 ng/mL in the 50 mg BID group and 830, 925, 938 and 1010 ng/mL in the 75 mg BID group (Table S2; Figure S9). The less than dose proportional increase likely reflects target‐mediated drug disposition, where high affinity binding to complement factor B leads to receptor saturation and increased hepatic extraction at higher doses.
Pharmacodynamic assessments at steady state (Weeks 2, 4, 8 and 12) showed >80% predose inhibition of the alternative complement pathway in both dose groups. Although the 50 mg BID cohort exhibited greater variability (with some subjects slightly below 80% inhibition), this variability did not significantly impact the efficacy outcomes for Hb or LDH changes (Table S3; Figure S10).
DISCUSSION
In this study, both dosage groups of HRS‐5965 demonstrated substantial haematological improvements and effective inhibition of complement‐mediated haemolysis in complement inhibitor–naïve patients with PNH. At Week 12, patients receiving 50 mg BID experienced a mean Hb increase of 37.6 g/L, while those receiving 75 mg BID achieved an increase of 37.7 g/L. These outcomes are consistent with the APPOINT‐PNH study of iptacopan, a comparable oral factor B inhibitor, and underscore the robust haematological efficacy of HRS‐5965 in this patient population. 14 Notably, 100% of patients in the 50 mg BID group and 83.3% in the 75 mg BID group achieved an Hb increase of ≥20 g/L, with 25% of patients in both groups reaching levels ≥12 g/dL. Although the treatment duration was relatively short, these results reflect a promising therapeutic response that is likely to continue improving with longer treatment exposure.
Rapid control of intravascular haemolysis is especially critical in complement inhibitor–naïve patients, as ongoing haemolysis drives thromboembolic events and organ damage in PNH. In this study, HRS‐5965 achieved rapid and robust suppression of intravascular haemolysis, evidenced by marked reductions in LDH, a well‐established biomarker. By Week 12, LDH levels had fallen by 87% in the 50 mg BID group and by 85% in the 75 mg BID group, mirroring results seen with other proximal inhibitors such as iptacopan and pegcetacoplan. 18 These findings indicate that HRS‐5965 can promptly protect treatment–naïve patients from haemolysis‐driven complications.
An additional noteworthy finding was the expansion of the PNH red‐cell clone, which reached mean proportions of 88.0% and 91.4% in the 50 and 75 mg BID groups respectively. This suggests that HRS‐5965 effectively protects PNH erythrocytes from complement‐mediated destruction, allowing for their persistence in circulation. Although an expanded PNH clone could theoretically increase the risk of breakthrough haemolysis under complement‐amplifying conditions, no treatment‐related breakthrough episodes were observed during the 12‐week study period. This outcome is reassuring, particularly given the concerns reported with other proximal complement inhibitors. 19
Improvements were also observed across secondary haematological markers. Declines in reticulocyte counts reflect reduced erythropoietic stress, while reductions in total and unconjugated bilirubin further confirm the attenuation of haemolytic activity. The concurrent increase in haptoglobin supports the restoration of red blood cell homeostasis.
HRS‐5965 was generally well‐tolerated. Most TRAEs were mild to moderate in severity, with transient increases in blood ALP and ALT being the most frequently reported. Importantly, majority of these biochemical abnormalities did not result in dose interruptions or treatment discontinuations. Serious AEs occurred in one patient in the 50 mg BID group (gastroenteritis) and two patients in the 75 mg BID group: One developed DVT, and the other progressed to MDS with decreased PLT and breakthrough haemolysis. The patient who progressed to MDS entered a dose‐tapering phase after completing treatment and subsequently discontinued therapy due to decreased PLT, experiencing breakthrough haemolysis after treatment discontinuation. All these events were considered unrelated to the study drug by the investigators. Additionally, the emergence of bone marrow disorders in two patients (one with AA in the 50 mg BID group and one with MDS in the 75 mg BID group) is considered consistent with the natural course of PNH and not directly attributable to HRS‐5965. 20
Pharmacokinetic assessments indicated that steady‐state trough concentrations rose in a less‐than‐dose‐proportional manner, likely due to target‐mediated drug disposition related to high‐affinity binding to factor B. Despite this, pharmacodynamic evaluations confirmed potent inhibition of the alternative complement pathway, with suppression exceeding 80% in both dosing groups and slightly greater consistency in the 75 mg BID regimen.
This study has several limitations. The small sample size and relatively short treatment duration limit conclusions about long‐term efficacy and safety. Moreover, the open‐label design without a comparator arm introduces potential bias, although the use of objective laboratory end‐points mitigates this concern. Larger, randomized trials with extended follow‐up are needed to validate these findings and optimize dosing strategies.
In conclusion, HRS‐5965 monotherapy at both 50 and 75 mg BID achieved rapid and sustained control of intravascular haemolysis, substantial Hb improvement and favourable safety in complement inhibitor–naïve PNH patients.
AUTHOR CONTRIBUTIONS
Fengkui Zhang and Bing Han contributed to the study design and served as the principal investigators. Li Zhang, Ziwei Liu, Xin Zhao, Bin Hu, Chang Shu, Fengkui Zhang and Bing Han enrolled patients and participated in the collection and assessment of data, while Rong Hua participated in data analysis. All authors participated in data interpretation. Li Zhang, Fengkui Zhang and Bing Han contributed to manuscript preparation, and all authors contributed to the critical review and revision of the manuscript and provided final approval for submission.
FUNDING INFORMATION
This work was supported by the National High‐Level Hospital Clinical Research Funding (Grant No. 2022‐PUMCH‐C‐026) and by Jiangsu Hengrui Pharmaceuticals, which provided HRS‐5965 for patients enrolled in the clinical protocol and additional funding for ancillary studies.
CONFLICT OF INTEREST STATEMENT
Bin Hu, Rong Huang and Chang Shu are employees of Jiangsu Hengrui Pharmaceuticals Co., Ltd. All other coauthors declare no competing interests.
ETHICS STATEMENT
The protocol and its amendments were approved by the Ethics Review Committee of the Blood Disease Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences) (Approval Numbers: XY2023049‐EC‐1 and XY2023049‐EC‐2) and by the Ethics Committee for Drug Clinical Trials at the Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (Approval Number: KS20231340). These approvals included conflict of interest clearance, as well as comprehensive ethics and safety reviews.
PATIENT CONSENT STATEMENT
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients provided written informed consent prior to any study procedures.
CLINICAL TRIAL REGISTRATION
This trial was registered with the National Clinical Trials database as NCT06051357.
Supporting information
Appendix S1.
ACKNOWLEDGEMENTS
We thank all the patients and their families, investigators and personnel at the study sites for participating in the study. Editorial and medical writing support, under the guidance of the authors, was provided by senior medical writer, Lin Dong, PhD (Jiangsu Hengrui Pharmaceuticals), in accordance with the Good Publication Practice Guidelines. None of these contributors were compensated beyond a regular salary.
Zhang L, Liu Z, Zhao X, Hu B, Huang R, Shu C, et al. Efficacy and safety of HRS‐5965 monotherapy in complement inhibitor–naïve patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2025;207(2): 571–581. 10.1111/bjh.20230
Contributor Information
Fengkui Zhang, Email: fkzhang@ihcams.ac.cn.
Bing Han, Email: hanbing_li@sina.com.cn.
DATA AVAILABILITY STATEMENT
Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request after the product and indication have been approved by major health authorities. Data may be requested 24 months after study completion. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requiring the data. The leading clinical site and sponsor will check whether the request is subject to any intellectual property restrictions. Use of data must also comply with the requirements of Human Genetics Resources Administration of China and other country‐ or region‐specific regulations. A signed data access agreement with the sponsor is required before accessing shared data.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1.
Data Availability Statement
Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request after the product and indication have been approved by major health authorities. Data may be requested 24 months after study completion. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requiring the data. The leading clinical site and sponsor will check whether the request is subject to any intellectual property restrictions. Use of data must also comply with the requirements of Human Genetics Resources Administration of China and other country‐ or region‐specific regulations. A signed data access agreement with the sponsor is required before accessing shared data.