Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare and complex blood disorder with limited conventional treatment options, resulting in low survival rates and poor quality of life for patients. Innovative drugs and treatments are urgently needed to improve hemolysis control, reduce the risk of complications, and enhance survival rates and quality of life for these patients. At the 2024 European Hematology Association (EHA) Annual Meeting held in Madrid, Spain, Professor Bing Han from Peking Union Medical College Hospital presented exciting research results. The dual-functional C5 antibody/H factor fusion protein KP104 showed long-term efficacy in previously untreated PNH patients (S187). "Oncology Frontier - Hematology Frontier" conducted an interview with Professor Han to discuss this research and her insights on further optimizing PNH management.Research Overview
Background: PNH is a rare and life-threatening blood disorder characterized by intravascular (IVH) and extravascular hemolysis (EVH) mediated by effectors of the terminal pathway (TP) and the alternative pathway (AP) of the complement system. KP104 is a novel dual-functional recombinant fusion protein composed of a humanized anti-C5 monoclonal antibody and the N-terminal functional domain of complement regulator factor H, capable of simultaneously inhibiting TP and AP. In an interim analysis of the phase II study (NCT05476887), KP104 demonstrated good safety and effective control of IVH and EVH in PNH patients who had not previously received complement inhibitors (n=18) by week 24/25, including rapid and sustained normalization of lactate dehydrogenase (LDH), significant improvement in hemoglobin (Hgb), complete avoidance of transfusions, and clinically meaningful improvements in FACIT-Fatigue scores (ASH 2023).
Objective: This report provides updated long-term data from the KP104 phase II study. As of January 4, 2024, patients had received 33-58 weeks of treatment, with at least 16 weeks under the optimal biological dose (OBD) regimen.
Methods: Eighteen PNH patients who had not previously received complement inhibitors were enrolled in three dose-escalation cohorts, with six patients per cohort. After completing the initial 12/13-week treatment phase, all patients entered the long-term extension phase, transitioning from the initial dose to the weight-based OBD: 1920 mg subcutaneously every two weeks for patients weighing 45-79 kg, and 2400 mg subcutaneously every two weeks for patients weighing 80-120 kg.
Results: Except for one patient with coexisting myeloproliferative neoplasm (MPN) in the third cohort, the clinical improvements observed at week 24/25 were maintained and/or further enhanced in all patients (Figure 1). As of the data cut-off date, 100% (18/18) of patients had a hemoglobin increase of ≥2 g/dL from baseline, with an average (SD) increase of 7.0 (2.1) g/dL, and 88.9% (16/18) achieved hemoglobin normalization (≥12 g/dL). Additionally, 94.4% (17/18) of patients achieved LDH <1.5xULN (excluding the MPN patient), with an average (SD) LDH reduction of 84.3 (8.7)%. Furthermore, 100% (18/18) of patients were free from red blood cell transfusions, and 94.4% (17/18) did not experience breakthrough hemolysis (BTH).
KP104 continued to demonstrate good tolerability, with no serious adverse events or treatment-related adverse events (TEAEs) leading to discontinuation or withdrawal from the study. None of the 18 patients experienced major adverse vascular events or reported severe adverse events. The most commonly reported TEAEs included COVID-19 (38.9%), injection site induration (27.8%), hyperuricemia (16.7%), headache (11.1%), nasopharyngitis (11.1%), and influenza-like illness (11.1%). One patient in the lowest dose cohort temporarily experienced BTH due to gastroenteritis before transitioning to the OBD. After increasing the dose, the issue was quickly resolved, and the patient did not experience BTH post-transition.
Conclusion: The long-term treatment results from this phase II study indicate that KP104’s safety profile remains consistent with the findings at week 24/25, with improved clinical responses, confirming the durable efficacy of KP104 in controlling IVH and EVH in PNH patients who had not previously received complement inhibitors. The data provide compelling clinical evidence that KP104, as a potent “First-in-Class” dual-functional complement inhibitor, offers ideal efficacy and safety, potentially representing a new first-line monotherapy (NEJM 2022).
Expert Interview
Oncology Frontier – Hematology Frontier: Please introduce the background of this study and its breakthrough significance for existing PNH treatments.
Professor Bing Han: PNH is an extremely rare disease with very limited treatment options historically. Aside from bone marrow transplantation, conventional supportive treatments have been largely ineffective, leading to a high mortality rate of about 35% within five years. However, with the advent of complement inhibitors, we now have more treatment options, such as eculizumab, ravulizumab, and iptacopan, which are available in China. Despite these advancements, these drugs also have limitations, as they are not effective for all patients, and some may experience breakthrough hemolysis or extravascular hemolysis. The new drug KP104 mentioned in our report is an innovative first-in-class therapeutic that targets two complement pathways: C5 and complement regulator factor H. This dual-target approach theoretically offers better complement inhibition, greater control over hemolysis, and reduced complications.
Oncology Frontier – Hematology Frontier: How did KP104 perform in terms of long-term efficacy in controlling hemolysis symptoms in PNH patients during this phase II study? Were there any new safety issues or adverse reactions observed during the treatment?
Professor Bing Han: This report presented the long-term follow-up data after transitioning to the optimal biological dose (OBD). The observation period for this dose lasted over six months for all patients, with most being monitored for a year since the study began. During the study, patients’ efficacy improved further, especially after transitioning to the OBD, with 89% achieving hemoglobin normalization, surpassing results from previous clinical trials. Additionally, 100% of patients achieved a hemoglobin increase of 2 g/dL or more, and this improvement occurred rapidly. This means that all patients became transfusion-independent. In terms of safety, KP104 showed excellent performance, with no significant adverse reactions observed. The most common issues were injection site pain and COVID-19 infections, but their incidence was low. Other adverse reactions were extremely rare, making this treatment highly ideal from a safety perspective.
Oncology Frontier – Hematology Frontier: In the long-term extension phase, patients transitioned from the initial dose to the weight-based OBD, and KP104’s efficacy improved further. How did this weight-based dose adjustment affect treatment outcomes and patient tolerance?
Professor Bing Han: Among the enrolled patients, one overweight patient experienced breakthrough hemolysis during the initial study. However, after transitioning to the weight-based OBD, this patient’s hemolysis was successfully controlled, resulting in excellent sustained efficacy. Upon dose optimization, all patients achieved significant treatment outcomes. Specifically, 16 out of 18 patients had normalized hemoglobin levels, accounting for 89%, which is the best result achieved so far.
Oncology Frontier – Hematology Frontier: Beyond developing new drugs like KP104, what other areas of research and improvement do you believe are necessary for managing and treating PNH patients?
Professor Bing Han: Managing PNH is a significant challenge. Although it is a benign disease, it has been life-threatening in the era before widespread use of complement inhibitors. With new drugs, PNH is gradually becoming a chronic condition. Managing PNH involves the lifelong use of complement inhibitors, which presents challenges in ensuring patient compliance. Some patients may stop medication or miss doses for various reasons, especially during surgery, trauma, or infections, raising new questions about drug adjustments. Chinese doctors are still becoming familiar with these aspects, necessitating further standardization and management. Additionally, research on PNH diagnosis, biomarker monitoring, and predicting complement inhibitor efficacy is ongoing. These studies will help optimize treatment choices and monitor outcomes, leading to better management and improved quality of life for PNH patients.
Final Note
KP104, developed by Professor Wenru Song’s team at Staidson Biopharma, is the world’s first dual-target complement inhibitor (C5 and H factor), capable of targeting both the bypass and terminal pathways of the complement system. This provides a more precise treatment option for complement-mediated diseases. KP104’s impressive performance in PNH treatment has been highlighted at multiple international conferences, including last year’s ASH and this year’s EHA. These studies demonstrate KP104’s potential as a new single-agent therapy for PNH with best-in-class potential. Notably, at this year’s EHA meeting, KP104 was featured in the Presidential Session, presented by Dr. Risitano, Chairman of the International PNH Interest Group (IPIG), further highlighting KP104’s significant value and potential.
