KP104, a Bifunctional C5 Mab-Factor H Fusion Protein, Demonstrates Sustained Long-Term Efficacy and Safety in Complement Inhibitor-Naïve PNH Patients: Updated Results from a Phase 2 Study at 36/38 Weeks of Obd Treatment

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic condition marked by intravascular and extravascular hemolysis (IVH and EVH), driven by the complement terminal and proximal effectors of the alternative pathway, respectively. KP104, a novel bifunctional recombinant fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H, can simultaneously inhibit both terminal and proximal complement activations.

We previously reported data from an ongoing Phase II study (NCT05476887) involving 18 complement inhibitor-naïve PNH patients treated with KP104 for ≥24/26 weeks at the Optimal Biological Dose (OBD). KP104 demonstrated a favorable safety and efficacy profile, achieving effective control of both IVH and EVH as evidenced by rapid and sustained normalization or near-normalization of lactate dehydrogenase (LDH) levels, significant improvement in hemoglobin (Hgb) levels, complete avoidance of blood transfusions, and clinically meaningful enhancements in FACIT-Fatigue scores (Han, EHA 2024).

Aims: We present updated long-term data from this ongoing Phase II trial. As of the data cutoff date of May 23, 2024, all patients had received KP104 at OBD for ≥36/38 weeks, with a total treatment duration of 53-77 weeks. Results from ≥48 weeks of treatment at OBD will become available in September 2024 and be included in the meeting presentation.

Methods: A total of 18 complement inhibitor-naïve PNH patients were enrolled in three dose-ascending cohorts, with 6 patients per cohort. After completing 12/13 weeks of the primary treatment phase, all patients entered a long-term extension phase, during which they transitioned from their starting dose to a weight-tiered OBD regimen: 1,920 mg SC Q2W for those weighing 45-79 kg and 2,400 mg SC Q2W for those weighing 80-120 kg.

Results: Substantial clinical improvements observed at ≥24/26 weeks post-OBD treatment were sustained through ≥36/38 weeks post-OBD in all patients. As of the data cutoff, 100% (18/18) of patients maintained a Hgb increase of ≥2 g/dL from baseline, with mean (SD) Hgb levels reaching an average of 13.1 (2.0) g/dL and a 6.2 (2.1) g/dL improvement from baseline. Additionally, 83.3% (15/18) of patients achieved Hgb normalization (≥12 g/dL). LDH levels of <1.5x ULN were sustained in 94.4% (17/18) of patients, with normal or near-normal LDH. Moreover, 100% (18/18) of patients remained free from red blood cell transfusions and 88.9% (16/18) avoided breakthrough hemolysis (BTH).

KP104 continued to be safe and well-tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) leading to drug discontinuation or study withdrawal. No new safety signals were identified. All 18 patients remained free from major adverse vascular events, and no severe adverse events were reported. The most frequently reported TEAEs to date were COVID-19 (38.9%), injection site induration (27.8%), hyperuricemia (16.7%), hyperlipidemia (11.1%), headache (11.1%), nasopharyngitis (11.1%), influenza (11.1%), and influenza-like illness (11.1%). Two cases of BTH were observed during the study. The first case, associated with gastroenteritis, occurred at the lowest starting dose cohort before the transition to OBD. After switching to OBD, the patient remained free of BTH. The second case of BTH occurred in a patient with co-existing myeloproliferative neoplasms (MPN).

Conclusion: The long-term results from this Phase II study of 53-77 weeks of KP104 treatment, including ≥36/38 weeks at OBD, demonstrate sustained clinical benefits and a favorable safety profile, affirming the durable efficacy of KP104 in controlling both intravascular and extravascular hemolysis in complement inhibitor-naïve PNH patients. The data continue to provide compelling clinical evidence to support the development of KP104 as a novel first-line monotherapy option for PNH patients with desired efficacy and safety (Notaro & Luzzatto, NEJM 2022).