KP104 seen to control red blood cell destruction of PNH in Phase 2 trial

Potential treatment targets both intravascular and extravascular hemolysis

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by Steve Bryson PhD |

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Long-term treatment with KP104, a first-in-class dual-function complement inhibitor, controlled red blood cell destruction occurring both inside and outside the blood vessels of people with paroxysmal nocturnal hemoglobinuria (PNH), according to data from a Phase 2 trial.

Based on these findings, Kira Pharmaceuticals, its developer, plans to launch a global Phase 3 study.

“The encouraging long-term safety and efficacy data demonstrate the potential of KP104 as an optimal and safe first-line monotherapy for PNH patients,” Wenru Song, MD, PhD, Kira’s head of research and development, said in a company press release. “We are actively preparing for global Phase 3 development and remain dedicated to bringing this innovative therapy to patients as quickly as possible.”

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Trial findings will be presented in an oral session at the 2024 European Hematology Association Hybrid Congress, set to take place in Madrid in June.

The oral presentation is titled, “KP104, a bifunctional C5 mAb-factor H fusion protein, effectively controls intravascular and extravascular hemolysis in complement inhibitor-naïve PNH patients: long-term results from a phase 2 study.”

PNH is a disease characterized by hemolysis, or red blood cell destruction, occurring both inside (intravascular) and outside (extravascular) blood vessels. Such destruction in PNH patients is caused by the abnormal activation of the complement cascade, a group of immune proteins.

Standard therapies, such as Soliris (eculizumab) and Ultomiris (ravulizumab), can help prevent hemolysis, particularly intravascular hemolysis, by targeting a complement protein called C5 to block complement activation. Still, about 20% of patients using these therapies continue to experience extravascular hemolysis.

KP104 is a novel complement inhibitor that’s designed to stop both types of hemolysis by simultaneously targeting C5 and complement regulator factor H, effectively blocking the terminal and the alternative complement pathways.

The Phase 2 study (NCT05476887) enrolled 18 PNH patients new to a complement inhibitor therapy. Participants received an under-the-skin (subcutaneous) injection of KP104 every two weeks.

Sustained rise in hemoglobin levels seen across 33 to 58 weeks of KP104 use

In a six-month interim analysis, KP104 demonstrated a favorable safety profile, controlling both intravascular and extravascular hemolysis. Treatment led to a rapid and sustained normalization of lactate dehydrogenase (LDH), a marker of hemolysis, and substantially improved the levels of hemoglobin — the protein that carries oxygen in red blood cells.

At the same time, patients ceased requiring red blood cell transfusions and showed a clinically meaningful improvement in fatigue.

Data to be presented at the upcoming congress covers 33 to 58 weeks (almost eight months to more than a year) of KP104 treatment. For at least 16 weeks, participants received a weight-based optimal dose.

As of a Jan. 4, 2024, cutoff date, all KP104-treated patients had sustained hemoglobin increases of at least 2 grams per deciliter of blood (g/dL). Mean hemoglobin levels rose by 7 g/dL, and hemoglobin levels in 16 (88.9%) patients were within the normal range (levels equal to or higher than 12 g/dL).

A marked reduction in LDH occurred in 17 patients (94.4%), with a mean decrease of 84.3%. All patients continued to have no need for a transfusion, and 17 (94.4%) showed no signs of breakthrough hemolysis.

KP104 continued to be well tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) leading to treatment discontinuation or study withdrawal. All 18 patients also remained free of major blood vessel complications.

The most common TEAEs included COVID-19 (38.9%), injection site swelling (27.8%), elevated uric acid levels (16.7%), headache (11.1%), cold-like symptoms (11.1%), and influenza-like illness (11.1%).

“The long-term results of KP104 treatment in this Phase II study demonstrate consistent safety and improved clinical response over those observed at week 24/25, affirming KP104’s durable efficacy in controlling both IVH and EVH [intravascular and extravascular hemolysis] in complement inhibitor-naïve PNH patients,” the researchers wrote.

“We are excited to share these promising Phase 2 results of KP104 at the upcoming EHA 2024 Hybrid Congress, which represents a significant advancement in addressing the unmet medical needs of patients with PNH,” Song said.

The trial, taking place in China, is due to conclude early next year.