[ASH 2024] Proximal inhibitors transform PNH treatment landscape: expert

SAN DIEGO, Calif. – By Lee Han-soo/Korea Biomedical Review correspondent -- At this year's American Society of Hematology (ASH) meeting in San Diego, Professor Jang Jun-ho of the Department of Hematology-Oncology at Samsung Medical Center shared his insights on the evolving landscape of paroxysmal nocturnal hemoglobinuria (PNH) treatment.

In an exclusive interview with Korea Biomedical Review, he discussed the current standard of care as well as emerging therapies that are improving patient outcomes.

PNH is a rare blood disorder where red blood cells are destroyed within blood vessels, leading to symptoms such as dark-colored urine and potentially life-threatening complications including acute kidney failure. While the global incidence is estimated at 1.5 cases per million people, East Asian countries, including Korea, China, and Japan, show higher prevalence rates. In Korea alone, the number of PNH patients has doubled from 260 in 2010 to 504 in 2023.

"The PNH treatment field experienced a breakthrough 13 years ago with the development of eculizumab, a C5 inhibitor," Jang said. "While it transformed patients' lives, no treatment is without unmet needs.”

The biweekly hospital visits and fixed dosing regimen sometimes led to "breakthrough hemolysis" in certain patients, Jang added. Breakthrough hemolysis refers to the return of intravascular hemolysis and reappearance of classical PNH symptoms.

However, the introduction of Ultomiris (ingredient: ravulizumab) helped address some of these challenges.

"Patients only need treatment every eight weeks, and the weight-based dosing has reduced breakthrough hemolysis events," he said.

However, he emphasized that even with C5 inhibitors, extravascular hemolysis (EVH) remains a significant concern.

"About 12 percent of Korean patients fail to achieve treatment goals due to EVH," he said. "While theoretically, EVH can occur in up to 60 percent of PNH patients, clinically significant cases affect 12-20 percent of patients, requiring continued transfusions and steroid use despite C5 inhibitor therapy."

The introduction of Voydeya (ingredient: danicopan) to the Korean market has garnered significant interest.

"As a D-factor inhibitor approved for combination therapy with existing C5 inhibitors, danicopan has shown remarkable results in suboptimal responders," Jang said. "When added to treatment, we've seen significant improvements in hemoglobin levels and EVH resolution."

Discussing the complexities of treatment selection with multiple proximal inhibitors now available, Professor Jang emphasized patient safety.

"While B-factor inhibitors like Fabhalta (ingredient: iptacopan) show promising data, the lack of long-term safety data and guidelines for managing severe breakthrough hemolysis remains a concern,” he said. “Currently, adding proximal inhibitors to terminal inhibitors seems the most ideal approach."

Recent ASH 2024 data comparing pegcetacoplan monotherapy with C5 inhibitor plus danicopan combination therapy showed significantly fewer breakthrough hemolysis events in the combination group.

"This was expected," Professor Jang said. "Mechanistically, C3 inhibition alone inevitably exposes patients to severe breakthrough hemolysis due to the continuous activation of the alternative pathway."

Regarding treatment convenience, Professor Jang offered a unique perspective on Asian patient preferences.

"Many Asian patients are hesitant to self-administer subcutaneous injections,” he said. “Among my patients, older individuals prefer bi-monthly hospital visits for injections, while younger patients favor oral medications."

Looking ahead, Professor Jang highlighted remaining challenges.

"While patient life expectancy has improved dramatically, treatment accessibility remains a concern,” he said. “Of approximately 300 hemolytic PNH patients in Korea requiring treatment, only about 220 currently receive either standard therapy or clinical trial medications.”

Making these life-changing treatments more affordable and accessible to all patients who need them remains our ultimate goal, he added.