Next month, new oral agent will be introduced to the market for paroxysmal nocturnal hemoglobinuria (PNH). Injectables, such as Soliris and Ultomiris, currently dominate the PNH market.

Attention is drawn to whether this oral agent will enhance patient satisfaction, as it offers the convenience of administration compared to the previous treatments.

According to pharmaceutical industry sources, the Ministry of Health and Welfare (MOHW) has recently given an administrative announcement on the revision to the "The detailed measure on the application standards and methods of medical reimbursements," which affects the reimbursement status of the Novartis Factor B inhibitor 'Fabhalta (iptacopan).' If there are no special circumstances, Fabhalta can be approved for reimbursement in July.

PNH is currently known as a disease with no fundamental cure. However, the approach to treatment is changing with the development of therapies that inhibit the activity of the complement system. The complement system is a core component of innate immunity, serving as a powerful defense mechanism that directly attacks and destroys pathogens.

The complement system includes several pathways, including C3 and C5, and ultimately functions to destroy red blood cells by forming the 'Membrane Attack Complex (MAC).'

Previous treatments primarily target the terminal component within the complement system's alternative pathway. Treatment settings have been improved with the introduction of Soliris (eculizumab),' a once every 2 weeks injection, and then, 'Ultomiris (eculizumab),' which can be administered via injection at 8-week intervals. These treatments are still commonly used in clinical practices.

Fabhalta works by inhibiting Factor B, a crucial component in the activation of C3. In addition to this novel mechanism, Fabhalta is also the first and only single oral agent for PNH treatment in South Korea, offering the advantage of twice-daily dosing.

The efficacy of Fabhalta was confirmed in the Phase 3 APPLY-PNH clinical study, which enrolled 97 adult PNH patients (18 years or older) who had received C5 inhibitors for at least 6 months but still experienced anemia (with average hemoglobin levels below 10 g/dL). In a randomized assignment, 35 out of 97 patients continued C5 inhibitor treatment, while the remaining 62 switched to Fabhalta. The impact on treatment outcomes was assessed over 24 weeks.

Clinical results showed that patients who switched to Fabhalta experienced normalized hemoglobin levels starting from week 4, with the effect sustained until week 24. Hemoglobin normalization was observed in approximately two-thirds of patients. Furthermore, four out of five patients exhibited a clinically significant increase in hemoglobin levels, and 95% of patients overcame transfusion dependence.

Based on these findings, the MOHW plans to apply reimbursement starting next month for PNH patients meeting specific criteria: ▲adults aged 18 or older with a PNH granulocyte clone size of 10% or more (as measured by flow cytometry) with lactate dehydrogenase (LDH) levels at least 1.5 times the upper limit of normal, and for whom C5 inhibitors (Soliris or Ultomiris injections) cannot be administered due to medical reasons.

Additionally, ▲reimbursement will apply if patients have received C5 inhibitors for more than 6 months under reimbursement criteria but have hemoglobin (Hb) levels below 10 g/dL or if there is a need for drug switching due to side effects.

As a result, clinical practices expect Fabhalta to be able to resolve unmet medical needs that could not be addressed with conventional treatments.

Currently, some PNH patients experience unmet needs such as persistent fatigue, insufficient symptom improvement, and transfusion dependency. Even with C5 inhibition, upstream C3 activation continues, often leading to repeated situations where red blood cells are prematurely removed from the bloodstream in the liver·spleen, necessitating transfusions.

As a result, Novartis is expected to establish a dedicated team and focus on addressing these unmet medical needs.

Dr. Jun Ho Jang, a professor at Samsung Medical Center Seoul, said, "Factor B is a proximal factor that acts as a gate upstream of C5 in the alternative complement pathway. In other words, inhibiting Factor B affects not only C5 but also C3, significantly improving hemolysis that occurs both intravascularly and extravascularly." Dr. Jang added, "Based on these mechanistic characteristics, the efficacy and safety profile of Fabhalta has not only been confirmed in clinical trials for patients without prior C5 inhibitor treatment experience but also showed superior results in patients who switched from anti-C5 therapy to Fabhalta compared to those who continued anti-C5 therapy."

Dr. Jang emphasized, "Fabhalta as a single oral formulation offers high convenience for taking medication. It is favorable that we have an effective treatment option with a new mechanism that did not exist before. A paradigm shift in PNH treatment is expected."

Meanwhile, PNH is a chronic, complement-mediated blood disorder, a severe rare disease that can be life-threatening. PNH patients have acquired mutations in some hematopoietic stem cells, leading to the production of red blood cells prone to premature destruction, resulting in intravascular hemolysis (IVH) and extravascular hemolysis (EVH).

PNH can cause complications such as thrombosis, renal failure, and pulmonary hypertension, potentially leading to death, with a 5-year mortality rate of 35% and a 10-year mortality rate of approximately 50%. It can also impact the quality of life due to symptoms such as anemia and weakness.