‘Oral drug Fabhalta changes PNH treatment paradigm'

Youngil Koh, Professor of Hematology/Medical Oncology, Seoul National University Hospital

Overcomes the limitations of existing C5 inhibitors... Improving anemia and blood transfusion dependence

First oral drug to enter the market... ”Expected to improve treatment satisfaction”

Youngil Koh, Professor of Hematology/Medical Oncology, Seoul National University Hospital

“While significant progress has been made in the treatment of paroxysmal nocturnal hemoglobinuria (PNH), unmet needs remain.

 

Given the relatively young age of patients, there is an increasing emphasis on the need for treatment strategies that not only ensure survival but also improve anemia and enable patients to return to their daily lives.

 

Therefore, I believe that Fabhalta, which improves ease of administration and has been shown to be effective in improving anemia, will become more widely used." Youngil Koh, Professor of Hematology/Medical Oncology, at Seoul National University Hospital, emphasized so in a recent interview with Dailypharm regarding the paradigm shift being made in the PNH treatment landscape.

 

PNH is a rare condition caused by acquired genetic mutations.

 

While the term “acquired mutation” often brings to mind cancer, PNH is classified as a type of “clonal hematopoiesis,” not a blood cancer.

 

While multiple mutations in hematopoietic stem cells can lead to blood cancer, PNH occurs when a single mutation occurs in the PIGA gene, which is located on the X chromosome.

 

PNH is currently known to have no fundamental cure.

 

However, with advancements in science, treatment approaches have been evolving with therapies developed to inhibit the activity of the complement system.

 

The complement system is a core component of the innate immune system, serving as a powerful defense mechanism that directly attacks and destroys pathogens.

 

This system consists of multiple pathways, including C3 and C5, and ultimately forms the “membrane attack complex (MAC),” which destroys red blood cells.

 

Until now, treatments that inhibit C5, located at the terminal pathway of the complement system, have been primarily used.

 

Notably, the introduction of Soliris, an injectable medication administered every 2 weeks, followed by Ultomiris, which can be administered every 8 weeks, has improved the treatment landscape.

 

Many patients still manage their condition using these treatments.

 

However, among the PNH patients receiving treatment, unmet needs still remain in those suffering from persistent fatigue, insufficient symptom improvement, and blood transfusion dependence.

 

In particular, even when C5 is inhibited, the activation of the upstream C3 pathway continues, leading to the premature removal of red blood cells in the liver and spleen and the repeated need for blood transfusions.

 

Professor Koh said, “Statistically, only about 20% of all PNH patients are reported to have their symptoms sufficiently controlled by C5 inhibitors alone to enable them to live normal lives.

 

The remaining 80% of patients cannot completely control their symptoms, and about half of them clearly need other treatment options.” He added, “The complement system is composed of multiple pathways, with C3 located at the upper stage and C5 at the lower stage.

 

While existing C5 inhibitors have acted by blocking the lower stage, it has been confirmed in actual clinical settings that inhibiting C5 alone may still pose issues due to the activation of C3 at the upper stage.” Introduction of Fabhalta, the first oral option Fabhalta was developed to address these issues and works by inhibiting complement factor B, which plays an important role in C3 activation.

 

By regulating the overactivation of C3, it enables a new therapeutic approach to areas that were not addressed by existing C5 treatments.

 

Based on this mechanism of action, Fabhalta is attracting attention as a new treatment option that can meet unmet needs that could not be addressed with existing C5 inhibitors alone.

 

In particular, this treatment has the advantage of being effective against anemia and extravascular hemolysis.

 

Fabhalta demonstrated efficacy in the APPLY-PNH Phase III clinical trial, which enrolled 97 adult PNH patients aged 18 years and older with residual anemia (mean hemoglobin level less than 10 g/dL) despite receiving C5 inhibitors for at least 6 months.

 

Through random assignment, 35 of the 97 patients continued C5 inhibitor treatment, while the remaining 62 switched to Fabhalta, and the effects of the treatments were evaluated for 24 weeks.

 

The clinical results showed that patients who switched to Fabhalta had normalized hemoglobin levels from week 4, and this effect continued through week 24.

 

Hemoglobin normalization was confirmed in approximately two out of three patients.

 

In addition, four out of five patients showed clinically significant increases in hemoglobin levels, and 95% of patients overcame their blood transfusion dependence.

 

No adverse reactions requiring discontinuation of treatment occurred with Fabhalta.

 

The incidence of acute hemolysis was significantly lower than that of C5 inhibitors, and although headaches, diarrhea, and nausea occurred, they were generally mild and resolved within one week.

 

Professor Koh said, “The main purpose of this clinical trial was to confirm the effectiveness of Fabhalta in improving anemia, and the results showed that the hemoglobin level improved in more than 80% of the Fabhalta group and that blood transfusions were avoided in about 90% of the cases.

 

On the other hand, no such improvement was observed in the group of patients who received only conventional C5 inhibitors.” He added, “These results are considered to have served as clinical proof that Fabhalta is a treatment option that can improve anemia that could not be resolved with existing treatments and significantly reduce dependence on blood transfusions.” The strength of Fabhalta lies in its formulation.

 

As an oral medication, Fabhalta is easier to administer than existing intravenous formulations such as Soliris and Ultomiris.

 

Many patients in clinical practice have expressed their desire to switch to Fabhalta if it becomes reimbursed by insurance, and Koh explained that patient satisfaction with treatment is likely to increase not only because of improved hemoglobin levels but also because of the switch to an oral formulation.

 

Professor Koh stated, “PNH has an average onset age in the early 40s, making it more common in relatively younger age groups.

 

In actual practice, many patients continue working while undergoing treatment.

 

Among existing treatments, Ultomiris is an injectable medication administered every 2 months, which reduces the burden of hospital visits compared to Soliris, significantly improving patient satisfaction.

 

Based on this experience, Fabhalta is the first oral medication that can be taken without visiting a hospital, which is a big change for patients in terms of the method of administration alone." Unmet demand remains…Treatment environment needs improvement Professor Koh expressed a very positive outlook on the ongoing development of therapies with various complement inhibition mechanisms because these can potentially address the unmet needs that could not be resolved with existing C5 inhibitors.

 

For example, Fabhalta inhibits factor B, Empaveli (pegcetacoplan) inhibits factor C3, and Voydeya (danicopan) inhibits factor D, with each drug having a different treatment profile because they act at different sites.

 

Professor Koh said, “All of these treatments can be effective in meeting unmet needs, but they have distinct advantages and disadvantages in terms of dosage method and whether they are used in combination.

 

Empaveli requires twice-weekly subcutaneous injections, which can be burdensome, but it can be an effective option for patients who have little aversion to injections.

 

On the other hand, Voydeya requires combination therapy with a C5 inhibitor, which increases the medication burden, but it also has the advantage of potentially improving adherence through the use of a combination injection.” He added, “However, under the current reimbursement standards in Korea, initial treatment must still begin with C5 inhibitors, so in practice, we discuss which drug patients may switch to when unmet needs arise, such as anemia.” Novartis Korea is currently negotiating Fabhalta’s drug prices with the National Health Insurance Service, the final gatekeeper for insurance reimbursement.

 

Professor Koh said, “When discussing with patients, there are quite a few cases where they are waiting for reimbursement for Fabhalta.

 

We have recommended Empalveli to some patients, but many of them feel burdened by the twice-weekly injections and have expressed their intention to switch to oral medication once it becomes covered by insurance.

 

This tendency is particularly prominent among young patients who are socially active.” He added, “Fabhalta has shown potential as a first-line treatment option.

 

In the future, newly developed drugs with new mechanisms of action must be adopted as first-line treatments so that PNH patients can be said to be receiving more practical and comprehensive care.”