Ultra-Rare Disease Report
④ ‘The illness is there, but I can’t prove it’: The final barrier blocking PFIC patients

[BizHankook] Progressive Familial Intrahepatic Cholestasis (PFIC) is an ultra-rare liver disease known to occur in roughly 1 out of every 50,000 to 100,000 newborns. Last October, the treatment "Bylvay (ingredient: odevixibat)" cleared the threshold for health insurance coverage, significantly improving the treatment environment for patients.

However, voices in the medical field are saying that "reimbursement is just the beginning." This is because there are patients who do not respond to the medication, and there are still patients who cannot receive state support despite clear clinical symptoms of PFIC because the causative mutation cannot be identified through genetic testing.

Children scratching until they bleed… Only about 50 patients in Korea

Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare hereditary liver disease that occurs when bile produced in the liver cannot be properly excreted and accumulates inside the liver. Usually discovered in infancy, it is estimated that there are fewer than 50 patients in South Korea.

When bile acids accumulate in the body, young patients suffer from extreme pruritus (itching) to the point where they cannot sleep at night. It is not uncommon for small children to scratch their bodies until they bleed and their skin becomes inflamed. In addition, fat-soluble vitamins (A, D, E, and K) are not absorbed properly, leading to growth delays, and as the disease progresses, it can worsen into liver fibrosis and cirrhosis.

What changed the treatment environment was the IBAT (ileal bile acid transporter) inhibitor Bylvay, developed by the global pharmaceutical company Ipsen.

Bylvay is a treatment that reduces the accumulation of bile acids in the body by inhibiting the reabsorption process of bile acids in the intestines. It is expected to alleviate extreme itching, slow the deterioration of liver function, and in some patients, delay the need for a liver transplant.

According to the Health Insurance Review and Assessment Service (HIRA), Bylvay is a super-expensive medication with a price ceiling ranging from 138,566 KRW to 829,807 KRW per capsule. Depending on the therapeutic dosage, the annual drug cost can exceed 300 million KRW, but health insurance coverage has significantly eased the financial burden on patients eligible for the special calculation benefit.

However, reimbursement does not solve every problem. Some patients exhibit drug resistance, failing to respond sufficiently to the medication, meaning bile stagnation continues and the risk of severe complications such as liver transplantation or hepatocellular carcinoma remains. In fact, there are patients who have experienced such drug resistance.

Kim Ji-soo, representative of the PFIC Patient Association, who attended the book talk held on the 4th at the Kyowon Tour Building in Jongno-gu, Seoul, shared her experience with her child who took Bylvay but saw no improvement in bile acid levels. "The effect of taking Bylvay was minimal, so we ended up preparing for a liver transplant. In the process, we also discovered hepatoblastoma, a type of pediatric liver cancer, which left us terrified," she recalled. "At the time, the word 'liver transplant' itself was a source of immense fear."

Since Bylvay is not a gene therapy that fundamentally corrects the cause of the disease but a treatment that manages symptoms and disease progression, it requires long-term administration and continuous observation. Furthermore, adverse digestive events such as diarrhea can occur, and fat-soluble vitamin (A, D, E, K) levels must be continuously monitored according to changes in bile acid metabolism, with supplementary treatment provided if necessary.

Cleared the special benefit hurdle, but "barriers" remain

Once registered for the rare and intractable disease special calculation benefit, patients can use the expensive Bylvay with a relatively low co-payment through health insurance support. On the other hand, patients for whom a pathological mutation has not been identified in the currently known PFIC-causing genes often struggle to register for the special benefit even if they are strongly suspected of having PFIC clinically, effectively severely limiting their access to treatment.

A pair of brothers being treated by Professor Ko Hong of Severance Children's Hospital and Professor Hur Moon-haeng of Seoul National University Hospital is a prime example.

These brothers exhibited the typical clinical symptoms of PFIC, including recurring jaundice, liver dysfunction, and extreme itching, and were diagnosed with PFIC by medical staff. Taking family history and clinical progress into account, the medical team determined that the possibility of PFIC was very high.

However, since no pathological mutation was identified in the known PFIC-causing genes during genetic testing, both brothers were excluded from the rare and intractable disease special benefit registration. The medical staff determined that the possibility of a new, unidentified causative gene or a mutation difficult to detect with current testing technology could not be ruled out. However, under current special benefit criteria, there is virtually no way to receive state support without a confirmed diagnosis through genetic testing.

The guardian of the brothers who attended the book talk stated, "Beyond visiting the hospital to check their condition, they aren't receiving any special treatment," adding, "It is a recurring cycle where symptoms seem okay for a while, only to worsen again as time passes."

The more ultra-rare a disease is, the higher the likelihood of such cases occurring. While various genetic abnormalities are known to cause PFIC, it is possible that there are still unidentified genes, and genetic analysis technology continues to evolve.

The cost of genetic testing, which can reach millions of won, is also a significant burden for patients and guardians. While the medical community suggests that retesting is necessary every so often to identify new genetic mutations, there is criticism that there are limits to the current coverage of genetic testing in Korea.

Professor Ko pointed out, "Genetic analysis technology continues to advance, but not all causative genes have been identified yet," adding, "Excluding patients who are clearly clinically ill from support just based on genetic test results can be a huge burden on them."

Professor Ko emphasized that the reimbursement of a new drug is not the end of treatment, and urged the patient association to play an active role. "The most powerful driving force for changing institutions and policies is not the academic appeal of medical staff, but the vivid voices raised directly to the world by patients and their guardians," he said. "The patient association must take the lead in raising their voices so that neighbors in the shadows can also receive the benefits of treatment. Only when such solidarity and action from patients are backed can the efforts of doctors to improve the system gain substantial power."

The reimbursement of Bylvay has become a major turning point in PFIC treatment. However, the medical community agrees that ultra-rare disease patients will only be able to fully enjoy the benefits of new drugs when institutional improvements are followed to expand treatment opportunities to patients who are unresponsive to medication or remain undiagnosed by genetic testing.