The Hereditary Periodic Fever (HPF) syndromes cause not just fever and pain but affect various aspects, such as patient's growth and development, psychological elements. The reimbursement coverage of a new treatment in nine years has increased patient satisfaction."

Clinical practices have high hopes for changes to the treatment setting as Ilaris (canakinumab), a treatment for Hereditary Periodic Fever (HPF) syndromes, passed the reimbursement hurdle nine years after approval.

Although doctors still face difficulties finding the appropriate dosage, analysis suggests that reimbursement will solve unmet needs for ultra-rare disease treatment where treatment options have been limited.

Experts believe that systematic improvements are needed to overcome the limitations, such as genetic testing, in the long term.

Daily Pharm met with Dr. Soyoung Lee, a Professor of Pediatric & Adolescent Medicine at Hallym University Sacred Heart Hospital, with years of prescribing experience, and heard about changes to HPF syndrome treatment settings following reimbursement coverage of Ilaris.

The HPF syndromes are rare autoinflammatory diseases that occur shortly after birth or in childhood. Unexplained and periodic episodes of full body fever and rashes characterize these diseases.

The HPF syndromes are categorized into various disorders based on abnormal genes. Symptoms such as fever and rashes most commonly occur, but other symptoms vary by disorder.

"In my opinion, it is more suitable to call this disorder periodic fever syndromes (PFS) rather than the HPF syndromes," Dr. Lee said. "In contrast to other autoimmune diseases, these disorders are categorized as autoinflammatory disorders. A single gene causes some of these disorders, whereas several genes are indicated to contribute to the disorder," Dr. Lee explained.

In South Korea, common cases include Cryopyrin-Associated Periodic Syndrome (CAPS), Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), and Hyper IgD Syndrome (HIDS). These disorders are all single-gene disorders.

According to Dr. Lee, the most common treatments for these disorders include nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids to alleviate pain and fever.

"In 2010, the introduction of the IL-1 inhibitor Anakinra allowed for the replacement of steroids, enabling most patients to discontinue unnecessary medications. However, since the injection had to be administered daily at a fixed time, patients faced significant challenges," Dr. Lee remarked.

"Typically, the dosage of the medication must be increased depending on the severity of the disease/ Because of the limitation of dosage that can be administered at a single injection, patients often suffer serious pain, and the other problem is that the required dosage required two separate injections," Dr. Lee stated.

In other words, Dr. Lee says that existing treatments had limitations in terms of long-term effects and patient quality of life despite the nature of HPF syndromes in affecting various aspects, such as patient's growth and development, psychological elements, and causing fever and pain.

"Reimbursed Ilaris provides benefits in terms of treatment effects‧administration interval"

Changes to the treatment setting have been apparent since August of last year, following reimbursement coverage of Ilaris for CAPS, TRAPS, and FMF."

What changes have been made to the treatment setting with reimbursed Ilaris? Dr. Lee says only few cases can be compared because it is a rare disease, but reimbursed Ilaris provided significant benefits in symptom improvements and improved patient quality of life.

"As patients switch to Ilaris based on insurance criteria, there have been no cases where patients gave up treatment despite the process being tough finding the appropriate dosage after starting with a low dosage," Dr. Lee said. "Since the administration interval is longer than the other treatments, patients can now be treated with more freedom."

"Additionally, patients can get injections at the hospital, so they are now freed from the burden of being injected at home by non-experts," Dr. Lee added. "The half-life of Ilaris is about 26 days, which minimizes the burden of drug administration time. Consequently, Ilaris provides a crucial turning point for patients."

While reimbursed Ilaris provides various benefits, the remaining issues are the dosage and managing side effects due to the longer administration interval.

Depending on the type of HPF syndromes, Ilrais is given every 8 weeks or 4 weeks. Doctors are concerned about dosage adjustment or symptom management if symptoms occur during treatment.

"The process of determining the appropriate dosage was not easy, but all five patients currently undergoing treatment have found their optimal dose and are continuing treatment stably," Dr. Lee said. "Although it has been just over four months since starting Ilaris, we now have more flexibility in adjusting the dosage for the next cycle while closely monitoring weight gain and symptoms."

Adjusting treatment dosage remains a challenge…"We must consider a patient-customized treatment"

Yet, another challenge is to help patients with HPF syndromes to receive reimbursement coverage.

"Currently, Ilaris can only be used if a patient's genetic mutation is confirmed. However, genetic testing fails to provide a diagnosis in up to 40% of cases." Dr. Lee added, "According to foreign studies, despite advancements in genetic analysis technology, 20–30% of cases still rely solely on clinical diagnosis to initiate treatment, highlighting the need for further discussion on this issue."

"Because the starting dosage is set too low, patients face challenges finding appropriate dosage. If the system is improved so that dosages can be flexibly determined under the doctor's supervision, patient-customized treatment will offer better treatment settings," Dr. Lee mentioned.

Ultimately, Dr. Lee highlights the need for efforts to improve the diagnostic rate of the HPF syndromes, which is a rare disease, in the long term.

"The number of patients with CAPS is recorded to be 2 plus 3 in 2022, but more undiagnosed patients likely exist," Dr. Lee said. "To provide more accurate and professional information, we hope academic organizations provide educational sessions for doctors interested in this field."

Dr. Lee added, "Genetic testing is an important tool for diagnosing (very) rare diseases, but its usefulness assessment varies by how it is used. "In my opinion, it is more effective to conduct genetic testing only when doctors determine it is necessary, after thoroughly evaluating the patient's symptoms and diagnostic course."