“If Hemibra prophylaxis is started early, healthy joints can be maintained. It can also restore pathologic abnormalities in soft tissue joints. This maintenance and improvement of joint health can affect future exercise, work, and school activities, leading to improved physical, mental, and social functioning. Improving social activities will ease the burden of treatment for patients and their caregivers, increasing the contribution of hemophilia patients to society.”

Professor Midori Shima of the Department of Pediatric Hematology-Oncology at Nara University in Japan said so while explaining the benefits of long-term prophylaxis with Hemlibra (emicizumab) during a news conference at the Intercontinental Seoul COEX last Saturday.

Hemlibra is an innovative new drug that mimics factor VIII, a blood clotting factor deficient in hemophilia patients. It is the only hemophilia A treatment available for antibody and non-antibody patients resistant to existing treatments. It provides long-lasting protection with once-weekly subcutaneous injections for up to four weeks.

Hemlibra confirmed the long-term safety and joint health benefits of the AOZORA trial. Specifically, the AOZORA trial was a post-marketing, phase 4 study of 30 non-antibody-positive patients with severe hemophilia A under 12 years of age treated with existing factor VIII products. The study looked at long-term safety and joint health for up to three years (Week 145) after treatment with Hemlibra.

Results showed that the average annualized bleed rate (ABR) decreased from 3.7 pre-Hemlibra to 0.7 post-Hemlibra. The frequency of joint bleeds requiring treatment improved from 0.4 to 0.2.

The number of patients experiencing synovial hyperplasia, an overgrowth of the lubricating membrane that facilitates joint movement, and hemosiderin, a darkening of the skin due to the deposition of hemosiderin pigment in the blood, each decreased from 10 at Week 1 to two at Week 145. The Hemophilia Joint Health Score (HJHS) improved from 0.90 at Week 1 to 0.44 at Week 145. HJHS is an index that evaluates the joint health of hemophilia patients, and the more severe the joint damage, the higher the score.

Korea Biomedical Review spoke with Professor Shima, who attended a symposium organized by JW Pharmaceutical to commemorate the first anniversary of Hemlibra's health insurance coverage, about the benefits of Hemlibra and the challenges of making Hemlibra the standard treatment for hemophilia A in the global market.

Professor Shima is a leading authority on hemophilia care in Japan and was a key player in the development of Hemlibra, participating in a global phase 3 clinical trial that demonstrated significant bleeding reduction and safety compared to existing factor VIII products.

Question: Japan has used Hemlibra to treat hemophilia A before Korea, including in clinical trials. How have patients responded?

Answer: Japan has the longest experience with Hemlibra, having started a phase 1 trial in 2013. Patients in the phase 1 trial have taken Hemlibra for over ten years. In these long-term patients, we compared their bleeding patterns, joint health, daily activities limited by hemophilia, and emotions before and after Hemlibra. We found that all patients experienced a reduction in bleeding patterns to mild to moderate levels after receiving Hemlibra. The time to hemostasis after bleeding was also significantly reduced. Regarding joint health, most patients experienced reduced joint pain and swelling. Regarding daily life and emotions, most patients reported that they could exercise more after taking Hemlibra, which made their lives at the workplace and school easier.

Q: What are the most important complications of hemophilia treatment?

A: The development and progression of hemophilic arthropathy is most serious. Hemosiderin is deposited in the synovial membrane, causing cytokine production and the development of synovitis, which leads to thickening of the synovial membrane. Neovascularization also increases, which predisposes to repeated joint bleeding. As synovitis progresses, osteoclasts (cells that destroy bone tissue) increase, causing cartilage and bone to degenerate and break down. At this stage, the patient's joint mobility becomes extremely impaired, and the patient's quality of life (QOL) is greatly reduced, as they are usually forced to walk on crutches or live in a wheelchair.

The development of antibodies (inhibitors) to factor VIII is also an important complication. While the treatment of hemophilia is usually replacement therapy, which involves administering the deficient clotting factor, inhibitors, which recognize the clotting factor in the treatment as foreign and neutralize the clotting factor activity, occur with an incidence of about 30 percent, especially in severe hemophilia A. When inhibitors occur, the effectiveness of clotting factor preparations is significantly reduced or eliminated, making treatment difficult.

Q: What are the benefits of Hemlibra as a preventive therapy?

A: The answer is reduced treatment burden on patients and families. Traditional factor VIII formulations require intravenous administration twice to three times weekly or every other day to prevent bleeding. This can be a burden for children with difficult vascular access or older adults who need assistance with injections. The same can be said of patients’ caregivers. Hemlibra is a much simpler subcutaneous injection with a half-life of 30 days, much longer than the 10 to 15 hours of traditional factor VIII formulations, and a dosing interval once every one to four weeks to prevent bleeding.

Whereas the trough value for factor VIII activity is 12-15 percent for traditional factor VIII products, Hemlibra maintains a sustained level of 15 percent. Due to the short half-life of conventional products, the level of clotting factor in the blood rises and falls. Still, Hemlibra can maintain the 15 percent above activity 24 hours a day, seven days a week, Monday through Sunday. As a result, two-thirds of patients on Hemlibra did not have a bleed, and when they did, it was only one or two bleeds a year, providing excellent bleed prevention.

The AOZORA trial demonstrated that Hemlibra prophylaxis administered at an early age can maintain healthy joints. Soft tissue joint pathologies can also be reversed. This maintenance and improvement in joint health can impact future exercise, work, and school activities, leading to improved physical, mental, and social functioning. These improved social activities will ease the burden of care for patients and their caregivers, increasing the contribution of people with hemophilia to society. In particular, Hemlibra does not require the development of antibodies to factor VIII and is equally effective and safe in patients with antibodies.

Q: The safety and efficacy of long-term administration is a concern for patients who should take the drug for the rest of their lives. We understand that the AOZORA study confirmed the long-term safety of Hemlibra prophylaxis. Can you give us a brief overview of this study?

A: The AOZORA trial is a post-marketing phase 4 study to determine long-term safety data and joint health in pediatric hemophilia A patients under 12 years of age who do not have antibodies to factor VIII. Thirty patients were enrolled in the first phase to evaluate safety endpoints, including adverse events, and joint health and function. Joint health was assessed using the Hemophilia Joint Health Score (HJHS) score and the International Prophylaxis Study Group (IPSG) score as determined by MRI. The exploratory endpoint was the average annualized bleeding rate (ABR) requiring treatment. Results were pooled for approximately three years, up to week 145 post-Hemlibra.

The study was divided into two groups: one consisting of 10 patients from the HOHOEMI trial who had received Hemlibra for six years, and the other consisting of 20 newly enrolled patients in the AOZORA trial.

In 11 patients, 42.3 percent of the total, IPSG results were normalized to 0 from Week 1 to Week 145, confirming healthy joints, as measured by IPSG MRI.

Pathologically significant markers, such as synovial hypertrophy and hemosiderin, were also identified in seven of 29 patients from week 1, before Hemlibra, despite the younger pediatric patients being prophylactically treated with a factor VIII agent.

However, after 145 weeks of Hemlibra treatment, venous hypertrophy and hemosiderin were absent in five of the seven patients identified. In two patients, venous hypertrophy and hemosiderin were reduced and improved. This suggests that Hemlibra prevention may be able to help patients maintain healthy joints or reverse synovial membrane changes.

Q: The ongoing HAVEN7 trial seems particularly important because it will determine the safety and effectiveness of Hemlibra prevention in infants and children under one year of age. What is the effectiveness of Hemlibra prophylaxis in patients under one year of age?

A: If Hemlibra is administered at a younger age, joint health can be maintained without bleeding. Therefore, we believe that the earlier we start, the better the outcome. It also reduces the worry of developing antibodies against factor VIII. This is why Hemlibra is increasingly given to children under one in Japan.

There are no safety concerns. Although prophylaxis with factor VIII could be started at a younger age, a growing body of evidence shows that it does not prevent joint damage, even if it is started early. Therefore, I think that Hemlibra can be used from the time hemophilia is diagnosed to maintain joint health.

Another benefit is the prevention of intracranial hemorrhage (ICH), which is the leading cause of death in people with hemophilia.

Q: What is the current prescribing status of Hemlibra in Japan?

A: Globally, 24,000 people with hemophilia A are treated with Hemlibra. More than 2,000 of the 5,776 people with hemophilia A are using it in Japan. About 35 percent are being treated with Hemlibra by choice. We believe this means that globally, Hemlibra is the standard of care for hemophilia and an important option for treatment

Q: Despite Hemlibra's many advantages, why do you think patients in Japan are not quickly switching to it?

A: Adult patients may resist changing the hemophilia medication they are used to. Many patients, especially in Japan, are conservative about switching medications. After switching to Hemlibra, I often wonder why I didn't switch to Hemlibra sooner. Some parents are reluctant to switch because they learned how to give intravenous injections (IVs) the hard way and are afraid that they will forget how to give themselves IVs after switching to Hemlibra.

Doctors, even hemophilia specialists, believe it is important only to administer factor VIII to treat hemophilia, so when patients ask to switch to Hemlibra, they are often told that it is not recommended.

In particular, there are myths circulating about the lack of factor VIII, which makes bones weaker and more prone to fracture, and the use of Hemlibra, which makes them more prone to fracture. To address these issues, it is important to communicate the right knowledge.

Q: Recently, Sanofi's once-weekly hemophilia A treatment Altuviiio was designated as an orphan drug in Korea, and it is being watched closely to see if it will change the domestic hemophilia treatment market. How does Hemlibra compare to other hemophilia A drugs from other pharmaceutical companies, including Sanofi and Takeda?

A: In terms of the drug's effectiveness, Sanofi's Altuviiio can maintain the lowest clotting factor activity level of 15 percent, which is quite similar to Hemlibra. However, Altuviiio requires weekly intravenous administration and carries a risk of antibody development. In other words, although the effectiveness of the two agents is similar, Hemlibra is a better option for now, considering that it can be administered subcutaneously once every four weeks and can be used for both antibody and non-antibody patients without the risk of antibody development.

Q: Finally, what message would you like to convey to Korean medical professionals?

A: I would like to hear more from patients. Doctors who are not considering using Hemlibra at all may change their minds if they hear from doctors who have actually prescribed the new drug and share their clinical experiences. To this end, we need patients and doctors who have encountered the new treatment to spread their experiences and voices.