Determined to reduce the risk of bleeds

EuroBiotech_ Who developed the Hemlibra concept?
Levy_ Hemlibra was discovered by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche and Genentech. Hemlibra is the first new prophylactic medicine in over 20 years to treat people with haemophilia A with inhibitors to factor VIII. It’s a bispecific factor IXa- and factor X-directed antibody designed to bring together factor IXa and factor X, which activate the natural coagulation cascade and restore the blood clotting process for people with haemophilia A. Hemlibra resulted from the persistence of our Chugai scientists to screen more than 40,000 monoclonal antibodies over ten years.

EuroBiotech_ How many haemophilia A patients resistant to factor VIII prophylaxis may be treated with this new treatment option?
Levy_ Nearly one in three people with severe haemophilia A can develop inhibitors to factor VIII replacement therapies, putting them at greater risk for life-threatening bleeds or repeated bleeds that can cause long-term joint damage. In addition, people with inhibitors have a 70% increased risk of death compared to those without inhibitors.

EuroBiotech_ What is the major benefit of Hemlibra for patients with haemophilia A compared to factor VIII prophylaxis? Could you please summarise the clinical results that led to FDA and EMA approval of Hemlibra?
Levy_ Hemlibra is as a once-weekly subcutaneous injection. In 2017, the US FDA approved Hemlibra for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with haemophilia A with factor VIII inhibitors, and earlier this year, the European Commission approved Hemlibra for people with haemophilia A with inhibitors. The approvals were based on pivotal clinical studies in people with haemophilia A with factor VIII inhibitors:

• In the phase III HAVEN 1 study, people 12 years or older who received Hemlibra prophylaxis had a statistically significant reduction in treated bleeds of 87% compared to those who received no prophylaxis. In a first-of-its-kind intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant reduction in treated bleeds of 79% compared to previous treatment with bypassing agent prophylaxis for which data were collected in a non-interventional study prior to enrolment into the pivotal study.
• Interim results from the pivotal HAVEN 2 study in children 12 years or younger showed that 87% of children who received Hemlibra prophylaxis experienced zero treated bleeds. In an intra-patient analysis of 13 children who had participated in the non-interventional study, Hemlibra prophylaxis resulted in a 99% reduction in treated bleeds compared to previous treatment with a BPA either as prophylaxis (n=12) or on-demand (n=1).
• In addition, the US FDA also granted Breakthrough Designation (BTD) for Hemlibra in haemophilia A without inhibitors in April 2018. This additional designation is based on data from the phase III HAVEN 3 study in people 12 years or older with haemophilia A without factor VIII inhibitors. Hemlibra was the first medicine to show superior efficacy compared to prior factor VIII prophylaxis; this was done as an in an intra-patient comparison in patients who had previously participated in the non-interventional study. These new data are not yet covered  in the market authorisation but have been submitted to health authorities.
• Roche also reported positive interim results from the phase III HAVEN 4 study evaluating Hemlibra prophylaxis dosed once every four weeks in adults and adolescents 12 years of age or older with haemophilia A with and without inhibitors to factor VIII.

EuroBiotech_ Did you observe any adverse effects during treatment with Hemlibra?
Levy_ In the clinical studies supporting the US and EU approvals in people with haemophilia A with inhibitors to factor VIII, the most common adverse events from pooled clinical studies, occurring in 10% or more of people treated with Hemlibra, were injection site reactions and headache. In the HAVEN 1 study, three people experienced thrombotic microangiopathy (TMA) events and two people experienced serious thrombotic events when on average, a cumulative amount of more than 100 U/kg/24 hours of activated prothrombin complex concentrate was administered for 24 hours or more while receiving Hemlibra prophylaxis. In the HAVEN 2 study, the most common AEs, occurring in 10% or more of people treated with Hemlibra in pooled studies, were injection site reactions, headache and joint pain, so-called arthralgia.

EuroBiotech_What’s the current interpretation of the five patient deaths that occurred in course of Hemlibra treatment?
Levy_For all five, the treating physician or investigator’s assessment was that the cause of death was unrelated to Hemlibra. Three of these patients had been participating in a compassionate use programme, one had participated in a clinical trial, and one was taking Hemlibra through an expanded access programme, which allows patients who are not participating in a clinical trial to have access to investigational medicines prior to approval. We were deeply saddened to learn about these deaths and take all reports of death and safety events very seriously. For each report, we followed our safety assessment and reporting processes to ensure prompt evaluation of the event and continued broader patient safety.

EuroBiotech_ What percentage of patients formed antibodies against Hemlibra in the clinical trials you conducted?
Levy_ We recently learned that a patient in our phase III HAVEN 2 clinical trial developed an anti-drug antibody to Hemlibra that led to reduced efficacy. As with all therapeutic proteins, there is a potential for the development of anti-drug antibodies with Hemlibra, as indicated on the US and EU Hemlibra product labels. The patient and his family have decided to discontinue treatment with Hemlibra, and he will resume treatment with his previous medicine. To date, more than 600 people with haemophilia A have been treated with Hemlibra worldwide, including in clinical trials. This is the first confirmed report of a detectable anti-drug antibody that has impacted the efficacy of Hemlibra in a person with haemophilia A. We continue to monitor for the development of anti-drug antibodies to Hemlibra in ongoing studies globally.The development of anti-drug antibodies to Hemlibra is distinct from the development of inhibitors to factor VIII. Anti-drug antibodies to Hemlibra may affect whether the medicine works, but they do not change the severity of the underlying disorder. On the other hand, for the nearly one in five people with haemophilia A who develop inhibitors to factor VIII, the inhibitors not only affect the efficacy of factor VIII replacement therapies, but they can also affect any natural factor VIII in the body. Inhibitors to factor VIII put people with haemophilia A at greater risk for life-threatening bleeds or repeated bleeds that can cause long-term joint damage.

Gallia Levy, PhD, Associate Group Medical Director at Roche is the Global Development Team Leader, Hemlibra. Prior to leading the global development program for Hemlibra, Gallia Levy held a number of positions in early and late stage drug development. Following her MD and PhD at the University of Michigan, Dr. Levy practiced internal medicine at Stanford University and pursued a hematology fellowship at the University of California. She is board-certified in hematology.

First published in European Biotechnology Summer Edition 2018