Type of information: Granting of a Market Authorisation in the EU
Product name: Hemlibra®
Compound: emicizumab (ACE910 - anti-factor IXa x anti-factor X humanized bispecific antibody)
Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases
- bispecific antibody. Emicizumab is a bispecific antibody that works by mimicking the coagulation function of factor VIII.
- Emicizumab was designated as a Breakthrough Therapy by the FDA in September 2015.
Company: Chugai Pharmaceutical (Japan) Roche (Switzerland)
Disease: hemophilia A with factor VIII inhibitors in adult and pediatric patients
- • On February 23, 2018, the European Commission has approved Hemlibra® (emicizumab) for routine prophylaxis of bleeding episodes in people with haemophilia A with factor VIII inhibitors. Hemlibra® can be used in all age groups. The approval is based on two of the largest pivotal clinical studies in people with haemophilia A with inhibitors, in which Hemlibra® demonstrated superior efficacy compared to prior treatment with bypassing agents (BPA) as prophylaxis or on-demand. In the HAVEN 1 study in adults and adolescents (12 years of age or older) with haemophilia A with inhibitors, Hemlibra® prophylaxis showed a statistically significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, p<0.0001) compared to no prophylaxis. In a first-of-its-kind intra-patient analysis, Hemlibra® prophylaxis resulted in a statistically significant reduction in treated bleeds of 79% (RR=0.21, p=0.0003) compared to previous treatment with bypassing agent (BPA) prophylaxis collected in a non-interventional study (NIS) prior to enrolment.
Interim results from the HAVEN 2 study in children younger than 12 years of age with haemophilia A with inhibitors showed that 87% (95% CI: 66.4; 97.2) of children who received Hemlibra® prophylaxis experienced zero treated bleeds. In an intra-patient analysis of 13 children who had participated in the NIS, Hemlibra® prophylaxis resulted in a 99% (RR=0.01, 95% CI: 0.004; 0.044) reduction in treated bleeds compared to previous treatment with a BPA.
The most common adverse events (AEs) 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 (aPCC) (FEIBA®) was administered for 24 hours or more while receiving Hemlibra® prophylaxis.
- • On January 24, 2018, the Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation for Hemlibra® (emicizumab), a first-in-class medicine to prevent bleeding or reduce the frequency of bleeding episodes in patients with haemophilia A with factor VIII inhibitors, in patients of all ages. Hemlibra® is the first monoclonal antibody to be recommended for use in patients with haemophilia A with inhibitors. The treatment is given weekly via a subcutaneous injection, making it more convenient than bypassing agents (medicines that bypass factor VIII) which are the current standard of care but which require frequent, prolonged administration by infusion (drip). The CHMP reviewed the application for Hemlibra under its accelerated assessment procedure, which allows the speeding up of patients’ access to medicines that address unmet medical needs.
- The safety and efficacy of the medicine was evaluated in two phase III clinical trials: a randomised, open-label study conducted in 109 patients aged 12 years or older, and an ongoing single-arm, open-label study in children under 12 years of age, for which results in 60 patients were included in the application. Overall, the prophylactic use of emicizumab in haemophilia A patients with inhibitors reduced bleeding episodes that needed treatment with coagulation factors by around 80-90% compared to on-demand use of bypassing agents without prophylactic treatment.
- The most common adverse events observed were reactions at the site of injection, headache, thrombotic microangiopathy (damage to small blood vessels supplying organs such as the kidney), fever, diarrhoea and joint and muscle pain .
- • On November 16, 2017, the FDA approved Hemlibra® (emicizumab) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. Approval was based on data from two clinical trials—an adult and adolescent trial (HAVEN 1) and a pediatric trial (HAVEN 2).
- HAVEN 1 was a randomized, multicenter, open-label, phase 3 trial in 109 adult and adolescent males (aged 12 to 75 years and >40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients on prior episodic treatment were randomized 2:1 to weekly emicizumab-kxwh prophylaxis (3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly, thereafter) or no prophylaxis. Patients randomized to no prophylaxis could switch to emicizumab-kxwh prophylaxis after 24 weeks. For patients receiving emicizumab-kxwh prophylaxis, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 (95% CI; 1.7, 5.0) compared with 23.3 (95% CI: 12.3, 43.9) for patients not receiving prophylaxis corresponding to an 87% ABR reduction (95% CI: 72.3%, 94.3%), p<0.0001. In addition, improvements in patient-reported hemophilia-related symptoms and physical functioning in patients receiving emicizumab-kxwh prophylaxis were observed.
- HAVEN 2 was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12-17 years who weigh ?40 kg) with hemophilia A with FVIII inhibitors. Patients received emicizumab-kxwh prophylaxis at the dose and schedule described above. In 23 patients evaluated at the interim analysis, ABR for treated bleeds was 0.2 (95% CI: 0.1, 0.6). ABR for all bleeds was 2.9 (95% CI: 1.8, 4.9).The most common adverse reactions (occurring in ? 10% of patients taking emicizumab-kxwh) are injection site reactions, headache, and arthralgia. Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab-kxwh prophylaxis. The prescribing information contains a boxed warning to monitor for thrombotic microangiopathy and thrombotic events when aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab-kxwh should be suspended.
- The recommended dose of emicizumab is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly.
- Emicizumab was approved 3.3 months prior to the assigned regulatory action date. FDA granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation for this indication.
- Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).
- Hemlibra was reviewed by the FDA under Priority Review and granted Breakthrough Therapy Designation by the FDA in people 12 years of age or older with haemophilia A with inhibitors in September 2015. Data from HAVEN 1 and HAVEN 2 are being reviewed under accelerated assessment by the European Medicines Agency (EMA) and submissions to health authorities around the world are ongoing.
Hemlibra is being studied in a robust clinical development programme that includes two additional phase III studies. HAVEN 3 is evaluating Hemlibra prophylaxis dosed once weekly or once every other week in people 12 years of age or older with haemophilia A without inhibitors to factor VIII. HAVEN 4 is evaluating Hemlibra prophylaxis dosed every four weeks in people 12 years of age or older with haemophilia A with or without inhibitors.
- • On August 24, 2017, Chugai Pharmaceutical announced that the FDA has accepted the Biologics License Application (BLA) and has granted Priority Review for emicizumab prophylaxis as a once-weekly subcutaneous treatment for adults, adolescents and children with hemophilia A with factor VIII inhibitors. The FDA is expected to make a decision on approval by February 23, 2018. Both the filing and the Priority Review designation were made based on the results of HAVEN 1 study and the interim analysis of HAVEN 2 study, both of which have been conducted under a collaboration between Chugai, Roche and Genentech.
- • On July 21, 2017, Chugai Pharmaceutical announced that it filed a new drug application for its anti-coagulation factor IXa/X humanized bispecific monoclonal antibody emicizumab to the Ministry of Health, Labour and Welfare (MHLW) for the planned indication of “Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with congenital factor VIII deficiency (hemophilia A) with factor VIII inhibitors.
- This filing is based on the results of HAVEN 1 study and the interim analysis of HAVEN 2 study, both of which have been conducted under a collaboration between Chugai, Roche and Genentech. The two studies have been carried out in hemophilia A patients with factor VIII inhibitors in order to evaluate the efficacy, safety and pharmacokinetics of the once-weekly subcutaneous injection of emicizumab, while HAVEN 1 is for adult and adolescent patients (12 years of age or older) and HAVEN 2 is for pediatric patients (younger than 12 years of age).
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-11-16
UE authorization: 2018-02-23
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2014-01-10
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On December 14, 2017, Shire filed a motion for preliminary injunction against Roche subsidiaries Genentech and Chugai Pharmaceutical , as part of its ongoing U.S. patent infringement lawsuit to protect its ‘590 patent from infringement by Roche’s emicizumab. Shire indicated that its motion is not seeking a blanket prohibition of emicizumab sales, but rather the request proposes a carve-out to enable those patients with the greatest need continue to have access to the treatment. Until the court‘s decision on the motion for the preliminary injunction is made, expected summer 2018, there will be no patient impact. Although Shire has proactively proposed a carve-out in its request for a preliminary injunction, the scope of the injunction and any carve-out provision is ultimately a matter for the court to decide.
- • On July 9 2017, Shire announced that it has obtained a preliminary injunction in a court of Hamburg, Germany against Roche to address incomplete and misleading statements that may impact important issues of patient safety regarding emicizumab. Under the injunction, Shire seeks to prevent further dissemination of the inaccurate and misleading characterization of the serious adverse events that occurred in the HAVEN 1 Phase 3 trial of emicizumab, specifically the assertion that “all events occurred when repeated high aPCC (activated Prothrombin Complex Concentrate) doses were used concurrently with emicizumab.” The injunction also seeks to correct promotion of the primary data results relative to “treated bleeds” (a secondary endpoint) as compared to the primary endpoint of “number of bleeds over time” established at the outset of the trial
- Based on Roche’s publically available information to date (as of 7 July 2017), physicians, patients and caregivers may be misinformed about the appropriate management of breakthrough bleeds uncontrolled by emicizumab. In addition, through these actions, Shire believes Roche has unlawfully disparaged Shire’s proven bypassing agent, FEIBA (Anti-Inhibitor Coagulant Complex). Shire has issued multiple unheeded requests to Roche in an effort to resolve these concerns in an appropriate manner. As a result, Shire made the decision to seek court intervention.
- Shire’s goal with this action is to ensure the hemophilia community receives sufficient, accurate information from Roche about the reported serious adverse events (SAEs) in the Phase 3 emicizumab trial, enabling physicians and their patients to make properly informed decisions about patient care. The preliminary injunction is an interim measure which can be appealed by Roche.