Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved the bispecific factor IXa- and factor X-directed antibody emicizumab (Hemlibra), according to Chugai Pharmaceutical Co., Ltd.
Emicizumab is now approved for use in Japan as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A and factor VIII inhibitors.
There are a few conditions for this approval, including requirements for a risk management plan, early phase post-marketing vigilance, and post-marketing drug use surveillance.
A risk management plan is intended to assess measures for appropriate management of the risks associated with a drug, either at regular intervals or in response to the progress of post-marketing surveillance.
According to Japan’s Pharmaceuticals and Medical Devices Agency, a risk management plan must consist of 3 elements:
- Safety specification—Important adverse drug reactions and missing information
- Pharmacovigilance activities—Information collection activities performed in the post-marketing period
For the early phase post-marketing vigilance requirement, Chugai must provide safety information to healthcare professionals and collect information on adverse reactions to emicizumab in the early post-marketing phase.
Post-marketing drug use surveillance for emicizumab will include all patients receiving the product and is scheduled to continue until data is collected from approximately 100 people. The goal is to understand background information on patients receiving emicizumab, as well as to collect safety and efficacy data on the product and take necessary measures for the appropriate use of emicizumab.
The data collected via this surveillance effort will be reviewed to determine whether new surveillance or further safety measures are needed. Results of the surveillance will be reported to the regulatory authorities, and the data will be presented at scientific meetings, according to Chugai.
Phase 3 studies
The MHLW’s approval of emicizumab is based on data from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs). Three had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.