Type of information: Granting of a Market Authorisation in the EU
Product name: Zinplava®
Therapeutic area: Infectious diseases
Action mechanism: monoclonal antibody. Bezlotoxumab is a selective, fully-human, monoclonal antibody designed to neutralize C. difficile toxin B, a toxin that can damage the gut wall and cause inflammation, leading to the symptoms of C. difficile enteritis, which include abdominal pain and watery diarrhea. Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and licensed to Merck&Co in 2009 for development as a potential therapeutic for C. difficile infection.
Company: Merck&Co (USA - NJ)
Disease: Clostridium difficile infection recurrence
- • On December 16, 2016, the Committee for Medicinal Products for Human Use (CHMP) announced that in addition to the positive opinions adopted at its December meeting, the CHMP recommenced granting a marketing authorization for Zinplava® (bezlotoxumab) to prevent the recurrence of Clostridium difficile infection via written procedure on 22 November 2016.
- • On October 21, 2016, Merck&Co announced that the FDA has approved Zinplava™ (bezlotoxumab) Injection 25 mg/mL. The company anticipates making Zinplava™ available in first quarter 2017. The drug is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence. Zinplava™ is not indicated for the treatment of CDI. It should only be used in conjunction with antibacterial drug treatment of CDI.
- Heart failure was reported more commonly in the two Phase 3 clinical trials in Zinplava™-treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of Zinplava™-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in Zinplava™-treated patients [19.5% (23/118)] than in placebo-treated patients [12.5% (13/104)] during the 12-week study period. The causes of death varied, and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, Zinplava™ (bezlotoxumab) should be reserved for use when the benefit outweighs the risk.
- The most common adverse reactions occurring within 4 weeks of infusion with a frequency greater than placebo and reported in ?4% of patients treated with Zinplava™ and Standard of Care (SoC) antibacterial drug therapy vs placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%).
- Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of Zinplava™-treated patients and 33% of placebo-treated patients. Heart failure was reported as a serious adverse reaction in 2.3% of Zinplava™-treated patients and 1.0% of placebo-treated patients.
- In Zinplava™-treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after, the infusion. Infusion specific adverse reactions reported in ?0.5% of patients receiving Zinplava™ and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% experienced mild adverse reactions, and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset.
- As with all therapeutic proteins, there is a potential for immunogenicity following administration of Zinplava™. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in two Phase 3 studies with the incidence of antibodies in other studies or to other products may be misleading. Following treatment with Zinplava™ in these two studies, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.
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: 2016-10-21
UE authorization: 2017-01-18
Favourable opinion UE: 2016-11-22
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: