A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG)

Abstract

Background Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an antirabies monoclonal antibody cocktail. Methods This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with WHO category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, Human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the two arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥ 0.5 IU/mL on day 14. Results A total of 308 patients were equally randomized into the two arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and, 94.37% in the HRIG arm. The Geometric Mean of RFFIT titres in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. Conclusions This study confirmed that TwinrabTM is non-inferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with one WHO approved vaccine regimen (Essen). Trials Registration CTRI/2017/07/009038

Isolation and Characterization of Cross-Reactive Human Monoclonal Antibodies That Potently Neutralize Australian Bat Lyssavirus Variants and Other Phylogroup 1 Lyssaviruses

“…Similar to EBOV, several mAb cocktails have been developed for use against RABV infections [28,[42][43][44][45][46][47]. In phase 2/3 clinical trials, PEP regimens containing anti-rabies mAb cocktail TwinrabTM (docaravimab and miromavimab) [48] or mAb SII RMAb (Rabishield) [49] demonstrated noninferiority to HRIG in the window of protection and rabies virus neutralizing activity respectively. However, since mAb cocktail therapy is still a developing field, it is important to consider potential escape mutants that result from cocktail treatments [50,51].…”

A broad-spectrum and highly potent human monoclonal antibody cocktail for rabies prophylaxis

“…Since up to 99% of the cases of rabies infection in human are dog-mediated, one of the main strategies to develop anti-rabies mAbs firstly focused on neutralizing activity against canine rabies viruses. Therefore, 28 selected mAbs were tested with three representative canine rabies viruses (i.e., Gabon dog, India dog and China dog) in Asia and Africa [ 10 , 21 ]. Besides canine isolates, VNA activity to other wildlife derived rabies viruses were also tested.…”

“…Considering costs and supply limitations of HRIG and RIG, new WHO recommendations support more prudent use of RIG and encourage development of mAbs. In an updated position statement, WHO recommends that a registry be maintained to monitor the clinical use of mAbs and, as a research priority, supports development of biologics containing two or more mAbs with non-overlapping epitopes, to increase the efficacy and breadth of global rabies virus neutralization [ 21 ]. Considering these WHO recommendations, objective of this study was to develop mAbs that satisfy the following criteria: high virus neutralizing antibody (VNA) titers; an ability in vitro to cross react against diverse street viruses of public health relevance over representative continents (Africa, Asia, Europe, the Americas, etc.…”

Safety, Pharmacokinetics, and Neutralizing Activity of SYN023, a Mixture of Two Novel Antirabies Monoclonal Antibodies Intended for Use in Postrabies Exposure Prophylaxis

“…Rabishield consists of a single mAb, thus does not address the potential for development of viral escape mutants, and is unable to neutralize a rare rabies variant identified in a Peruvian bat 13 . Rabimabs (Twinrab), a mixture of 2 murine mAbs, has been licensed for use in India based on phase 3 data with concomitant rabies vaccination showing noninferiority to HRIG in terms of the proportion of subjects with RVNA levels ≥0.5 IU/mL at 14 days after treatment administration 14 . Notably, At 7 days after treatment administration, only 24% and 33% of subjects in the Rabimabs and HRIG treatment groups respectively had RVNA levels ≥0.5 IU/mL.…”