Antivenoms for snakebite envenoming: what is in the research pipeline?
Authors: Emilie Alirol, Pauline Lechevalier, Federica Zamatto, François Chappuis, Gabriel Alcoba, and Julien Potet
Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers. Tens of thousands die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone and up to 32,000 in sub-Saharan Africa. Yet there are few sources of effective, safe and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved.
The Fav-Afrique antivenom, produced by Sanofi-Pasteur (France), is considered safe and effective and is one of the few antivenoms to be approved by a Stringent Regulatory Authority (French National Regulatory Authority), although limited formal evidence has been published. It is polyvalent, targeting most of the medically important snake species in sub-Saharan Africa. In particular, it is highly effective in treating envenoming by Echis ocellatus, the West African saw-scaled viper that causes great morbidity and mortality throughout the West and Central African savannah. The venom of E. ocellatus may induce systemic haemorrhage, coagulopathy and shock, as well as extensive local tissue damage. In the absence of treatment, the case fatality rate is 10-20%. Médecins Sans Frontières (MSF) uses Fav-Afrique in its projects in sub-Saharan Africa, notably in Paoua in Central African Republic (CAR), where E. ocellatus envenoming is frequent. Worryingly, MSF has been informed that the production of Fav-Afrique by Sanofi Aventis will be permanently discontinued. The last batch was released in January 2014, with an expiry date of June 2016. All the vials produced have already been sold by Sanofi-Pasteur.
Although several alternative antivenom products target a similar list of species as Fav-Afrique, there is currently no evidence of their safety and effectiveness. We aimed to review the evidence for the efficacy and safety of existing and in-development snake antivenoms, and to list the alternatives to Fav-Afrique in sub-Saharan Africa.
We searched clinical trial registries (NIH clinicaltrials.gov and WHO ICTRP) and a publication database (EMBASE) to identify on-going and completed clinical trials. The registries were searched by condition using the keywords “snakebite” OR “snake bite” OR “snake envenom*” OR “envenom*” OR “bite”. Publication database search strategy was based on the MeSH terms “clinical trial” AND “snake bites” AND “polyclonal antiserum OR snake venom antiserum OR venom antiserum”. All terms were explored and results limited to studies conducted in humans. No time limits were imposed. Searches were conducted in September 2014 and included all records from the launch of the databases. Only those studies with a design compatible with that of a clinical trial (prospective, comparative and interventional) and with the definition given by the CONSORT glossary were included. Prospective, single-arm cohorts were not considered as clinical trials.
The way forward
Sanofi-Pasteur urgently needs to disclose its plan to mitigate the negative impact of the decision to stop producing Fav-Afrique. Over the longer term, the multi-component strategy described by the Global Snakebite Initiative must be fully financed: both innovations for better products and interventions and access to quality care need to be enhanced. The vast majority of the trials that we identified were sponsored by public organizations. The snakebite antivenom market so far appears poorly lucrative, unpredictable and fragmented, hindering investment from pharmaceutical companies. A major donor needs to step in, provide support, and importantly, encourage existing global health initiatives, such as DNDi, the GAVI-Alliance or the European and Developing Countries Clinical Trials Partnership (EDCTP), to extend their remits to life-saving treatments for snakebites. Finally, WHO should fully include snakebite envenoming in its list and programme of NTDs, support national regulatory authorities in performing adequate evaluations of existing antivenom products, and establish partnerships for access to existing and future antivenoms. Snakebite envenoming has been a most neglected disease for far too long.