Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline?

Abstract

Introduction Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers [1]. Tens of thousands of people die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone [2] and up to 32,000 in sub-Saharan Africa [3]. Yet there are few sources of effective, safe, and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved [4]. 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 [5,6]. 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 [5–7] 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% [8]. 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 [9]. 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. Search Strategy We searched clinical trial registries (National Institutes of Health clinicaltrials.gov and WHO International Clinical Trial Registry Platform) and a publication database (EMBASE) to identify ongoing 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 Medical Subject Heading (MeSH) terms “clinical trial” AND “snake bites” AND “polyclonal antiserum OR snake venom antiserum OR venom antiserum.” All terms were explored, and results were 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. Search Results The registry searches yielded 29 records, four of which were observational studies. Among the interventional studies, 12 investigated antivenom as an intervention (eight were retrieved out of 176,201 records in clinicaltrials.gov and 12 out of 254,285 in ICTRP). Table 1 summarises the characteristics of the 12 trials. Four trials were sponsored by pharmaceutical companies and the remainder, by an individual researcher or academic institution. Four trials were open for recruitment and five were completed or terminated. A total of 11 different antivenoms were being investigated, most in only one trial. 10.1371/journal.pntd.0003896.t001 Table 1 List of clinical trials investigating snake antivenom published in clinical trials registries. Trial ID number Title Sponsor Type of funding Location Year of trial registration Recruitment status Results published NCT00303303 The Efficacy of Crotaline Fab Antivenom for Copperhead Snake Envenomations Carolinas Healthcare System Government United States 2006 Terminated No NCT00636116 Phase 3 Multicenter Comparative Study to Confirm Safety and Effectiveness of the F(ab)2 Antivenom Anavip Instituto Bioclon S.A. de C.V. Industry US 2008 Completed No NCT00639951 Study to Evaluate the Efficacy of Two Treatment Schemes With Antivipmyn for the Treatment of Snake Bite Envenomation Instituto Bioclon S.A. de C.V. Industry Mexico 2008 Recruiting NA NCT00811239 A Controlled Clinical Trial on The Use of a Specific Antivenom Against Envenoming by Bungarus Multicinctus Hanoi Medical University Government Vietnam 2008 Completed Yes [21] NCT00868309 A Comparison of Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom (Anavip) and Crotalidae Polyvalent Immune Fab, Ovine Antivenom (CroFab) in the Treatment of Pit Viper Envenomation Instituto Bioclon S.A. de C.V. Industry US 2008 Completed Yes [22] ISRCTN01257358 Clinical trial of two new anti-snake venoms for the treatment of patients bitten by poisonous snakes in Nigeria Nigeria MoH Unknown Nigeria 2009 Completed Yes [23] SLCTR/2010/006 Low dose versus high dose of Indian polyvalent snake antivenom in reversing neurotoxic paralysis in common krait (Bungarus caeruleus) bites: an open labelled randomised controlled clinical trial in Sri Lanka Individual researcher None Sri Lanka 2010 Not recruiting No ACTRN12611000588998 A randomised controlled trial of antivenom and corticosteroids for red-bellied black snake envenoming Individual researcher Government Australia 2011 Not recruiting No NCT01284855 Comparison of Two Dose Regimens of Snake Antivenom for the Treatment of Snake Bites Envenoming in Nepal University of Geneva Government Nepal 2011 Not recruiting No NCT01337245 Emergency Treatment of Coral Snake Envenomation With Antivenom University of Arizona Government US 2011 Recruiting NA ACTRN12612001062819 A randomized controlled trial (RCT) of a new monovalent antivenom (ICP Papuan taipan antivenom) for the treatment of Papuan taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea University of Melbourne Government Papua New Guinea 2012 Recruiting NA NCT01864200 A Randomized, Double-Blind, Placebo-Controlled Study Comparing CroFab Versus Placebo With Rescue Treatment for Copperhead Snake Envenomation (Copperhead RCT) BTG International Inc. Industry US 2013 Recruiting NA The publication database search yielded 97 results (Fig 1). After cleaning, 82 records were retained, of which 30 had a design consistent with clinical trials. The remainder included 26 reviews or commentaries, 18 cohorts or cases series, four retrospective analyses of medical records, two case studies, one diagnostic study, and one cross-sectional survey. A search of references yielded an additional 11 reports of clinical trials. Of the 41 clinical trials thus identified, 32 investigated antivenom as an intervention. The locations of the 32 studies were Latin America (Brazil n = 3, Columbia n = 5, Ecuador n = 1); Asia (India n = 4, Thailand n = 5, Sri Lanka n = 3, Myanmar n = 1, Malaysia n = 1); Africa (Nigeria n = 5), and US (n = 4). 27 were sponsored by a public organization (e.g., university or public hospital). Most trials (n = 20) were conducted before 2000, the oldest dated from 1960 [10]. A total of 30 antivenoms were investigated; half were investigated in only one trial. 10.1371/journal.pntd.0003896.g001 Fig 1 Flow diagram of the selection process used in this study. The search was conducted on 15 September 2014. Merging the search results gave a total of 41 clinical trials investigating the efficacy or safety of snake antivenoms, of which four were active. A total of 36 different antivenoms were investigated (see Table 2). Based on the trial design (Phase I to IV), ten products were considered still “under development,” although development appears to have stalled for most of them. Our search strategy appears robust; a report conducted in 2010 identified a total of 43 randomized controlled trials on snakebite envenoming, 28 of which investigated antivenom properties [11]. We retrieved all except two of these trials [12,51]; the discrepancy could be due to differences in the criteria used to define clinical trials. 10.1371/journal.pntd.0003896.t002 Table 2 List of antivenoms investigated in clinical trials published in peer-reviewed journals or on public registries. Product name Other name/product specifications Manufacturer Development stage 1 Target region Publications Clinical trials registry number CroFab Polyvalent ovine antivenom (Fab) against Crotalid Protherics Phase III–IV North America [22,24,25] NCT00303303 NCT00636116 NCT00868309 NCT01864200 Anavip Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) Instituto Bioclon S.A. Terminated after Phase III North America [22] NCT00868309 NCT00636116 Antivypmin Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) Instituto Bioclon S.A. Phase III North America None NCT00639951 NA Polyvalent equine antivenom (Fab2) against North American Coral snakes (Micrurus) University of Arizona Phase III North America None NCT01337245 Tiger snake antivenom Monovalent equine (Fab) against Notechis scutatus CSL Phase III–IV Australia None ACTRN12611000588998 Taipan antivenom Monovalent equine (Fab) against Oxyuranus scutellatus CSL Phase I–II Australia None ACTRN12612001062819 Antibotropico IVB Instituto Vital Brazil Phase II Latin America [26] None Antibotropico Butantan Polyvalent equine antivenom against Bothrops species Instituo Butantan Phase II–III Latin America [26–29] None Antibotropico FUNED Fundação Ezequiel Dias Terminated Latin America [26] None Antibotropico-laquetico Butantan Bothrops-Lachesis polyvalent equine antivenom Instituo Butantan Phase II Latin America [30] None Antiofiodico botropico polivalente Polyvalent equine antivenom (IgG) against Bothrops asper, Bothrops atrox, and Bothrops xanthogrammus Instituto Nacional de Higiene y Medicina Tropical "Leopoldo Izquieta Pérez" Phase II–III Latin America [28] None Monovalent B. atrox equine antivenom Instituto Clodomiro Picado Terminated Latin America [31,32] None Monovalent B. atrox equine antivenom Instituto Nacional de Salud Terminated Latin America [29] None B. atrox–Lachesis antivenom Polyvalent equine antivenom (IgG) against B. atrox and Lachesis muta muta Fundação Ezequiel Dias Terminated Latin America [30] None Polyvalent Antivenom Polyvalent equine antivenom (IgG) against B. asper, Crotalus durissus, and L. muta Instituto Nacional de Salud ? Latin America [28] None Polyvalent antivenom ICP Polyvalent equine antivenom (IgG or Fab2) against B. asper, Crotalus simus, and Lachesis stenophrys Instituto Clodomiro Picado (University of Costa Rica) Phase II Latin America [31–34] None EchiTab Monovalent ovine antivenom (Fab) against Echis oscellatus Therapeutic Antibodies/Micropharm ? Sub-Saharan Africa [35] None EchiTab Plus Polyvalent equine antivenom against Bitis arietans, E. oscellatus, and Naja nigricollis Instituto Clodomiro Picado (University of Costa Rica) Phase I–II Sub-Saharan Africa [23,36] ISRCTN01257358 EchiTab G Monovalent antivenom (IgG) against E. oscellatus Micropharm Phase I–II Sub-Saharan Africa [23,36] ISRCTN01257358 EgyVac antivenom Equine polivalent antivenom against B. arietans, E. oscellatus, and N. nigricollis Vacsera Ltd Terminated after Phase I Sub-Saharan Africa [36] None Ipser Africa Antivenom Polyvalent equine (Fab2) antivenom against B. arietans, Bitis gabonica, Echis leucogaster, N. nigricollis, Naja haje, Naja melanoleuca, Dendroaspis viridis, Dendroaspis jamesoni, and Dendroaspis augisticeps Institut Pasteur ? Sub-Saharan Africa [35] None Monospecific antivenom against E. oscellatus Institut Pasteur ? Sub-Saharan Africa [37,38] None SAIMR Echis antivenom Monovalent equine antivenom (IgG or Fab2) against Echis carinatus / ocellatus South African Vaccines Producer ? Sub-Saharan Africa [38] None North and West African polyvalent antivenom (Echis, Bitis, Naja) Behningwerke ? Sub-Saharan Africa [37,38] None Malayan pit viper antivenom Monovalent equine antivenom against Calloselasma rhodostoma Queen Saovabha Memorial Institute Phase I–II South East Asia [11,39–41] None Malayan pit viper antivenom Monovalent caprine antivenom against C. rhodostoma Twyford Pharmaceutical Phase I–II South East Asia [39–41] None Malayan pit viper antivenom Monovalent equine antivenom against C. rhodostoma Thai Government Pharmaceutical Organisation Phase I–II South East Asia [39–41] None Monocellate cobra antivenom Monovalent equine antivenom against aja. kaouthia Queen Saovabha Memorial Institute ? South East Asia [42] None Green pit viper antivenin (QSMI) Polyvalent equine antivenom (Fab2) against green pit vipers Queen Saovabha Memorial Institute Phase I–II South East Asia [41,43] None B. multicinctus and B. candidus antivenom Polyvalent equine antivenom (Fab2) against Bungarus multicinctus and Bungarus candidus Vietnam Poison Control Center, Hanoi Medical University Phase I–II South East Asia [21] NCT00811239 Monospecific antivenom against D. russelii Myanmar Pharmaceutical Factory ? South East Asia [44] None ProlongaTab Monovalent ovine antivenom (Fab) against Daboia russelii Therapeutic Antibodies Inc Terminated South Asia [45,46] None SII Polyvalent ASV IP Polyvalent equine antivenom (Fab2) against Naja naja, E. carinatus, D. russelii and Bungarus caeruleus India Serum Institute ? South Asia [47–49] None Snake antivenin IP Polyvalent equine antivenom (Fab2) against N. naja, E. carinatus, D. russelii and B. caeruleus Haffkine Biopharmaceutical Corporation Ltd Phase II South Asia [45,46,50,51] None Snake venom anti-serum Polyvalent equine F(ab)2 against B. caeruleus, N. naja, D. russelii and E. carinatus VINS bioproducts Phase II South Asia None SLCTR/2010/006 NCT01284855 Snake venom antiserum Polyvalent equine F(ab)2 against B. caeruleus, N. naja, D. russelii and E. carinatus Bharat Serum and Vaccines Ltd Phase II South Asia None SLCTR/2010/006 1 Not all publications mentioned the trial phase, and development status was established based on trial design, primary objectives, and number of subjects. This classification, though, bears some limitations, especially with regards to snake antivenoms development, in which Phase I with healthy volunteers are generally not conducted. Urgent Need for More Research Our results highlight the paucity of adequately conducted clinical trials and corroborate previous findings on the scarcity of safe, effective, and quality-assured snake antivenoms [4]. Comparison with dengue fever, which has a similar burden (11.97 Disability-Adjusted Life Years (DALYs) per 100,000 [4.99–20.46] versus venomous animal contacts 39.62 DALYs per 100,000 [22.46–69.74]) [13], is particularly revealing. In 2011, of 79 identified trials on dengue fever, 27 were recruiting patients, with six new products in development [14]. By contrast, the research pipeline for snakebite remains desperately dry, despite numerous calls for action [15–17]. Antivenoms in Sub-Saharan Africa To determine how many antivenom products are currently available in sub-Saharan Africa, we searched WHO “Venomous snakes and antivenoms database” and held bilateral discussions with snakebite experts and pharmaceutical companies. We found that 12 antivenom products were commercially available in sub-Saharan countries as of September 2014 (Table 3), only three of which had been tested in at least one clinical trial, and many of which may lack efficacy [18]. 10.1371/journal.pntd.0003896.t003 Table 3 Available snake antivenom products in sub-Saharan Africa, as of September 2014. Product Company Country of production Antivipmyn-Africa Instituto Bioclon/Silanes Mexico ASNA-C Bharat Serums and Vaccines India ASNA-D Bharat Serums and Vaccines India EchiTabG MicroPharm United Kingdom EchiTabPlus Instituto Clodomiro Picado Costa Rica Fav-Afrique Sanofi Pasteur France Inoserp PanAfrica Inosan Spain SAIMR Boomslang antivenom South African Vaccine Producers South Africa SAIMR Echis antivenom South African Vaccine Producers South Africa SAIMR Polyvalent Snake antivenom South African Vaccine Producers South Africa Snake Venom Antiserum (Pan-African) VINS Bioproducts India Snake venom antiserum Echis ocellatus VINS Bioproducts India Case study: The MSF experience in Central African Republic The experience of MSF in CAR suggests that there are indeed significant variations in the efficacy of antivenoms against African snake venoms. MSF has been using Fav-Afrique to manage patients presenting with features of snakebite envenoming in Paoua, CAR, since 2008. In the first half of 2013, Fav-Afrique was temporarily unavailable, and an alternative product was identified, directed against the venoms of 11 species of African snakes, including E. ocellatus. This antivenom was used for six months, with the same criteria for therapy as for Fav-Afrique. Although a methodologically sound study could not be conducted, a retrospective analysis of MSF medical records showed that the case fatality rate increased from 0.47% (three of 644 treated patients) with Fav-Afrique [9] to 10% (five of 50 treated patients) with the alternative antivenom. While more than 80% of patients were successfully treated with only one dose of Fav-Afrique, more than 60% treated with the alternative antivenom (31 of 50) required more than one dose to control envenoming. Worryingly, the first dose of the alternative antivenom was not able to alleviate spontaneous bleeding at admission in ten of 13 patients, and the administration of additional doses was required. These field data need cautious interpretation. However, they echo findings on the availability of ineffective and potentially harmful antivenoms in sub-Saharan Africa and support the conclusion that post-marketing surveillance is crucial [18]. They also call for a more robust and systematic evaluation of marketed products by regulatory authorities in the affected countries. 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 [19]; 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 [4]. A major donor needs to step in, provide support, and, importantly, encourage existing global health initiatives, such as Drugs for Neglected Diseases initiative (DNDi), the Global Alliance for Vaccine and Immunization (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.