A global core outcome measurement set for snakebite clinical trials

Walker, Sarah; Abouyannis, Michael; Aggarwal, Dinesh; Alcoba, Gabriel; Alphan, Hassan J; Cammack, Nick; Casewell, Nicholas R.; Chippaux, Jean‐Philippe; Coldiron, Matthew E; Esmail, Hanif; Gutiérrez, José Marı́a; Habib, Abdulrazaq G.; Hamaluba, Mainga; Harrison, Robert A.; Isbister, Geoffrey K.; Lalloo, David G.; Martins, Diogo; Mumba, Noni; Mwalukore, Salim; Mwangudzah, Hope; Ngama, Mwanajuma; Ribeiro, Isabela; Walker, A. Sarah; Watson, James A; Williams, David J.; Yeri, Betty K; Bammigatti, Chanaveerappa; Carter, Rebecca W; Gerardo, Charles J.; Silva, H Janaka de; Lamb, Thomas; Lewin, Matthew R.; Monteiro, Wuelton Marcelo; Stienstra, Ymkje

doi:10.1016/s2214-109x(22)00479-x

Cited by 15 publications

(6 citation statements)

References 20 publications

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“…As identified in this study and in the literature [ 10 , 11 ], not only is clinical trial data heterogenous but there is also variability in the results and outcomes assessed, meaning the availability of clinical data does not in itself necessarily translate to safe and effective products. Recently, a global core outcome measurement set for snakebite clinical trials was published, an important first step towards standardisation and improving clinical trial feasibility [ 6 ]. However, while traditional Phase III studies remain the gold-standard, innovative approaches that could shorten duration and reduce costs of late-stage R&D may be considered in certain strictly defined circumstances such as areas of high incidence of snakebites or seasons involving snakes possessing venoms known to be highly potent and with no available products that are proven effective.…”

Section: Discussionmentioning

confidence: 99%

“…This includes the official inclusion of SBE in the World Health Organization (WHO) Neglected Tropical Disease (NTD) portfolio in 2017, a resolution on SBE adopted by the World Health Assembly in 2018, and the launch of the WHO 2019–2030 roadmap to prevent and control SBE in 2019 [ 2 , 3 ]. Looking to R&D, the community has seen progress in the development of the WHO Target Product Profile for sub-Saharan African antivenoms [ 4 ], a WHO risk-benefit assessment program for antivenoms [ 5 ], and a set of global core outcome measurements for clinical trials on SBE [ 6 ]. As work in this space progresses, there is a continued and growing need to provide the sector with data and information to guide funding decisions and research agendas.…”

Section: Introductionmentioning

confidence: 99%

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Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Borri,

Gutiérrez,

Knudsen

et al. 2024

PLoS Negl Trop Dis

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Background Progress in snakebite envenoming (SBE) therapeutics has suffered from a critical lack of data on the research and development (R&D) landscape. A database characterising this information would be a powerful tool for coordinating and accelerating SBE R&D. To address this need, we aimed to identify and categorise all active investigational candidates in development for SBE and all available or marketed products. Methodology/Principal findings In this landscape study, publicly available data and literature were reviewed to canvas the state of the SBE therapeutics market and research pipeline by identifying, characterising, and validating all investigational drug and biologic candidates with direct action on snake venom toxins, and all products available or marketed from 2015 to 2022. We identified 127 marketed products and 196 candidates in the pipeline, describing a very homogenous market of similar but geographically bespoke products and a diverse but immature pipeline, as most investigational candidates are at an early stage of development, with only eight candidates in clinical development. Conclusions/Significance Further investment and research is needed to address the shortfalls in products already on the market and to accelerate R&D for new therapeutics. This should be accompanied by efforts to converge on shared priorities and reshape the current SBE R&D ecosystem to ensure translation of innovation and access.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Borri,

Gutiérrez,

Knudsen

et al. 2024

PLoS Negl Trop Dis

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“…Finally, the importance of monitoring infection in snake-bitten patients is of note. 96 Financial support: The current article processing charges (publication fees) were funded by the Research Unit, Universidad Continental, Huancayo, Peru (granted to D. K. Bonilla-Aldana).…”

Section: Discussionmentioning

confidence: 99%

Snakebite-Associated Infections: A Systematic Review and Meta-Analysis

Bonilla-Aldana,

Ulloque-Badaracco

et al. 2024

The American Journal of Tropical Medicine and Hygiene

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ABSTRACT. Snakebites still constitute a significant public health problem in developing countries and are considered a neglected tropical condition by the WHO. Snake accidents are associated with substantial morbidity and mortality and may produce secondary complications, such as severe infections. The objective of this systematic review was to determine the prevalence of snakebite infections and characterize the bacteria isolated from these infections. A systematic literature review in five databases was carried out to assess the prevalence of snakebite infection. A meta-analysis was performed using a random-effects model to calculate the pooled prevalence and 95% CIs. Cochran’s Q test and the I2 statistic were used to assess between-study heterogeneity. The pooled prevalence of infection due to snakebite was 27.0% (95% CI: 22.0–32.0%), with high heterogeneity among studies (I2 = 99.7%). The prevalence was higher in Asia (32%) than in the Americas (21%). Snakebite infections required surgical interventions in 68% (95% CI: 37.0–98.0%). The leading group of pathogens identified corresponded to Gram-negative bacteria (63%), particularly Morganella morganii (32%), but also, Gram-positive cocci (40%), especially Enterococcus spp. (23%) and Staphylococcus aureus (15%). However, multiple other pathogens, including anaerobes, were found. A high prevalence of snakebite-associated infection has been described, primarily due to M. morganii, with the corresponding implications for empirical therapy. Rational use of antimicrobials is recommended, and this should guide initial empirical treatment. Moreover, isolation and identification of the possible bacteria present in snakebite wounds is recommended in all cases to confirm or rule out associated infection.

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“…Only clinical examination by veterinarians was used to assess if the weakness was attributed by us to neurotoxicity, but unmeasured hypotension could have contributed to weakness [ 22 , 24 , 29 ]. In both preclinical and clinical studies, there is a need to better discriminate between neurotoxicity and cardiovascular instability [ 15 , 61 , 62 ]. We did not specifically examine mechanisms behind the reversal of weakness in this study, though this has recently been studied by Oliveira and colleagues in a mouse model [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Oral and IV Varespladib Rescue Experiments in Juvenile Pigs with Weakness Induced by Australian and Papuan Oxyuranus scutellatus Venoms

Gilliam,

Samuel

et al. 2023

Toxins

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Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan (Oxyuranus scutellatus) subspecies in juvenile pigs (Sus domesticus). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg, n = 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg, n = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from Oxyuranus envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data.

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A global core outcome measurement set for snakebite clinical trials

Cited by 15 publications

References 20 publications

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Snakebite-Associated Infections: A Systematic Review and Meta-Analysis

Oral and IV Varespladib Rescue Experiments in Juvenile Pigs with Weakness Induced by Australian and Papuan Oxyuranus scutellatus Venoms

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