TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults)

Abstract

Background: Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning. In vivo experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication. Methods: This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination. Conclusions: This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite. Pan African Clinical Trials Registry: PACTR202103718625048 (3/3/2021)

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

“…in contrast with intravenously-injected antivenom), considerable research effort should focus around this space to pursue the translation of safe, affordable, community-level interventions to reduce existing treatment delays in rural tropical communities, thus improving patient outcomes. To that end it is worth noting that DMPS is already undergoing Phase I clinical trials to determine both its safety and a PK-informed oral dosing regimen for snakebite indication 73 , while methyl varespladib has recently entered Phase II trials to assess its safety, tolerability, and efficacy in snakebite victims (https://clinicaltrials.gov/ct2/show/NCT04996264). These studies emphasise the growing confidence the research community has in specific small molecule drugs as novel oral treatments for snakebite envenoming, though the data presented here highlight that additional research to develop these (among other) drugs into combination therapies is likely to yield treatments with superior pan-snake species effectiveness than any single drug alone.…”

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming

“…In conclusion, if successful, the BRAVO trial design may begin to help develop templates for future trials of novel treatments for SBE that allows for direct comparison between clinical trial results independent of intervention or SBE syndrome, some structures for which others have recently focused, and are, as well beginning clinical studies such as with unithiol [ 44 , 55 ]. This trial’s design and future iterations should allow for the clinical evaluation of oral varespladib and other candidate therapies with SoC in patients with SBE from diverse snake species found in India and the US.…”

Paediatric snakebite in Kilifi County, Kenya: A 19-year observational study

“…Despite local envenoming being the most frequent indication for administering antivenom in much of Africa, its effectiveness for this indication is unproven, particularly if it is given late, and clinical trials are urgently needed [19]. Novel oral small molecule therapeutics may hold promise, particularly if they can be administered in rural clinics and thus reduce the time to treatment [20][21][22].…”