Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite

Summary

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.

Timeline

Start

2021-08-15

Primary completion

2023-06-07

Completion

2023-06-08

Publications

• Background Varespladib. Am J Cardiovasc Drugs. 2011;11(2):137-43. doi: 10.2165/11533650-000000000-00000.
• Background Alangode A, Rajan K, Nair BG. Snake antivenom: Challenges and alternate approaches. Biochem Pharmacol. 2020 Nov;181:114135. doi: 10.1016/j.bcp.2020.114135. Epub 2020 Jul 3.
• Background Albulescu LO, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, Dawson CA, Softley R, Bartlett KE, Harrison RA, Kool J, Casewell NR. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun. 2020 Dec 15;11(1):6094. doi: 10.1038/s41467-020-19981-6.
• Background Anderson BO, Moore EE, Banerjee A. Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. J Surg Res. 1994 Feb;56(2):199-205. doi: 10.1006/jsre.1994.1032.
• Background Arce-Bejarano R, Lomonte B, Gutierrez JM. Intravascular hemolysis induced by the venom of the Eastern coral snake, Micrurus fulvius, in a mouse model: identification of directly hemolytic phospholipases A2. Toxicon. 2014 Nov;90:26-35. doi: 10.1016/j.toxicon.2014.07.010. Epub 2014 Aug 1.
• Background Bittenbinder MA, Zdenek CN, Op den Brouw B, Youngman NJ, Dobson JS, Naude A, Vonk FJ, Fry BG. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins (Basel). 2018 Dec 4;10(12):516. doi: 10.3390/toxins10120516.
• Background Bryan-Quiros W, Fernandez J, Gutierrez JM, Lewin MR, Lomonte B. Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2. Toxicon. 2019 Jan;157:1-7. doi: 10.1016/j.toxicon.2018.11.292. Epub 2018 Nov 14.
• Background Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite. J Trop Med. 2018 Jul 30;2018:4320175. doi: 10.1155/2018/4320175. eCollection 2018.
• Background Chippaux JP. Estimate of the burden of snakebites in sub-Saharan Africa: a meta-analytic approach. Toxicon. 2011 Mar 15;57(4):586-99. doi: 10.1016/j.toxicon.2010.12.022. Epub 2011 Jan 9.
• Background Fernandez ML, Quartino PY, Arce-Bejarano R, Fernandez J, Camacho LF, Gutierrez JM, Kuemmel D, Fidelio G, Lomonte B. Intravascular hemolysis induced by phospholipases A2 from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms. Toxicol Lett. 2018 Apr;286:39-47. doi: 10.1016/j.toxlet.2017.11.037. Epub 2017 Nov 29.
• Background Fontana Oliveira IC, Gutierrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) inhibits neuromuscular blockade induced by Oxyuranus scutellatus venom in a nerve-muscle preparation. Toxicon. 2020 Nov;187:101-104. doi: 10.1016/j.toxicon.2020.08.023. Epub 2020 Sep 2.
• Background Gerardo CJ, Vissoci JRN, Evans CS, Simel DL, Lavonas EJ. Does This Patient Have a Severe Snake Envenomation?: The Rational Clinical Examination Systematic Review. JAMA Surg. 2019 Apr 1;154(4):346-354. doi: 10.1001/jamasurg.2018.5069.
• Background Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017 Sep 14;3:17063. doi: 10.1038/nrdp.2017.63.
• Background Gutierrez JM, Lewin MR, Williams DJ, Lomonte B. Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. Toxins (Basel). 2020 Feb 20;12(2):131. doi: 10.3390/toxins12020131.
• Background Halilu S, Iliyasu G, Hamza M, Chippaux JP, Kuznik A, Habib AG. Snakebite burden in Sub-Saharan Africa: estimates from 41 countries. Toxicon. 2019 Mar 1;159:1-4. doi: 10.1016/j.toxicon.2018.12.002. Epub 2018 Dec 27.
• Background Kazandjian TD, Petras D, Robinson SD, van Thiel J, Greene HW, Arbuckle K, Barlow A, Carter DA, Wouters RM, Whiteley G, Wagstaff SC, Arias AS, Albulescu LO, Plettenberg Laing A, Hall C, Heap A, Penrhyn-Lowe S, McCabe CV, Ainsworth S, da Silva RR, Dorrestein PC, Richardson MK, Gutierrez JM, Calvete JJ, Harrison RA, Vetter I, Undheim EAB, Wuster W, Casewell NR. Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science. 2021 Jan 22;371(6527):386-390. doi: 10.1126/science.abb9303.
• Background Le Geyt J, Pach S, Gutierrez JM, Habib AG, Maduwage KP, Hardcastle TC, Hernandez Diaz R, Avila-Aguero ML, Ya KT, Williams D, Halbert J. Paediatric snakebite envenoming: recognition and management of cases. Arch Dis Child. 2021 Jan;106(1):14-19. doi: 10.1136/archdischild-2020-319428. Epub 2020 Oct 28.
• Background Lewin M, Samuel S, Merkel J, Bickler P. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins (Basel). 2016 Aug 25;8(9):248. doi: 10.3390/toxins8090248.
• Background Lewin MR, Gilliam LL, Gilliam J, Samuel SP, Bulfone TC, Bickler PE, Gutierrez JM. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins (Basel). 2018 Nov 17;10(11):479. doi: 10.3390/toxins10110479.
• Background Lewin MR, Gutierrez JM, Samuel SP, Herrera M, Bryan-Quiros W, Lomonte B, Bickler PE, Bulfone TC, Williams DJ. Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins (Basel). 2018 Sep 20;10(10):380. doi: 10.3390/toxins10100380.
• Background Longbottom J, Shearer FM, Devine M, Alcoba G, Chappuis F, Weiss DJ, Ray SE, Ray N, Warrell DA, Ruiz de Castaneda R, Williams DJ, Hay SI, Pigott DM. Vulnerability to snakebite envenoming: a global mapping of hotspots. Lancet. 2018 Aug 25;392(10148):673-684. doi: 10.1016/S0140-6736(18)31224-8. Epub 2018 Jul 17.
• Background Pach S, Le Geyt J, Gutierrez JM, Williams D, Maduwage KP, Habib AG, Gustin R, Avila-Aguero ML, Ya KT, Halbert J. Paediatric snakebite envenoming: the world's most neglected 'Neglected Tropical Disease'? Arch Dis Child. 2020 Dec;105(12):1135-1139. doi: 10.1136/archdischild-2020-319417. Epub 2020 Sep 30.
• Background PARRISH HM. SNAKE VENENATION IN ILLINOIS. IMJ Ill Med J. 1965 Jun;127:671-7. No abstract available.
• Background Prasarnpun S, Walsh J, Awad SS, Harris JB. Envenoming bites by kraits: the biological basis of treatment-resistant neuromuscular paralysis. Brain. 2005 Dec;128(Pt 12):2987-96. doi: 10.1093/brain/awh642. Epub 2005 Sep 29.
• Background Ruha AM, Kleinschmidt KC, Greene S, Spyres MB, Brent J, Wax P, Padilla-Jones A, Campleman S; ToxIC Snakebite Study Group. The Epidemiology, Clinical Course, and Management of Snakebites in the North American Snakebite Registry. J Med Toxicol. 2017 Dec;13(4):309-320. doi: 10.1007/s13181-017-0633-5. Epub 2017 Oct 3.
• Background Salvador GHM, Gomes AAS, Bryan-Quiros W, Fernandez J, Lewin MR, Gutierrez JM, Lomonte B, Fontes MRM. Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920). Sci Rep. 2019 Nov 20;9(1):17203. doi: 10.1038/s41598-019-53755-5.
• Background Sankar J, Nabeel R, Sankar MJ, Priyambada L, Mahadevan S. Factors affecting outcome in children with snake envenomation: a prospective observational study. Arch Dis Child. 2013 Aug;98(8):596-601. doi: 10.1136/archdischild-2012-303025. Epub 2013 May 28.
• Background Schulte J, Domanski K, Smith EA, Menendez A, Kleinschmidt KC, Roth BA. Childhood Victims of Snakebites: 2000-2013. Pediatrics. 2016 Nov;138(5):e20160491. doi: 10.1542/peds.2016-0491.
• Background Seifert SA, Boyer LV, Benson BE, Rogers JJ. AAPCC database characterization of native U.S. venomous snake exposures, 2001-2005. Clin Toxicol (Phila). 2009 Apr;47(4):327-35. doi: 10.1080/15563650902870277.
• Background Snyder DW, Bach NJ, Dillard RD, Draheim SE, Carlson DG, Fox N, Roehm NW, Armstrong CT, Chang CH, Hartley LW, Johnson LM, Roman CR, Smith AC, Song M, Fleisch JH. Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. J Pharmacol Exp Ther. 1999 Mar;288(3):1117-24.
• Background Sorensen J, Kald B, Tagesson C, Lindahl M. Platelet-activating factor and phospholipase A2 in patients with septic shock and trauma. Intensive Care Med. 1994 Nov;20(8):555-61. doi: 10.1007/BF01705721.
• Background Tasoulis T, Isbister GK. A Review and Database of Snake Venom Proteomes. Toxins (Basel). 2017 Sep 18;9(9):290. doi: 10.3390/toxins9090290.
• Background Uhl W, Beger HG, Hoffmann G, Hanisch E, Schild A, Waydhas C, Entholzner E, Muller K, Kellermann W, Vogeser M, et al. A multicenter study of phospholipase A2 in patients in intensive care units. J Am Coll Surg. 1995 Mar;180(3):323-31.
• Background Vaiyapuri S, Vaiyapuri R, Ashokan R, Ramasamy K, Nattamaisundar K, Jeyaraj A, Chandran V, Gajjeraman P, Baksh MF, Gibbins JM, Hutchinson EG. Snakebite and its socio-economic impact on the rural population of Tamil Nadu, India. PLoS One. 2013 Nov 21;8(11):e80090. doi: 10.1371/journal.pone.0080090. eCollection 2013.
• Background Williams DJ, Faiz MA, Abela-Ridder B, Ainsworth S, Bulfone TC, Nickerson AD, Habib AG, Junghanss T, Fan HW, Turner M, Harrison RA, Warrell DA. Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007059. doi: 10.1371/journal.pntd.0007059. eCollection 2019 Feb. No abstract available.
• Background Xie C, Albulescu LO, Bittenbinder MA, Somsen GW, Vonk FJ, Casewell NR, Kool J. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines. 2020 Aug 20;8(9):297. doi: 10.3390/biomedicines8090297.
• Background Zinenko O, Tovstukha I, Korniyenko Y. PLA2 Inhibitor Varespladib as an Alternative to the Antivenom Treatment for Bites from Nikolsky's Viper Vipera berus nikolskii. Toxins (Basel). 2020 May 29;12(6):356. doi: 10.3390/toxins12060356.

Drugs

Indications