toxins
Communication
Delayed Oral LY333013 Rescues Mice from Highly
Neurotoxic, Lethal Doses of Papuan Taipan
(Oxyuranus scutellatus) Venom
Matthew R. Lewin 1,2,*, José María Gutiérrez 3,* , Stephen P. Samuel 2,4, María Herrera 3,
Wendy Bryan-Quirós 3, Bruno Lomonte 3 , Philip E. Bickler 5, Tommaso C. Bulfone 1,2
and David J. Williams 6
1 Ophirex, Inc., Corte Madera, CA 94925, USA; tommaso.bulfone@gmail.com
2 California Academy of Sciences, San Francisco, CA 94118, USA; paulshania@yahoo.co.uk
3 Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, an José 11501-2060,
Costa Rica; MARIA.HERRERA_V@ucr.ac.cr (M.H.); wenjbq@gmail.com (W.B.-Q.);
bruno.lomonte@ucr.ac.cr (B.L.)
4 Queen Elizabeth Hospital, Kings Lynn, Norfolk PE30 4ET, UK
5 Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, USA;
philip.bickler@ucsf.edu
6 Department of Pharmacology and Therapeutics, Australian Venom Research Unit, University of Melbourne,
Parkville, VIC 3010, Australia; david.williams@unimelb.edu.au
* Correspondence: mlewin@calacademy.org (M.R.L.); jose.gutierrez@ucr.ac.cr (J.M.G.)




Received: 5 September 2018; Accepted: 17 September 2018; Published: 20 September 2018 

Abstract: There is an unmet need for economical snakebite therapies with long shelf lives
that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory
phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe
snakebite envenoming in both field and hospital use. A murine model of lethal envenoming
by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral
administration, improves the chances of survival. Furthermore, LY333013 improves the performance
of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration
that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window
of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential
to reduce death and disability and should be considered for the initial and adjunct treatment of
snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these
endpoints requires further investigation and development efforts.
Keywords: snakebite; envenoming; neglected tropical disease; field antidote; inhibitor; taipan; PLA2;
phospholipase A2; neurotoxicity; antivenom
Key Contribution: The small molecule LY333013, given orally for initial treatment of a snakebite,
may allow for an initiation of treatment at the time of the bite and be a useful adjunct to antivenom.
1. Introduction
Snakebite envenoming is a threat to more than five billion people and at least 750 million who
live more than 1 h from a health care facility [1]. Additionally, snakebite envenoming also represents a
substantial risk to livestock [2]. In the modern era, snakebite envenoming kills 81,000–138,000 people
annually and leaves hundreds of thousands with amputations, disfiguring injuries, and both chronic
physical and psychological sequelae [3,4]. Nearly 130 years ago, Sir Joseph Fayrer wrote, “Until some
Toxins 2018, 10, 380; doi:10.3390/toxins10100380 www.mdpi.com/journal/toxins
Toxins 2018, 10, 380 2 of 7
such measures are generally and systematically resorted to, there will be no diminution in loss of
human life from snakebite” [5]. Only in the last two years has snakebite received recognition as a
Neglected Tropical Disease; Fayrer′s words are as relevant today as they were more than a century
ago [3,5].
Currently, the definitive treatment for snakebite envenoming requires the intravenous
administration of animal-derived antivenoms at a health care facility [3,6]. Use of intensive and
often catastrophically expensive resuscitative measures such as mechanical ventilation and operative
interventions have reduced the rates of in-hospital morbidity and mortality from snakebite. However,
more than 75% of deaths from snakebite envenoming occur before reaching hospital care [1,7].
Poverty and proximity to hospital care are risk factors associated with poor outcomes [1,3,8].
An effective, field-administered antidote to snakebites would address many of the limitations of
antivenom and reduce both the economic and technical barriers to initiating care for these life and
limb threatening emergencies [9–16].
Snake venom phospholipases (PLA2S) are almost universally present amongst the world’s most
lethal venomous snakes [17]. The blockade of these enzymes after an envenoming snakebite could
prevent rapid lethality from neurotoxicity, as well as potentially reduce other harmful morbidities, such
as myonecrosis, acute kidney injury, and venom-induced endogenous inflammatory responses [18–22].
LY315920 and its orally bioavailable prodrug, LY333013, have been found to have extremely
potent, broad-spectrum activity against snake venom PLA2S and have been proposed as a promising
initial treatment for envenoming snakebite [9]. This work was recently replicated and extended
when LY315920 preserved life and prevented haemorrhagic, myonecrotic, and neurological effects
in mice injected with krait, cobra, or viper venoms from medically important species in China [23].
LY315920 and LY333013 were previously abandoned following Phase II and Phase III of human clinical
trials for sepsis, rheumatoid arthritis, and cardiovascular disease, but could be repositioned at a low
development cost for the initial treatment of snakebite [24]. Along with known safety profiles, LY315920
and LY333013 pharmacodynamics and pharmacokinetics in short-term use is well-understood, but
unfortunately these potent sPLA2-blocking drugs were abandoned for lack of efficacy after more
than 25 clinical trials; they were never considered for use in the setting of snakebite [24]. As proof
of a concept experiment, we sought to examine how these drugs might perform both alone and
with antivenom in a scenario of lethal envenoming by Papuan taipan. Papuan taipan venom was
selected because its main toxicity relies on the action of a potent presynaptically-acting neurotoxic
heterotrimeric PLA2, taipoxin [18,25].
The key unknown in this experiment was whether LY333013 would be effective in preventing
neurotoxicity and lethality from Papuan taipan (Oxyuranus scutellatus) venom if given orally after
venom injection, both immediately after envenoming and at a time when specific antivenom is no
longer effective in preventing lethality. To begin answering this question, we tested the ability of
LY333013 (10 mg/kg) when administered orally. We administered LY333013 either immediately (within
five min) or in one h (60 min) following the subcutaneous administration of venom. We used an
empirically selected venom dose ultimately corresponding to 12LD50S, in order to model a severe
envenoming. Mice died within a range of three to five h, thus allowing for the administration of the
drug after envenoming. The LY333013 dose was chosen based on historical preclinical and human
clinical trial data at a dose deemed well within the known safety margin [24]. The effect of the drug,
when administered orally, was compared to a monospecific taipan antivenom, administered by the
intravenous route at a dose of 5 mL/kg in fewer than five min (“urgent” administration) or at 60 min
following administration of the venom (“delayed” administration). Additionally, to examine another
clinically plausible scenario, antivenom was administered one h after envenoming, immediately
followed by oral administration of LY333013, as it might be administered in the acute setting such
as entry to the hospital triage, but prior to antivenom administration. A detailed description of the
procedures is included in the Methods section.
Toxins 2018, 10, 380 3 of 7
Toxins 2018, 10, x FOR PEER REVIEW  3 of 7 
2.. Resulltts 
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honaef ther avfetenro vmeninojmec tiinojnec, taiollnm, aiclel msuircvei vsuedrvwivietdh owutitrheosuidt uraelsisdigunals soifgnes uorfo tnoexuicroittyox(Ficiigtuy r(eF1ig).uTreh u1)s., 
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sccliennicaarilo scinentahreioe vino ltuhteio envoflustnioanke obfi tsentarkeeabtmit e ntrtesa. tments. 
 
Figure 1. AA sisningglel eoroarla dl odsoes oef oLfYL3Y333031031 r3esrteosrteosr ethset hefefeecftf eocft aonftiavnetnivoemn oevmene vaeftnera aftne rotahnerowthiseer wfaitsael 
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tsapiepcaifnics panectiivfiecnaonmti v(5e nmoLm/k(g5)m adLm/kingi)staedrmedi nuirsgternetdlyu (rwgietnhtilny 5( wmiitnh)i nfo5llomwinin)gfo slulobwcuintagnseuobucsu itnajnecetoiouns 
ionfj e1c2ti o×n LoDf 1502 O×. LsDcu5t0elOla.tsucsu tveellnatoums  vreensoumlterde suinl tesdurivnisvuarl voivf aal lol ftaelsltteeds temdicme.i cAe. Asinsignlgel eddooses eooff oral 
LY333013 admiiniisstteerreed wiitthh aa 6600 miinnd deellaayyf foollolowwininggt hthee1 122× × LD5500 rresulltted in survival of seven out 
of nine mice, whereas only one out of ffiive mice receiving antivenom wiitth a 60 miin dellay surviived.. 
The ccoombbiinnaattiioonno offL YLY3 330310313a nadndan atinvteivneonmomat taht isthsiasm seam60e m60in mtiimn etirmeseu lrtesduilntesdu rinv isvuarlvfoivraall lfomri caell. 
mice. 
3. Discussion
3. DiTschuesseifofenc tiveness of antivenom to prevent the development of neurotoxicity in mice injected
with Ttahiep aenffvecetnivoemnecsosr roefl aatnestiwveinthomcli ntoic aplroevbesenrtv tahteio dnesvineldoipcamtienngt tohfa tnpeuatrioetnotxsicreitcye iivni nmgiacen tiinvjeencotemd 
wwiitthhi ntaifpouanr  hve(ngoenme rcaolrlyreplartieosr wtoitohn csleitnoicfasle ovbesreernveautiroontso xinicdiitcya)tainreg stihganti pfiacatinetnltys lreescseliivkienlgy atontdiveevneolomp 
lwifiet-htihnr efoautern hin (ggeonreorpahllayr pyrnigoer atlo noenusreot mofu ssecvuelraer npeaurraolytosxisi.citByy) acroen stirgansitf,ic>a6n0t%ly olefsps alitkieenlyt stoin dewvheolomp 
alinfet-ivtherneoamtenaindgm oinriosptrhaatrioynngweaals ndeeulraoymedus>cu4lahr rpeaqruailryesdis.e nBdyo ctroancthraesatl, i>n6t0u%ba toifo npaatniedntms einc hwanhiocmal 
vanentitvileantioomn, oafdtemnifnoirstprraotiloonng wedaps edrieoldasy,eidn o>r4d ehr toresquusitraeind liefned[2o6t]r.aIcnhoeaulr minotuubseatmioond ealn, tdh emliemcihtaatnioicnasl 
ovfenantitliavteionno,m oaftdemn infoisrt eprreodloonngeehda fpteerrieondvse, nionm oirndgeirs itno asgurseteamine nlitfwe i[t2h6c].l inInic aolurre pmorotus soef pmroogdreels, sitnhge 
nliemuirtoattoioxnicsi toyf danestipvietenoanmti vadenmoimnisintepreadti eonntes hw ahfotehra evnevaelnreoamdiyngd eivs einlo apgerdeseimgnesnto wf nitehu rcolitnoixciacli tryepporirotsr 
toof apnrtoigvreensosminga dnmeuirnoistotrxaitciiotyn [d2e6s,p27it]e. Tanhtiisvuennodmer sicno rpeastioennetso fwthhoe lhimavieta atilorenasdoyf adnetvievleonpoemd sthigenras poyf, 
ensepuercoitaollxyiciintyr uprrailosre ttoti nagnstiwvehneoremt haedamrrinivisatlrtaotimone d[2ic6a,2l 7fa].c iTlihtiiess umnadyertsackoeresesv oenrael ohfo tuhres .liFmurittahteiromnso roef, 
tahnetilvimenitoamtio tnhseoraf panyt, iveesnpoecmiaalldyd iitnio rnuarlalyl hsiegthtilnigghs tswthheerree ltehvea nacreriovfadl etvoe lmopeidnigcailn efxapcielintsieivs emthaeyr atpaikees 
several hours. Furthermore, the limitations of antivenom additionally highlights the relevance of 
developing inexpensive therapies that could be used immediately following the bite of a snake 
 
Toxins 2018, 10, 380 4 of 7
that could be used immediately following the bite of a snake safely in the pre-hospital setting, with or
without specific species identification or any special training.
Our observations of LY333013 are important, since oral administration of this drug prevented
both the development of neurotoxicity when given early, and also prevented neurotoxicity and
lethality past the point at which antivenom could treat severe envenoming. To our knowledge, our
study is the first demonstration that shows an intervention outside the range at which antivenom
can prevent neurotoxicity, other than sustained mechanical ventilation to rescue animals from
lethal envenoming [28]. The mechanisms behind this phenomenon need to be further investigated.
Three substituted indoles from which LY333013 is a member could be an invaluable research tool in
understanding fundamental aspects of sPLA2 in the context of snakebite envenoming.
The combination of LY333013 and antivenom, when treatment was delayed for one h, gave better
results than either treatment alone. Since taipan venom has other toxic components in addition to
taipoxin, such as α-neurotoxins and procoagulant serine proteinases [29], the neutralization of these
toxins by antivenom antibodies complements the inhibition of taipoxin by antibodies and LY333013,
when in circulation or when LY333013 has reached peripheral tissues. Thus, our results suggest that
early oral administration of this PLA2 inhibitor in the field or hospital, followed by the infusion of
antivenom at a medical facility could be a robust therapeutic approach for envenomings by Papuan
taipans and, potentially, other types of snakebites whose main toxicity is based on the action of
PLA2S or a severe inflammatory response to other venom components mediated by endogenous
sPLA2 [3,22,30].
Oral LY333013 and its intravenously administered active ingredient, LY315920, are small molecules
ripe for further testing in the pipeline of drug candidates being considered for development as initial
treatments and antivenom adjuncts [9,23]. In the situation of a lethal taipan bite, the preclinical efficacy,
safety profile of three substituted indoles, and availability of high quality antivenom and hospital care,
suggest the need for trials of drug-antivenom combinations. Further examination of these inhibitors
for other snake venom-induced SPLA2 pathology is additionally warranted [19,23,30].
4. Materials and Methods
4.1. Experimental Design to Assess the Efficacy of Drug and Antivenom
Groups of CD-1 mice of both sexes (18–20 g body weight) were used. We utilized Prism 7
(GraphPad Software, Inc., La Jolla, CA, USA) for the statistical analyses based on historical data from
similar experiments we had performed on CD-1 mice. The experimental design was approved by the
Institutional Committee for the Care and Use of Animals (CICUA) of the University of Costa Rica
(CICUA 27-14, 15 July 2014) and met the International Guiding Principles for Biomedical Research
Involving Animals (CIOMS).
Mice were subcutaneously injected with 100 µL of PBS containing 3 µg venom. This corresponds
to approximately 12 Median Lethal Doses (LD50) of venom. The dosage was chosen based on time to
lethality deemed appropriate for a model of severe envenomation and therapeutic intervention [31].
A control group of mice received an oral dose of 200 µL of gum Arabic solution (8% w/v) after
venom injection. Two groups of envenomed mice were treated immediately after venom injection
with either LY333013 (a dose of 10 mg/kg administered orally in 200 µL gum Arabic solution) or
with antivenom (a dose of 5 mL/kg by the intravenous route in a volume of 100 µL). Two additional
groups of envenomed mice were treated with the same doses of LY333013 and/or antivenom one h
after venom injection. Mice were observed continuously for at least the first 12 h and deaths recorded.
Deaths occurring during the 72 h experimental period were recorded as the time last observed,
regardless of clinical condition.
Toxins 2018, 10, 380 5 of 7
4.2. Venom
The venom of adult specimens of Oxyuranus scutellatus from Papua New Guinea was kindly
provided by the University of Melbourne. Upon extraction, venom was snap frozen and then
freeze-dried. Venom solutions were prepared immediately before use by dissolving dry venom
in 0.12 M NaCl, 0.04 M phosphate, pH 7.2 (PBS). Subcutaneous LD50 for this specific batch of venom
was previously established by Herrera et al [31] and is the same batch used to produce taipan specific
antivenom for Papua New Guinea by the manufacturer, Instituto Clodomiro Picado.
4.3. sPLA2 Inhibitor and Antivenom
The PLA2 inhibitor LY333013 (CAS NO: 172733-08-3), with a molecular weight of 394.4, was
supplied by Ophirex, Inc. (Chemietek, Indianapolis, Indiana; Lot 02: 99.99% purity by NMR). LY333013
was then dissolved in 8% w/v gum Arabic in water based on empirical experience related to reliability
of mixing, as well as ease of passage through appropriately sized stainless-steel rodent feeding needles.
The monospecific taipan antivenom produced at Instituto Clodomiro Picado (University of Costa
Rica; batch number 4511209) was used. It was a whole IgG preparation obtained by caprylic acid
precipitation of plasma of horses immunized with the venom of O. scutellatus from Papua New Guinea.
The Median Effective Dose (ED50) of the antivenom, when tested following World Health Organization
standard procedures—i.e., incubating venom and antivenom before injection in mice is 3.96 mg venom
neutralized per mL antivenom (95% confidence limits: 2.99–5.54 mg venom/mL antivenom).
Author Contributions: M.R.L., J.M.G. and D.J.W. conceived the collaboration; M.R.L. and J.M.G. made the final
experimental designs; J.M.G. administered venom and antivenom to all animals; M.R.L. administered the study
drug, LY333013; M.R.L., W.B.-Q. and J.M.G. additionally monitored the experiments and wrote the manuscript.
W.B.-Q., B.L. and M.H. performed experiments and helped to write the manuscript as did D.J.W., M.R.L., S.P.S.,
and T.C.B.; P.E.B. helped design and/or perform preliminary LY333013 experiments, statistical analyses (T.C.B.),
and helped write the manuscript.
Funding: Reprints and permissions information are available from the corresponding authors and funding
agencies (reference Contract: U.S. W81XWH-17-C-0069). Additional funding sources included Departmental
research funds of Ophirex, Inc. and Vicerrectoría de Investigación (Universidad de Costa Rica). DJW is supported
by a Doherty Biomedical Postdoctoral Fellowship from the Australian National Health and Medical Research
Council. Correspondence should be addressed to José María Gutiérrez (jose.gutierrez@ucr.ac.cr) or Matthew
Lewin (matt@ophirex.com or mlewin@calacademy.org)
Acknowledgments: We thank our funders, logistical supporters and readers, notably: Alison Marquis, Jerry
Harrison, Nancy Koch, Sunita Rao, Daniel Z. Lewin, Oscar Ringneck, Sarah Eclectus and Rebecca Carter.
Conflicts of Interest: M.R.L. is employed by Ophirex, Inc. and has stock; S.P.S., T.C.B. and P.B. have consulted
for Ophirex, Inc. for compensation. Author contributions from the study sponsor are detailed, above. Ophirex,
Inc. is a Public Benefit Corporation. J.M.G., W.B.-Q., B.L., M.H., D.J.W. and P.E.B. have no competing interests.
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