2009_-_Le_marché_des_antivenins

7/28/2019 2009_-_Le_march_des_antivenins

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THE MARKET OF

SNAKE ANTIVENOMS

Indeed although the snake is the symbol of medicine,

globally, medicine seems to have forgotten aboutsnake bite

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WHATARETHEVENOMSCOMPONENTS?

Procoagulant, anticoagulantenzymes (Viperidae):incoagulable blood

Haemorrhagins: zinc metalloproteinase :spontaneous systemic haemorrhage

Cytolyticornecrotictoxins : hyaluronidase,phospholipases A, polypeptide toxins : increasepermeability

HaemolyticandmyolyticphospholipasesA2:damage cell membranes and tissues

Neurotoxins (pre or postsynaptic)

Phosphodiesterase: decline of the blood pressure

Snake antivenoms, made of fragments ofantibodies, are the only effective medecine inthe treatment of snakebites

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PARTICULARLYHIGHIN:

ASIA SOUTHAND EAST,SUB SAHARANAFRICAAND LATINA AMERICA

THEINCIDENCEOFENVENOMINGSINTHEWORLD

5 MILLIONSSNAKEBITES, RESULTINGIN 2.5 MILLIONSENVENOMINGS

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The repartition of snake species vary from region to region.The venom composition changes with different snake species.

Its impossible to produce an universal antivenom


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WHATARETHESYMPTOMSOFENVENOMING ?

General : nausea, vomiting, malaise

Cardiovascular: hypotension, heartfailure

Haemostasis : haemorrhages

Neurological : paresthaesiae, paralysis,respiratory arrest

Muscles : generalised myalgia, musclestiffness

Kidneys : haematuria, haemoglobinuria,myoglobinuria

Endocrine : shock and hypoglycaemia

Consequences:o Damage tissueso Necrosiso Limb amputationo Death

Symptoms vary according to the species of snakes responsible forthe bite

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0

2

4

6

8

% deaths

0

20000

40000

60000

80000

100000

Deaths by snakebites

Resulting in 125,000 deathsby snakebites around theworld.

But its probably under-estimated

MORTALITYBYSNAKEBITESINDIFFERENTREGIONSOFTHEWORLD

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CSL Limited

South African Vaccine Producers(SAVP)

THE ANTIVENOM MANUFACTURERS

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ANTIVENOMSNAKEPRODUCTION

First Stage:

Collection ofvenom snakes

Injected 10 to 15

times during 2 to 15months

Second stage: Horse

immunizationprotocols

Blood horse is nextcollected into an

anticoagulant

Third stage:Fractionation and

purification

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Lyophilisation or not

Dialysis or ultrafiltration to remove salt Thermocoagulation or ammonium sulfate precipitation or ionexchange chromatography or acid caprilic treatment to remove Fcfragments Centrifugation (elimination of denatured protein) Affinity chromatography to purify Sterile filtration

Whole IgGPapain cleavage

pH 7 8Fab

Pepsin cleavagepH 2

(Fab)

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++ + +++

+ + +++

++ + +++

10% 30% 0,8%

Volume ofDistribution

Tissue affinity

Rapidelimination

Hypersensitivityreactions

But theresno differences provenin the ability to neutralise the toxic effects of venoms in human 9


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SAFETYOFANTIVENOMSRELATEDTOTHEINCIDENCEOFADVERSEREACTIONS

Early adversesreactions (EARs) : urticaria, itching,fever, tachycardia,vomiting, abdominal

colic, headache,bronchospasm,hypotension andangioedema

Late adverse

reactions Transmission of viralagents

EARs

Presence ofproteinaggregates

Poor stability ofproteins

Presence ofbacteria

Deficiencies duringfractionnation or

freeze drying

Total amountof proteinadministered

Contaminantproteins

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HOWTOEVALUATEANTIVENOMSEFFICACY ?

The efficacy is often tested in a mouse model.

Lethal dose: LD50 = Dose of venom(g/mouse) kills 50% of mice

ED50 : effective dose for an antivenom

ED50 = dose of antivenom (l) saves 50% of miceConversion en mg of venom neutralized per vial

Study of antivenom efficacy is made in biological activity (neutralization

potency)

XxLD50QUANTITY OF

ANTIVENOM

QUANTITY OFVENOM

LD50 : lethal dose for venom

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THERESACONTRASTINTHEMARKETOFANTIVENOMS

Africa:

How to survive to this

disease? Crisis of supply in

snake antivenoms

New antivenoms mayresolve crisis

Pan African, AntivipmynAfrica

Usa:

The example of CroFab,marketed by Protherics

Australia:

Influence of CSL Limited

Countries indevelopement

The rich countries

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PROFILTYPEOFVICTIMESDUETOSNAKEBITEINDEVELOPINGCOUNTRIES

WHO estimates in 2 million DALYs(Disability Adjusted Life Years) per

year for subsaharan africa

Man in rural areas less than 30 y.oldChildren represents 25% of the victims,more amputations than adult.

During working activities During the rainy seasons

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CRISISINANTIVENOMSUPPLYIN AFRICA

It was precipitated by :

The withdrawal from antivenom production ofBehringwerke (Germany)

Delayed and decreased production by Sanofi Pasteur(France)

The only Africa producer, SAIMR, knew financialproblems

( privatisation and lack of capital )

There was a decrease of the supply of antivenom to


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PRICEANDAVAILABILITYOFANTIVENOMSIN AFRICA

Product Genus neutralized Company Availability

Central AfricaPolyvalent

Antivenin

Bitis, Naja,Hemachatus,Dendroaspis

Behringwerke AG No longer produced since1990

PolyvalentSnake Antivenin

Bitis, Naja,Hemachatus,Dendroaspis, Echis

National HealthLaboratory Service(ex: SAIMR)

No longer produced since2001

EchiTab Echis ocellatus Micropharm Ltd Yes, >1000 per vial

FAV Africa Bitis, Naja,Dendroaspis, Echis

Sanofi Pasteur Yes, About 73,50 per vial

Snake VeninAntisera

Bitis, Daboia,Dendroaspis, Echis

Serum Institute ofIndia

Yes, but productionstopped? About 30 per

vial

The cost of snakebite treatment oftenrepresents a high portion of the yearly

income of a rural worker

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THEVICIOUSCYCLEWHICHLEDTOTHECRISISOFSUPPLYIN AFRICA

African healthsystems

decrease orcease their

purchase

Patients prefertraditional healers and

practitioners

Insufficient training of thehealth personnel

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Such circumstances may encourage

procurement of:

Cheaper antivenoms which areuntested and ineffective,

Fake antivenoms sold byunscrupulous marketors

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FAV-Afrique (FAV-A) Asna Antivenom C (AV-C)

Producer

France

Bharat serumand vaccines ;

India

Type of fragment polyvalent equine F(ab)2 polyvalent equine

Use ofEchis ocellatus venom YES NO

Method of production two ammoniumsulphate precipitation ,heat coagulation,

aluminium gel absorption,chromatography,two diafiltrations

No data available

Cost US$139 US$36.75

ANEXAMPLEOFCHEAPERANDINEFFECTIVEANTIVENOM: IN GHANA

AV-C is less expensive than FAV-A

In 2003, Ministry of health of Ghana, FAV-Awas replaced by AV-C

Both treat Echis ocellatus snakebite

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0

10

20

30

40

50

6070

1 dose 2 doses 3 doses 4 or more

doses

%

Doses require to restaure coagulation

FAV-Afrique (n=33)

Asna Antivenom CIndia (n=41)

Asna Antivenom C appears to be less effective than Fav-Afrique


More dosesrequired

Probability ofEARs 19


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FAV-Afrique(Sanofi pasteur)

Asna Antivenom C(Bharat)

N of patients 278 66

N of initial ampoules 3,9 5,1

N of repeat ampoules 5,3 11,9

N total of ampoules 5.2 11.7

Deaths 5 (1,8%) 8 (12,1%)

Allergic reactions - 5


A six fold mortality increase after AV-C replaced FAV-A

Asna Antivenom C was withdrawn from the market in February 2005

This illustrates the absolute need for regional pilottests to assess the effectiveness of new antivenom 20


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PROFILTYPEOFTHEANTIVENOMNEEDEDINDEVELOPINGCOUNTRIES

High quality, usually expressed as generating lowlevels of adverse reactions

High effectiveness in terms of its capability to

neutralize venom

Must carry a low cost

Polyvalent antivenom that cover the common species of snake of the region

Lyophilised preparation which can be stored for years at tropical roomtemperature

TOSIMPLIFYINGDISTRIBUTION

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THEWAYTOFOLLOWINORDERTOINCREASESUPPLYINANTIVENOM

Public educationcompaigns

Closecommunication

between the differentactioners

Implementation of state

agencies in charge ofacquisition and

distribution

Development ofregional or national

guidelines

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0

50000

100000

150000

Cost(US$)

Volume of plasma

Cost of F(ab) production

Thirdstage

Secondstage

Firststage

0

50000

100000

150000

100L

200L

1000L

Cost

(US$)

Volume of plasma

Cost of IgG production

Whole IgG production provides a much higher yield of antibodies than F(ab) production60% vs 30%

IgG production shows best rentability results

THEECONOMICALBENEFITOFTHEPRODUCTIONOFAWHOLEIGG SNAKEANTIVENOM

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0

5

10

15

20

25

30

100 L200 L

1000 L

Costpervial(US$)

Effect on cost per vial

F(ab')

IgG

THEECONOMICALBENEFITOFTHEPRODUCTIONOFAWHOLE IGG SNAKEANTIVENOM

A single annual batch of 100L issufficient for the requirement in

antivenoms of a country with a middleincidence of envenomings

Theres a need to:

Find another markets for themanufacturer Have a collaboration betweenthe countries to make antivenomavailable in health centers 24


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PAN-AFRICANPOLYSPECIFICANTIVENOMPRODUCEDFOR AFRICAMARKET

Constitute of a whole IgG

Produced in Costa Rica (ammonium sulfate precipitation)or in Colombia (caprylic acid precipitation)

Its the result of an inter-regional collaborationbetween:

the Liverpool School of Tropical Medecinethe Nigerian Ministry of Health

Echis40%

Bitis30%

Naja

30% Prepared from the venoms of Threedangerous species of African snakes

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0 50

EchiTab (Micropharm Ltd)

AHLS (SAIMR)

IPSER Africa (Pasteur)

Pan African (Colombia)

Pan African (Costa Rica)

ED50 (l/challenge dose)

Comparison of efficacy on elimination of the letaleffect induced by E.ocellatus

A RELATIVEGOODEFFICCACYOF PAN AFRICANANTIVENOMCOMPAREDWITHCOMPETITORS

The Pan African antivenom also possesses :

Strong neutralising potency against the venom of B. arietans

Moderate potency against N. nigricollis venom

Polyvalentantivenoms

Monovalentantivenoms


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APROMISINGANTIVENOMFOR AFRICA: ANTIVIPMYNAFRICA

Purified lyophilized polyvalent equine (fab)2antivenom

Obtained by immunization with the venoms of 11species of African snakes

0

50

100

150

200

250300

Effect on specific venoms

0

50

100

150

200

250300

Effect on para specific venoms

ED50 l

Antivipmyn effective on specific venoms and on some

para specific venoms

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0

50

100

150

ED50 (L) in 2006 and in 2007 for a same batch

2006

2007

Theres no changes in neutralisation potency

Permitting transport, storage andappropriate stocks

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Activity Neutralizing dose

Hemorrhagic 15, 3l

Defibrinogenating 12,5l

Pro-coagulant 6,3l >15min

Necrotizing 19,2l

neutralization of Echis ocellatus venom activities

All of Echis ocellatus venom activities are neutralized

AntivipmynAfrica may be expected to be oftherapeutic value in many regions of Africa

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Choice of Benin:

Safety: correct managment ofsnake biteSpeed: high incidence ofsnakebiteEconomy: health center close

to each other

Including 11 health centers

No comparative trial

Main objective: to measure theearly tolerance (incidence andseverity of adverse effects)

CLINICALTRIALOF ANTIVIPMYNAFRICA:ANEXAMPLETOBETAKEN

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ANTIVIPMYNAFRICA: PROFILEOFSAFETY

0%

2%

4%

6%

8%

10%12%

14%

16%

18%

20%

Prevalence of symptoms observed

after administration of antivenom Prevalence of adverse reactionswas 11%

Adverse effects are observed :

in 13% of patients after thefirst injection

in 19% of patients after alltreatments

Trial showed satisfactorytolerability of the new

antivenom31


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ANTIVIPMYNAFRICA :AFUTURELAUNCHONSNAKEANTIVENOMMARKET

Study was made from september 2007 to january 2008 tospecify minimal doses and to define protocol ofadministration of this antivenom

Other study was made from february 2008 to june 2008 toobserve the hematologic evolution

AMM in january 2008 and current marketing

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SITUATIONINTHE USA

Profil type of victims: Hikers or tourists in the desert

It occur between April and October

Each year 8000 venomous snake bitesNo more than 12 fatality cases

reported/year

99 % were caused by the Crotalidae(rattlesnakes, cottonmouths, copperheads)

Coral snake of the micrurus of Elapidae familyare responsible of a minority of snakebites in

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IN 2000 : TWOANTIVENOMSFORTHETREATMENTOF CROTALINESNAKEBITE

Antivenin (Crotalidae)Polyvalent

ACP

Crotalidae Polyvalent ImmuneFab (Ovine)

CroFab

Producer

Year marketed 1954 Approuved by the FDA in October 2000

Animal source Horse Sheep

Type of fragment IgG 18,9% Fab >85%

Production Use 4 Snakes venomsCrotalus atroxC. adamanteusC. durissus terrificusBothrops atrox

Purification by ammonium sulfateprecipitation

Lyophilized

Result of the final combinaison of 4 monovalentantivenoms against:

C. atroxC. adamanteusC. scutulatus scutulatus

Agkistrodon piscivorus

Purification on ion-exchange and affinity

chromatography columnsLyophilized

Components

Total proteinAlbumine

2,1 g/vial120mg/vial ( 18,9%)


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EFFICACYOFCROFAB

2

2.5

3

3.5

4

4.5

5

Baseline After Crofabinfusion

Hour 1 Hour 4 or 6 Hour 12

Evolution of Snake Severity Score

Pilot Study n=11

As needed n=16

Scheduled n=15

o Evaluation by the SnakebiteSeverity Score

mesure the severity ofenvenomation

Improvements of symptoms

Efficacy of Crofab35

oTwo clinical trials usingCrofab

pilot trial ,N = 11randomized

comparative trial ,N = 31


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COMPARISONBETWEEN CROFABAND ACP

Antivenin (Crotalidae)Polyvalent

ACP

Crotalidae PolyvalentImmune Fab (Ovine)

CroFab

Safety During infusion 23% to 56% allergic events3 deaths by anaphylaxis

14,3%Events mild or moderate

Serum sickness

70 %for patients treated with 3

or more vials 3%

Dosing minimal env. Difficult to determine

dosereassessdosereassess

Treatment algorithmInitial Dose (3 to 12 vials)

2 vials doses at 6,12,18h

moderate env.

severe env.

Time of reconstitution 90 min 40 min

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CROFAB: THESUCEEDINUSMARKET

Wyeth stopped its production of ACP in 2003

But its expensive and short supply

19.3 20.4

2731.5

0

5

10

15

2025

30

35

2005 2006 2007 2008

Sales of Crofab M$

The only available antivenom used to treatCrotaline snakebite in North America

Price :US$750.00/vial(10mL)Recommended dose: 40 60mL

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A SERIOUSCONCURENTFORCROFAB:ANTIVIPMYN

Antivipmyn

Animal source Horse

Type offragment

F(ab)2

Production Use 2 Snakes venomsLyophilized

Cost US$27.80/vial.

Coverage Species :All Crotalus and Bothrops species of the

American continent

a similar product produced in Mexico from horse serum maycompete with CroFabif it obtains regulatory approval in

the U.S.

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OTHERSBIOCLONSNAKEANTIVENOMSONTHEMARKET

Future projects in development in 2009:

Snake antivenom for America Latina :

Snake antivenom for North Africa and Moyen orient

Antivenom fraction Fab for Europe

Enregistrement

Enregistrement

Phase 3

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SITUATIONIN AUSTRALIA

oThe incidence of snakebite is estimated 1000-3000 events/year

oIt results in few deaths/year

oThe Commonwealth Serum Laboratories is the solemanufacturer and markets antivenoms

Founded in 1916 Focused on vaccine manufacture Privatisation in 1994

In 2007,The Government has a four-year agreement withCSL for the manufacture of antivenom products at a cost of$15.1 million ($1.7 million in new funding) 40

Australia : a large choice of snake antivenoms


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Antivenom (first sales) Type offragments

Against specifically venomsof

Effective on para-specific venoms of

Black snake (1959) (Fab) Pseudechis australis 5 species

Brown snake (1956) (Fab) Pseudonaja textilis 2 species

Death adder (1958) (Fab) Acanthophis antarcticus 2 species

Sea snake(1961) (Fab) Ehnydrina schistosaNotechis scutatus 12 species

Taipan(1955) (Fab) Oxyuranus scutellatus One specie

Tiger snake(1930) (Fab) Notechis scutatus 7 species

Australia : a large choice of snake antivenoms

And the CSL polyvalent snake antivenom (1962) against:Acanthophis antarcticus

Oxyuranus microlepidatus

Pseudonaja textilis

Pseudonaja textilis

Destinated for patients on whom the identification of the snake

responsible is impossible

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AUSTRALIA : THE BEST IN THE MANAGEMENT OF ENVENOMATION


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AUSTRALIA : THEBESTINTHEMANAGEMENTOFENVENOMATION

CSL Limited product a Snake VenomDetection Kit (SVDK) specifically toidentify the presence and type ofaustralian snake venom

Elisa method

Samples used: a bite site swab, the

fangs, urine or blood Gives results in 20 min

Positive SVDK result doesnt mean thepatient requires antivenom

It gives relate directly to the mostappropriate antivenom to use

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THE SAFETY PROFILE OF AUSTRALIAN CSL SNAKE ANTIVENOMS


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0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%

40.00%

45.00%

Frequency of hypersensitivity reactions foreach snake antivenom

Mild

Moderate

Severe

Hypersensitivity reactionsoccurred in 25% of the

patients.

Mild reactions represent14%.

Severe reactions were

uncommon (5%) andcharacterised mainlyby hypotension.

There were no deathsattributed to allergic

reactions.

Australian CSLantivenoms present agood safety profile

THESAFETYPROFILEOF AUSTRALIAN CSL SNAKEANTIVENOMS

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In USA and in Australia, effective snake antivenoms are available, but their costare expensive

Contrary to in developing countries where there is few effective antivenoms, the

situation may improve by:Intervention of health agenciesClose collaboration between the countries in need and with manufacturersin rich countriesFinancial contribution (Bill and Melinda Gates foundation)

CONCLUSION

The market of snake antivenoms vary according to the differentregions of the world and their ability to product their ownantivenom or to buy foreign antivenoms


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THANKYOU

AMANDINE LADEN, THOMAS DUTERTE,

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Be careful..

2009_-_Le_marché_des_antivenins

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