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THE MARKET OF SNAKE ANTIVENOMS

Indeed although the snake is the symbol of medicine, globally, medicine seems to have forgotten about snake bite

WHAT ARE THE VENOMS COMPONENTS?


Procoagulant, anticoagulant enzymes (Viperidae): incoagulable blood Haemorrhagins: zinc metalloproteinase : spontaneous systemic haemorrhage Cytolytic or necrotic toxins : hyaluronidase, phospholipases A, polypeptide toxins : increase permeability Haemolytic and myolytic phospholipases A2: damage cell membranes and tissues Neurotoxins (pre or postsynaptic) Phosphodiesterase: decline of the blood pressure

Snake antivenoms, made of fragments of antibodies, are the only effective medecine in the treatment of snakebites

THE INCIDENCE OF ENVENOMINGS IN THE WORLD

PARTICULARLY HIGH IN: The repartition of snake species vary from region to region. ASIAcomposition SOUTH AND EAST ,SUB S AHARAN The venom changes with different snake species.

Its impossible to produce an universal antivenom


5 MILLIONS SNAKE BITES, RESULTING IN 2.5 MILLIONS ENVENOMINGS

AFRICA AND LATINA AMERICA

WHAT ARE THE SYMPTOMS OF ENVENOMING ?


Symptoms vary according to the species of snakes responsible for the bite

General : nausea, vomiting, malaise Cardiovascular : hypotension, heart failure Haemostasis : haemorrhages

Kidneys : haematuria, haemoglobinuria, myoglobinuria Endocrine : shock and hypoglycaemia

Neurological : paresthaesiae, paralysis, respiratory arrest


Muscles : generalised myalgia, muscle stiffness

Consequences: o Damage tissues o Necrosis


o Limb amputation o Death
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MORTALITY BY SNAKEBITES IN DIFFERENT REGIONS OF THE WORLD


Deaths by snakebites
100000
80000 60000 40000 20000 0 8 6

% deaths

4
2 0

Resulting in 125,000 deaths by snakebites around the world. 5


But its probably under-estimated

THE ANTIVENOM MANUFACTURERS

CSL Limited 6
South African Vaccine Producers (SAVP)

ANTIVENOM SNAKE PRODUCTION


Injected 10 to 15 times during 2 to 15 months

First Stage: Collection of venom snakes

Second stage: Horse immunization protocols

Blood horse is next collected into an anticoagulant Third stage:Fractionation and purification
7

Pepsin cleavage pH 2 (Fab)

Whole IgG

Papain cleavage pH 7 8 Fab

Dialysis or ultrafiltration to remove salt


Thermocoagulation or ammonium sulfate precipitation or ion exchange chromatography or acid caprilic treatment to remove Fc fragments Centrifugation (elimination of denatured protein) Affinity chromatography to purify Sterile filtration

Lyophilisation or not

Volume of Distribution

++ + ++ 10%

+ + + 30%

+++ +++ +++ 0,8%

Tissue affinity
Rapid elimination
Hypersensitivity reactions

But theres no differences proven in the ability to neutralise the toxic effects of venoms in human

SAFETY OF ANTIVENOMS

RELATED TO THE INCIDENCE OF ADVERSE REACTIONS

Early adverses reactions (EARs) :


urticaria, itching, fever, tachycardia, vomiting, abdominal colic, headache, bronchospasm, hypotension and angioedema Poor stability of proteins

Presence of bacteria

Deficiencies during fractionnation or freeze drying

Contaminant proteins

Late adverse reactions


Transmission of viral agents

EARs
Presence of protein aggregates
Total amount of protein administered

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HOW TO EVALUATE ANTIVENOMS EFFICACY ?


The efficacy is often tested in a mouse model. LD50 : lethal dose for venom
QUANTITY OF VENOM

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

ED50 : effective dose for an antivenom

XxLD50
ED50 = dose of antivenom (l) saves 50% of mice Conversion en mg of venom neutralized per vial

QUANTITY OF ANTIVENOM

Study of antivenom efficacy is made in biological activity (neutralization potency)

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THERE S A CONTRAST IN THE MARKET OF ANTIVENOMS


Countries in developement Africa: How to survive to this disease? Crisis of supply in snake antivenoms

The rich countries Usa: The example of CroFab, marketed by Protherics Australia: Influence of CSL Limited

New antivenoms may resolve crisis Pan African, Antivipmyn Africa

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PROFIL TYPE OF VICTIMES DUE TO SNAKE BITE IN DEVELOPING


COUNTRIES

Man in rural areas less than 30 y.old Children represents 25% of the victims, more amputations than adult. During working activities During the rainy seasons

WHO estimates in 2 million DALYs (Disability Adjusted Life Years) per13 year for subsaharan africa

CRISIS IN ANTIVENOM SUPPLY IN AFRICA


It was precipitated by : The withdrawal from antivenom production of Behringwerke (Germany) Delayed and decreased production by Sanofi Pasteur (France) The only Africa producer, SAIMR, knew financial problems ( privatisation and lack of capital )

There was a decrease of the supply of antivenom to

<20 000 ampoules/year

The estimated need is 1.5-2 million doses/year

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PRICE AND AVAILABILITY OF ANTIVENOMS IN AFRICA


Product Genus neutralized Company Availability

Central Africa Polyvalent Antivenin Polyvalent Snake Antivenin

Bitis, Naja, Hemachatus, Dendroaspis Bitis, Naja, Hemachatus, Dendroaspis, Echis Echis ocellatus Bitis, Naja, Dendroaspis, Echis Bitis, Daboia, Dendroaspis, Echis

Behringwerke AG

No longer produced since 1990 No longer produced since 2001

National Health Laboratory Service (ex: SAIMR) Micropharm Ltd Sanofi Pasteur Serum Institute of India

EchiTab FAV Africa Snake Venin Antisera

Yes, >1000 per vial Yes, About 73,50 per vial Yes, but production stopped? About 30 per vial

The cost of snakebite treatment often represents a high portion of the yearly income of a rural worker

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THE VICIOUS CYCLE WHICH LED TO THE CRISIS OF SUPPLY IN AFRICA

African health systems decrease or cease their purchase

Patients prefer traditional healers and practitioners

Insufficient training of the health personnel

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Such circumstances may encourage procurement of:

Cheaper antivenoms which are untested and ineffective, Fake antivenoms sold by unscrupulous marketors

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AN EXAMPLE OF CHEAPER AND INEFFECTIVE ANTIVENOM: IN GHANA


In 2003, Ministry of health of Ghana, FAV-A was replaced by AV-C Both treat Echis ocellatus snakebite
FAV-Afrique (FAV-A) Producer France Type of fragment Use of Echis ocellatus venom Method of production polyvalent equine F(ab)2 YES two ammonium sulphate precipitation , heat coagulation, aluminium gel absorption, chromatography, two diafiltrations Asna Antivenom C (AV-C) Bharat serum and vaccines ; India polyvalent equine NO

No data available

Cost

US$139

US$36.75

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AV-C is less expensive than FAV-A

AN EXAMPLE OF CHEAPER AND INEFFECTIVE ANTIVENOM: IN GHANA

Doses require to restaure coagulation

70 % 60 50 40 30 20 10 0
1 dose 2 doses

FAV-Afrique (n=33) Asna Antivenom C India (n=41)

4 or more Asna Antivenom C appears to be less effective than Fav-Afrique doses

3 doses

More doses required

Probability of EARs

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AN EXAMPLE OF CHEAPER AND INEFFECTIVE ANTIVENOM: IN GHANA

FAV-Afrique (Sanofi pasteur) N of patients N of initial ampoules N of repeat ampoules N total of ampoules Deaths Allergic reactions 278 3,9 5,3 5.2 5 (1,8%) 66

Asna Antivenom C (Bharat)

5,1 11,9 11.7 8 (12,1%) 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 pilot tests to assess the effectiveness of new antivenom

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PROFIL TYPE OF THE ANTIVENOM NEEDED IN DEVELOPING


COUNTRIES
High

quality, usually expressed as generating low levels 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 room temperature

TO SIMPLIFYING
DISTRIBUTION

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THE WAY TO FOLLOW IN ORDER TO INCREASE SUPPLY IN ANTIVENOM

Close communication between the different actioners

Implementation of state agencies in charge of acquisition and distribution

Public education compaigns

Development of regional or national guidelines


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THE ECONOMICAL BENEFIT OF THE PRODUCTION OF A WHOLE IGG SNAKE ANTIVENOM


Cost of F(ab) production Cost of IgG production

150000 100000
Cost (US$)

Third stage Second stage First stage


Volume of plasma Cost (US$)

150000
100000 50000 0
Volume of plasma

50000 0

100 200 1000 L L L

Whole IgG production provides a much higher yield of antibodies than F(ab) production 60% vs 30%
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IgG production shows best rentability results

THE ECONOMICAL BENEFIT OF THE PRODUCTION OF A WHOLE IGG SNAKE ANTIVENOM


Effect on cost per vial
Cost per vial (US$) 30 F(ab') 25 IgG A single annual batch of 100L is sufficient for the requirement in antivenoms of a country with a middle incidence of envenomings

20
15 10 5 0 100 L 200 L

1000 L

Theres a need to: Find another markets for the manufacturer Have a collaboration between the countries to make antivenom 24 available in health centers

PAN-AFRICAN POLYSPECIFIC ANTIVENOM PRODUCED FOR AFRICA


MARKET

Constitute of a whole IgG Produced in Costa Rica (ammonium sulfate precipitation) or in Colombia (caprylic acid precipitation)

Prepared from the venoms of Three dangerous species of African snakes

Naja 30%

Echis 40% Bitis 30%

Its the result of an inter-regional between:

collaboration
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the Liverpool School of Tropical Medecine the Nigerian Ministry of Health

A RELATIVE GOOD EFFICCACY OF PAN AFRICAN ANTIVENOM COMPARED WITH


COMPETITORS Comparison of efficacy on elimination of the letal effect induced by E.ocellatus
Pan African (Costa Rica) Pan African (Colombia) IPSER Africa (Pasteur)

Polyvalent antivenoms

AHLS (SAIMR)
EchiTab (Micropharm Ltd)

Monovalent antivenoms
ED50 (l/challenge dose)

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The Pan African antivenom also possesses :

Strong neutralising potency against the venom of B. arietans Moderate potency against N. nigricollis venom

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A PROMISING ANTIVENOM FOR AFRICA: ANTIVIPMYNAFRICA


Purified lyophilized polyvalent equine (fab)2antivenom Obtained by immunization with the venoms of 11 species of African snakes

Effect on specific venoms


300 250 200 150 100 50 0 300 250 200 150 100 50 0

Effect on para specific venoms

ED50 l

Antivipmyn effective on specific venoms and on some para specific venoms

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A PROMISING ANTIVENOM FOR AFRICA: ANTIVIPMYNAFRICA


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

150 100 50 0 2006 2007

Theres no changes in neutralisation potency

Permitting transport, storage and appropriate stocks

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A PROMISING ANTIVENOM FOR AFRICA: ANTIVIPMYNAFRICA

neutralization of Echis ocellatus venom activities Activity Hemorrhagic Defibrinogenating Pro-coagulant Neutralizing dose 15, 3l 12,5l 6,3l >15min

Necrotizing

19,2l

All of Echis ocellatus venom activities are neutralized

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


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CLINICAL TRIAL OF ANTIVIPMYNAFRICA: AN EXAMPLE TO BE


TAKEN

Choice of Benin: Safety: correct managment of snake bite Speed: high incidence of snakebite Economy: health center close to each other Including 11 health centers No comparative trial Main objective: to measure the early tolerance (incidence and severity of adverse effects)

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ANTIVIPMYNAFRICA: PROFILE OF SAFETY


Prevalence of symptoms observed after administration of antivenom

20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0%

Prevalence of adverse reactions was 11%

Adverse effects are observed : in 13% of patients after the first injection in 19% of patients after all treatments

Trial showed satisfactory tolerability of the new 31 antivenom

ANTIVIPMYNAFRICA : A FUTURE LAUNCH ON SNAKE ANTIVENOM


MARKET

Study was made from september 2007 to january 2008 to specify minimal doses and to define protocol of administration of this antivenom Other study was made from february 2008 to june 2008 to observe the hematologic evolution

AMM in january 2008 and current marketing

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SITUATION IN THE USA


Profil type of victims: Hikers or tourists in the desert It occur between April and October

Each year 8000 venomous snake bites No more than 12 fatality cases reported/year

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

Coral snake of the micrurus of Elapidae family are responsible of a minority of snakebites in US

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IN 2000 : TWO ANTIVENOMS FOR THE TREATMENT OF CROTALINE SNAKEBITE


Antivenin (Crotalidae) Polyvalent ACP
Producer

Crotalidae Polyvalent Immune Fab (Ovine) CroFab

Year marketed Animal source Type of fragment Production

1954 Horse

Approuved by the FDA in October 2000 Sheep

IgG 18,9%
Use 4 Snakes venoms

Fab >85%
Result of the final combinaison of 4 monovalent antivenoms against:

Crotalus atrox C. adamanteus C. durissus terrificus Bothrops atrox


Purification by ammonium sulfate precipitation Lyophilized Components

C. atrox C. adamanteus C. scutulatus scutulatus Agkistrodon piscivorus


Purification on ion-exchange and affinity chromatography columns Lyophilized <1,5g/vial <0,5 %

Total protein Albumine

2,1 g/vial 120mg/vial ( 18,9%)

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Preclinical study: CroFab 5,2 times more potent (ED50)

EFFICACY OF CROFAB
Evolution of Snake Severity Score

oTwo clinical trials using Crofab

pilot trial ,N = 11 randomized comparative trial ,N = 31

4.5
Pilot Study n=11 As needed n=16

Scheduled n=15

3.5

o Evaluation by the Snakebite Severity Score mesure the severity of envenomation

2.5

Improvements of symptoms Efficacy of Crofab

2
Baseline After Crofab infusion Hour 1 Hour 4 or 6 Hour 12

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COMPARISON BETWEEN CROFAB AND ACP


Antivenin (Crotalidae) Polyvalent ACP
Safety During infusion

Crotalidae Polyvalent Immune Fab (Ovine) CroFab 14,3%


Events mild or moderate

23% to 56% allergic events


3 deaths by anaphylaxis

Serum sickness

70 % for patients treated with 3


or more vials

3% Treatment algorithm
Initial Dose (3 to 12 vials)

Dosing

minimal env. moderate env. severe env.

Difficult to determine
dosereassessdosereassess

2 vials doses at 6,12,18h

Time of reconstitution

90 min

40 min

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CROFAB: THE SUCEED IN US MARKET

The only available antivenom used to treat Crotaline snakebite in North America

Wyeth stopped its production of ACP in 2003


Sales of Crofab M$ 35 30 25 20 15 10 5 0

31.5 27 19.3

20.4

2005

2006

2007

2008

But its expensive and short supply

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

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A SERIOUS CONCURENT FOR CROFAB: ANTIVIPMYN


a similar product produced in Mexico from horse serum may compete with CroFab if it obtains regulatory approval in the U.S.

Antivipmyn
Animal source Type of fragment Production Cost

Horse F(ab)2 Use 2 Snakes venoms Lyophilized US$27.80/vial.

Coverage Species : All Crotalus and Bothrops species of the American continent

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OTHERS BIOCLON SNAKE ANTIVENOMS ON THE MARKET

Future projects in development in 2009: Snake antivenom for America Latina :

Enregistrement Enregistrement

Snake antivenom for North Africa and Moyen orient


Antivenom fraction Fab for Europe

Phase 3

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SITUATION IN AUSTRALIA
o The incidence of snakebite is estimated 1000-3000 events/year
o It results in few deaths/year

oThe Commonwealth Serum Laboratories is the sole


manufacturer and markets antivenoms Founded in 1916 Focused on vaccine manufacture Privatisation in 1994

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

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Australia : a large choice of snake antivenoms


Antivenom (first sales) Type of fragments Against specifically venoms of

Effective on paraspecific venoms of

Black snake (1959)

(Fab) (Fab) (Fab) (Fab) (Fab) (Fab)

Pseudechis australis

5 species

Brown snake (1956)


Death adder (1958) Sea snake(1961) Taipan(1955) Tiger snake(1930)

Pseudonaja textilis
Acanthophis antarcticus Ehnydrina schistosa Notechis scutatus Oxyuranus scutellatus Notechis scutatus

2 species
2 species 12 species One specie 7 species

And the CSL polyvalent snake antivenom (1962) against:


Acanthophis antarcticus Oxyuranus microlepidatus Pseudonaja textilis Pseudonaja textilis
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Destinated for patients on whom the identification of the snake responsible is impossible

AUSTRALIA : THE BEST IN THE MANAGEMENT OF ENVENOMATION


CSL Limited product a Snake Venom Detection Kit (SVDK) specifically to identify the presence and type of australian 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 the patient requires antivenom

It gives relate directly to the most appropriate antivenom to use

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THE SAFETY PROFILE OF AUSTRALIAN CSL SNAKE ANTIVENOMS


Frequency of hypersensitivity reactions for each snake antivenom
45.00% 40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00%

Hypersensitivity reactions occurred in 25% of the patients. Mild reactions represent 14%. Severe reactions were uncommon (5%) and characterised mainly by hypotension. There were no deaths attributed to allergic reactions.

Mild
Moderate Severe

Australian CSL antivenoms present 43 a good safety profile

CONCLUSION
The market of snake antivenoms vary according to the different regions of the world and their ability to product their own antivenom or to buy foreign antivenoms

In USA and in Australia, effective snake antivenoms are available, but their cost are expensive Contrary to in developing countries where there is few effective antivenoms, the situation may improve by: Intervention of health agencies Close collaboration between the countries in need and with manufacturers in rich countries Financial contribution (Bill and Melinda Gates foundation)

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THANK YOU

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Be careful..
AMANDINE LADEN, THOMAS DUTERTE, (FRANOIS FLAMENT)

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