Antivenom: the most cost effective treatment in the world

1
Antivenom the most cost effective treatment in
the world?

• Dr Nick Brown
• Institute of Biotechnology
• Dr John Landon
• MicroPharm Ltd.

2
Where we left off

• Antivenom supply outstrips demand
• The Problem poor demand suppresses supply
• Efforts must focus on increasing market demand
• Even in areas where demand is high and good
  quality, inexpensive antivenoms exist,
  availability is not assured
• Not enough and market consistency
• Commercial and economic realities are paramount

3
What is needed?

• Reliable sources of funding are needed to turn
  the (multi-faceted) cogs.
• Other important and valuable initiatives will be
  futile without financial security
• Political will
• Financial stimulus

4

• How to improve political will and generate
  financial stimulus for antivenoms?

• Demonstrate worth
• Importance of the problem (its impact)
• Human
• economic
• Demonstrate value for money
• Improve overall effectiveness
• Cost v benefit
• Reduce costs
• Simplify production and treatment
• Improve potency (reduce amount AV required)
• Avoid waste

5
Micropharm Ltd

• Improving value for money
• Improving overall effectiveness
• Improving cost v benefit
• Reducing costs
• Simplify production and treatment
• Improve potency (reduce amount AV required)
• Avoid waste

6
History

• 1990s Therapeutic Antibodies
• Freeze dried, Fab fragments of ovine IgG.
• Each ampoule 500mg of total Fab which provided
  500 neutralising units
• 2 - 4 ampoules required per treatment
• Cost 240 per treatment
• EchiTAb proved to be effective and safe and was
  registered under that name by the Nigerian
  Regulatory Authorities.

7
History

• 1998 Therapeutic Antibodies listed LSE
• 1999 Micropharm Ltd. formed
• EchiTab was relaunched - equivalent to TAb
  product
• 250-300 units per 250mg of Fab
• 200 per treatment 4 ampoules
• 2000 Innovative Manufacturing Initiative
• inexpensive antivenom
• Small size of ovine Fab (MW 60,000) high renal
  excretion
• EchiTab2 - Pepsin digestion to F(ab)2 (MW
  120,000)
• No renal excretion
• 300-400 neutralising units per 250mg
• 100 per treatment 2 ampoules

8
History

• 2005 EchiTabG
• based on work in South America
• Whole ovine IgG
• Caprylic Acid
• 750 mouse neutralising units per 250mg
• 40 per treatment
• Future projects
• Transfer technology to Nigeria
• reducing cost of lyophilisation to lt5/ampoule
• Double-blinded, randomised, comparative trial of
  whole IgG, F(ab) and F(ab)2 AV for Echis
  ocellatus

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Mouse LD50 neutralising units per ampoule
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Reducing Costs

• Variable costs
• Reagents
• consumables
• Fixed costs
• Staff
• Equipment
• Rent/utilities
• Maintenance
• Regulatory costs
• Economies of scale

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Economies of scale

• Increase batch size
• Increasing workload 25 100 rise in throughput
• Fixed costs remain the same
• Some consumables can be used for multiple
  batches, eg. filters
• Increase manufacture of other (profitable)
  products
• Cost could fall to 20/amp if production
  increased to 100,000 amps per year

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Low cost attributes

• Mono specific Echis ocellatus
• Small snake
• Only 5mg venom
• 90 of bites
• Easy identification - 20WBCT
• Compared to
• Spp. with larger amounts of venom require larger
  amounts of specific antibodies
• Polyspecific antivenoms are larger volume with
  larger total smounts of specific antibodies
• More foreign protein - ? Adverse reactions

13
Low cost attributes

• Antivenom provided direct to NMOH
• No distribution networks
• NMOH funded RD and clinical trials
• Innovative production techniques
• Source reliable Nigerian Echis spp. venom from
  Liverpool School of Tropical Medicine
• Ensures relevance and potency

14
High cost attributes

• Significant Fixed costs and low throughput
• Aseptic technique - HVAC air filters, clean rooms
  etc. (compared to antiseptic techniques)
• Salaries
• Regulatory requirements
• QC and QA

15
Improved (and cheaper) analytical procedures

• ED50 - complex, cruel
• ELISA - expensive, time consuming, lacks
  precision (coefficient variance gt35)
• New small scale affinity chromatography
• Determines levels of specific antibody
• More precise (CV lt8)
• 20 batches correlated closely with ED50
• Rapid
• Requires only spectrophotometer
• also Gel electrophoresis

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Maximising specific Ab

• Eg. 6g/L specific Ab compared to 3g/L
• 50 fewer animals are required (? cost)
• 50 less foreign protein (? cost and SEs)
• Using SSAC, humoral immune responses
• Sheep goats gt horses gt hens rabbits
• Total IgG levels 25g/L
• Circulating specific Ab 6-7g/L
• Sheep goats - highest and most sustained
• Horses - variable and fluctuating response

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Factors affecting Ovine yield

• gt 20 years experience
• Breed
• Age
• Time from immunisation to bleedling
• Adjuvant
• Stable water-in-oil emulsion of venom adjuvant
• Number and site of immunisations
• Amount of venom used
• Perform dose-response studies
• Confirm amount of venom required to elicit
  response
• remove poor responders from flock (if lt5g/L)

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Ovine yield

• Specific antibody levels 6g/L (5g/L-7.2g/L)
• Fab (papain) 60
• F(ab)2 (pepsin 75
• IgG (Caprylic Acid) 85
• 4 litres of antiserum/year/sheep
• 300 treatments

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Simplify manufacturing

• Every step adds costs, increases losses, impairs
  venom-Ab binding/neutralising
• Employ simplest procedure that yields effective
  and safe products
• Pepsin digestion of Fc fragment increased yield
  to 75, but need ion-exchange step to remove
  pepsin
• Change to
• Caprylic Acid precipitation of serum proteins
• Fewer steps
• No aggregation
• 85 yield

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Simplify manufacturing

• Bag technology
• Sterile and Disposable (no cleaning,
  re-sterilisation)
• 20 litres antiserum saline caprylic acid
  mixed for 30 minutes
• Stand for 60 minutes
• Aliquoted into smaller bags and centrifuged
• IgG supernatant separated, pooled and filtered
  with 30,000 MW cut-off
• Concentrated to 250g/L in citrate buffer, pH 6.0
• Final filtration 0.2uM
• Sterile filled into 10ml amps of 250mg intact IgG

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Outcome

• Recovery increased from 16g/L to 26g/L specific
  antibody
• Neutralising potency from 250 units/amp to 750
  units/amp
• 70-80 of patients can be treated with 1 ampoule,
  i.e. 40
• Cost to supply Nigerias annual need
• 4 million (many variables)

22
Micropharm increasing value

• Cost reduction summary
• Appropriate venom, immunogen mix and use, and
  selection of animals
• Simplify procedures (few steps, reduce waste)
• Improve Ab yield
• Streamline analytical techniques
• High throughput

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Do not ignore this!

• Summary
• EchiTabG efficacious, safe, simple
• Good reputation
• Inexpensive
• Simplified production methods - less expensive
  faster
• Employ steps to reduce cost
• Provides EchiTabG at cost (no profit)
• Regulated by UK Home Office to European standards
• Very willing to provide assistance to other
  companies
• Very willing to increase production
• Current output 0!
• Could be even cheaper

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• Micropharm saves more lives than any other Welsh
  company
• - Prof John Landon, founder

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• Demonstrate value for money
• Improve overall effectiveness
• Reduce costs
• Simplify production and treatment
• Improve potency (reduce amount AV required)
• Avoid waste
• Cost v benefit

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Cost effectiveness

• Disability Adjusted Life Years (DALYs)
• Years of life lost years lived with disability
  (YLL YLD)
• Estimated snakebite burden in SSA
• 2 million DALYs per year
• Complex formula
• Age of onset
• Disability weighting
• Discounting
• Reducing the cost of AV treatment will
  drastically improve its value

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Calculations

• Assuming
• Mortality 4
• Morbidity 10
• Average age of victim in SSA 20 y.o.
• Life expectancy in SSA 47 years
• Disability weighting 0.102 (amputation)
• Cost of antivenom treatment 100
• DALYs averted 1.14
• Cost per DALY averted 87.53

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Calculations - Echis ocellatus

• Assuming
• Morbidity 40
• Mortality 20
• Average age of victim in SSA 15 y.o.
• Life expectancy in SSA 47 years
• Disability weighting 0.102 (amputation)
• Cost of antivenom treatment 40
• DALYs averted 7.12
• Cost per DALY averted 5.61

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HIV/AIDS

• Average age of newly Dx patient 20 y.o.
• Disability weighting 0.505
• Effect of HAART adds 6 years of life
• HIV/AIDS without Rx dead in 2 years
• HIV/AIDS with Rx dead in 8 years
• Cost of HAART per patient per year 215-1120
• No of DALYs averted 1.06
• Cost per DALY averted 202 - 1056

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AV v HAART

• AV provides more bang for your buck
• Antivenom provides 2.3x - 12x more benefit per
  dollar than HAART
• Echis antivenom provides 36x - 188x more benefit
• Conclusions
• AV is affordable
• AV is good value
• AV should be funded
• Therapeutic v palliative
• Importance of more accurate epidemiological data
• A study with more accurate numbers is needed
• Although there is enough to identify trends
• Should include more than just the cost of
  medication

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Other socio-economic costs

• Cost of treatment to patient
• Ancilliary health costs
• Lost productivity
• (J.P. Chippaux) Adults 14,000 days lost per
  year
• Children 9,000 days lost per year
• Loss of prime-age male 11 decrease in total
  land cultivated
• Loss of prime-aged female 3 decrease in total
  land cultivated
• Loss of male head 20 decrease in total land
  cultivated and 13 decrease in overall household
  income
• Loss of male head increases likelihood of selling
  livestock assets
• This affects a countrys GDP - ?how much

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What is needed?

• Long term Ongoing multi-faceted approach
• Standardised production
• Quality control/prequalification
• Infrastructure
• Health personnel training
• Community education
• Prevention, etc.
• Global network of collaborators to allow
  organisations, like Micropharm, to provide
  guidance and leadership for others.
• Short term financial support
• sustain those areas currently producing
  successful solutions
• Use as case studies/pilot programs!

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Conclusion

• A priority must be securing financial support
• (the system will not work without money)
• (recognise the commercial imperatives)
• Demonstrate value to those who control the purse
  string!
• Science and business must collaborate
• Ensure appropriate funding
• Support for areas currently proving successful
• Continue to improve AV effectiveness
• Continue to reduce AV costs
• Continue a multi-faceted approach

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Thank you!
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40?

• Variable costs
• Venom 2/amp
• Antisera 8 /amp (currently have 1000L in
  stock)
• 1000 ampoules 16L antisera 8000 (2000 per
  sheep)
• Manufacturing consumables 6.80/amp
• Manufacturing salaries 9.20/amp
• Sterile filling and packaging 8.20/amp
• 4.20/amp for consumables 4.00/amp for
  salaries
• QA/QC (120 amps per batch) 7.00/amp
• 7000 per batch
• 2000 for ED50 testing
• 2000 for external tests
• 1400 for in-house testing
• 1600 for salaries

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40?

• Fixed costs
• Salaries and administrative costs
• Accounting and legal
• Rent and rates
• Utilities and depreciation
• And rising
• For 24,000 amps per year (2,000/month), toal cost
  
• 35/amp while stocks of antisera are available
• (3-10years)
• 45/amp thereafter
• Could fall to 20/amp if 100,000 amps per year