Arizona Center for Innovation (AzCI) presents: Antivenom FDA Approval - a case study from the University of Arizona This presentation is part of a series developed for a workshop on "How to Navigate the Biotech Regulatory Process" The Arizona Center for Innovation is an incubator and innovation center and provides resources in support of startups getting to the next level and become successful enterprises.

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6. Leslie Boyer, MD
Director, Venom Immunochemistry,
Pharmacology and Emergency Response
(VIPER) Institute
Perspectives from Academe
Antivenom Development

7. Disclosure
• This speaker has every conflict of interest in the
book. I have been an investigator, an expert
witness, a consultant, a member of the
speaker’s bureau, and/or a gadfly for every
manufacturer and distributor of antivenom in the
US or Mexico excepting possibly Merck and
Birmex.

8. Antivenom is Antibodies
• Serotherapy (1st
generation)
• Immunotherapy (2nd)
• “Fabotherapy” (3rd)

9. There is a global shortage of
antivenom.
WHO, 2007: envenomation is a neglected
worldwide disease: 5M cases, 200K deaths.

10. Why we care
• Approximately 2,000,000 cases /year, worldwide
• Approximately 100,000 deaths
• Disability from amputation, contractures
• Worldwide, pharma has been getting out of the
antivenom business, leaving a huge medical and
economic gap
• Venoms are biologically fascinating, full of potential for
development of future pharmaceuticals and other
chemicals

11. Pre-1960
• MYN
• Zapata
• Inst de
Higiene
1960-1990
• Pharma
• I de H ->
Birmex
1990-now
• Bioclon
• Birmex…
Pre-1960
• Mulford
• Merck
• Myn
• Wyeth ACP
• ASC
• Serpentaria
1960-1990
• Merck
• Wyeth
• ASU
• Zoos
• Bill Haast
1990-now
• Merck…
• Wyeth…
• Protherics
• Bioclon
• Zoos
Antivenom Availability in the U.S.
Antivenom Availability in Mexico

12. Antivenom Approvals, FDA
• 1927Viper (Mulford)
• 1936 BlackWidow (Merck)
• 1949 Scorpion (Myn)
• 1954 ACP (Wyeth)
• 1967 Coral (Wyeth)
• 2000 CroFab (Protherics)
• 2011 Anascorp (Bioclon)

13. The technological challenge
Old recipe, new rules: how to apply/ improve a
known concept to make safe, effective, but
low-cost antidotes

14. What “N” does it take?
Product Eligible/yr Phase 2 and 3 trials Ratio
Merck Latrodectus 1000 ? ?
Wyeth Polyvalent 1000 ? ?
Wyeth M. fulvius 50 Efficacy panel N/A
Tab/Protherics
CroFab
4000 42 1%
BioclonAnascorp 150-15,000 15-2000 10% - 13%
BioclonAnalatro 2500 1oo??? 10%???
BioclonAnavip 4000 >100??? 2.5%???
Coral???? 50-100 55??? 100???
Exotic (typical) <1 ? ?

15. Working with a small N and a potential market
Challenge of endpoint
selection for statistics
Logistical challenge of
multicenter design
Cost justifiable to Pharma
because there is a good
chance of later profit
“Normal” INDA with
industry sponsor

16. Working with a small N and a public health problem
Antivenom recipients recovered faster,
required less midazolam, and had lower
venom levels than placebo recipients.
NEJM, May 14 2009
• Ethical challenge of placebo
design
• Funding challenge, requiring
grants for rare condition
• Difficult for industry to justify
• “Normal” INDA but with very
close academic collaboration

17. Working with a very small N
• NOT worth the investment
for Pharma
• Investigator-sponsored
INDA
• Public Health involvement
• Grant funded
• Blood Products Committee
found clinical trials “neither
ethical nor feasible”
• Historical Controls
• Is a snake a “weapon”?
• Future licensure very
uncertain

18. Working with an N of 1
• Readiness for exotic snakebite is analogous to
military preparedness. We have millions of
cobras, mambas and other snakes in US homes
and collections.
• The most obvious answer is emergency depots
kept for public use. But lacking a legal
mechanism for this, we use zoos as our
national system.
• “Zoo INDA” mechanism is related to
Emergency Use IND.
• Essentially no physicians comply with the
regulations.

19. If licensure is NOT feasible:
http://www.fda.gov/cber/ind/antiven.htm#import
But who pays
attention to quality
and safety here?

20. The future
• US public policy: orphan drugs, exotic antivenoms, coral
snakes and zoos: we need a national antivenom policy
• FDA rules: public health exemption from PDUFA fees for
antivenoms should be explicit; animal rule should be
applicable under established guidance in cases where low
N make studies neither ethical nor feasible
• The world: we need legal, ethical and cost-effective ways
to collaborate internationally on neglected tropical
diseases that occasionally affect Americans.

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©Arizona Center for Innovation 2015