Rare Disease Day 2016 Conference March 9 - 10 Day 2

1. Developing an Orphan
Drug in Canada
ASFOTASE ALFA (STRENSIQ®) AN ENZYME REPLACEMENT THERAPY FOR
HYPOPHOSPHATASIA (HPP)
LESSONS FROM THE ENOBIA STORY

2. What is Hypophosphatasia (HPP)
Inherited disease of bone mineral metabolism
Caused by muta4ons in the gene encoding Tissue Non Specific
Alkaline Phosphatase (TSNALP)
Important role in controlling bone mineraliza4on
Inac4va4ng muta4ons lead to:
◦ Rickets (in children)
◦ Osteomalacia (soH bones) in adults
2

3. HPP: A Highly Variable Clinical PresentaNon
3
• Perinatal
• InfanNle
• Childhood
• Adult
• Odonto
AgeofdiagnosNc
Severity
Published incidence: 1/100,000 for most severe cases

4. HPP: An Obvious Candidate for Enzyme Replacement
Therapy
Aim: Reintroduce bone levels of TNSALP compa4ble with normal
mineraliza4on
Asfotase alfa: a bone-targeted form of TNSALP
First-in-class, bone-targeted enzyme
replacement therapy (ERT) for HPP
Administered by SC injec4on
4

5. Asfotase alfa Prevents Mineralization
Defects
5
5 5
Abnormal Normal
Vehicle (16) 14 2
ENB-0040 (21) 0 21
Radiographs of representative
left foot
specimens
Distribu(on of bone a/er blind assessment of
Faxitron X-ray images
Akp2-/-
Tx
WT
Day 44
Akp2-/- WT
Day 18
Mineraliza(on of feet were improved
(p<0.0001) at 44 days

6. Asfotase Alfa Increases Survival in Akp2-/- mice
6
0 5 10 15 20 25 30 35 40 45
0
25
50
75
100
Vehicle
ENB-0040
WT
Days
Percentsurvival
P< 0.0001
• Median survival of Akp2-/- mice in the Vehicle group was 20 days
• At end of study 95% of ENB-0040 treated Akp2-/- mice were alive

7. First patient ever treated with asfotase alfa: very severe case of
infantile HPP
7 Whyte MP, Greenberg CR, Salman NJ et al. Supplement. NEJM. 2012. 366;10.
Dr Cheryl Greenberg
Department of Pediatrics
& Children’ Hospital University of
Manitoba

8. First patient ever treated with asfotase alfa: very severe
case of infantile HPP
Treatment is con4nued for life
Administra4on of the drug is through
subcutaneous injec4ons
Injec4ons are done at home and do not
require lengthy infusions in hospital
8 Whyte MP, Greenberg CR, Salman NJ et al. Supplement. NEJM. 2012. 366;10.

9. Treated
Patient Age (Years)
Survival
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Patients at Risk (Historical Controls):
48 20 14 13 11 9 8 8 6 6 6 5 5 4 3 3 3 3 3 1 0
Patients at Risk (Treated):
37 33 26 22 18 15 8 4 2 0
100%
0%
20%
40%
60%
80%
Historical controls
Survival after Treatment with Asfotase Alfa
† KM Product Limit Estimate* KM Log-Rank test 9

10. Health Research in Canada
Very healthy indeed
Canadian health science research performance is within the top 5 in
the world (several metrics)
Well suited for research in rare diseases
◦ Strong emphasis in collabora4ve research
◦ Strong links between basic scien4sts and clinicians
◦ Data sharing/biobanks
◦ Network and Centers of Excellence
◦ Worldwide recogni4on for its excellence of gene4c research

11. Health Benefits of InnovaNon
Innova4ve medicine save moneys
For every dollar spent on new medica3ons, non-medica3on healthcare expenses
dropped by more than seven dollars
Economic benefits of pharmaceu4cal spending in Ontario from 2007 to
2012 “…spending $1.22 billion generated offseAng health and societal
benefits of nearly $2.44 billion—a 2:1 benefit-to-cost ra3o that
increases over 3me.”
Data provided by Conference Board of Canada (2013).
See: hgp://innova4vemedicines.ca/about/

12. Spin-off Companies as Motors of the
Economy
Companies spun-off from university laboratories that commercialize
intellectual property are significant drivers of innova4on
Canadian spin-offs are created at a much higher rate per research
dollar than in the U.S. (both in IT and biotech fields)
(Reports from the Associa4on of University Technology Managers)
Survival rate of spin-offs are low in Canada

13. Canadian Spin-off Failure
“…if Canadian universi3es were as effec3ve in
genera3ng commercial benefits as their American
counterparts, they would have contributed $1.5 billion
more in economic benefits and generated 12,788
more jobs in 1997 than was actually the case.”
(Advisory Council on Science and Technology )

14. Why do Spin-offs Fail in Canada?
Premature out-licensing of technology by universi4es
◦ Not mature enough=low valua4on
◦ Few resources (money and staff in University OTTs)
◦ Inadequate transla4onal research funding
◦ Patent filing support limited to ini4al phase (oHen
provisional filing)
◦ Canadian scien4sts are mostly ignorant of commercial
ventures

15. Why do Spin-offs Fail in Canada?
Venture capital
◦ S4ll hesitant inves4ng in untested markets (orphan vs big
disease)
◦ Exit strategy driven by quick profit
◦ Private transac4on with foreign company preferred
◦ Companies unlikely to go public (long term sustainability)

16. Canadians don’t have Nmely access to
innovaNve medicines
Canadians wait over 460 days to get access to new,
poten4ally life-saving medicines in public drug plans
Many new approved medicines are not reimbursed at
all

17. Conclusions
It is possible to develop a drug for a rare disease in Canada
It is much harder to con4nue its development 4ll marke4ng
◦ Pa4ents wait longer to get access to innova4ve drugs
◦ Canadian economy suffers
Possible remedies for Canada:
◦ Streamline complex and slow regulatory system
◦ Increase investments into transla4onal and clinical research for innova4ve
therapies
◦ Develop a workforce capable of bringing the product to the market
◦ Impose a lower tax rate on profits made by Canadian companies when they
market innova4ve products in Canada

18. Thank You

19. The Patent Drain in Canada
Biotechnology patent filing: consistently ranked 5 in the world
Net ouklow of IP: 8 % of patents filed by Canadian inventors are
assigned to foreign owners (Compiled by Science-Metrix from USPTO
data)
◦ Research done in Canada by subsidiaries of foreign firms
◦ Selec4ve in-licensing of patents where inven4on is reduced to prac4ce
◦ By comparison:
◦ US has net inflow of patents
◦ Big winners for inflow of patents are countries such as Switzerland with strong pharmaceu4cal
industry

20. The Patent Drain in Canada: the Worst is
yet to Come
Patent drain not likely to improve in the future
◦ Restructura4on of big pharma
◦ Minimizing early drug development risk through partnering with
academic lab
◦ Contractual research: inventors oHen assign their IP rights to
sponsor
◦ Big pharma more and more entering rare disease markets
◦ Major biotech companies likely to follow trend