Rare Disease Day 2016 Conference: Day 1

1. Advances in the Care and Treatment of
Hemophilia A and B
Rare Disease Day
Ottawa, March 9, 2016
David Page
National Executive Director
Canadian Hemophilia Society

2. Incidence of bleeding disorders
Incidence # of cases
in Canada
# of
cases in
world
Hemophilia A 1 in 10,000 3091 600,000
Hemophilia B 1 in 50,000 694 120,000
von Willebrand
disease
1 in 1000
symptomatic
30,000 6 million
8 rare factor
deficiencies
1 in 250,000 to
1 in 5,000,000
800 150,000
Platelet function
disorders
? ? ?

3. What is hemophilia?

4. What is hemophilia?
• Recessive sex-linked inheritance
• Caused by a deficiency in one of the
proteins involved in blood coagulation
(factor VIII or IX)
• Severe form usually affects only males
• Women are carriers (and can suffer
symptoms themselves, usually not as
severe)
• Severe cases manifest in first year of life
• Life-long
• No cure (yet)

5. Current situation in the world
75% of people with hemophilia
receive little or no treatment
§ Life expectancy: 20 years
§ Those who survive suffer
terrible pain and become
physically disabled

6. Treatment
• IV infusion of factor
VIII and IX concentrates
(plasma-derived or
recombinant)
• Home infusion, 2 – 3
times per week
• Goal: Minimum of 1%
of normal level of FVIII
and IX
• Efficacious (except in
presence of inhibitor!)

8. Health care environment
• Based on inter-disciplinary
comprehensive care
• National network of 25
centres across Canada
• Very expensive disease to
treat
• $60,000 to $400,000 per year
per patient with severe
hemophilia
• Rare cases (inhibitors) even
more expensive
• 10 to 12 pharmaceutical
companies in global market
• Total sales world-wide: $6 to 8
billion

9. What is new and exciting?

10. Extended half-life factor concentrates
• Introduced in Canada in 2016
• Factor VIII
• FVIII molecule fused with immune globulin
• Half-life increased from 12 to 18 hours
• # of infusions reduced from 3 to 2 per week
• 52 fewer infusions per year
• Factor IX
• FIX molecule fused with immune globulin or albumin
• Half-life increased from 18 to 45 or 90 hours
• 1 infusion per 7 or 10 days, instead of 2 per week
• 52 to 78 fewer infusions per year
• Potential for increased protection from bleeding
(1% is not enough!)

11. Innovative non-factor concentrates
• ACE-910
• A bi-specific
monoclonal antibody
that mimics coagulation
factor VIII
• Half-life of 3 weeks
• Sub-cutaneous infusion
• Can treat people with
FVIII with or without
inhibitors
• In Phase III trials
• Breakthrough
designation and
expedited review from
FDA

12. Innovative non-factor concentrates
• ALN-AT3 (fitusiran)
• A subcutaneously
delivered RNAi
(interference)
therapeutic
• Down-regulates
antithrombin by 80%,
thus increasing
thrombin generation
• Potential across many
bleeding disorders
• Entering Phase III trial
• Once-a-month dosing

13. Gene therapy
• Factor IX
• At least 6 Phase I/II
clinical trials underway
• Using adeno-
associcated virus
(AAV-5 or 8) vectors
• A single IV infusion
targeting liver
• Several studies show
>5% expression in
certain subjects after
more than two years
• Factor VIII
• One Phase I/II trial
underway
If successful, how much
will one shot cost?

14. Advances in clinical care
• Individualized care
• Pharmacokinetic (PK) dosing (rather than weight-based)
based on individual recovery, half-life and bleeding
patterns
• Potential to improve outcomes without increasing
utilization (or cost)
• WAPPS-HEMO (Web-Accessible Pharmacokinetics Service
(independent research and infrastructure at McMaster)
The WAPPS-Hemo project is a centralized, web-accessible,
database that allows hemophilia centres to input factor VIII/
IX plasma levels from 2 to 3 samples of their patients,
returning individual pharmacokinetic estimates (PK).

15. Patient registry
• The Canadian Bleeding Disorder Registry (CBDR)
• Launched in June 2015 by clinician group (AHCDC) and
McMaster University, copied on Australian BDR, with
support from CHS (replaces CHARMS and CHR)
• To be implemented in all Canadian treatment centres by
end of 2016
• It includes:
• Clinical module to complement hospital electronic
patient record (CBDR)
• Patient module to record bleeding events and home
infusions, and transmit information to clinicians via
computer application and smartphone app (MyCBDR)
• A national patient registry
• National database for utilization monitoring and
health outcome research

16. David Page
Treatment Date/Time:*
Treatment Type:*
Product:* Select Product
Treatment Notes:
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17. Patient organization assessment of
health services
• Conducted by CHS in 2014-15 with support
of treatment centre personnel
• The assessment included:
• A one-day visit to each centre in Canada
• Interviews with 152 health care providers in
these centres
• Patient satisfaction survey with 350 responses
• Vetting of reports by centre directors

18. Patient organization assessment of
health services
• Results
• 24 individual centre reports provided to treatment
centres, hospitals, regional health authorities and
Ministries of Health, which included…
• Strengths and weaknesses of centres with regard to accepted
Standards of Care
• Recommendations for local improvements (staffing levels, provincial
integration, monitoring of factor concentrate use …)
• Patient-reported evaluation of services
• A national report called Penny-wise, Pound-foolish with
observations and key national recommendations
(http://www.hemophilia.ca/en/care-and-treatment/penny-wise--
pound-foolish---the-national-clinic-assessment/)
• A paper published in the medical journal, Haemophilia
(March 2016)

19. Particularities of hemophilia (advantages?)
• Rare but not ultra-rare
• Severe symptoms, often fatal if untreated, easily
diagnosed early in life
• Efficacious therapies (in most cases)
• High value of therapies
• $$ for research
• $ for community support
• Multiple pharmaceutical players
• Prospect of a cure
• 60-year tradition of patient-physician
collaboration, both in Canada and internationally

20. 10 lessons to be learned
1. Collaborative national network of centres
2. Collaborative national and international research
3. Robust patient registry and research database
4. National standards of care
5. National collaboration and sharing of best
practices among core teams (physicians, nurses,
physiotherapists and social workers)
6. Patient association involvement in health care
design and evaluation
7. Inter-disciplinary approach to comprehensive care
8. Centralized care with outreach
9. Patient association advocacy
10. Time and tenacity

21. Thank you
dpage@hemophilia.ca