Webinar 2: Oct 23, 2020 (12 -1 pm ET). How can we access preventive and risk-reduction therapies: examples from rare blood disorders. What are the benefits of therapies that can prevent or reduce the risk of serious symptomology in rare diseases? What are challenges in approval of these therapies through HTA process? What are the challenges to accessing these preventive therapies through public and private drug plans? Why are these therapies especially relevant in the time of a pandemic? Cablivi to reduce risk of relapse in acquired Thrombotic Thrombocytopenic Purpura (aTTP) Reblozyl to reduce frequency of transfusions in beta-Thalassemia Hemlibra to reduce risk of bleeds in Hemophilia A Panel Discussion: What are the outcomes that these therapies provide to patients? What are the risks-benefits decisions that patients need to make (in consultation with their clinicians) about taking these therapies? How important are these therapies relative to other options for treating these conditions? Do these serve “unmet” needs? Presentation: Durhane Wong-Rieger, CORD Panel Discussion Dr. Kevin Kuo (University Health Network) Dr. Katerina Pavenski (St. Michael’s Hospital) David Page (Canadian Hemophilia Society) aTTP, Thalassemia, Hemophilia, Patient Panel

1. Countdown to:
Canada’s Rare Drug Strategy 2022
Fall 2020
- Webinar 2
Access to Preventive and Risk Reduction
October 23, 2020

2. Canada’s Rare Opportunity of a Lifetime!
v (Exp) Oct 2020: Patented Medicines Pricing Review Board new guidelines “designed
to assure non-excessive pricing of rare disease drugs”
v Sep 2020: Speech from the Throne, government committed to an overall Rare
Disease Strategy, recognizing that:
v optimal drug access is premised on accurate diagnosis, expert clinical care,
supportive programs
v Feb 2019: Canadian government committed $1 billion to a national Rare Disease
Drug Strategy to be put in place in 2022
v Jun 2019: Pharmacare for All (Hoskins Report) “distinct pathway for consideration of
expensive drugs for rare diseases and …
v “a national expert panel to work with patients and their clinicians to determine
which rare disease drugs should be funded for which patients”
v Nov 2018: Provincial/Territorial Expensive Drugs for Rare Diseases Working Group
announced the development of a Supplemental Process for managed access to
complex/specialty drugs [including rare disease drugs]
v Nov 2018: Modernization of drug regulatory process, Health Canada produced a
designated “regulatory approach to drugs for rare diseases: orphan drugs.”

3. Countdown to Canada’s Rare Drug Strategy 2022:
Webinar Series
WEBINAR 1
OCT 9
@ 12PM (ET)
Time for a
Canadian Orphan
Drug Policy
WEBINAR 2
OCT 23
@ 12PM (ET)
Preventive & Risk
Reduction
Therapies
WEBINAR 3
NOV 6
@ 12PM (ET)
Individualized
Needs for Rare
Therapies
WEBINAR 4
NOV 20
@ 12PM (ET)
Streamlined
Regulatory, HTA,
Pricing
WEBINAR 5
DEC 4
@ 12PM (ET)
Innovative
Funding for Rare
Disease Drugs

4. Cross Canada Consultation Dates (TBC)
• National consultation forum: December 2020
• Provincial consultation forums: January to April 2021
• “What We Heard” Consolidated Feedback: May 2021
• Public Consultations (Survey and focus groups): June to August 2021
• Collaborative Document: October 2021
• Ready to go on January 1, 2022

5. Webinar 2: Access to
Preventive and Risk Reduction
Why are Key Issues?
• What are the benefits of therapies that can prevent or reduce the risk of
serious symptomology in rare diseases?
• What are challenges in approval of these therapies through HTA process?
• What are the challenges to accessing these preventive therapies through
public and private drug plans?
• Why are these therapies especially relevant in the time of a pandemic?

6. Webinar 2: Access to
Preventive and Risk Reduction
Presentations/Panel
• Dr. Katerina Pavenski, St. Michaels Hospital
• Dr. Kevin Kuo, University Health Network
• David Page, Canadian Hemophilia Society
• Persons Living With Rare Blood Disorders
• Yhulan, Uzma, Leanne
• Moderator: Durhane Wong-Rieger, CORD

7. Caplacizumab for Treatment of
Immune (acquired) Thrombotic
Thrombocytopenic Purpura
K. Pavenski, MD FRCPC
October 23 2020
Canada Rare Disease Drug Strategy-Webinar 2

8. TTP: Presentation and Epidemiology
• MicroAngiopathic Hemolytic Anemia (MAHA)
• Anemia
• Fragments (schistocytes) on blood film
• Evidence of hemolysis
• Thrombocytopenia
• Microvascular Thrombosis –heart, brain, kidney
• Annual incidence of acquired TTP estimated at 2.17
cases per million (about 200 episodes/year in Canada)
• Affects mainly adults
• Peak incidence in the third to fifth decades of life
• Female to male ratio: about 3 to 1
George & Nester NEJM 2014; Scully et al JTH 2017; Kremer Hovinga et al Nature Reviews 2017
Image: Bhandari and Kumar NEJM 2019

9. TTP: Pathophysiology
• TTP is defined by severe ADAMTS13 deficiency
• ADAMTS13 is a disintegrin and metalloprotease with thrombospondin type 1 motifs-13
• Cleaves VWF within the central A2 domain
• Severe deficiency = activity <10% or <0.1Units
• Types of TTP
• Hereditary (rare) – deficiency due to defect(s) in ADAMTS13 gene
• Immune (>90% of adult cases) – deficiency due to IgG autoantibody
Camilleri et al 2012; Rieger et al 2005; Pos et al 2011; Kremer Hovinga et al Nature Reviews 2017

10. TTP: Pathophysiology
Kremer Hovinga et al Nature Reviews 2017

11. Immune (Acquired) TTP: Treatment
Joly et al 2017
Standard of Care in Canada:
1) Plasmapheresis
2) High dose steroids
3) Rituximab for refractory
or relapsed disease
Platelet count determines
when plasmapheresis is
stopped

12. TTP: Acute Complications
• Heart:
• myocardial ischemia or infarction, arrhythmia
• 54% have abnormal cardiac enzymes
• Brain:
• imaging: microangiopathic changes, microbleeds, territorial infarction
• 53% have severe neurologic abnormalities (transient focal events most
common)
• Kidney:
• 48% have acute kidney injury stage 1 or higher
• Mortality:
• With plasmapheresis (+/-immunosuppression): 10-20%
• Untreated: >90%
Hughes et al. J Thromb Haemost. 2009; 7: 529–36; Noorbakhsh-Sabet N, et al. J Stroke Cerebrovasc Dis. 2016; 25:e214–e215.

13. TTP: Long-term Complications
• Lifetime risk of relapse is about 40%
• Permanent neurological deficits
• Persistent cognitive abnormalities
• May see progressive decline even in the absence of relapse
• More frequent/worse headaches vs sex-matched controls
• Increased incidence of depression
• Increased incidence of HTN when compared to age/sex/race-matched controls
• Increased incidence of pregnancy-related complications
• Worse health-related quality of life
• No improvement seen within 5 years even in the absence of relapse
Ben-Yehuda et al. Am J Hematol. 1988; 29:74-8; Kennedy AS, et al Transfusion. 2009; 49:1092-101; Cataland et al. J Thromb Haemost. 2015; 13 Suppl 1:S223–9;
Han et al. Am J Hematol. 2015; 90:709-14; Falter T, et al. Transfusion. 2017; 57:1152–1162; Saultz et al. Ann Hematol. 2015; 94:1473-6; Deford CC et al. Blood.
2013; 122:2023–2029; Scully et al. Blood. 2014; 124:211-9; Lewis QF, et al. Transfusion. 2009; 49:118-24.

14. Caplacizumab
• Nanobody which specifically neutralizes platelet receptor GPIb preventing
adhesion of platelets to VWF and thus formation of microthrombi
• Intended to be used in addition to standard therapy (plasmapheresis +
immunosuppression)
• Start as soon as diagnosis is made, continue daily during plasmapheresis and extend
for up to 30 days after cessation of plasmapheresis
• 2 randomized controlled trials – TITAN and HERCULES
• Total participants: 108 in caplacizumab arm versus 112 in placebo
• Major findings
• Caplacizumab significantly reduces time to platelet count normalization
• Favourable side effect profile: mild mucocutaneous bleeding

15. Caplacizumab
• Other findings
• Reduces mortality and refractory disease
• Reduces the incidence of a composite endpoint of TTP-related death,
exacerbation, or ≥1 major thromboembolic event during treatment
• Prevents recurrence of disease during treatment (exacerbations)
• Reduces days on plasmapheresis (5 vs 7.5 days)
• Reduces days in critical/intensive care unit and days in hospital
The trials also showed that all patients with ADAMTS13 activity below 10% at the end of treatment are likely
to exacerbate/recur:
recommended monitoring of ADAMTS13 activity AND further immunosuppression (ex. adding Rituximab)

16. Caplacizumab
• Both INESS and CADTH recommended against reimbursement of
caplacizumab
• CADTH cited limitations in the design of RCTs as the main reason
• Platelet count was the primary outcome, not clinically important outcomes
• Follow-up not long enough
• Disease is heterogeneous, therefore unable to identify a group most likely to benefit
• Of note, the most significant study in TTP which randomized patients to
plasmapheresis versus plasma infusion (responsible for improvement in
TTP mortality from >90% to <20%) enrolled 102 patients and used platelet
response as primary outcome (Rock et al, NEJM 1991; 325:393-397)

17. Living with Thalassemia in
Canada
CORD Consultation Toward Canada’s Rare Disease Drug Strategy
Session 2
October 23, 2020
Kevin H.M. Kuo, MD, MSc, FRCPC
Clinician-Investigator, Red Blood Cell Disorders Program, Therapeutic Apheresis Program,
Division of Medical Oncology and Hematology, University Health Network
Assistant Professor, Division of Hematology,
Department of Medicine, University of Toronto

18. Conflict of Interest Disclosures
• Grants/Research Support: NHLBI/NIH: 1R33HL147845, Thalassemia
Foundation Canada, Peter Munk Cardiac Centre, University of Toronto,
Cincinnati Children's Hospital Medical Center, Canadian Hematology
Society, Pfizer;
• Consultancy: Agios, Alexion, Apellis, Aruvant, Bluebirdbio, Celgene/BMS,
Novartis, Pfizer
• Chair of Data Safety Monitoring Board: Bioverativ/Sanofi (ZFN gene editing
trial for sickle cell disease NCT03653247)
• Research collaboration: Phoenicia Biosciences, Abfero
• Research funding: Pfizer
• Site-PI: ACE-536-B-Thal-001
• Lead investigator: AG-348-C-010

19. Caring for Transfusion-Dependent
Thalassemia (TDT) Patients in Canada
• Canadian estimate is ~600 (1.6 per 100,000)
• Data accuracy is limited by lack of a national registry
• ~170 TDTs, ~13 new patients per year (mainly immigration)

20. Types of Thalassemias
• Phenotypic severity is driven in a large part by the degree of Imbalance
in globin chain production
a b
a
b
a bE
bA / bA
b0 / b0
bE / b+ or bE / b0
Normal
a b a b+a b+
bA / b0
b+ / b0b+ / b+
Trait
Major
Intermedia
a a a
(+ aaa or aaaa)
Intermedia
Transfusion-Dependent

21. The Paradoxical Logic in Thalassemia Care
Transfusion
Iron
Overload
Chelation
Chelator
side-effects
Diabetes
Hypothyroidism
Hypogonadism
Cirrhosis
Cardiomyopathy
Treatment
Side-effect

22. Journey of TDT patients in Canada
3 Seldom performed due to risk of infection,
thrombosis, pulmonary hypertension, and
accelerated iron loading
Birth
4 yrs
4 mo
Puberty
12 yrs
18 yrs
Bone Marrow Transplant
(< 1%) 1
1 Limited by donor availability and toxicity
Splenectomy 3 to reduce
transfusion burden
Transfusion
Labs &
Imaging
Drug
Therapy

23. Luspatercept is an erythroid maturation agent that neutralizes
select TGF-β superfamily ligands to inhibit aberrant Smad2/3
signaling and enhance late-stage erythropoiesis
ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; TGF-β, transforming growth factor beta
Attie KM, et al. Am J Hematol. 2014;89:766-770; Suragani RN, et al. Nat Med. 2014;20:408-414.
Modified
extracellular
domain of
ActRIIB
Human
IgG1 Fc
domain
Luspatercept
ActRIIB / IgG1 Fc recombinant
fusion protein
Cytoplasm
Nucleus
Erythroid maturation
Smad2/3
Complex
P
TGF-β superfamily
ligand
ActRIIB

24. BELIEVE trial study design
a β-thalassemia or hemoglobin E / β-thalassemia (β-thalassemia with mutation and / or multiplication of α-globin was allowed. b RBC transfusions and iron chelation
therapy to maintain each patient’s baseline hemoglobin level. c The trial is fully enrolled and patients continue to receive treatment or follow-up.
BSC, best supportive care; RBC, red blood cell; s.c., subcutaneously.
β-thalassemiaa
patients
≥ 18 years, requiring
regular RBC
transfusions
(defined as:
6–20 RBC units in the 24
weeks prior to
randomization with no ≥
35-day transfusion-free
period during that time)
(N = 336)
Luspaterceptb
1 mg/kg s.c. every 21 days + BSC
(n = 224)
Placebob
s.c. every 21 days + BSC
(n = 112)
Post-
treatment
follow-up
(3 years)
Randomized
2:1
Study
unblinding
12 week period
historical
transfusions
Double-blind period
(48 weeks)
Crossover permitted
Open-
label
(up to 5
years)
12-week period
screening / run-in
transfusions
May be titrated up to 1.25 mg/kg

25. Primary and key secondary outcomes
Primary endpoint:
• 21.4% luspatercept-treated patients achieved a ≥ 33% reduction from
baseline in transfusion burden during weeks 13 to 24, vs. 4.5% in
placebo (OR 5.79, 95%CI 10.4–23.6, P < 0.0001)
Key secondary endpoints:
• ≥ 33% reduction, weeks 37–48:
• 19.6% vs. 3.6% (OR 6.44, 95% CI 9.8–22.3, P < 0.0001)
• ≥ 50% reduction, weeks 13–24:
• 7.6% vs. 1.8% (OR 4.55, 95% CI 1.6–10.1, P = 0.0303)
• ≥ 50% reduction, weeks 37–48:
• 10.3% vs. 0.9% (OR 11.92, 95% CI 5.0–13.7, P = 0.0017)

26. Mean change in iron parameters from
baseline by response status
-500
-400
-300
-200
-100
0
100
200
300
Meanchangeinserumferritin
frombaseline(µg/L)
Luspatercept
Placebo
All patients
Responders
0.23
0.10.16
0.99
-0.38
-1.33-1.5
-1
-0.5
0
0.5
1
1.5
2
Week 48 Week 96
Serum ferritin LICc
Number of patients 207 151 165 130 101 32 202 159 88 76 103 38
Week 48
Week 48
Week 96
Week 48
Luspatercept
Placebo
Improvement
Improvement
Change of Iron Parameters from baseline at week 96 Luspatercept (N = 223)
Serum ferritin: ≥ 1,000 to < 1,000 μg/L 42/98 (42.9)
LIC: > 15 to ≤ 15 mg/g dw 11/25 (44.0)
Cardiac MRI T2*: ≤ 20 ms to > 20 ms 3/14 (21.4)

27. Grade ≥ 3 TEAES by frequency ≥ 1% in Either Arm
a Safety population. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DVT, deep vein thrombosis; PE, pulmonary embolism;
TEAE, treatment-emergent adverse event.
Grade ≥ 3 TEAEs (≥ 1% of Patients in Either Arm), n (%)
Luspatercept
(n = 223a)
Placebo
(n = 109a)
Anemia 7 (3.1) 0
Increased LIC 6 (2.7) 1 (0.9)
Hyperuricemia 6 (2.7) 0
Hypertension 4 (1.8) 0
Syncope 4 (1.8) 0
Back pain 3 (1.3) 1 (0.9)
Bone pain 3 (1.3) 0
Increased AST 3 (1.3) 0
Increased ALT 2 (0.9) 3 (2.8)
• There were 2 (0.9%) grade ≥ 3 thromboembolic events reported in the luspatercept arm
• Thromboembolic events (all grades) including DVT, PE, portal vein thrombosis, ischemic stroke, thrombophlebitis
superficial/phlebitis, were reported in 8 of 223 (3.6%) luspatercept versus 1 of 109 (0.9%) placebo-treated patients; in all cases
the assignment of causality was confounded by patients having multiple additional risk factors

28. A.B.
• 34 year-old female
• Beta-thalassemia major (b0/b0)
• Transfusion-dependent since age 1
• indication: failure to thrive, severe symptomatic anemia
• Splenectomy at age 3 but failed to reduce transfusion burden
• On deferoxamine sc 5-7 nights/week from age 9 to 20
• On deferasirox po (dissolvable) from age 21 to 29
• Transfusion stabilized at 3 units every 4 weeks in adulthood
• Reduced adherence due to deferasirox-induced diarrhea led to severe hepatic
and moderate cardiac iron overload, resumed deferoxamine IV for 3 years
• Changed to low dose deferasirox po and deferiprone po combination therapy

29. A.B.
• Joined BELIEVE trial on 2 years ago
• Transfusion burden reduced to 1 unit every 3 weeks
• Liver iron concentration normalized from 4.0 to 1.0 mg/g dw
• Currently on low-dose deferasirox (jadenu 10 mg/kg daily) single
agent chelation therapy

30. C.D.
• 25 year-old gentleman
• Transfusion-dependent thalassemia (HbE/b0 + quadruplicated a)
• Began transfusion at age 3
• Deferoxamine sc until age 14, then switched to deferasirox
• Moderate adherence to deferasirox
• 4 units of RBC every 4 weeks as an adult
• Joined BELIEVE trial on 2 years ago
• Transfusion burden reduced to 2 unit every 3 weeks
• Liver iron concentration remained stable between 2.0 and 5.9 mg/g dw

31. Conclusions
• Management of thalassemia syndromes traditionally has relied on chronic
transfusion and iron chelation
• The unsustainability of this strategy is the chief reason for development of
complications from transfusion and iron overload
• Luspatercept is the first disease modifying agent for thalassemia
• Luspatercept showed a statistically significant improvement in the primary
endpoint of ≥ 33% reduction in transfusion burden compared with placebo, as
well as all secondary endpoints
• There was a trend for decrease in LIC with longer follow-up at 96 Weeks; the
decrease was more pronounced among responders versus non-responders
• Luspatercept was generally well tolerated in this patient population

32. Improving Patient Outcomes and
Reducing the Burden: Hemlibra in the
Treatment of Hemophilia A
CORD Consultation Toward Canada’s Rare Disease Drug Strategy
Autumn 2020 Webinar Series – WEBINAR 2, October 23
David Page
National Director of Health Policy
Canadian Hemophilia Society

33. What is hemophilia?
Bleeding into
muscles and soft
tissues
Bleeding into knees and
ankles
Bleeding into
elbow joints
Following trauma or for no apparent cause

34. • Replacement of missing factor
VIII by IV infusion
• By patient or caregiver at home
• 2 – 3 infusions per week
• Efficacious in 90% of severe
cases (10% develop FVIII
antibodies)
• Normal life expectancy … but
• Patients continue to have
bleeds (1 to 12 per year)
• Joint damage still occurs
What is current treatment?

35. • CVADs often used
in babies and
young children
• High burden of care
• Risk of infection
and thrombosis
What is current treatment?

36. • FVIII has a
short half-
life
• Infusions
need to be
frequent
• 3 IV
infusions
per week
• Goal:
trough level
of 1% of
normal
factor VIII
A typical week

37. • A monoclonal antibody
that mimics factor VIII
• Injected subcutaneously
once a week to prevent
bleeding
• Steady state hemostasis
• Equivalent to a factor VIII
level of 10% - 15% of
normal
• Efficacious in 99.9% of
people (0.1% develop anti-
drug antibodies)
What is Hemlibra (emicizumab)?
• Patients have fewer
bleeds (average of 1)
• Less joint damage in
long term? Too early
to say

38. FVIII Hemlibra
Pros
• Human molecule (almost)
• Long history
• Safe (except for inhibitors)
• Efficacious if given
frequently
• High peak levels
• Mono therapy
Cons
• IV infusion
• Difficult adherence
• Inevitable joint damage
• 10-30% inhibitor rate
• Low protection near trough
levels (1% of normal)
Pros
• Steady-state hemostasis (10-
15% of normal)
• No troughs
• Improved efficacy
• Sub-cutaneous injection
• Easy adherence
• Patient preference
• Extensive research (400
subjects)
• Wide use (7000+ patients)
Cons
• Short experience
• No peak levels
• Need for FVIII for surgery
• More costly?

39. Non-treatment direct
savings
• Hospitalization
• Emerg visits
• Visits to physicians and HCPs
• Pathology tests
• Diagnostic imaging
• Other medications
• Alternative therapies
• Professional caregivers
• Residential care
• Transport
Savings with Hemlibra’s improved efficacy
Indirect savings
• Disability support
• Productivity
• Work absenteeism
(patients and caregivers)
• Work presenteeism
(patients and caregivers)
* Brown LJ, La HA, Li J, Brunner M, Snoke M, Kerr AM. The societal burden of haemophilia A.III –
The potential impact of emicizumab on costs of haemophilia A in Australia. Haemophilia.
2020;26(Suppl. 5): 21–29. https://doi.org/10.1111/hae.14082
We found a 30.7% reduction in non-
treatment direct costs (AUD$3.77M)
and a 19.1% reduction in indirect costs
(AUD$2.73M).*

40. In February 2019, in an analysis for CBS, CADTH
concluded Hemlibra had a very, very large budget
impact compared to factor VIII. CADTH …
• did not consult with the patient or physician
associations;
• compared apples with oranges in terms of pricing
(list price for innovation vs. negotiated price for
comparator);
• wildly exaggerated numbers of patients and uptake
of therapy.
Garbage in, garbage out!
Barriers to access: HTAs, HTAs, HTAs …

41. In December 2019, INESSS concluded “lack of
evidence of non-inferiority” of Hemlibra compared to
factor VIII and recommended it not to be funded.
INESSS …
• accepted low annual bleed rates cited for
comparator products in very small studies;
• rejected evidence of low annual bleed rates with
Hemlibra despite much larger studies;
• consulted a single physician with known bias;
• discounted patient perspective on burden of
treatment and lack of efficacy of current
treatments.
Barriers to access: HTAs, HTAs, HTAs …

42. Our experience is that Canadian HTA bodies …
• don’t properly consult the patient community and
discount their experience in the actual decision;
• don’t properly consult the medical community and
rely on single voices;
• don’t adjust to the reality of rare diseases and
small numbers in research;
• don’t take into account real-world treatment costs
and actual drug prices;
• don’t take into account the non-drug-related
savings of innovative therapies.
Barriers to access: HTAs, HTAs, HTAs …

43. Thank you!