CORD Mar 23-24 2022 Rare Drug Strategy Webinar

1. CORD Rare Drug Strategy
Webinar
March 23-24 2022 (virtual)
Building Canada’s Smart Rare Drug Strategy:
Meeting Patient Needs
Day 1
Old Challenges, New Opportunities for Rare Drug Access

2. Challenge 1: Delayed/denied access
across patient communities
Dr. Cheryl Rockman-Greenberg
University of Manitoba, Winnipeg, MB
Hypophosphatasia

3. Cheryl Rockman-Greenberg: Disclosures
• Scientific Advisory Board of several Pharma Boards
and Patient Advocacy groups
• Principal Investigator of Industry- sponsored clinical
trials (Sanofi Genzyme; Alexion Pharma;
Shire/Takeda Pharmaceuticals; VitaFlo; Actelion) &
Industry-Sponsored Registries
• Received honoraria for invited Symposia

4. Health Equity: Challenges the Integrity of our Public Health System

5. Hypophosphatasia (HPP)
Six clinical forms, actually a continuum of severity &
severity inversely proportional to age of onset
Odonto-HPP
Perinatal
HPP
Odonto
Adult
Childhood
Infantile
Perinatal
Prenatal
benign
Always
recessive Recessive or dominant
5
Rockman-Greenberg C. Pediatr Endocrinol Rev. 2013; 10(suppl 2):380-8.

6. HPP Infantile and Perinatal Examples
Infantile
Perinatal

7. Juvenile

8. Adult Hypophosphatasia
• Skeletal Disease (typically during middle age)
• May have history consistent with Juv HPP
(followed by clinical remission or improvement)
• Premature Loss of Adult Teeth
• Osteopenia
• Recurrent Metatarsal Stress Fractures
• Pseudogout/Chondrocalcinosis
• Femoral Pseudofractures
• Muscular or rheumatologic manifestations in most with debilitating
functional consequences- assistive devices

9. Mennonite Population: Overall survival1
1. Leung EC et al. JIMD Rep 2013; 11: 73–8.

10. Clinical Studies: Overview
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
001-08 [n=6], adult
002-08 [n=11], infants < 3yrs
003-08 [n=10], infant ext.
006-09 [n=13], juvenile
008-010 [n=12], juv. ext
010-10 [n~28], infants <5 yrs
009-10 [n=19], adolescents & adults
Age at start, in years
011-10 [n=48], infants retro

11. Survival
Asfotase Alfa Treated HPP Patients Demonstrated
Significantly Better Overall Survival Vs Historical Controls*
P<0.0001*
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
100%
0%
20%
40%
60%
80%
Historical Controls
† KM Product Limit Estimate
* KM Log-Rank test

12. Efficacy and Safety of Asfotase Alfa in Infants
and Young Children With Hypophosphatasia:
A Phase 2 Open-Label Study
J Clin Endocrinol Metab, July 2019, 104(7):2735–2747
Hofmann et al

13. The Asfotase Alfa Notice of Compliance with Conditions (NOCc)
Issued by Health Canada in September 2015
• The submitted indication to Health Canada for asfotase alfa is:
“for long-term enzyme replacement therapy in patients with
paediatric-onset hypophosphatasia”
• Asfotase alfa is Canadian discovered and developed to meet the
needs of HPP patients in Canada and around the world
• The NOCc issued in September 2015
• Alexion Canada made a submission to the CDR within 90 days
prior to NOCc
• CDR of CADTH recommended listing drug on provincial
formularies for pediatric – onset HPP for children under 18
years of age at reduced price March 23, 2016
• pCPA began negotiations price in May 2016

14. Challenges
• Making the diagnosis
• ERT approved only for pediatric –onset HPP provided ERT begins
before adulthood
• <2 dozen infants & children in Canada with HPP on ERT
• Adults with pediatric or adult onset HPP not approved for ERT
on provincial formularies
• Private insurers occasionally approve
• Compassionate access approved for ~8 adults
• Evidence poor and cost very high
• diagnostic criteria and indications for ERT in adults under
review by expert consortium
• Very heterogeneous population
• National Clinical Expert committee makes recommendations
www.Garrod.ca

15. • Craniosynostosis
• Nephrocalcinosis
• Allodynia and hyperalgia
• Improved muscle strength & reduced pain in treated
patients
• Inflammation in HPP patients?
• Is there a risk of cardiovascular complications in adult
HPP patients if treated with mineral- targetedasfotase
alfa?
What we don’t yet understand!

16. Pillars of Research
BASIC
SCIENCE
CLINICAL
TRIALS
PRECISION
MEDICINE
REAL
WORLD
EVIDENCE

17. What is Natural History?
• Refers to how a disease process progresses over time, without definitive
treatment
• HPP is highly variable clinically within and between families
• Natural history in the absence of enzyme replacement therapy well-
outlined in infants and children
• Natural history in adults with HPP whether pediatric- onset or adult – onset
less well understood but information emerging
• Can we use natural history data to inform ERT treatment criteria in
Canada?

18. The vast majority of data around patient exposure to interventions
occurs outside of traditional clinical trials
4
Copyright @2018 IQVIA, All Rights Reserved – Real World Evidence – An Industry Perspective 1
8

19. Improving the Use of Real World Evidence in
the Regulatory Environment:
Where Are We Heading in Canada?
Rhonda Kropp
Marketed Health Products Directorate, Health Canada
rhonda.kropp@canada.ca
e only

20. Current Status in Canada: We already use RWE…..
4
• Pre-Market:
• Where a conventional RCT was unfeasible or unethical & RWE was therefore submitted and assessed in lieu
• Where a product was previously approved and marketed in a foreign jurisdiction and RWE from clinical registries in the
foreign jurisdiction was used in the Canadian submission
• Post-Market:
• Submitted to address requirements in the Risk Management Plans (RMP) to address residual risks
• Monitor for adverse reactions and signals domestically and internationally
• To inform change in indications, monograph or label revisions for products already marketed in Canada
– Can ask/compel MAH to develop the evidence:
– Minister of Health can require holders of drug product (and establishment) licenses to perform tests or other monitoring related
to their products (but not NHPs) where…
– Significant uncertainties exist about the drug’s harms or benefits (or activities of license holders)
– Company is unable to provide the needed information, & it is not available through other regulatory powers
– Can undertake or solicit research: Canada’s Drug Safety and Effectiveness Network (DSEN)
– CIHR and Health Canada have partnered to establish the DSEN to increase..
» …evidence on drug safety and effectiveness available
» …capacity within Canada to undertake high-quality post-market research in this area
Transitioning to new Post-Marketing Drug Evaluation Programme
(PMDE) (CADTH)

21. RWE - Challenges & Opportunities
• Not a replacement for comparative RCT data
• Different questions require different data
• What type(s) of evidence for which decisions?
• Need “good” data on the outcomes that matter
• Quality, timeliness, efficiency
• Require collaboration & linkages
• use data collected by others
• inform subsequent data needs
• e.g., HC, CIHI, CIHR
• Appetite to re-visit decisions in light of new evidence?
28

22. HPP Registry
• The Alexion HPP Registry is a worldwide collection of data aimed at enhancing
our understanding of HPP for a better management of our patients
• https://hppregistry.com
• Multinational, multicenter, observational, prospective, long-term registry
• First initiated in 2014
• Fulfils post-marketing regulatory requirements by providing follow-up
• Contributions from academics and Alexion
• A single, global HPP Registry can best capture information on HPP, treatment
effects, safety and efficacy data
• HPP Registry has a Scientific Advisory Board (SAB) and an advocacy group
• Membership includes external clinical experts & one Alexion medical rep
• 1076 enrolled (Dec 2021); 446 <18 yrs/ 622 >18 yrs; 12 countries

23. 23 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S .
K E Y TA K E AWAY S O F T H E H P P M A N U S C R I P T S
Manuscript Key Takeaways
Seefried L, Dahir K, Petryk A, Högler W, Linglart A, Martos-
Moreno GÁ, Ozono K, Fang S, Rockman-Greenberg C,
Kishnani PS. Burden of Illness in Adults With
Hypophosphatasia: Data From the Global
Hypophosphatasia Patient Registry. J Bone Miner Res.
2020 Nov;35(11):2171-2178
Key takeaways: Adults in the Global HPP Registry have a
substantial burden of illness that is associated with reduced
patient-reported health-related quality of life, assessed by
surveys, regardless of age of disease onset.
Högler W, Langman C, Gomes da Silva H, Fang S, Linglart
A, Ozono K, Petryk A, Rockman-Greenberg C, Seefried L,
Kishnani PS. Diagnostic delay is common among patients
with hypophosphatasia: initial findings from a longitudinal,
prospective, global registry. BMC Musculoskelet Disord.
2019 Feb 14;20(1):80. doi: 10.1186/s12891-019-2420-8.
Key takeaways: The median delay in diagnosis in children
from first reported symptoms of HPP was 1.5 years, while it
was 10 years for adults with HPP. Many patients diagnosed
with HPP manifestations in childhood, highlighting the
importance of taking thorough medical histories to ensure
timely diagnosis.
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24. JOHANNES KEPLER
UNIVERSITY LINZ
Altenberger Straße 69
4040 Linz, Austria
jku.at
Wolfgang Högler
ALPL Gene Variant Database and
Consortium Project Status

25. Thank you