This document summarizes a presentation on inborn errors of metabolism (IEM) and the multidisciplinary clinical trials research team in Winnipeg (MDCTRT). It discusses the challenges of treating individually rare but collectively common IEM disorders. It outlines the multidisciplinary team approach used including multiple health professionals. It provides an overview of the MDCTRT's goals to establish infrastructure for IEM clinical trials and registries to contribute evidence on new treatments and improve patient outcomes. An administrative leave was also used to enhance documentation of patients in clinical trials and registries and establish strategies for innovative IEM research and treatment access nationally.

1. Rare Disease Day Conference
March 5-7, 2015
Day 1
Canadian Strategy for Rare Diseases

2. Multidisciplinary teams for diagnosis
and treatment of children (and adults)
with inborn errors of metabolism
Dr. Cheryl Rockman-Greenberg

3. Disclosure
Scientific Advisory Board of Alexion Pharma and patient
advocacy groups
Principal Investigator of Industry- sponsored clinical
trials (Alexion Pharma; Shire Pharmaceuticals;
VitaFlo; Actelion)
Receive honoraria for invited Webinars and Symposia
(Alexion Pharma)

4. Inborn Errors of Metabolism (IEM)
• Genetically determined disorders caused
by abnormalities in the quantity or
structure of a specific enzyme or protein
• ~ 7,000 Mendelian disorders described in
OMIM
• ~ 3,400 causal genes identified
• >550 Inborn Errors of Metabolism (IEM)
• Term coined by Sir Archibald Garrod in
1908
• Blocking a metabolic pathway leads to:
– absence of end product
– accumulation of substrate
• Individually rare, collectively common
and constitute significant burden of
disease

5. Challenges
• IEM individually are considered rare but collectively pose a
significant impact on health services.
• The complexity of IEM necessitates multidisciplinary, long-
term, lifelong care for better clinical outcome and optimal
utilization of health services.
• There is an expanding patient cohort and rapidly evolving
options
– need for additional resources.
• The rarity of inborn errors of metabolism poses a challenge
for families to be able to interact with other families with the
same diagnosis

6. Multidisciplinary Team Approach

7. Our Multidisciplinary Team
• The paediatric metabolic clinic combines the skills of
metabolic geneticists, pediatric dieticians, clinical
pharmacists, social workers, metabolic nurses and genetic
counselors and other health professionals as needed
• During each visit as needed each team member will meet
with patient & family, depending on needs

8. http://www.irdirc.org/wp-
content/uploads/2013/06/IRDiRC_Policies_Longversion_24May2013.pdf

9. MDCTRT Winnipeg:
Metabolic Disorders Clinical Trials Research Team Winnipeg

10. What is the MDCTRT
• Team of multidisciplinary professionals committed to IEM
• Dedicated to develop a framework, providing the
infrastructure for clinical trials for new drugs/treatments for
IEM and their ongoing surveillance
• The MDCTRT will complement the clinical metabolic service
and contribute “evidence” locally, nationally & internationally
regarding the natural history of known diseases,
epidemiology, newborn screening advances, new treatments,
applications for licensure of new drugs with equitable access
to new drugs and ongoing surveillance and participation in
Registries.
• The MDCTRT will help foster new innovative research around
the prevention, diagnosis and management of rare diseases.

11. Specific Aims
• Forum to consolidate all Clinical Trial and Registry initiatives
(Approved and in Progress or in Development Phase) and
collaborations with Basic Science
• Serve as a communication tool among members of the
research team re ongoing studies, updates, upcoming meetings,
presentations and abstracts with deadlines
• Serve as a forum for brainstorming re research ideas and
networking within the University and outside of Winnipeg
• Prepare annual reports
• Consolidate our role in Canadian Metabolic Disorders Research
Network (CMDRN), Canadian Fabry Disease Network (CFDI) and
other Networks

12. What I did on my “admin leave”..
• THIS YEAR ON ADMINISTRATIVE LEAVE IT IS A YEAR TO 'TAKE STOCK" AND
PERHAPS HAVE SOME SPARE TIME AND ACHIEVE A MORE BALANCED
WORK- LIFE BALANCE, FILLED WITH THE JOYS OF SPENDING TIME WITH
MY FAMILY, GRANDCHILDREN AND FRIENDS.
BUT the reality is research excites me and I feel the pressure of time…
• A GENERATION FROM NOW THE WHOLE FIELD OF METABOLIC GENETICS
WILL LOOK VERY DIFFERENT-- NEWBORN SCREENING WILL BE DIFFERENT,
MANY MORE TREATMENTS WILL BECOME AVAILABLE AND OUR HOPE IS
THAT THE MDCTRT TODAY WILL HELP LAY THE GROUNDWORK FOR THE
EXCITING ADVANCES NEW AND INNOVATIVE TECHNOLOGY IS BRINGING
TO THIS FIELD- WE WANT TO BE SURE WE ARE AT THE FOREFRONT OF
RESEARCH IN RARE AND ULTRARARE DIDORERS SO THAT OUR PATIENTS
AND THEIR FAMILIES ARE BEST POSITIONED TO REAP ITS BENEFITS IN
THE FUTURE.

13. My admin leave to date
• Enhance documentation of 50 patients with rare and
ultrarare Inborn Errors of Metabolism who are enrolled in
various ERT and SRT clinical trials, in clinical trials of other
new therapies and in Patient Registries.
• Hire new admin assistant for MDCTRT- Launch March 17!
• Create Shared Drive for the MDCTRT
• Working with the WRHA, provincial government and
national partners to create a National Strategy for Rare and
Ultra-rare Disorders, to create framework to expedite
licensure and to facilitate reimbursement protocols for
orphan drugs for ultra-rare metabolic disorders
• Working with Patient Advocacy Groups re equitable access
to treatments and health services delivery

14. Treatment TrialsDOB
M F dd/mm/yyyy Fabrazyme Dose
KMH Fabry x 22/12/2001 Fabrazyme 85 mg
RBA Fabry x 29/05/1966 Replagal 19.9mg x
ECM Fabry x 8/10/1946 Replagal 14.3mg x
CTF Fabry x 4/8/2000 Fabrazyme 70mg
CF Fabry x 3/9/1969 Fabrazyme 80mg
CT Fabry x 31/10/2002 Fabrazyme 40mg
JM Fabry x 26/02/1976 Fabrazyme 65mg
MEA Fabry x 19/04/1944 Fabrazyme 80mg
RD Fabry x 12/11/1997 Fabrazyme 60mg
MM Fabry x 1/28/1968 Replagal 15.5mg x
KD Pompe x 5/12/1954 Myozyme 2000 mg
SW Pompe x 14/03/2000 Myozyme 1400 mg
SF Gaucher- 1 x 11/6/1967 Cerezyme 1600 units
MP Gaucher- 1 x 4/11/1958 Cerezyme 2400units
KW Gaucher- 1 x 29/09/1974 Cerezyme 60units/kg/q3w
PS Gaucher- 1 x 12/11/1967 Zavesca 300mg bid
AC Gaucher- 3 x 7/29/1997 Zavesca/Cerezyme
MC Gaucher- 3 x 4/21/1993 Zavesca/Cerezyme
WT HPP* x 4/9/2002 $
Asfotase alfa 1mg/kg/6x/wk x
JF HPP x 10/2/2002 Asfotase alfa 1mg/kg/6x/wk x
AH HPP x 1/21/1999 Asfotase alfa 1mg/kg/6x/wk x
TR HPP x 12/31/1999 Asfotase alfa 1mg/kg/6x/wk x
TL HPP x 5/29/1954 Asfotase alfa 1mg/kg/6x/wk x
ED HPP x 7/18/1946 Asfotase alfa 1mg/kg/6/week x
CS HPP x 1/15/1984 Asfotase alfa 1mg/kg/6x/wk x
AM HPP x 7/24/1997 Asfotase alfa 1mg/kg/6x/wk x
RH HPP x 11/23/1952 Asfotase alfa 1mg/kg/6x/wk x
CJ HPP x 12/16/1993 Asfotase alfa 1mg/kg/6/week x
AP HPP x 6/28/1966 Asfotase alfa 1mg/kg/6x/wk x
RL HPP x 5/29/1955 Asfotase alfa 1mg/kg/6x/wk x
JP HPP x 3/26/2010 Asfotase alfa 1mg/kg/6x/wk x
GS HPP x 10/4/2010 Asfotase alfa 1mg/kg/6x/wk x
MF HPP x 8/3/2005 Asfotase alfa 1mg/kg/6x/wk x
SD HPP x 4/27/2006 Asfotase alfa 1mg/kg/6x/wk x
TW HPP x 10/26/2006 Asfotase alfa 1mg/kg/6x/wk x
SP HPP x 11/5/2007 Asfotase alfa 1mg/kg/6x/wk x
AS HPP x 3/17/2014 Asfotase alfa 1mg/kg/6x/wk x
EF HPP x 3/10/2014 Asfotase alfa 1mg/kg/6x/wk x
NM HPP x 11/10/2011 Asfotase alfa 1mg/kg/6x/wk x
RV GSD 1#
x 5/5/2009 Glycosade 90 gm x
BV GSD 1 x 7/9/2007 Glycosade 90 gm x
KA GSD 1 x 12/17/2002 Glycosade 120 gm x
EH GSD 1 x 6/6/2006 Glycosade 90 gm x
* hypophosphatasia
#
glycogen storage disease type 1
$
maximum dose - 80mg
Pt Initials
Gender
Diagnosis Clinical trial
Medical Therapy

15. Glycogen Storage Disorders:
Updates from the Metabolic Clinic-2013Updates from the Metabolic Clinic-2013
Glycogen Storage Disorders:
Updates from the Metabolic Clinic-2013Updates from the Metabolic Clinic-2013

16. GSD type 1

17. Extended Release Cornstarch Therapy (Glycosade) in GSD1Extended Release Cornstarch Therapy (Glycosade) in GSD1
• Hypothesis: A new modified starch,
Glycosade, will allow pts with GSD1 to sleep
without continuous overnight dextrose
infusions via gastrostomy tubes & have
improved QOL without sacrificing metabolic
control.

18. Comparison of the Effect of a Novel Starch (Glycosade®)
Versus Gastrostomy tube-Dextrose infusion on Overnight
Euglycaemia Control in Children with GSD Type I:
• Open Label Demonstration Trial led by the CRU
• 4 patients with GSD1 > 5 yrs admitted overnight
• Single dose of Glycosade® administered at 2100
• No O/N continuous dextrose infused via gastrostomy tube
• Glucose monitored overnight with CRU nurse at bedside
• Trial ended at 0700 or if blood glucose < 4
• Biochemical surveillance repeated prior to breakfast
– All 4 maintain euglycemia for at least 8 hours
– All now transitioned to single dose of Glycosade® for
overnight treatment
• Challenge now reimbursement

19. Enteral & Parenteral Nutrition
Formulary Addition Request
Send the completed form and attendant documentation to:
• Winnipeg Regional Health Authority
• Nutrition & Food Services
• c/o Heather Worona
• 300-287 Broadway
• Winnipeg, MB R3C 0R9
• Contact a dietitian if you require assistance with the completion of this Formulary Addition Request. Please print or type and ensure complete information is submitted.
• PRODUCT INFORMATION
•  Enteral Nutrition Product  Parenteral Nutrition Product
• Product Name:
• Manufacturer:
• Product Description (include volume(s), concentration, container type):
•  Ready To Use (RTU)  Requires Preparation
• Cost/tin or container: Cost/100 kcal:
• JUSTIFICATION FOR REQUEST
• Include the following information on a separate sheet of paper.
• specific indication(s) for use
• nutritional attributes
• volume to meet RNI
• special precautions/contraindications
• comparative data with available formulary enteral or parenteral nutrition products in terms of clinical efficacy/ safety/ advantages and disadvantages
• References (i.e. peer reviewed, controlled studies) to support these claims should be attached to the submission.
• C. CRITERIA FOR USE
• 1. Will this replace an existing formulary nutrition product?
•  Yes, specify which product(s)
•  No, list reasons why not
•
•
2. Are you recommending this product be restricted to a specific physician, service, program or facility?
•  No  Yes If yes, specify
•
• Reason(s) why restrictions recommended:
•
•
• 3. Summarize this product’s role in therapy. What are the specific criteria for use? What are the major advantages of this product that warrant it being added to formulary?
Are there any measurable enhancements or improvements to patient outcome?
•

20. Networks
• CIMDRN== “Practice based research thhat generates evidence
• Newborn Screening Ontario
and the Canadian Newborn & Child Screening Network
• Canadian Fabry Disease Initiative (CFDI)
• Care for Rare
• CORD (Canadian Association for Rare Disorders)-patient advocacy group
• PHENOME Central
• co-led by Dr. Michael Brudno and Dr. Kym Boycott
• developed by Centre for Computational Medicine at Sickkids
• a new matchmaking web portal launched on Rare Disease Day (February 28, 2014)
• “PhenomeCentral securely stores clinical and genetic information on patients with undiagnosed
rare diseases. Clinicians will upload information and the database will automatically and
anonymously match patients with similar genome and phenotypes. This will enable faster
diagnoses and simpler identification of the genetic cause of rare diseases”
• Born out of “CARE for RARE” which is a pan-Canadian research initiative that goes beyond
identifying rare disease genes to develop treatments for better health outcomes
• Global partners of PhenomeCentral include the NIH Undiagnosed Diseases Program in the USA,
CARE for RARE Australia, Finding of Rare Disease Genes (Canada), RD-Connect (Europe and
Australia), and the International Rare Disease Research Consortium.

21. Practice-Based Research to Improve Care for Children
with Rare Metabolic Diseases:
the Canadian Inherited Metabolic Diseases Research Network

22. Canadian Inherited Metabolic Diseases
Research Network (CIMDRN)
• Since 2012, the Canadian Inherited Metabolic
Research Network (CIMDRN) has been
developing a pan-Canadian research
infrastructure to collect and assemble
pediatric patient data from a range of sources
to generate evidence that will inform
improved health care and outcomes for
patients with inborn errors of metabolism
(IEM).

23. Value
• By identifying the current patterns of
interventions and systems of care that
are associated with best outcomes for
children with IMD, CIMDRN aims to
directly inform care
• CIMDRN is creating a sustainable
network and data resource to support
on-going research
www.cimdrn.ca