1. Overview of Therapeutic Approaches to the Mucopolysaccharidoses
Emil Kakkis MD, PhD
Christine Haller, MD
Ultragenyx Pharmaceutical Inc.

2. Disclosures Emil Kakkis. Employee and stockholder
Disclosures Emil Kakkis Employee and stockholder in Ultragenyx; Stockholder in BioMarin Christine Haller Employee and stockholder in Ultragenyx

3. Outline History of Enzyme Replacement Therapy in MPS
Then and now – progress since first treatment for MPS I
40 years from bench to bedside for MPS VII
New therapeutic approaches
Alternative routes for administration of ERT
Stem Cell Therapy (SCT) / Bone Marrow Transplant (BMT)
Gene Editing and Gene Therapy
Other treatments
Conclusions

4. The Golden Age for Rare Disease Treatments
Emil D. Kakkis, M.D., Ph.D.
Chief Executive Officer and President, Ultragenyx
President, EveryLife Foundation for Rare Diseases

5. Treating Genetics Disorders in Golden Age The last 10 years have greatly changed the available modalities
mRNA
Therapy
Transcription
Induction
Splicing Modification
(exon skipping)
Gene Therapy
Antisense
or SiRNA
Crispr/
Cas9
Nonsense
Suppression
Chaperones
Folding
Protein Replacement Therapy

6. Multiple Modes Approved A sampling of recent rare disease approvals
Protein
Folding
Protein
Activity
DNA
RNA
Gene therapy
Antisense RNA
Potentiator
Exon skipping
Enzyme
replacement

7. Mucopolysaccharidosis Type 1

8. Enzyme Replacement Therapy in MPS Disorders

9. Mark
Dant
UCLA 1994
Ryan

10. First Dose: December 19, 1997

11. Families speak up for treatment Advisory Committee Vote 12-0
BLA Filing Team

13. Ryan 19 years on ERT
Graduating at U. Louisvile May 2017

14. New MPS 1 kids get treated

15. Coarse with Bone Disease
Three Sibs Started at Different Ages on ERT Earliest treatment has best outcome
Child ID
Age at Rx Start
Phenotype
After Rx
Height After Rx
FVC/Walk After Rx
Eldest Girl
6 yo
Coarse with Bone Disease
-3.82 z
Improved/
Not normal
Middle Boy
2.5 yo
Mild with
Minimal Bone
-0.65 z
Stable/not worsened
Youngest Girl
0.33 yo
Not Coarse/
+1.32 z
Normal

16. ERT for MPS VII: 20 years from bedside to lab and 20 more to clinic
MPS VII is caused by a deficiency of lysosomal enzyme beta-glucuronidase (GUS)
leads to cellular accumulation of GAGs: dermatan sulfate, chondroitin sulfate and heparan sulfate
1973: First patient described with GUS deficiency
1993: First ERT research in mouse model of MPS VII
2013: First ERT treatment of an MPS VII patient in a clinical trial
Proposed Mechanism of Action
ERT with rhGUS
rhGUS (UX003) is a tetrameric protein
produced by CHO cells for IV infusion
Longer half-life than other ERTs allows for more convenient every other week dosing

17. Timeline for MPS VII Development Over 40 years from bench to bedside
1970’s 80’s 90’s ’s
ERT in mouse model studies
Ultragenyx ERT development began 2011
1973: Sly first described MPS VII
ERT for MPS VII development discontinued ‘99
Ultragenyx Mfg development
1st MPS VII patient dosed Oct 2013 via US eIND
ERT for MPS VII restarted and discontinued
Ph 1/2 Study
Dec 2013
Ph 3 Study ; FPI Dec 2014
48 week data released June 2016
Ph 2 < 5yr Study
FPI Aug 2015
BLA/MAA 2017

18. New Therapeutic Approaches to MPS

19. Evolution in MPS Patient Care
Multidisciplinary care: neurologic, orthopedic, pulmonary, nutritional, cardiac, physiotherapy, vision, hearing, occupational, dental remain as major treatments for patients
Ongoing efforts over past 25 years to develop new approaches to correct metabolic and genetic defects
In addition to intravenous ERT, new experimental therapies and new drug delivery approaches are under intense investigation:
Intrathecal ERT
Intracerebroventricular (ICV) ERT
Bone Marrow/ Stem Cell Transplant
Gene Editing (Zinc finger, CRISPR)
Gene Therapy (IV, IT, intranasal)
Fusion Proteins
Pentosan Polysulfate
Genistein

20. Intravenous Enzyme Replacement Therapy (ERT) remains standard of care
Demonstrated efficacy with regular IV infusion of recombinant human enzymes
4 Approved MPS Enzyme Replacement Therapies (ERTs)
MPS I (Aldurazyme®)
MPS II (Elaprase®)
MPS IVA (Vimizim®)
MPS VI (Naglazyme®)
Vestronidase alfa is investigational ERT for MPS VII
Limitations: poor penetration of central nervous system (CNS); only partial improvement of significantly damaged tissues such as bone/cartilage/heart valves; immune response
MPS are a family of 11 similar lysosomal storage disorders characterized by a deficiency of a specific enzyme involved in the multi-step degradation of GAGs in the cellular lysosome. Cell and tissue damage in multiple organs results from accumulation of GAG over time which overwhelms the cytoplasmic storage capacity and eventually results in cell lysis and spillage of GAG into the urine. Additionally, there is an induced inflammatory response and cytokine release which results in systemic symptoms such as fatigue and anorexia.

21. Alternative Routes for Delivery of ERT: targeting the central nervous system
Goal: penetrate blood-brain barrier (BBB), deliver enzyme to CNS to alleviate spinal cord compression and preserve neurological function
ICV – under investigation for MPS IIIA, IIIB
Fusion proteins – antibody to human insulin receptor fused to enzyme; given IV as “Trojan horse” to pass through BBB
MPS I ( AGT-181): improved cognitive function in 4 of 5 patients dosed in Phase I/II
MPS II ( AGT-182): Phase I enrolling
Intrathecal (IT) – effective in
MPS I and II; investigational
for MPS IIIA

22. Hematopoietic Stem Cell Transplantation (HSCT) in MPS 1H
Generally considered 1st line treatment for Hurler syndrome patients < 2.5 years old
Retrospective review of 217 patients with MPS 1H and successful HSCT showed clinical course strikingly improved but significant residual disease burden remains:
Improved long-term outcome if transplanted at young age after early diagnosis, ideally through newborn screening
Improved outcome if post-transplant IDUA enzyme level is normal (more likely using non-carrier donor cells, particularly cord blood)

23. Hematopoietic Stem Cell Transplantation (HSCT) in Other MPSs
HSCT also performed in patients with other MPS disorders: MPS II, IIIA, IVA and VII
Hunter Syndrome: 2nd most common MPS treated with HSCT
Improvement in non-neurological disease but impact on neurological deterioration not clearly seen, even with transplant as young as age 3 mos
Very few instances of HSCT in other MPS disorders
MPS IIIA patient transplanted at age 2.5 years showed stabilization in neurological function at age 10 years
Risks of HSCT include death due to transplant-associated complications, graft-versus host disease and failure to engraft

24. Gene Therapy – active area of therapeutic research for numerous diseases; mostly unproven in humans as yet
Functional copy of gene that codes for correct enzyme is delivered to body by modified common cold virus (e.g. adeno-associated virus vector – AAV)
Either directly injected into blood and taken up by patient’s cells
Or, introduced into patient stem cells collected and grown in lab
If successful, may result in long-lasting enzyme production
If doesn’t work or effect wanes, patient cannot be dosed again with same viral vector due to immune response

25. Gene Therapy in MPS Diseases
No approved gene therapies for any MPS or lysosomal storage disease but active area of research
Gene therapies currently under investigation for:
MPS I: intranasal therapy – animal study
MPS II: IV therapy – clinical study; IT – animal study
MPS III A, III B: IV therapy – clinical; ICV – clinical study
MPS IIIC: ICV therapy
MPS VII: IT therapy – animal study

26. Gene Editing: repair defective genes or manipulate other functional genes into surrogate enzyme production
Specific DNA regions targeted and edited to enable capacity to make missing enzymes and other proteins
CRISPR/Cas9 – pioneer in genome sequence scan/repair technology
ZFN – zinc finger nuclease makes use of highly expressed albumin gene in liver cells
Phase I studies in MPS I and MPS II: IV delivery of AAV-based ZFN to insert correct gene sequences into albumin gene and enable liver to produce therapeutic levels of enzymes

27. Other Experimental Therapies: Reducing production of GAGs
Substrate reduction – therapeutic approach to reduce body’s production of GAGs
Genistein, a soy derivative, shown in laboratory tests to inhibit both GAG synthesis and accumulation in cells from patients with MPS IIIA and MPS VII
Oral Genistein is being investigated in clinical trial for MPS III A, B, C
Could be used in combination with other therapies that improve enzyme activity
Clinical effectiveness unclear
Soy isoflavones also have anti-inflammatory properties
and cross the blood-brain barrier so of particular interest in MPS disorders with CNS involvement

28. Other Experimental Therapies: Reducing secondary effects of GAG
Anti-inflammation - GAG storage in cells leads to inflammation and cell destruction, particularly in cartilage
Pentosan polysulfate (PPS) – approved oral and Sub-Q anti-inflammatory agent shown to reduce joint inflammation in patients with osteoarthritis
Non-clinical studies showed PPS reduced inflammatory markers and GAGs in MPS animals
Improved bone and teeth in MPS VI rats
Reduced brain inflammation in MPS I dogs and MPS IIIA rats
PPS treatment in 4 MPS 1 (H-S, S) patients also on ERT reduced GAGs
clinical improvement seen after 24 weeks (less pain, better joint motion)

29. Safety of MPS Treatments: More is known about ERT than experimental therapies
ERT has a risk of serious allergic reactions including anaphylaxis
Most reactions are not severe (rash, hives, abdominal pain, vomiting) and resolve with rate slowing or pre-medication with steroids, anti-histamines
BMT/SCT has a risk of graft-versus-host disease where the body is recognized as foreign by the immune system
Several severe complications can result including damage to the GI tract and kidneys
IT/ICV has a risk of infection and headache
Gene therapy risks are unknown

30. Conclusions
Significant progress has been made in treatment of MPS disorders
4 approved ERTs; 1 under review
Alternative delivery approaches for ERT showing promise
Unmet medical needs and challenges in MPS remain:
Need for early diagnosis and prompt intervention before substantial disease damage occurs
Delivery of therapy to CNS
New therapeutic approaches – gene therapy, substrate reduction, novel ERTs
Combination approaches and targeted (personalized) therapies of focus in future

31. Thank You
Thank you to all the people and families who have participated in clinical trials
If you have additional questions, please
MRCM-UX