Experts from our medical, regulatory and operational teams discuss the new and exciting landscape for advanced therapies in rare disease

1. M A K I N G T H E C O M P L E X S E A M L E S S1
How Advanced Therapies are
Changing the Landscape
of Rare Disease
PRESENTERS:
Todd Banks, PharmD, RPh.
Director of Regulatory Affairs and Regulatory
Intelligence, Medpace
Marco Tangelder, MD, PhD
Senior Medical Director, Medpace
Madhavi Malladi, PhD
Clinical Trial Manager, Medpace

2. M A K I N G T H E C O M P L E X S E A M L E S S
• Regulatory Landscape
• Scientific Advancements in Gene Therapy
• Operational Considerations
AGENDA
2

3. REGULATORY
LANDSCAPE

4. M A K I N G T H E C O M P L E X S E A M L E S S
• Definitions
• Rare disease metrics
• Global criteria
• Challenges associated with rare disease research
• Real world evidence and natural history
• Resources
RARE DISEASE – REGULATORY PERSPECTIVE
OUTLINE
4

5. M A K I N G T H E C O M P L E X S E A M L E S S
DEFINITIONS
• “Orphan disease” and “rare disease” are
synonymous
• Orphan drugs are used to treat rare disease
• In the USA, 'orphan drug' applies to
pharmaceutical, biological, medical devices
and dietary products
• No harmonized global definition for “rare
disease”
• A rare disease in 1 geography may not be
rare in another geography
• In general, “rarity” is defined in terms of
prevalence
< 4 to 6 per 10,000 people
“Rare diseases are rare,
but rare disease
patients are numerous”
– Orphanet
5

6. M A K I N G T H E C O M P L E X S E A M L E S S
RARE DISEASE METRICS
• ~7000 known rare diseases (RDs)
• ~85% of RDs are genetic
• ~62% of orphan drug applications are submitted in parallel to US & EU
• ~50% of those affected with a RD are children
• ~35% of deaths by age 1 are associated with a RD
• ~6 – 8% of the world’s population is affected by RD
• ~5% of RDs have an FDA-approved therapy
• Most RDs are inherited or caused by gene alteration/defects
• Time to an accurate rare disease diagnosis: 5 – 7 years
• Orphan drug legislation: US (1983), Singapore (1991), Japan (1993),
Australia (1997), EU (1999), Taiwan (2000), South Korea (2003)
6

7. M A K I N G T H E C O M P L E X S E A M L E S S
GLOBAL CRITERIA
7
USA EU JAPAN
DEFINITION OF A RD
<200,000 patients
(<6.37 in 10,000)
<5 in 10,000
(<250,000 patients)
<50,000 patients
(<4 in 10,000)
EXCLUSIVITY 7 years 10 years* 10 years
EXPEDITED REGULATORY
PATHWAYS
Priority review, fast-
track, breakthrough, or
accelerated approval
PRIME and conditional
approvals
Orphan drug priority
review
*EU exclusivity may be forfeited if the marketing authorization holder is unable to meet demand or the product is highly profitable
There is no global or universally accepted definition of a rare disease
In general, application for orphan drug designation can be applied for at
any stage of the investigational development – strategic considerations

8. M A K I N G T H E C O M P L E X S E A M L E S S
RARE DISEASE DEVELOPMENT INCENTIVES
• Each country with established
orphan medicinal product
legislation offers companies
incentives to develop drugs to
treat rare disorders
‒ Application fee
reduction/elimination
‒ Pre-licensing access
‒ Accelerated review procedures
‒ Scientific advice and protocol
assistance
‒ Market exclusivity
‒ Pediatric vouchers
‒ Research grants
‒ Tax exemptions/credit
‒ Smaller trial sizes
• Essentially, all existing legislation
provides a stepwise approach for
orphan drug authorization:
– Orphan drug application for designation
status
– Orphan product marketing authorization
8

9. M A K I N G T H E C O M P L E X S E A M L E S S
RARE DISEASE METRICS – FDA (ODD REQUESTS)
9
All Medpace offices
around the world
operate under the
same procedures
FDA Law Blog, Karst, KR, February 28, 2018, derived from
FDA Orphan Drug Designations and Approvals Database

10. M A K I N G T H E C O M P L E X S E A M L E S S
RARE DISEASE METRICS – FDA (DESIGNATIONS)
10
All Medpace offices
around the world
operate under the
same procedures
FDA Law Blog, Karst, KR, February 28, 2018, derived from
FDA Orphan Drug Designations and Approvals Database

11. M A K I N G T H E C O M P L E X S E A M L E S S
RARE DISEASE METRICS – FDA (APPROVED)
11
All Medpace offices
around the world
operate under the
same procedures
FDA Law Blog, Karst, KR, February 28, 2018, derived from
FDA Orphan Drug Designations and Approvals Database

12. M A K I N G T H E C O M P L E X S E A M L E S S
GLOBAL OVERVIEW OF ORPHAN DRUG FRAMEWORK
12
All Medpace offices
around the world
operate under the
same procedures
US EU JAPAN AUSTRALIA SINGAPORE
SOUTH
KOREA
TAIWAN BRAZIL CHINA SWITZERLAND
ORPHAN DRUG
LEGISLATION         X 
COMPETENT AUTHORITY FDA EMA
PED;
PMDA;
NIBIO
TGA HSA CPAC; MFDS TFDA ANVISA X Swissmedic
PREVALENCE
THRESHOLD
200K 5/10K 50K 5/10K 20K 20K - 65/1K X 5/10K
RESEARCH GRANTS    X X   X X X
TAX EXEMPTIONS    X X X X X X 
SCIENTIFIC ADVICE/
PROTOCOL ASSISTANCE     X X  X X X
SMALLER TRIAL SIZES     X     X
PRE-LICENSING ACCESS      X X X X 
FEE REDUCTIONS     X   X X 
ACCELERATED REVIEW
PROCEDURES    X X X   X 
MARKET EXCLUSIVITY 7 years 10 years 10 years 5 years 10 years 10 +2years X X X X

13. M A K I N G T H E C O M P L E X S E A M L E S S13
EU USA JAPAN
AUTHORITIES INVOLVED EMA FDA PMDA
PROCEDURAL JURISDICTION EMA – COMP & EC FDA OOPD MHLW, PAFSC & PMDA
LEGAL FRAMEWORK Regulation (CE) N°141/2000 (2000) Orphan Drug Act (1983) Article 77-2 of the Pharmaceutical Affairs Law (1993)
PREVALENCE CRITERIA <5 in 10,000 patients <200,000 patients <50,000 patients
REVIEW PERIOD Max. of 90-day procedure Review cycle ~90 days None specified
INCENTIVES
FINANCIAL INCENTIVES
• Regulatory fee reductions generally favor small
and medium-sized companies
• No general tax credit on clinical trials and no
specific subsidies for clinical trials
• User fees paid to the FDA for review of the
sponsors’ application for marketing
authorization are waived
• Tax credits can apply to as much as 25% of
qualified clinical development costs (USA
studies)
• User fee waivers, 15% tax credits, up to 20%
corporate tax reduction and a 30% reduction in
marketing application fees
• Financial subsidies for up to 50% of expenses for
clinical and nonclinical research
MARKETING EXCLUSIVITY
10-year market exclusivity (protects against a similar
drug being authorized for the same therapeutic
indication)
7-year marketing exclusivity (FDA cannot
approve another marketing application for the
“same” drug treating the “same” orphan
diseases or conditions)
Extension of the re-examination period to 10 years at
marketing authorization
SCIENTIFIC ADVICE
(PROTOCOL ASSISTANCE)
• Access to free-of-charge protocol assistance at the
EMA for SME
• Guidance on the regulatory requirements
regarding quality, non-clinical development and the
design of the clinical trials necessary to fulfil the
regulatory requirements for the demonstration of
efficacy and safety of the drug
• Access to free scientific guidance at the
FDA
• Guidance by the relevant review division at
the FDA on the regulatory requirements for
quality, non-clinical development and the
design of the clinical trials to demonstrate
the efficacy and safety of the drug
• A 30% fee reduction for protocol
• Assistance guidance is given on the regulatory
requirements regarding quality and non-clinical
development, as well as on the design of the clinical
trials necessary to fulfil the regulatory requirements
for marketing authorization
REGULATORY TOOLS TO
ACCELERATE DRUG
APPROVAL
• Priority medicines (PRIME)
• Accelerated assessment
• Conditional marketing
• Exceptional circumstance authorization
• Fast-track approval
• Breakthrough designation
• Accelerated approval
• Priority review design
• Priority review
• Fast-track approval
GRANTS Funding is available from the European Commission
and other sources
Orphan Products Grants Program
Funding is available from National Institute of Biomedical
Innovation (NIBIO)

14. M A K I N G T H E C O M P L E X S E A M L E S S
CHALLENGES ASSOCIATED
WITH RARE DISEASE RESEARCH
• Limited knowledge of disease etiology and
pathophysiology
• No or limited preclinical models
• Standard of care may not be established
• Surrogate indicators (biomarkers) may not
exist
• Clinical endpoints may be ill-defined or lack
clinician consensus
• Few patients and geographical dispersion
• Small portion of treatment-naïve patients
• Patient heterogeneity/late diagnosis
• Disease severity
• Challenges with proximity to treatment center
• Limited number of experienced clinical investigators
• Recruitment and retention of patients
• Study power limitations
• Dose optimization challenges
• Traditionally, drugs are investigated in adults before
testing in children
14
There is commonality in the 1000’s of different pathologies defined as “rare”

15. M A K I N G T H E C O M P L E X S E A M L E S S
REAL WORLD EVIDENCE & NATURAL HISTORY
• Rare disease natural history studies are essential to gain clinical insights
and assist in determining clinical endpoints
‒ Defining the disease population, including disease manifestations and disease
subtypes
‒ Developing and selecting outcome measures that are specific to the disease
‒ Developing new or optimized biomarkers that may provide proof-of-concept (POC)
information, guide dose selection, allow early recognition of safety concerns, or
provide supportive evidence of efficacy
‒ In some cases, biomarkers can be used as surrogate endpoints
• In 2012, FDA (FDASIA) expanded the list of acceptable surrogate
endpoints to include: epidemiological, pathophysiological, pharmacological
and biomarkers
• Natural history studies include:
‒ Retrospective vs prospective and cross-sectional vs longitudinal
15

16. M A K I N G T H E C O M P L E X S E A M L E S S
RESOURCES
• US FDA: orphan@fda.hhs.gov
• US: NORD (National Organization for Rare Disorders)
• US: GARD (Genetic and Rare Diseases), NIH
• EU: EURORDIS (European Rare Disease Organization)
• EU: ERDITI (European Rare Disease Therapeutic Initiative)
• Orphanet (Global Consortium of 40 countries)
• IRDiRC (International Rare Disease Research Consortium)
• Patient organizations
16

17. SCIENTIFIC
ADVANCEMENTS IN
GENE THERAPY

18. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS GENE THERAPY?
• Gene therapy uses genes to treat or prevent disease by inserting a
gene into a patient’s cells
• There are several approaches to gene therapy including:
‒ Replacing a mutated gene that causes disease with a healthy copy of the gene
‒ Introducing a new gene into the body to help fight a disease
‒ Inactivating, or “knocking out,” a mutated gene that is functioning improperly
18

19. M A K I N G T H E C O M P L E X S E A M L E S S
WAYS OF DELIVERY OF GENE THERAPY
• Gene therapy is delivered via a vector or genetic editing
• Non-viral vector: transfection
‒ Plasmids (naked DNA), liposomes or particle-mediated gene transfer
• Viral vector: transduction
‒ Adeno-associated viruses
19

20. M A K I N G T H E C O M P L E X S E A M L E S S
ADENO-ASSOCIATED
VIRUS (AAV) BASED GENE THERAPY
20
Source: US National Library of Medicine

21. M A K I N G T H E C O M P L E X S E A M L E S S
CHOICE OF AAV: VECTOR TROPISM/INFECTION
POTENCY AND NABS
• Delivering to target cells
21
Divergent serotype
Low prevalence of nAB’s
Vance MA et al. 2010, AAV Biology, Infectivity and Therapeutic Use:
from Bench to Clinic. In: "Gene Therapy - Principles and Challenges”

22. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS NEEDED FOR A VIABLE AAV GENE
THERAPY PRODUCT?
• Efficacy
‒ Durable and clinical meaningful expression
• Safety
‒ No target-organ damage
‒ No immunogenicity
• Antibodies
‒ Low prevalence of pre-existing antibodies against the AAV serotype
• Commercial manufacturing
‒ Scalability, reproducibility, cost of goods
22

23. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT CAN WE TREAT WITH GENE THERAPY?
23
OCULAR DISEASES
2016 33
2019 104
Adapted from The Journal of Gene Medicine,
© 2019 John Wiley and Sons Ltd

24. M A K I N G T H E C O M P L E X S E A M L E S S
2012: APPROVAL OF GLYBERA™ FOR LPLD
24
Regulatory approval of the
first gene therapy in Europe

25. M A K I N G T H E C O M P L E X S E A M L E S S
2017: FDA APPROVES SPARK THERAPEUTICS’
LUXTURNA™ (VORETIGENE NEPARVOVEC-RZYL),
A one-time gene therapy for
patients with confirmed
Biallelic RPE65 mutation-
associated retinal dystrophy
25

26. M A K I N G T H E C O M P L E X S E A M L E S S
ADVANCES IN OPHTHALMOLOGY
BIALLELIC RPE65 MUTATION-ASSOCIATED RETINAL DYSTROPHY
26
Mutations in the RPE65 gene lead
to vision loss due to loss of function
(or death) of RPE cells and eventual
degeneration of photoreceptors
Adapted from LUXTURNA
all-trans-
retinal
all-trans-
retinol
all-trans
retinyl
Ester
11-cis-
retinol
11-cis-
retinal
RPE65
protein
Light
Visual cycle

27. M A K I N G T H E C O M P L E X S E A M L E S S
VORETIGENE NEPARVOVEC PHASE 3 PRIMARY (MLMT
LUX SCORE) AND KEY SECONDARY (FST) ENDPOINTS
27
Mean bilateral MLMT lux score
Baseline Day
30
Day
90
Day
180
1 year
p=0.0038
p=0.004
Russell S, et al. Lancet 2017; 390:849-60
Mean white light FST (both eyes)

28. M A K I N G T H E C O M P L E X S E A M L E S S
• Control of bleeding with effective protection against spontaneous
bleeds
• Elimination of the requirement for continuous prophylaxis
• Establish long term, multi-year benefit from a one-time procedure
• Improvement in quality of life
ADVANCES IN HEMOPHILIA
GOAL OF GENE THERAPY IN HEMOPHILIA B: TRANSFORMATION OF DISEASE SEVERITY
28
PHENOTYPE
SPONTANEOUS
BLEEDING
PROPHYLAXIS
RECOMMENDED
FIX ACTIVITY
Severe Frequent Yes <1%
Moderate Rare Variable 1-5%
Mild Very rare No 5-40%
Adapted from: Srivastava A, et al. Guidelines for the
management of hemophilia. Haemophilia 2013

29. M A K I N G T H E C O M P L E X S E A M L E S S
AMT-060
AAV5 CAPSID WITH WILDTYPE FIX CASSETTE
29
AAV5 Capsid
•Low prevalence of clinically-relevant
pre-existing neutralizing antibodies1, 3
•Previously tested in human clinical trials
with no safety signals or detectable
immune activation2 Expression cassette
•Wildtype hFIX
•Clinically demonstrated safe and durable
increases in FIX activity with meaningful
improvement in clinical outcomes3,4
Human wild type FIX
(codon optimized)
LP1
(Liver-specific
promoter)
1Boutin et al, Human Gen Ther 2010; 21::704-12. 2D’Avola et al, Journal of Hepatology
2016; doi: http://dx.doi.org/10.1016/j.jhep.2016.05.012. 3Nathwani et al. NEJM 2014;
371:1994-2004. 4Nathwani Oral Presentation, ESGCT October 2016. FIX, factor IX.

30. M A K I N G T H E C O M P L E X S E A M L E S S
AMT-060 PHASE 1/2
STABLE INCREASES IN ENDOGENOUS FIX ACTIVITY OBSERVED IN BOTH COHORTS
30
0
2
4
6
8
10
12
14
16
18
20
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116
EndogenousFIXactivity(IU/dL)
Participant 1 (7.5%) Participant 2 (5.6%) Participant 3 (1.1%)*
Participant 4 (10.3%)* Participant 5 (3.9%)*
0
2
4
6
8
10
12
14
16
18
20
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84
Participant 6 (11.1%) Participant 7 (8.9%) Participant 8 (8.7%)
Participant 9 (4.2%) Participant 10 (7.5%)
Weeks Weeks
Cohort 1: 5E12 gc/kg
mean FIX activity (95%CI): 4.8% (1.6%-8.0%)
Cohort 2: 2E13 gc/kg
mean FIX activity (95%CI): 7.2% (3.5%-11%)

31. M A K I N G T H E C O M P L E X S E A M L E S S
• Patient FIX activity Weeks after administration
• #1 48% 16
• #2 25% 14
• #3 51% 12
• No FIX infusions
• No bleedings
• No immunosuppression for transaminase increase / loss of FIX activity
AMT-061 PHASE 2B
AIMING FOR ENHANCED FIX ACTIVITY WITH FIX-PADUA
31
Mean FIX activity at 12 weeks: 38% of normal
Source: UniQure.Inc. Feb. 08, 2019

32. M A K I N G T H E C O M P L E X S E A M L E S S
HEMOPHILIA B GENE THERAPY WITH A HIGH-
SPECIFIC-ACTIVITY FACTOR IX VARIANT – SPK-9001
32
George et al. N Eng J Med 2017

33. M A K I N G T H E C O M P L E X S E A M L E S S
SCIENTIFIC AND CLINICAL DEVELOPMENT
CHALLENGES WITH GENE THERAPY
• Trial related
‒ Developed for mainly rare diseases
‒ Control group: natural history / lead-in / sham or placebo
‒ Non-validated endpoints
‒ Sample sizes
‒ Long follow-up – patient retention
• Product related
‒ Delivery
‒ Transduction potency
‒ Immune responses
• Market access
‒ The price
‒ Reimbursement models
33

34. OPERATIONAL
CONSIDERATIONS

35. M A K I N G T H E C O M P L E X S E A M L E S S
SITE SELECTION
35
• Prior gene therapy experience
• Site Pharmacy qualifications
‒ Biological Safety Cabinets/ Isolator requirements
‒ Ensure compliance with SOPs and study-specific requirements during drug
preparation
• Site dosing capabilities
‒ Dosing equipment compatibility with the product
‒ Inter-departmental collaboration
• Number of potential subjects
‒ Critical to gather information on number of potential subjects interested in
gene therapy trial

36. M A K I N G T H E C O M P L E X S E A M L E S S
CENTRALIZED DOSING
36
Central Dosing Center
Local Sites

37. M A K I N G T H E C O M P L E X S E A M L E S S
CENTRALIZED DOSING
CONSIDERATIONS
37
• Collaborative effort between local and dosing sites
‒ Appropriate delegation of responsibilities
‒ Transfer of records
‒ Visit schedules
‒ Investigational product shipment

38. M A K I N G T H E C O M P L E X S E A M L E S S
CENTRALIZED DOSING
CONSIDERATIONS
38
• Regulatory requirements
‒ IRB/EC approvals
‒ Informed consent form language
‒ Clinical trial insurance

39. M A K I N G T H E C O M P L E X S E A M L E S S
CENTRALIZED DOSING
CONSIDERATIONS
39
• Appropriate clinical electronic data capture access to both local
and dosing site personnel
• Streamlined monitoring process to ensure continuity between the
sites
• Patient and caregiver travel logistics

40. M A K I N G T H E C O M P L E X S E A M L E S S
SITE START-UP
• NIH Recombinant DNA Advisory Committee (RAC)
‒ Per the changes proposed on August 17, 2018
• Eliminates RAC review and reporting requirements to the NIH for human
gene-therapy protocols
• Revise the responsibilities of institutional Biosafety Committees, which
have local oversight for this research
• Other approvals required
‒ Institutional review board
‒ Institutional biosafety committee
‒ Other site-specific scientific committees
40

41. M A K I N G T H E C O M P L E X S E A M L E S S
SITE TRAINING
• Gene therapy trials are typically single-dose trials
‒ Protocol training
‒ Discussing site-level logistics prior to patient screening
‒ Dry-run
• Streamlining coordination between departments
• Handling Investigational product
• Reviewing Pharmacy logistics
• Ensuring all the necessary equipment are in place prior to actual dosing
• Record-keeping
41

42. M A K I N G T H E C O M P L E X S E A M L E S S
RECRUITMENT AND RETENTION CHALLENGES
SMALL PATIENT POPULATION AND GEOGRAPHICAL DISTRIBUTION
42
• Recruitment strategies
‒ Advocacy groups
‒ Genetic counselors
‒ Physician referrals
‒ Advertisement campaigns
‒ Digital technology

43. M A K I N G T H E C O M P L E X S E A M L E S S
RECRUITMENT AND RETENTION CHALLENGES
PATIENT EDUCATION
43
• Quality of life
‒ Indication
‒ Age
‒ Potential benefit versus perceived risk of gene therapy
• Longer consenting times compared to non-gene therapy trials
• Encourage principal investigator to have informed discussion with subjects
• Patient brochures – “What is Gene Therapy?”
• Patients unwilling to participate in early phase trials
‒ Keep potential subjects abreast of any preliminary data from early phase trials

44. M A K I N G T H E C O M P L E X S E A M L E S S
RECRUITMENT AND RETENTION CHALLENGES
STUDY DESIGN
44
• Natural history
‒ Educate patients about the potential gene therapy intervention(s)
‒ Set expectations that participation in natural history study does not guarantee
participation in the interventional part of the trial
• Frequent post-dosing and long-term visits
‒ “Patient journey” brochures to patients
‒ Visit schedulers to the sites
‒ Home health services
‒ Phone call visits
‒ Review of medical records
‒ Providing travel arrangements

45. QUESTIONS
THANK YOU