Genable Technologies is developing RhoNova, a gene therapy using two AAV vectors, for the treatment of rhodopsin-linked autosomal dominant retinitis pigmentosa (RHO-adRP), a genetic disorder causing progressive vision loss. RhoNova aims to overcome the diversity of over 200 RHO mutations by using RNA interference to destroy mutant RHO mRNA and replacing RHO through a gene resistant to mutations. Proof of concept has been shown in animal models. Orphan drug status has been granted and GMP manufacturing and preclinical toxicology studies are underway to enable clinical trials in 2017.

1. Providing Unique Genetic
Solutions For Dominant Disorders
Gene Therapy 2014 Brussels

2. Outline
• Introduction to clinical research
– Terminology
– Conventions
• Drug development pathway
• Consent
• Rules & regulations
– History
– Declaration of Helsinki
– GCP
– EU Directive
• Clinical Trial Process
• Forthcoming developments

3. Introduction to Clinical Research
3

4. Clinical research
• Encompasses clinical trials of drugs,
medical devices, radiotherapy,
surgical procedures, psychotherapy
and any combination of the above.
• Important distinction is that research
is done prospectively (i.e. planned)
and not auditing previous work.

5. Clinical trial
• Any investigation in human subjects intended to discover or
verify the clinical, pharmacological and/or other
pharmacodynamic effects of investigational medicinal
products
• And/or to identify any adverse reactions to investigational
medicinal products
• And/or to study absorption, distribution, metabolism and
excretion of investigational medicinal products with the object
of ascertaining its safety and/or efficacy.

6. Key documents in a clinical trial
• Protocol
• Informed consent form/patient information
leaflet
• Case Report Form (CRF)
• Site file
• Patient notes
• Clinical Study Report

7. Protocol
• Every trial has a written, detailed action plan, called a protocol. The protocol provides
the background, specifies the objectives, and describes the design and organization of
the trial. Every site participating in the trial uses the same protocol, ensuring
consistency of procedures and enhancing communication. This uniformity ensures that
results from all sites can be combined and compared.
• The clinical trial protocol answers the following questions:
• What is the scientific rationale or basis for conducting the trial?
• What are the objectives?
• How many participants will be in the trial?
• Who is eligible to participate? (This is determined on the basis of factors such as age
and disease status.)
• What is the intervention, and what is its duration or schedule?
• What side effects might there be?
• What medical tests or follow up visits will participants have? How often?
• What information will be gathered about participants?
• What are the endpoints of the trial?

8. Drug Development Pathway
8

9. New Drug Development
 For everyone ONE
marketed medicinal
product, between
10,000-30,000
compounds must be
screened
 Cost is between $500
million- $2 billion
 Time is 12-15 years of
research and
development

10. Drug Development
Pharmaceutical R&D, which provides the foundation for the
treatments of today and the cures of tomorrow, is becoming
increasingly complex, lengthy and risky, due to a combination of
scientific, regulatory, commercial and political factors.
 50% of medicines that reach the final stage of clinical trials fail at that stage –
not solely for safety and efficacy reasons
 Only 3 out of 10 marketed medicines produce revenues that match or exceed
average R&D costs before losing patent protection
 Pediatric incentives ( PIP and PUMA)
 Orphan Drug incentives for rare diseases
10

12. Phase I
The goal of Phase I is to discover if the drug is safe in humans.
Determine what the safe dosing range is and if it should
move on to further development.
Overall:
– Gives an idea of interesting doses to be tested or avoided in phase II , dose
required to give reasonable blood levels
– Side effects to be anticipated
– Little (if any) indication of therapeutic activity
About one third of candidate drugs fail in phase I – absorption/tolerability
Referred to as IIa when a Phase I trial collects information in patients

13. Phase II
Evaluate the drug’s effectiveness in about 250 to 500 patients with
the disease condition under study.
Goal of Phase II is to answer these questions:
1. Is the drug working by the expected mechanism?
2. Does it improve the condition in question? (often using surrogate
endpoints)
3. What are the possible short-term side effects (adverse events)
4. What are the other short term risks associated with drug use?
Analysis of optimal dose strengths and schedules for using the drug (MED)

14. Phase III
Larger number (several hundred to several thousand) patients to
generate statistically significant data about safety, efficacy and
the overall benefit-risk relationship of the drug.
 This phase of research is key in determining whether the drug is
safe and effective. It also provides the basis for labeling
instructions to help ensure proper use of the drug (e.g.,
information on potential interactions with other medicines).
 Longer treatment period compared with Phase II but still short
compared with natural history of the disease

15. Phase IV
Post Marketing studies
Safety
Efficacy
15

16. Pricing and Reimbursement
Pricing and Reimbursements and Health Technology
Assessments (HTA’s)
 Authorisation does not automatically allow access to the market
 Pricing and reimbursement application to relevant national authority
required in most countries
 Assessment focused on clinical benefit and associated cost effectiveness
 Various pricing systems throughout Europe- complex
 Pharmacoeconomics : Important to support pricing and
reimbursement negotiations and is embedded into development
plans from Phase II onwards
16

17. Ethical Considerations Including Consent
17

18. Clinical Research
General Principles
• Protection of clinical trial subjects
All current principles have their origin in
The Declaration of Helsinki.
• Scientific Approach in Design & Analysis
Clinical trials should be designed,
conducted & analysed according to sound
scientific principles to achieve their
objectives.

19. Clinical Research
Declaration of Helsinki
• Fundamental guidance document in the
field of human ethics
• The World Medical Association have
developed the Declaration of Helsinki as a
statement of ethical principles to provide
guidance to physicians and other
participants in medical research involving
human subjects

20. Ethical Guidelines
• Ethical guidelines generally developed in response
to a problem— “born in scandal”.
• They generally respond to the controversy and do
not provide a systematic ethical framework.

21. Ethical Requirements
1) Social Value
2) Scientific Validity
3) Fair subject selection
4) Favourable risk-benefit ratio
5) Independent review
6) Informed consent
7) Respect for human subjects

22. Informed Consent
• Informed consent ensures individuals
decide whether they enroll in research and
whether research fits with their own
values, interests, and goals.
• For those who cannot consent—such as
children and mentally impaired—must be
sure research fits with their interests

23. Informed Consent
• Competence of the subject
• Disclosure of information to the subject
• Understanding or comprehension by the subject
Freely given consent

24. Purpose of Informed Consent
 Each prospective participant and/or the legal representative must:
 Understand the nature of research
 Be informed of purpose, risks, and benefits and alternative therapies
 Make a voluntary decision about study participation
Informed consent must be obtained prior to any protocol specific testing being
conducted
If protocol specific testing done the same day as informed consent document
signed, must be clear documentation of the chronological order
in the medical record/charts

25. Ethics Committee Responsibilities
 Review and approve all research protocols
 Ensure adequate provisions are made for obtaining
the permission e.g. vulnerable populations
 Determine whether children in study are capable of
providing assent and if so, confirm that adequate
provisions are made for obtaining their assent

26. s
Eight Elements of Informed Consent
 Statement that study is
research and information on
purposes / duration /
procedures / experimental
procedures
 Reasonably foreseeable risks
or discomforts
 Reasonably expected benefits
 Alternative procedures
 How confidentiality will be
maintained
 Information on compensation
for injuries (unless minimal
risk)
 Contact persons for
information on research,
injury, subject’s rights
 Voluntary participation, no
penalty or loss of benefits for
refusal or withdrawal

27. Additional Elements of Informed Consent
 Statement that there may
be risks which are
unforeseeable
 Under what circumstances
investigator could terminate
subject’s participation
 Additional costs to subjects
 Approximate number of
subjects in study
 Consequences of
subject’s withdrawal from
research
 Statement that will be
told of new findings

28. Rules & Regulations

29. What is Good Clinical Practice?
• A standard for the design, conduct,
performance, monitoring, auditing,
recording, analyses and reporting of
clinical trials that provides assurance that
the data and reported results are credible
and accurate and that the rights, integrity,
and confidentiality of trial subjects are
protected.

30. History of rules
1960’S Fraudulent clinical data were created,
Inadequate clinical data e.g. Thalidomide
1977 USA GCP (FDA)- 5 Principles
1977 - 87 FDA GCP
Principles applied to international studies by many Pharma companies
1986 UK ABPI guidelines
1987 France GCP guidelines,
Germany conduct of clinical trials
1987(1990) Ireland Clinical Trials Act
1991 EU GCP
1996 ICH GCP guidelines
2001 European Directive on Clinical Trials
2004 European Communities (Clinical Trials on
Medicinal Products for Human Use) Regulations
2005 GCP Commission Directive

31. The Rules!
Now we have:
• ICH Good Clinical Practice Guidelines
• Various directives and indirect rules including Annex 13 – Good
Manufacturing Practice Guidelines.
• The European Communities (Clinical Trials on Medicinal
Products for Human Use) Regulations, 2004 (EUCTD)
• Good Clinical Practice Commission Directive 2005/28/EC – April
2005
• Associated Detailed Guidances (Eudralex Vol 10)
Future:
• Revision of EUCTD to Eur Regulation on Clinical Trials published
in 2014, due to be enacted 2016

32. Life Cycle of a Clinical Study
 Protocol
Synopsis
 Schedule of
Activities
 Site Selection
 Sponsorship
 Protocol
 Informed Consent
Forms / Patient
Information Leaflets
 EC & CAApprovals
 Study Operations
Manual
 IMP /Pharmacy - Drug
Packaging/Labeling
 Laboratory/Phlebotomy
/Resp. Technicians
 Case Report Forms
(CRFs)
 Data Management Plan
 Statistical Analysis Plan
 Clinical Database
 Site Subcontracts/
Payment Schedule
 Third Party Vendor
Contracts
 Staff Training & Education
 File/documentation Maintenance
 Screen/Enroll Subjects
 Randomisation – Follow-Up
 Study Monitoring & Audits
 Study Drug Distribution &
Accountability
 Protocol Amendment (s)
 Pharmacovigilance
 SAEs
 Dosage Adjustments
 Premature Withdrawals
 Drug Disclosure
 Unblinding
 Data Query Process
 Clean/Close & Lock Database
 Transfer Database to Biostatistics
 Perform Primary/ Secondary
Analysis
 Submit Abstract
 Submit Manuscript
 Submit Clinical Trial Report
(CTR)
 Publish results
 Post-Hoc Analysis
Study Initiation
Database Locked &
Statistical Analysis
Project Funded Study Maintenance
ANALYSIS/
PUBLICATION
PHASE

33. Further reading
• http://clinicalresearch.nih.gov/
US NIH clinical research general reading
• http://www.ukcrc.org/publications/informationbooklets.aspx
UK cancer research group general reading
• http://www.cancer.gov/clinicaltrials/resources/basicworkbook
US oriented clinical research training
• http://www.clinicaltrials.gov/
Patient orientated clinical trial registry
• http://www.wma.net/e/policy/b3.htm
Declaration of Helsinki
• http://www.nihtraining.com/cc/ippcr/archive06f/menu.html
• NIH training files

34. RHO-adRP
Rhodopsin linked autosomal dominant retinitis pigmentosa
Inherited form of retinitis pigmentosa
caused by >200 mutations in the rhodopsin gene (RHO)
Affects ~1 in 25-30,000 people worldwide
>30,000 patients in developed economies
Patients suffer from visual dysfunction losing sight progressively from the periphery
of their vision & completely by middle age
loss of sight results from the death of rod and then the cone photoreceptor cells
cell death results from incorrect processing, folding, transport or function of the faulty
rhodopsin which induces apotosis
some evidence suggesting different mutations induce different apoptotic pathways
Treatment options
no treatments currently available for patients with retained sight
retinal chips approved in the US for end-stage blind patient

35. RHO-adRP – the retina
Last stageEarly stage Mid stage
Pigment leaking from
dead or dying
photoreceptor cells

36. The Patients Perspective of Retinitis Pigmentosa
“For patients the main difficulty in coming to terms with their diagnosis is the
knowledge that for the moment there is no cure and ultimately blindness is
unavoidable”
Symptom
Difficulty seeing in poor
light
Cataracts
Central vision loss
Implications for offspring
Difficulty navigating objects
and lots of trips and falls
Driving ability will be
affected
Surgery required
Reading and/or detailed
work problems
What to tell children and
when, decisions as to
whether to have children
Workplace/home adaptions and
changes are required. Career
choice considerations
Side effects of surgery
Activities of daily living as
well as work issues
Genetic and other counselling
may be required
Resulting Issues Implications

37. Patient Engagement

38. Patient input to Genable’s development
Patients
• Investment by affected patients & their families in basic research
Research
• Discovery of the Rhodopsin gene as causative for Rho-adRP
• Design of innovative gene therapy
Development
• Genable spun out to commercialise further development

39. Genable patient engagement story
 Fighting Blindness Ireland (FBI) provided funding that results in
identification of causative gene and subsequent development of gene
therapy
 Foundation Fighting Blindness (US) and FBI are board observers and key
advisers
 Attendance at relevant patient meetings
 Genable provide patient training in drug development and clinical research
 Patient focus groups in development to inform clinical development
 And the story continues……

40. RhoNovaTM
A Unique Therapeutic Solution

41. RhoNovaTM
– overcomes RHO mutational diversity
RHO-adRP
The challenge: >200 different RHO
mutations
adRP patient: single, simple
subretinal injection of
RhoNovaTM to the back of
the eye
RhoNova
TM
2 x AAV 2/5 vectors in fixed
proportions containing:
RHO RNAi suppression, and
Special RHO gene replacement gene
RHO mutant mRNA destroyed
RHO replacement survives due to
“wobble” at certain 3rd base pairs
+
RhoNova
TM
- a unique single solution for RHO-adRP caused by multiple RHO
mutations

42. RhoNova ™ Development
 Proof of concept established in mouse and pig models
 Orphan drug status in US & EU
 Pre-IND meeting with FDA in Jul-14 with input into development plan
 ATMP designation granted Oct-14
 Manufacturing agreements signed with Spark Therapeutics (US) and 1st GLP
batches delivered in Oct 2015
 Toxicology & biodistribution studies to commence in 2016
 Clinical studies to commence in 2017

43. Genable Technologies Limited
The Tower
Trinity Technology & Enterprise
Campus
Pearse Street
Dublin 2
Phone: +353 14433209
www.genable.net
sgaynor@genable.net