Alström syndrome is a rare genetic disease characterized by childhood obesity, insulin resistance, and fibrosis of multiple organs. There are currently no approved treatments. PBI-4050, a drug candidate from Prometic being developed for fibrosis, has potential as a novel treatment for Alström syndrome given its multi-organ anti-fibrotic activity. An ongoing proof-of-concept study of PBI-4050 in the UK represents the first clinical trial in Alström syndrome patients. Regulatory pathways like orphan drug designation and the EMA's PRIME program aim to facilitate development of treatments for rare diseases by providing scientific advice, accelerated assessment, and incentives for further research.

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2. Alström syndrome and PBI-4050:
A case-study of the challenges and
barriers facing patients, physicians
and industry in developing new
treatments for rare diseases
The regulatory - clinical development
perspective
Dr. Owen J. Vaughan
Senior Director, Regulatory Affairs
Prometic Pharma SMT Ltd.
CRDN (Cambridge, UK) – October 20, 2017

3. © Prometic Life Sciences Inc 2017
Alström syndrome – Overview
Key Eligibility Criteria
Alström syndrome 1 (ALMS1) - A rare autosomal recessive
disease (mutations in a large gene located on chromosome 2p13-
identified in 2002). Alström syndrome is a fibrotic multi-organ
disease with gradual unfolding of phenotypes.
Characterized by childhood onset obesity, extreme insulin
resistance, type 2 diabetes mellitus (T2DM), dyslipidaemia,
hypertension and multi-organ fibrosis.
Other features include retinal cone-rod dystrophy, hearing loss,
short stature, cardiomyopathy progressive cardiac, pulmonary,
hepatic, and renal dysfunction.
Complex, varied clinical picture. Limited natural history data.
Leads to delays in diagnosis. Reduced life expectancy.
Clinical challenges to develop treatment strategies and need for
specialised multi-disciplinary clinics.
Subject recruitment is a major challenge for clinical trials.
Figure: Frequency,
mean age at onset,
and age range of
selected clinical
features in Alström
Syndrome
Arch Intern Med. 2005;165:675-683

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Alström syndrome and PBI-4050 - Example of ‘matching’ drug development with a
rare (orphan) disease
ALMS is shown to be a complex,
fibrotic multi-organ disease.
There are no specific treatments
authorised, or being used off-
label, for the treatment of
patients with ALMS.ALMS is caused by mutations in
Alström Syndrome 1 (ALMS1), a
large gene located on chromosome
2p13 (identified in 2002)
PBI-4050 has the
potential to bring a major
therapeutic advantage to
ALMS patients, who have
a clear unmet medical
need
PBI-4050 being developed for targeting
multiple pathways in the fibrosis pathway
PBI-4050 is a lead drug candidate
being developed for
inflammatory/fibrosis-related
diseases.
In vivo, PBI-4050 has demonstrated
anti-fibrotic activity in multiple
organs (animal models of chronic
renal failure, diabetes, pulmonary
fibrosis, liver fibrosis, cardiac fibrosis,
Crohn’s disease and scleroderma)

5. © Prometic Life Sciences Inc 2017
Alström Syndrome and PBI-4050 - Development of first proof-of-concept (PoC) study
Key challenge is capability to
engage appropriate stakeholders
(clinical experts, industry etc.)
The heterogenous and varied
clinical variability, limited natural
history data are key areas for
development.
A key challenge going forward is
the acceptability of clinical
endpoints.
2013 2014 2015 2016 2017 2018
Serendipitous meeting
at WODC 2013,
initiated discussions
between Prometic and
Alström UK . This led to
a drug development
programme for PBI-
4050 in patients with
Alström syndrome
Alström UK
starts initial
discussions
with
Prometic
Prometic
introduced to
UK Centre for
Rare Diseases
(Birmingham)
PoC study commenced in
Birmingham
Ongoing support
from Alström UK
support for patients,
families, travel and
attending
Birmingham clinics
2019
UK Centre for Rare
Diseases is a
specialised multi-
disciplinary,
national clinic for
Alström syndrome.

6. © Prometic Life Sciences Inc 2017
Today
• PBI-4050: A potential, novel treatment for patients with Alström syndrome:
• Very rare condition
• Complex condition with multiple outcomes
• Natural course of the condition not well documented
• An ongoing, open-label, proof-of-concept, study PBI-4050-ATX-9-05, in United
Kingdom
Tomorrow
• An authorised and marketed product that patients with Alström syndrome have
access to as and when needed:
• Regulatory authorisation (quality, safety & efficacy)
• Health technology appraisal authorisation (health economics)
• Funding (budget)
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It’s all about patient access

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Patient access – Multiple stakeholders involved
• European Medicines Agency (EMA):
• Committee for Human Medicinal Products (CHMP)
• Paediatric Committee (PDCO)
• Committee for Advanced Therapies (CAT)
• Pharmacovigilance Risk Assessment Committee (PRAC)
• National regulatory authorities (e.g. MHRA in UK)
• Patients’ organisations (e.g. Alström Europe and Alström Syndrome UK)
• Rare disease organisations & alliances (e.g. EURODIS)
• Clinical investigators
• Paediatricians
• Health technology appraisal (HTA) authorities
• Payment & reimbursement authorities
• Patients
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Patient access – EU & national regulatory opportunities
PBI-4050 in
Alström Syndrome
Paediatric
Investigation
Plan (PIP)
Scientific
Advice
(Conditional)
Marketing
Authorisation
Health Technology
Appraisal (HTA)
Advice
Orphan Medicinal
Product
Designation
Accelerated
Assessment
Early Access to
Medicines’ Schemes
Clinical
Trials Design
Priority Medicine
(PRIME) Designation
Protocol
Assistance

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Distribution: Adult / Paediatric
Prevalence Marketing Authorisations
Orphan Designations
Orphan medicinal products (EU: 2000 – 2016)*
* Figures Taken from EMA Annual report on the use of the
special contribution for orphan medicinal products (January
25, 2017; EMA/40172/2017)
Alström
Syndrome

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Paediatrics (EU: 2004 – 2015)*
Paediatric Trials
New Products, Indications & Posology
Paediatric Investigation Plans for Orphan Medicinal Products
Paediatric Changes to Product Labelling
* Figures Taken from EMA Annual report on the use of the
special contribution for orphan medicinal products (October
27, 2016; EMA/231225/2015)

11. © Prometic Life Sciences Inc 2017
EU – EMA Priority Medicines (PRIME) designation
• Goal - To foster research on and development of medicines for
patients whose diseases cannot be treated or who need better
treatment options to help them live healthier lives
• Scheme to enhance early dialogue to facilitate accelerated
assessment of designated priority medicines
• Came into effect March 7, 2016
• ~18 months experience (early days)
• Eligibility:
• Product must address an unmet medical need
• Preliminary data must be available showing the potential to address
this need and bring a major therapeutic advantage to patients
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12. © Prometic Life Sciences Inc 2017
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EU PRIME eligibility requests*
* Figures Taken from EMA Website Oct 16,, 2017
Applications & Eligibility
Decisions
Type of Applicant
Therapeutic Areas
SME = Small & Medium Sized Enterprise

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Benefits of EU PRIME designation
Once a candidate has been selected for PRIME, the EMA:
• Appoints a Rapporteur from the CHMP (or CAT) to provide continuous support
and help to build knowledge ahead of marketing authorisation application;
• Organises a kick-off meeting with the CHMP (or CAT) Rapporteur and a
multidisciplinary group of experts from relevant EMA scientific committees and
working parties;
• Issues guidance on a company’s overall development plan and regulatory
strategy;
• Offers a dedicated EMA contact person;
• Provides scientific advice at key development milestones, involving additional
stakeholders as needed – e.g. health technology assessment bodies and patients.
Medicines eligible for PRIME are also potentially eligible for accelerated
assessment at the time of application for a marketing authorisations
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Products for rare diseases - Conclusions
• Same clinical, regulatory & quality standards as for common diseases – No short-cuts!
• Recognition that alternative approaches may be required
• EMA & national regulatory authorities are there to help – Talk to them!
• Orphan medicinal product designation
• Paediatric development – Don’t forget or ignore!
• Take a holistic View – Engage early with all stakeholders!
• Consider PRIME designation
• Development of products for rare diseases is challenging – But not impossible!
• Evidence that such products can successfully be developed
• Regulatory opportunities and tools available – Use them!
• Make good science work for patients
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Thank you