Pharma platforms

Initiating a Portfolio Pharma Company

Trans-dermal Approaches

Formuli

Transdermal Spray-On Patch Therapy For CNS Conditions Alternative Options to Improve Outcomes for patients with swallowing difficulties or

poor insight into their condition…

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s Overall Summary • A new technology means that low dose therapies can now

be delivered as a ‘spray-patch’ which cannot be felt after 30 seconds.

In CNS Medicine, this has great utility for many types of patients, but mainly those with swallowing difficulties, poor cognition, poor memory, aggression,

hostility, high impulsivity.

• There are many products that can be given through this technology. The main limitation is maximum dose per spray-on patch being 5-10mg. More than one patch can be sprayed on per dose.

• The pathway to regulatory approval is straightforward and low-cost in the US and Europe utilizing the 505b2 route in the US and the equivalent phase II/III waiver in Europe.

• For low investment, high and fast returns are highly probable.

Formuli

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Unmet Need Analysis • Chronic Movement Disorders Patients struggle to swallow (eg.

Parkinson’s Disease, Huntington’s Chorea) • Dementia patients struggle to remember their doses and lack of insight

and hostility means they often do not want to take their medication • Epilepsy Patients can have lack of insight, hostility and may be fitting, so

swallowing may be difficult • Addiction patients may be hostile • Aggression/Hostility in ADHD can make dosing difficult • Aggression/Hostility in Schizophrenia or Mania can make dosing difficult • Migraine patients cannot hold their tablets down if the migraine is too

advanced by the time they take their tablets • Other opportunities may exist for improved convenience however these

are thought to be the best opportunities to improve outcomes and therefore generate higher prices.

Viable Parkinson’s Disease Products: Ropinerole

Pramipexole

Biperiden Viable Alzheimer’s Disease Products: Memantine Donepezil Rivastigmine Galantamine Viable Anti-Convulsants/Benzos: Diazepam Tiagabine Viable Anti-Addiction/Pain: Bupronorphine + Naloxone Codeine Viable Anti-ADHD Drugs: Methylphenidate Viable Anti-Psychotics: Aripiprazole Olanzapine Risperidone Viable Anti-Migraine: Frovatriptan Eletriptan Almotriptan

Product Targets

Formuli

A/O/RS

Formuli

Prioritizing Product Development

MP = Methylphenidate Patch R = Ropinerole XR P = Pramipexole XR B = Biperiden XR MM = Memantine XR Do = Donezapil XR RV = Rivastigmine Patch G = Galantamine D = Diazepam Rectal T = Tiagabine B+N = Buprenorphine + Naloxone C = Codeine (OTC) A = Aripiprazole O = Olanzapine Melt RS = Risperidone

Regu

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High Moderate

= Market Size

Unmet Need

P/R B

Do/G

RV

MP

D/T

C

MM

B+N

First Targets: Methylphenidate - Daytrana Patch exists

Feasibility and proof of principal complete

Rivastigmine - Exelon Patch already exists

Feasibility Complete

Rationale: Reduced Regulatory Hurdles… 505b2 and European late stage waiver decisions are made based on the similarity of the Cmax & AUC data of the two different formulation options. If these are very similar, the waivers on later stage clinical trials are most likely. Existing formulations to be referenced with the transdermal spray-on patch for these molecules with most likelihood of achieving similar Cmax & AUC data are as follows: Methylphenidate: Traditional Transdermal Patch on the market Rivastigmine: Traditional Exelon Patch First stage feasibility data has been generated on transdermal spray-on patch formulations for these molecules and they are viable.

Low Regulatory Hurdle Product Target List

Formuli

First Targets: Methylphenidate

Rivastigmine

Rationale: Reduced Pricing Hurdles… Pricing decisions are made mainly on the basis of levels of unmet need, or ‘real world’ effectiveness. Parkinson’s Disease products are seen as meeting the most unmet need, and methylphenidate is excellent for the hostility seen in childhood ADHD. Alzheimers patients may be confused and take off any patches so a spray-on patch Rivastigmine also meets a high unmet need. Other products such as antipsychotics may also meet high unmet need, and full analysis should be made before selecting a priority order of products to develop.

Methylphenidate & Rivastigmine are the only products to feature on both ‘low’

Regulatory Hurdle and ‘high’ unmet need analysis so may prove the best

options to consider for development first.

Market Need Driven Product Target List

Formuli

MedSpray Methylphenidate POC Data

• Comparison of Daytrana with MedSpray

• Equivalent amounts of drug applied (ca.10 mg)

• Release experiment using silicone membrane

• MedSpray can match current marketed product

• MedSpray can enhance or prolong methylphenidate release

• Stability shown at 25 and 40 degrees for T=3 months- could be extrapolated.. Methylphenidate release (n=6, mean, ±SD)

Eg. Methylphenidate in vitro – already generated

MedSpray Methylphenidate POC Data

Methylphenidate epidermal sheet permeation (n=6, mean, ±SE)

Eg. Methylphenidate in vitro – already generated

CEO

Mr Russ Pendleton BSc MBA MIoD Astrazeneca, BASF Pharma, Sanofi, Runehealthcare, Zysis, Perimeter 15 years CEO & Managing Director, initiated one medical communications agency, several pharma start-ups. 12 years Commercial ‘big’ Pharma roles. Successful sales and marketing, fundraising, major product launches, licensing, business development and partnering track record. Responsibilities: Overall Project Management, Commercial Assessments, Marketing Strategy & Deliverables, HE Strategy & Deliverables, Out-licensing & Exit Revenue

Formuli Management – Overall Project Management

Formuli

CEO Dr Andrew Muddle PhD Dr. Andrew Muddle co-founded MedPharm in August 1999. Medpharm has already generated 24 transdermal and transbuccal products for pharma companies. Dr. Muddle has spent 21 years in the pharmaceutical industry in the drug delivery area and has worked for a number of companies of varying sizes. At PowderJect Pharmaceuticals plc, he was Technical Director (Pharmaceutical Development) with responsibility for pharmaceutical sciences, and both pre-clinical and clinical functions. He held this position for three and a half years and made a major contribution in the early development of the company, as well as being pivotal in the IPO in 1997. Dr. Muddle has managed development projects through to commercialisation of several transdermal patch products. Prior to this, he also held technical positions with drug delivery companies such as the Elan Corporation, Ethical Pharmaceuticals Ltd (U.K.), Controlled Therapeutics (Scotland) and Ciba-Geigy (now Novartis). Responsibilities: Generation of the ‘Product’, first stage testing, clinical trial batch supplies.

MedPharm Management – Transdermal Specialists

Formuli

CEO

Prof Alan Boyd

30 years’ in pharmaceuticals. Starting with Glaxo Group Research Ltd.

From 1988 head of ICI’s Cardiovascular medical research team, later assuming the role of Director of Clinical and Medical Affairs at ICI

Pharma, Canada. In 1995, became Head of Medical Research for Zeneca Pharmaceuticals.

In 1999 became Director of Research and Development for Ark Therapeutics Ltd responsible for delivering the majority of key

development milestones that have shaped the company. In particular the development of the gene based medicines portfolio.

In 2005, initiated Boyd Consultants. The focus of which is to aid and support early stage life-science based companies and groups in

Universities who have medicine based R&D projects. Clients now include many organisations and companies in Europe, North

America and Japan who are devoted to the development of medicines.

A graduate in Biochemistry and Medicine from the University of Birmingham, UK, a Fellow, Board Member and Chair of the Specialist

Advisory Committee in Pharmaceutical Medicine at the Faculty of Pharmaceutical Medicine, Royal College of Physicians, United

Kingdom. Elected Vice-President of the Faculty in November 2012.

In November 2009 appointed an Honorary Professor in the College of Medical and Dental Sciences at the University of Birmingham

Medical School, in recognition of his expertise in medicines development.

Responsibilities: Global Medical Director Role, including steering Clinical Trial activity and Regulatory Affairs to generate sufficient

data to ensure FDA/EMA approvals. Supporting Out-licensing activities.

Boyd Consultancy Management – Clinical & Regulatory

Formuli

Pharma platforms

Introducing

The Development

Path for Each Product

Formuli

• Executive Summary • RoI Analysis • Target Product Profile • Market Need, Size & Dynamics • Project Plan • Formulation Work • Clinical Work • Marketing & Health Economic Considerations • Interested Companies for Exit

Creating a TD CNS Product

Formuli

Executive Summary • To develop transdermal formulations of target molecules.

• A quick and straightforward route to approval using the 505b2 phase II/III waiver route.

• This is only achievable in the EU and US. • Phase III trials are required for other markets.

• To NDA Submission cost USD 2-3 M per product • To Market (incl. Commercial/HE/QoL package) cost USD 3-6 M per product.

• Further Marketing/HE/QoL costs are recommended in the order of USD 1-3 M depending on quality of outcome data desired.

• Intellectual Property Protection

• Trandermal (and Transbuccal) technologies have global patent protection to 2028. • Data exclusivity protection will apply.

• LCM & Fallback strategies • Many molecules can be dosed in this way

• Exit • Onward sale or outsourced commercialization

Formuli

Return on Investment Analysis per product Costs:

1. Cost of R&D USD 1-2 M 2. Cost of HE/QoL Study eg. USD 1-2 M 3. Cost of Launch eg. USD 1-2 M

Overall Cost USD 3-6 M by end 2018

Potential Returns: Assuming PYS Forecast USD 250-300 M in 2028 1. NPV (12%) USD 51 M at 2015 2. rNPV (20% of NPV) USD 10 M at 2015

Formuli Completing Product Potential

Target Product Profile (TPP)

• Transdermal Spray Formulation of Target Compound

– ‘Patch in a Can’ spray adhesive plus drug diameter of 1.5-2cm.

– Bonds to Skin, no sensation of substance felt to patient once dry (30secs), invisible

– No irritation.

– Dose Delivered over 4-5 hours

• Dose delivered without the need to swallow

• Other benefits can follow eg. for Biperiden, further gut interaction with L-DOPA is by-passed thus combination therapy with L-DOPA for Biperiden is now achievable.

• Rivastigmine gut side effects avoided.

Contact: Russ Pendleton +44 7878 201 416 rp@formuli.net

Formuli

Project Plan per product

Formuli Completing Product Potential

2016 Feasibility Testing Cost: USD 70K per product

2016-17 Perform pK Bridging Study for NDA Submission

Cost: USD 1.2 M

2017-18 Perform HE/QoL Patient Preference Study

Eg. Cost: USD 1-2 M

2018 Commercialisation Eg. Cost: USD 1-2 M

2016 Reformulate to TD/TB Cost: USD 330

2016 Clinical Supplies & Stability Cost: USD 400

Formulation Work (1)

Formuli

• Transparent Patch in a Can® – invisible

• Drug presented in a high thermodynamic state

o Enhanced drug delivery

• Self assembling

• Variable dosage forms

o Gel-film, water resistance, adherence, retention, viscosity, thickness

• Versatile

• Cost effective and safe components

• Already taken beyond Phase II

• Dermal or buccal/sublingual delivery route

MedSpray®

Skin

Surface

Formulation Work (2)

Formuli

MedSpray

Propellant dissipates before touching skin surface,

increase of drug concentration in solution

Saturated solution of

drug

Gel/film of drug,

solvents and

polymer

Evaporation of volatile

solvent, continued

increase of drug

concentration and thus

thermodynamic activity

Formulation Work (3)

Formuli

MedRo®

• MedSpray for the mouth

o Application to different oral mucosal regions, sub-lingual or

buccal

o Direct access to the systemic circulation

o Fast onset of action

o Mucoadhesive excipients improve formulation retention for

prolonged/sustained delivery

• Extensive scope for targeting a large number of conditions

using this technology to re-juvenate many molecules

• Alternative option should transdermal prove too difficult

Clinical Study Work

• pK Bridging Study

– Eg. 2.5mg is usual daily dose

– Two arm study • One arm - 2.5mg existing patch

• One arm – 2.5mg new spray patch

– Repeat dose study for 7-30 days

– Measure – Concentration in blood

• Sample Size – 20 Patients per study arm

• Compare blood levels of standard formulation with TD Spray utilizing FDA 1998 guidelines on well-categorized drugs, and 505b2 approval process

• Regulatory Costs included plus visits to EMA & FDA

• Anticipated Cost: USD 1.2 M

Contact: Russ Pendleton +44 7878 201 416 rp@formuli.net

Formuli

Eg. Market Research & Health Economics

Formuli Achieving Successful Launch

Preparation of Marketing Materials including:

****

Product Profiling Branding Detailing

Advertising Med Comms Conference Plan

Publications Planning Ambassador Training &

Outreach Packaging

Refined Forecasting Salesforce Training

Cost: USD 1 M

Preparation of HE Materials including:

****

Outcomes Research Markov Price Modelling Budgetary Impact Model

Market Access Strategy Analysis Value Proposition

Cost: USD 500 K

Interested Companies

• Exit Revenue is generated through onward licensing.

• Negotiations to be ongoing throughout the project, however target transaction timing is around the point of NDA Submission.

• Interested Companies to date are:

– Europe • 3 companies – ADHD, Alzheimers, Pain

– US • 3 companies – ADHD, Alzheimers

– MENA Region • 2 companies – Launched product dossiers

– China • 1 company - Alzheimers

– Turkey & Eastern Europe/Asia • 2 companies – Addiction, Pain

Contact: Russ Pendleton +44 7878 201 416 rp@formuli.net

Formuli

Finding the Global Solution

Contact: Russ Pendleton

+44 7878 201 416

rp@formuli.net

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