regenozene capstone project slidedeck

Regenozene Proposed DR-6 Inhibitor for the Treatment of Multiple Sclerosis

Manpreet Goraya | Michele Hom | Sara Wingate

Brooke Ethington | Kawin Thoncompeeravas | Tyler Holt | Rob Heggen

CSU Channel Islands – September 24, 2011 Martin V. Smith School of Business

Instructors - Doug Lane & Thomas Schulze

Contents Roadmap

•  Project Overview •  MS Pathogenesis •  Proposed Therapeutic & Mechanism

of Action •  Market Analysis •  Product Development Plan •  Financial Analysis •  Concluding Remarks •  Q/A

Project Overview

•  Team Project –  Analyze Death Receptor 6 (DR-6) for Commercial Opportunity

•  Proposed Therapeutic for Multiple Sclerosis –  Remyelination of neurons mediated by DR-6 inhibition

•  Proposed Therapeutic: Regenozene –  Recombinant Protein Molecule

•  Scientific and Business Development –  Virtual Business Model

Virtual Business Model

•  Minimize financial risk & maintain lean infrastructure

–  Low capital intensive, small infrastructure

•  Greater control over expenses, lower fixed expenses

–  Contract Research Organizations (CRO)

–  Contract Manufacturing Organizations (CMO)

•  Partnerships to leverage resources

–  Preclinical phases with Universities

–  Licensing agreement with Big Pharma

–  Revenue and profit through royalties

Multiple Sclerosis Pathogenesis

•  Chronic, systemic autoimmune disease, affects CNS •  Immune system destroys oligodendrocytes and myelin sheathes

–  Result is similar to “A live wire without insulation in water” •  Leads to build-up of scar tissue on nerves called sclerosis •  Cause is currently unknown

Multiple Sclerosis Pathogenesis

Multiple Sclerosis Symptoms

Visual Disturbances Mental Changes

Loss of sensation

Muscle Spasms

Limb Weakness

Bladder & Bowel Dysfunction

Types of MS In

crea

sing

Dis

abili

ty

Time

“Benign” MS

Relapsing-Remitting MS

Secondary Progressive MS

Primary Progressive MS

Diagnosis

- Cognitive Dysfunction Test - MRI

-  CSF Analysis -  Evoked Potential of Nerves

Treatment Options for Patients

Multiple Sclerosis

Counseling

Restorative Rehabilitation

Occupational Therapy

Physical Exercises Physiotherapy

Therapeutics Speech & Learning Therapy

Greatest Unmet Need…

…Reversing Disability


1.  Specificity –  Immune Modulators have adverse effects –  Immune System suppressed



1.  Specificity –  Immune Modulators have adverse effects –  Immune System suppressed

2.  Sensitivity –  Addresses Environment –  Does not improve oligodendrocyte survival or

proliferation


DR-6 Apoptosis Pathway

Adapted from Ashkenazi A. Nat Rev Cancer 2002;2:420–430. FADD, Fas-associated death domain; FLIP, FLICE (FADD-like interleukin 1β-converting enzyme) inhibitory protein.

Caspase 8, 10

Procaspase 8, 10

Pro-apoptotic ligand

DR6 DR6

FADD

Apoptosis

Caspase 3, 6, 7

Target Product Profile

Indication A disease modifying therapy in adults for the treatment of patients with relapsing Multiple Sclerosis to halt the experience of relapses and slow the progression of disability

Efficacy No direct comparator: When administered alone, significant improvement over Gilenya’s® annualized relapse rate (ARR) and disability progression (EDDS) studies

Safety At least as safe as Gilenya® (alone and in combination with Gilenya®), safe for use by

pregnant and nursing mothers, improved safety as compared to Ontak® diphtheria shuttle baseline

Contraindications

Patients who have not been vaccinated against diphtheria toxin. Persons exhibiting hypersensitivity to the DTP vaccine or any of the drug components. Special caution should be taken with patients with pre-existing cardiovascular disease.

Risk of infectious complications. Complete reversal of lesions would result in removal of patient from medication and

maintenance using other approved Multiple Sclerosis therapies. Drug Interactions None Route of Admin Insulin style pump (subcutaneous)

Treatment Regimen Chronic disease modifying lifetime treatment

Convenience Continuous basal administration; daily dose provided as a cartridge

(sterile, frozen solution in a sterile, single-use vial)

Shelf Life Room temp 30 hours, refrigerated (2-8C) up to 4 weeks, frozen (at or below -10C) up to 1 year

Target Regions United States, Canada First Launch 2023

Price $48K/year + 10% premium ($53K/year)

Reimbursement Expect 80%; two improved parameters over Gilenya® (improved disease progression, reduced relapse rate)

Other Indications (future) Other forms of MS, other autoimmune demyelinating disorders (Progressive Multifocal Leukoencephalopathy, Post-Infectious Encephalitis) and radiation injury

Mechanism of Action:

The Trojan Horse Principle

STOPPING THE DISEASE

Selectivity:




Selectivity: •  Cross the BBB




Selectivity: •  Cross the BBB •  Target Oligodendrocytes

Sensitivity: •  Deliver the therapeutic •  Suppress expression of DR-6

Safety: •  DR-6 fragments are packaged and destroyed •  Therapeutic components are expelled as waste

Mechanism of Action: The Trojan Horse Principle

Current Standards of Care Top 5 MS Drugs for 2010

(in Millions)

Current vs. Proposed Avonex® Gilenya® Regenozene

Principle

•  Anti-inflammatory •  Improves integrity of BBB •  Sequester lymphocytes

•  Suppression of DR-6 •  Prevents T-Cell proliferation

Efficacy •  Slows progression of disability •  Reduces relapse

•  Slows progression of disability

•  Reduces relapse

•  Slows progression of disability •  Stop relapse •  Regenerate myelin; restore physical

ability

Safety

•  Fever •  Chills •  Sweating •  Muscle aches •  Tiredness •  Liver failure

•  Slowing of heart rate •  Headache •  Flu-like symptoms •  Diarrhea •  Back pain •  Cough

Expected- safer than Avonex®, safer than Gilenya®. Will be a safety reference point. Safe in combination with Gilenya®

Convenience •  Once a week intramuscular

injection

•  Administered orally once a day

•  Requires a BASAL dose for continuous suppression via Insulin type pump

Future Standards of Care

0

5

10

15

20

25

30

Phase I Phase II Phase III Phase IV

6

20

27

1

5

18

13

3

0

6 4 4

1 2 0 0

4 2

0 0

2011 Pipeline

Small Molecule Protein Antibody Cell Therapy Procedure

MS is a Major Healthcare Concern

•  2.1 million patients worldwide (2008 data) •  400,000 patients in USA; 80,000 in Canada •  12,000 new diagnosed cases per year •  Typically diagnosed at ages 28-33 years. •  Incidence ratio of 2:1 women to men •  Most prevalent in Caucasians north of the equator

Market Analysis

Intellectual Property

•  Preliminary: No evidence of patent protection for

MOG(Fab)/DR-6/CRM-197 proposed therapeutic –  DR6: 398 hits

–  CRM197: 153 hits

–  MOG: 248 hits

–  DR6 and Multiple Sclerosis: 60 hits

•  GILENYA® patent earliest expiration: Sept 2015

–  Anticipated extended patent protection

Manufacturing FIH Process CPD Process Characterization

Valid. Runs (Comm. site)

Position sales force

Submit Mktg Apps

Clin plant mfg CPD Start Comm. site select CP2D Start

BLA | PLA | MAA Submissions

CTD

Marketing

Strategy Dev’l Competitive

Analysis

Publish P2 results

Prep sales force

Publish P3 results

Apply for TM

TPP

EOP2 POC

EOP1 POBA

EOP3 Reg Agency Mtg

IND submission & 30d wait

Market Conditioning

CA Launch

Pre-Clinical Phase I Post- Launch Phase 2 Phase 3

Clinical

Phase I Phase II Phase III Phase IV US Launch

Commit to PRODUCT

Commit to FILE

Commit to LAUNCH

Post-Launch Studies Wrap-up

File Launch

Product Development Plan

Regulatory

Pre-Clinical Phase I Phase 2 Phase 3 File Launch

Clinical Development Plan

Aim •  Synthesize recombinant protein •  Confirm drug delivery method •  Find safety and efficacy in animals

Factors •  Bioavailability and Bioequivalence •  Dose proportionality •  Pharmacodynamics and Pharmacokinetics

Focus •  Vital signs •  Adverse events •  Dose response and tolerance levels •  Brain biopsy and MRI for remyelination

Design •  Ascending dose

Duration 18-24 months

Population Animal models



Aim Find safety in a small sample size

Factors •  Bioavailability & Bioequivalence •  Dose proportionality •  Metabolism •  Pharmacodynamics & Pharmacokinetics

Focus •  Vital signs •  Plasma and serum levels •  Adverse events

Design •  Ascending doses •  Uncontrolled


Population Healthy and target RRMS patients

Size 50



Aim Find effectiveness and short term side effects

Factors •  Bioavailability •  Drug-disease & Drug-drug interactions •  Efficacy at various doses •  Pharmacodynamics & Pharmacokinetics •  Patient safety

Focus •  Dose response & tolerance •  Brain MRI for remyelination •  Adverse events •  Efficacy

Design •  Placebo and active controlled comparison


Population Target RRMS patients

Size 100



Aim Effectiveness, long-term side effects and overall risk-benefit in large population

Factors •  Drug-disease & Drug-drug interactions •  Risk-benefit analysis- Quality of life •  Efficacy and safety

Focus •  Laboratory data •  Efficacy •  Adverse events

Design •  Randomized •  Controlled •  More points of comparison •  Broader eligibility criteria


Population Broad RRMS patient profile Size 800-2000



BLA Filing – 2nd Quarter Preferred, Avoid 4th Quarter

Clinical Development Plan Post – Launch: Phase IV

Aim Monitor ongoing safety and additional uses that might be FDA approved

Factors •  Epidemiological data •  Efficacy and safety in diverse populations •  Pharmacoeconomics.

Focus •  Efficacy •  Pharmacoeconomics •  Epidemiology •  Adverse events

Design •  Uncontrolled •  Observations

Duration 120 months

Population New age groups, conditions etc.

Size Thousands

Area Of Risk: Go/No Go Questions: Determination Phase: Proof of Concept Does the small molecule suppress DR6? Preclinical

Does the platform deliver the therapeutic as expected? Preclinical Does the platform cross the BBB? Preclinical/Clinical

Clinical Proof of Concept Does the platform selectively target oligodendrocytes? Preclinical/Clinical Does the platform deliver the therapeutic as expected? Preclinical/Clinical

Tolerability Are the side effects tolerable considering potential? Clinical phase I-IV

Does the therapeutic cause side effects causing equal than or greater damage to quality of life than the original diagnosis? Clinical phase I-IV

Safety

Does the therapeutic affect the ability of females to successfully become pregnant and deliver healthy children? Clinical phase IV

Does the immune response to the therapeutic cause effects prohibitive to long term therapy? Clinical phase I-IV

Efficacy Does therapeutic stop the RRMS progression and promote remyelination? Preclinical-phase IV

Manufacturing Can therapeutic be prepared according to GMP and GLP requirements? Clinical phase III

Commercial Will the market produce a competitive therapeutic which promotes remyelination and a better product profile? Clinical phase IV

Is there room for product modifications and future commercial growth? Clinical phase IV

Value Has the IP ownership environment been dominated by another player? Clinical phase III

Is there room for IP growth? Clinical phase IV

Critical Portals

Probability of Technical and Regulatory Success

Risk Mitigation

Three Types of Risk 1.  Technical Risk 2.  Commercial Risk 3.  Value risk

2 Categories –  Internal: Scientific Technology and Clinical Endpoints

•  Further separated into functional areas

–  External: Competitors, Markets, and Governments

Risk Analysis

1) CMC of Regenozene 2) Poor In vitro efficacy

performance Prob

abili

ty

Impact

2

High

High Low

Low

1

Risk Analysis

3) Financing Risk 4) In vivo safety/toxicology; sufficient NOEL and safety margin 5) Established vs. unknown biological pathway 6) Not reaching superior safety over competitors

Prob

abili

ty

Impact

4

5

High

High Low

Low

3

6

Risk Analysis

7) Not as efficacious as current standard of care

8) Risk of superior competitor profiles

9) Non-validated mode of delivery

Prob

abili

ty

Impact

7,8,9

High

High Low

Low

Regenozene Sales

$0

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

$35,000

$40,000

$45,000

$0

$1,000

$2,000

$3,000

$4,000

$5,000

$6,000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Annual Sales (Millions)

Years After Launch

Target Optimal (+15%) Target Minimum (-15%)

Cumulative Sales (Millions)

-$10

$0

$10

$20

$30

$40

$50

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

rNPV

(Mill

ions

)

rNPV = $648 million

Risk Adjusted Net Present Value

Source: Biotechnology Valuations for the 21st Century April 2002 www.milkeninstitute.org

Meeting The Need…

Reversing Disability…

Meeting The Need…

1.  Specificity –  Cross BBB –  Target Oligodendrocytes


Meeting The Need…


2.  Sensitivity –  Deliver the therapeutic –  Suppress expression of DR-6


Meeting The Need…


2.  Sensitivity –  Deliver the therapeutic –  Suppress expression of DR-6

3.  Safety –  DR-6 fragments are packaged and destroyed –  Therapeutic components expelled as waste


Is It Worth It?

Visual Disturbances Mental Changes

Loss of sensation

Muscle Spasms

Limb Weakness

Bladder & Bowel Dysfunction

How Is It Not?

Acknowledgements Douglas C. Lane, MBA

President, Experigen Management Company

Thomas J. Schulze, PhD, PMP President, TAON Biopharma Consulting

Dan Mytych, PhD Principle Scientist, Amgen

Judy Willens Biologist/Chemist, Jacobs Environmental

Thank You!

Regenozene

Support Slides

Regenozene

Avonex Gilenya Regenozene

Mechanism of action

IFN-β reduces antigen presentation and T-cell proliferation, alters cytokine and matrix metalloproteinase (MMP) expression, and restores suppressor function

acts on S1PR1, cPLS2 inhibitor and ceramide synthaase inhibitor

Therapeutic enters the blood-brain barrier using the Diptheria Toxin shuttle. Selective uptake by Oligodendrocytes mediated by the MOG antibody Fab conjugation to part B. Blocks the ability of DR6 to traffic to the cell membrane by binding of a chemical entity intracellularly.

Pharmacological principle

anti-inflammatory properties, improves integrity of BBB

sequester lymphocytes, preventing them from moving to CNS

Trojan Horse principle- Diptheria Toxin is well characterized as a therapeutic shuttle. Drug consists of two parts. Part A; chemical entity is stable across a wide range of pH. Part B; biologic entity changes conformation in low pH environment. Part B; conjugated with Fab fragment of antibody. Excess intracellular DR6 is packaged in granules and destroyed by the cell. Suppression of DR6 prevents T-Cell proliferation in the area and demyelination

Action in MS

treat RRMS form of MS, to decrease the number of relapses, and slow the progression of physical disability

reduce immune attack in CNS and possibly help repair process of glial and precursor cells

Prevents DR6 mediated apoptosis in oligodendrocytes. Creates an environment where native OPCs can successfully remyelinate

Efficacy

slows down progression of physical disability, protects against flare-ups and reduced brain lesions and rate of brain shrinkage

been shown to reduce the frequency of clinical relapses and delay the accumulation of physical disability in relapsing forms of MS. Reduces risk of relapse by 52% compared to Avonex.

Expected- Reduction of plaque formation Reversal of existing plaques.Improved quality of life: improved balance, improved mobility, decreased sensory loss, improved urinary continence

Safety most common side effects are fever, chills, sweating, muscle aches and tiredness

after first dose there may be slowing of heart rate. The most common side effects are headache, flu, diarrhea, back pain and cough

Expected- safer than Avonex, safer than Gilenya. Will be a safety reference point. Safe in combination with Gilenya

Convenience once a week intramuscular injection administered orally once a day

Could deliver through many different modes. Requires a BASAL dose for continuous suppression: half life similar to IgG fraction~7.5 hrs. IgG ½ life 23 days.Patches, insulin type pump, pills, inhaled

Clinical Features

two randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis

Developed a well-studied safety and tolerability profile, which has been characterized in over 2,600 clinical trial patients, some of whom are in their seventh year of treatment, with more than 4,500 patient years of experience

Use other MS clinical studies as benchmarks: Gilenya or Avonex.Use other diptheria shuttle clinical studies as benchmarks: Ontak. Use of diptheria vaccination studies in safety study design

Clinical Endpoints

time to progression in disability, upper limb and lower limb function tests

reduction in relapses and disability progression

T-cell proliferation, inflammatory markers, MRI of lesions, relapse rate

Regulatory

regulated as a biological pharmaceutical regulated as a chemical pharmaceutical regulated as a chemical and a biological pharmaceutical

Outsourcing Considerations

•  Manufacturing •  Clinical vs. Commercial •  Experience •  Supply/Schedule •  Flexibility •  Up-Front Cost •  Audits vs Validation

– Facility and Environmental Controls – cGMP Systems – cGMP Equipment

•  Quality Control •  Increased Range of Tools •  Confirmation of Results •  Ability to Meet Demand

Outsourcing Considerations

•  Choosing a CMO •  Production capacity •  Experience & Reputation •  Quality and Regulatory history •  Protection of intellectual property •  Flexibility

•  Auditing/Inspecting a CMO •  Confidentiality agreement •  Validation •  Training/SOPs •  Maintenance/Calibration/EURs •  Manufacturing Specifications •  OOS records/investigations •  Deviation records/investigations •  “receipt of materials to release of product” •  Contracting with a CMO •  Technical and Quality Agreement (T&Q) •  Continue to audit through validation runs and beyond

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