Complex Therapeutics: Therapeutic Vaccines, Cell and Gene...

Complex Therapeutics: Therapeutic Vaccines, Cell and Gene Therapy –Will Pharma “Deliver” When the Product Is Not ‘Off-the Shelf’?

Jeffrey M. Bockman, PhD

© Defined Health, 2004

Disclaimer

The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change.


Key Meeting in Cell & Gene Therapy


Innovation - The Victorian Darwinism of Pharma

Is an oral pill really the highest form of pharmaceutical evolution?


Innovation Gap – The Graphs of Doom

NAS: IMS LifeCycle R&D focus R&D Spend: $15B to $33B (est.) [Source: PhRMA]

Innovation Gap


Innovation Gap – The Graphs of Doom

Source: Steve Burrill


Innovation Gap – Discussions at Dinner Parties


Innovation Gap – A Matter of Narrow Definitions?

• Open window (A) and fly kite (B). String (C) lifts small door (D) allowing moths (E) to escape and eat red flannel shirt (F). As weight of shirt becomes less, shoe (G) steps on switch (H) which heats electric iron (I) and burns hole in pants (J). Smoke (K) enters hole in tree (L), smoking out opossum (M) which jumps into basket (N), pulling rope (O)and lifting cage (P), allowing woodpecker (Q) to chew wood from pencil (R), exposing lead. Emergency knife (S) is always handy in case opossum or the woodpecker gets sick and can't work.

Pharma tries many ways to get its productivity numbers up


Innovation Gap

– Is one way to address the gap just to go another way?


Pharma – Late to the Monoclonal Party

“Antibodies Stage a Comeback in Cancer Treatment”Science, Volume 280, Number 5367 Issue of 22 May 1998, pp. 1196 - 1197



Cambridge Health Advisors: New Directions in Monoclonal Antibodies, Oct 2004

STILL ONLY MARINGALLY AT THE PARTY



Cambridge Health Advisors: New Directions in Monoclonal Antibodies, Oct 2004

Biogen-Elan’s Tysabri – MAb for Multiple Sclerosis –Approved Nov 2004

STILL ONLY MARINGALLY AT THE PARTY


Not Just Proteins, Device-Phobia

Respiratory Medicine – Lower Airway Disease (asthma, COPD)


Not Just Proteins, Device-Phobia

1997 Worldwide (MedAdNews, May 1998)

Asthma and COPD:

Atrovent (Boehringer Ingelheim), $691.7

Serevent (Glaxo Wellcome), $665.8

Pulmicort (Astra), $643.9

Ventolin (Glaxo Wellcome), $641.2

Beclovent (Glaxo Wellcome), $542.8

Flovent (Glaxo Wellcome), $516.6

Proventil (Schering-Plough), $283.0

Intal (Rhone-Poulenc Rorer), $230.7

Azmacort (Rhone-Poulenc Rorer), $229.7

Respiratory Medicine – Lower Airway Disease (Asthma, COPD)

2003 Worldwide (MedAdNews, May 2004)

Limited Players – Then…….and Now


A Complex Therapeutic Setting - Lysosomal Storage Diseases? Why Did Pharma (& Other Biotechs) Pass?

• Too small?

• No franchise synergies?

• Too complicated?

• No one bothered too think about it?

Evaluate PharmaSource: Gauchers News April 2003


Radiotherapy – Another Complex Therapy Example?

The hurdles for radiotherapies, even in cancer, are quite high where other non-labeled therapies exist – and these may serve as examples of the hurdles that cell and gene therapies, at premium pricing, will also face.

US Sales, Zevalin US Sales, Bexxar

US Sales, Rituxan


Tysabri – An Example of Hurdles Facing a “Non-Complex” Therapy

• Infusion centers

– Only 20% of neurologists have infusion capabilities in their offices

• Pharmaco-economics

– Nearly 50% more

• Reimbursement

– Medical benefits$2,259.61Not yet available300 mg infusionTysabri

$1,675.80$1,556.1512 syringes, 22 mcg

Rebif

$1,437.61$1,149.5130 syringes, 20 mg

Copaxone

$1,581.06$1,416.6315 syringes, 0.3 mg

Betaseron

$1,353.75$1,226.504 syringes, 30mcgAvonex

AWPCash PriceQuantity/DoseBrand

Monthly Prices for MS Medications

Source: Specialty Pharmacy News, Jan 2005 9 (from ivpcare inc.)

Tysabri may well become a blockbuster, but not without strong promotional & educational efforts


Primary Care & QD Orals – Past or Prologue?

0%

10%

20%

30%

40%

50%

60%

70%

80%19

93

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

E

2005

E

2006

E

2007

E

2008

E

Note: Includes AZ, Aventis, BMS, Eli Lilly, GSK, JNJ, Merck, Novartis, Pfizer, Roche. New product sales were not risk-adjusted.

Source: Evaluate Pharma and Defined Health estimates

% Contribution of PCP-Driven Products to Top 10 Pharma Sales Growth


Innovation Gap – Filling It a New Way


Cell and Gene Therapy Pipeline –Targeting Key Markets


Innovation Gap – Filling It a New Way

Cell and Gene Therapy Pipeline

Scott Burger, Advanced Cell and Gene TherapySource: Scott Burger, Advanced Cell and Gene Therapy


Key Acronym for the Future: OCTGT

OCTGT/CBER/FDA, FY 2004:

Source: Dr. Cynthia Rask, CBER/OCTGT

OCTGT - Office of Cellular, Tissue and Gene Therapies


Key Acronym for the Future: OCTGT

Agency-wide initiative intended to address a recent slowdown in innovative medical technologies submitted to FDA for approval:

– Seeks to develop a “new product development toolkit”, including scientific and technical methods to improve predictability and efficiency in moving from laboratory concept to commercial product.

Examples: animal and computer-based predictive models, biomarkers for safety and effectiveness, new clinical evaluation techniques.


Cell and Gene Therapies in Development

• WW pipeline

0

500

1000

1500

2000

2500

3000

CancerMonogeneticCVD

InfectiousEndocrineRespiratory

Contribution of Gene / Cell Therapies by Indication

Cell / Gene Therapy

Small Molecules /Biologics

IDDB3 Excludes preclinical


Cell and Gene Therapies in Development

• US only, Oncology

Adis R&D Insight Phase I-III, excluding launched

19%

81%

Cell, Gene orImmunomodulatingAll Other


Gene Therapy Clinical Trials by Indication

Cancer diseases

66%

Monogenic diseases

9%

Vascular diseases

8%

Other diseases3%Infectious

diseases7%

Healthy volunteers

2%

Gene marking5%

GT Pipeline Expanded

IDDB3 and Adis Insight


Gene Therapy Clinical Trials by Stage

Phase I/II209

Phase I643

Phase II139

Phase III18Phase II/III

11



Looking for some available late stage opportunities---look no further!


Gene Therapy Clinical Trials by Country

UK

USA

Germany

CanadaBelgium

FranceSwitzerland

OtherItaly

JapanMuti-country

Australia




A Tragic Day

http://www.frenchanderson.org/

0

20

40

60

80

100

120

Number of Trials

1989 1991 1993 1995 1997 1999 2001 2003 2005

Year

Number of Gene Therapy Clinical Trials Approved (WW)


Deal-Making: Complex Cancer Therapies

• Is any big pharma doing deals in this space?

• Is any big biotech?

Selected partnerships – sorry, selected lack of partnerships –because basically everything, gene and cell therapy, is as yet unpartnered


Deal-Making Analysis

Gene Therapy – Pharma Deals

Transkaryotic Therapies, Inc. has retaken from WyethPharmaceuticals (formerly Genetics Institute) its Factor VIII gene therapy rights in Europe. TKT's non-viral, ex vivo gene therapy system genetically modifies a patient's own cells to produce and deliver proteins within the body for extended periods of time. In 2002, TKT completed a Phase I clinical trial of its Factor VIII gene therapy product in 12 patients with severe hemophilia A.

TKT Retakes Factor VIII Gene Therapy Rights from Wyeth

--

Hemophilia ATerminationWyeth (US Public)

TranskaryoticTherapies Inc (US Public)

Factor VIII Gene Therapy

Product0.58/11/2003

A Deal terminated…

MedTrack




Schering AG, Germany, and US-based company Valentis, Inc. announced a multi-product license and option agreement to develop and commercialize gene-based therapeutic products. Under terms of the agreement Schering will obtain exclusive, world-wide rights to Valentis' PINC polymer based synthetic gene delivery and the GeneSwitch gene regulation technologies for use with up to two genes proprietary to Schering, and an option for non-exclusive rights to the PINC technology for a third gene.

Schering, Valentis In Multi-Product Gene Therapy Alliance

--

Gene DeliveryLicenseSchering Ag Adr (US Public)

ValentisInc (US Public)

Gene Delivery Technology, GeneSwitchtechnology

Technologyn/a12/20/2002

MedTrack




Amsterdam Molecular Therapeutics, announced the signing of a license agreement with Schering Plough Corporation, Kenilworth, USA, for use of interleukin-10 (IL-10) under Schering-Plough's extensive IL-10 patent portfolio, for ex vivo gene therapy in inflammatory diseases of the gastrointestinal tract. The agreement allows AMT to further develop its IL-10 ex vivo gene therapy for the maintenance of remission in Crohn's disease in collaboration with the Academic Medical Center (AMC) in Amsterdam.

Amsterdam Molecular Therapeutics (AMT) Licenses Rights On IL-10 For Ex-Vivo Gene Therapy From Schering-Plough Corporation

--

Crohn's diseaseLicenseSchering-Plough Corp (US Public)

Amsterdam Molecular Therapeutics B.V. (Global)

IL-10Productn/a9/2/2002

MedTrack




Boehringer Ingelheim and Genetronics Biomedical Corporation signed a Research and Option Agreement to evaluate the performance of Genetronics' electroporation technology for the delivery of nucleic acids into arterial walls for the treatment of Peripheral Vascular Disease (PVD). Financial terms of the agreement were not disclosed. Electroporationinvolves the use of brief, pulsed electric fields to temporarily permeabilize cell membranes, allowing the entry of various types of therapeutic molecules into the cell.

BoehringerIngelheim and GenetronicsSign Gene Therapy Research and Option Agreement

--

Peripheral Vascular Disease

Option, Research

GenetronicsBiomedical Corporation (US Public)

BoehringerIngelheim (Global)

--Miscellaneousn/a7/10/2002

MedTrack



Gene Therapy – Biotech Deal

Genzyme Corporation and Applied Genetic Technologies (AGTC), a private development-stage biotechnology company, announced today that they have entered into a research collaboration to jointly develop novel therapeutics involving gene therapy. Through the collaboration, Genzyme gains access to AGTC's extensive expertise using Adeno-Associated Virus (AAV) vectors to deliver genes to patients, including access to AGTC's novel high-yield manufacturing capabilities for AAV vectors. These vectors may have therapeutic advantages in several disease areas where Genzyme has active preclinical development programs, including lysosomal storage disorders, cardiovascular disease, central nervous system disorders, immune-mediated disorders, and others.

Genzyme, AGTC Announce Gene Therapy Collaboration

--

Drug discoveryCo-development, Collaboration, Research

Applied Genetic Technologies Corporation (Global)

Genzyme Corporation (US Public)

--Miscellaneousn/a12/6/2004

MedTrack


Deal-Making: Pharma’s Hesitancy

• Risk

• IP (cross-licensing maze)

• Stacking royalties and multiple partners (e.g., delivery)

• Liability

• Manufacturing & QC

• COGS

• Service models

• Logistics

Reasons & Excuses



• Logistics

Reasons & Excuses

Scott Burger, Advanced Cell and Gene Therapy



• Logistics

Reasons & Excuses

• Product definition–functional cells, not the products of

Cells: variability, heterogeneity

• Process scale–How to commercialize at 1 lot per patient for autologous?

• Limited infrastructure, technology, reagents


The Rosy Picture – Is It?

• $1.35B in cell and gene therapy product sales by 2009? Maybe…

Source: Steve Burrill

In 2009, Lipitor will be $13B and Taxotere$3B


Innovation Case Studies – First Generation -Genzyme



Carticel Indications and Usage

• Carticel is indicated for the repair of is indicated for the repair of symptomatic, cartilaginous defects of the symptomatic, femoral condyle(medial, lateral, or trochlear), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical procedure

Dr. John McPherson, Genzyme

Evaluate Pharma



• Focus efforts on true unmet medical needs

• Predictive animal models are crucial to establishing potential safety & efficacy

• Approach should fit with physicians practice

• Patient compliance/acceptance is important

• Pursuing research in an area where clinical research testing of your concept is feasible

• Commercial success will be ultimately be determined by cost/effectiveness of product

Dr. John McPherson, Genzyme


Innovation Case Studies –The Next Generation:

Cardio/Vascular Diseases

Cancer


Innovation Case Studies – Vasogen - Process

• Celacade (immune modulation therapy) is in phase III clinical development for the treatment of chronic heart failure and peripheral arterial disease.

• Celacade is designed to target the chronic inflammation underlying cardiovascular disease by activating the immune system’s physiological anti-inflammatory response to cells undergoing apoptosis.

• Celacade is administered to the patient once per month as a brief outpatient procedure. During the treatment, a small sample of a patient’s blood cells is drawn into our single-use disposable cartridge, exposed to controlled oxidative stress utilizing our proprietary medical device technology, and then administered to the patient intramuscularly.

Oxidative stress is known to induce cell apoptosis, affecting antigen presenting cells (APCs) of the immune system, including macrophages and dendritic cells, and leading to an up-regulation in the production of the anti-inflammatory cytokines IL-10 and TGF-β. Regulatory T cells affected by the above interactions traffic through the tissues of the body leading to reduced tissue levels of inflammatory cytokines such as TNF-α, IL-6, IFN-γ, and IL-1β, and a down-regulation of chronic inflammation.

Vasogen website


Innovation Case Studies - Vasogen - Process

ACCLAIM Phase III TrialA pivotal phase III double-blind, placebo-controlled clinical trial of Celacade™ (immune modulation therapy) in patients with advanced chronic heart failure. Vasogen’s ACCLAIM(Advanced Chronic Heart Failure CLinicalAssessment of Immune Modulation Therapy) trial, being conducted at cardiac centers throughout the United States and Canada, is evaluating the impact of Celacade™ on the risk of death and cardiovascular hospitalization in patients with advanced chronic heart failure to support regulatory approval and marketing in North America and Europe.

The primary outcome measure of ACCLAIM is the composite endpoint of all-cause mortality or hospitalization for cardiovascular causes (time to first event). The trial, which has been approved to enroll up to 2,016 patients, will conclude when a minimum of 701 outcome events have occurred and all patients have been followed for at least six months.

73-patient double-blind, placebo-controlled phase II trial in advanced chronic heart failure patients conducted at the Cleveland Clinic, Baylor College of Medicine, the Texas Heart Institute, and the University of Montreal.

Vasogen website


Innovation Case Studies - Vasogen - Process

SIMPADICO Phase III Trial A pivotal randomized, double-blind, placebo-controlled clinical trial of Celacade (immune modulation therapy) in patients with peripheral arterial disease. Vasogen’s SIMPADICO (Study of Immune Modulation Therapy in Peripheral Arterial Disease and Intermittent Claudication Outcomes) trial is investigating the impact of Celacade on improving the symptoms of intermittent claudication. The trial is being conducted at cardiac and vascular centers throughout the United States and Canada, and is designed to support regulatory approval and marketing in North America and Europe.

The SIMPADICO trial is designed to enroll up to 500 patients with Fontaine Stage II disease (symptomatic PAD) who have intermittent claudication. The primary endpoint of the trial is the change in maximal treadmill walking distance over six months, the endpoint recognized by the FDA and other regulatory authorities for approving new treatments for symptomatic peripheral arterial disease.

Phase II trial

• Is there sufficient justification for a premium, high tech approach here?• What pricing issues if any will be set by the CHF indication?

Vasogen website


Innovation Case Studies – MG Biotherapeutics –Cells

JV of Medtronic and Genzyme

Autologous processing of skeletal myoblasts

Dr. Bruce Wentworth, MG Biotehrapeutics


Innovation Case Studies – MG Biotherapeutics – Cells

The MAGIC Study -Myoblast Autologous Grafting for Ischemic Cardiomyopathy

To assess the safety and efficacy of two doses of skeletal myoblasts, as compared to placebo, in the treatment of ischemic heart failure. (EU trial)



Innovation Case Studies – MG Biotherapeutics – Cells

The MAGIC Study -Myoblast Autologous Grafting for Ischemic Cardiomyopathy


PHASE II PHASE II –European Trial European Trial300 Patients 300 Patients

Placebo Placebo-controlled, randomized, double controlled, randomized, double-blind blind

Pts followed through discharge and at 10 days, 1, 3, 6,12 and 24 months 12 and 24 months

Primary endpoint: Recovery of contractility (via echo)Secondary endpoint: 15% difference in 1-year MACE (major adverse cardiac events )


Innovation Case Studies - Corautus – Genes

Vascular regeneration with VEGF-2

THE GENASIS TRIAL

Genetic AngiogenicStimulation Investigational Study

In collaboration with Boston Scientific, who not only supplies device but will educate clinicians


Innovation Case Studies - Corautus – Genes

GENASIS Phase Ilb Clinical Trial Design

• National multi-center, double-blind, dose ranging

• N = 404, four cohorts (0, 20µg, 200µg, 800µg)

• Class III and IV angina “no op” patients

• Boston Scientific Stiletto catheter

• Efficacy data measured at 3 months, safety data at 1 year

• 25 clinical sites in the United States

• Primary Endpoint – Increase in Exercise Tolerance Time (“ETT”)

• Secondary Endpoint – SPECT Nuclear Imaging, Decreased angina

No Outcomes endpoints (events, mortality)


Innovation Case Studies – Why HF?

• CHF affects 5 million people in the US

– 500,000 new diagnoses per year

– 50% die within first 5 years of diagnosis

• Approx. $20B - $50B in direct costs in US

– On average, 6 meds and 2+ hospitalizations per year

Clear clinical need, as well as pharmaco-economics


Innovation Case Studies - Regulatory Hurdles –Dendreon’s Provenge


Regulatory Hurdles – Dendreon’s Provenge

FDA approached three years ago

Subgroup analysis showed benefit in Gleason score <7 (For these men, the probability of remaining progression free and free of cancer-related pain while on the study was more than two times higher than for patients treated with placebo. )

Request for further trial

Dendreon announced that 34% of those who received Provenge in that original trial were still alive after three years, compared with 11% of those who took a placebo. The median survival was 25.9 months for those who received Provenge, compared with 21.4 months for those who took the dummy vaccine, a 4.5-month increase in survival that is almost double the 2.5-month benefit shown in clinical trials of Taxotere in HRPC

• “When it comes to completely novel products like immune-boosting vaccines, the agency stumbles, forcing square pegs into round holes as it tries to adapt familiar regulatory models to technologies it doesn't fully understand. In the case of cancer vaccines, that might mean more markers of vaccine response like scientific tools that can measure whether the vaccine is generating an immune response that can serve as a proxy for effectiveness.”

Adviser Soapbox Prostate Drug Promise Vs. FDA Rigidity Dr. Scott Gottlieb, Forbes/Gottlieb Medical Technology Investor, 02.18.05, 9:45 AM ET


Complex Therapies’ Value Threshold


Where, Why, To What End?

• Serious medical condition

– morbidity

– mortality

• Significant clinical benefit

– outcomes

• Significant pharmaco-economic argument

• Significant benefit-logistics argument


Are the Obvious Candidates the Best Candidates?

Little Medical Need – Serious Condition – Life-threateningAva

ilabl

e Th

erap

ies

–Po

or T

hera

pies

–N

o Th

erap

ies

Cancer

Diabetes

Alzheimer's disease

Hypertension

Asthma

Alopecia



Technology Adoption

Dr. George Golumbeski, Phacilitate Cell & Gene Therapy Forum 2005



Technology Adoption

Source: Based on Phacilitate presentation of Bob Ward, Schering-Plough [Based on International Data Corporation’s Information Industry & Technology Update 1997-1998]


Acknowledgements

• Nabil Mouline

• Mike Price

• Ed Saltzman

Complex Therapeutics: Therapeutic Vaccines, Cell and Gene Therapy –Will Pharma “Deliver” When the Product Is Not ‘Off-the Shelf’?

Jeffrey M. Bockman, PhD

Complex Therapeutics: Therapeutic Vaccines, Cell and Gene...

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