Mikhail Sitkovsky Skolkovo im modernization of medicine

Skolkovo in modernization of medicine and fostering the cutting

edge biomedical enterprise in Russia

• The next 5 years…

The Cutting Edge Treatments and Technologies that stimulate and/or enable the world-class IP-generation In Russia.

• The thoughtfully arranged “repertoire” of networking Skolkovo companies…

• But how to ensure that the Skolkovo-generated IP is NOT lost!

• Because it is NOT validated in vivo!• Skolkovo Institute of Translational Medicine• =SITM: • But which Treatments and Technologies?• The Recruitment of Top Talent to Skolkovo

One of the desirable Skolkovo aims: to develop what

“everybody wants and nobody has”.

• But Skolkovo also should develop what USA has, but Russia does not have

• Or does not have IP to produce the needed treatment…

The “Cutting Edge” technologies

What is it that “everybody wants and nobody has”?

• For example, the effective immunotherapy of cancer.

• Requires combined use and improvement of many medical technologies..

• Immunotherapy is the Biomedical “Decathlon”!

• Immunotherapy can serve as an unifying focus in selecting and offering priorities…

• Attacking tumor with patient’s own anti-tumor CD8+ T-killer cells and Natural Killer Cells

• To get rid of the residual tumor and metastases…

• FDA USA: = 27 april 2010, “Provenge” Cancer Vaccine, Dendreon,

• But the success rate is still low: ~ + 4 months?

• Why?-Tumor protects itself from anti-tumor T-killer cells;

• “Hellstrom Paradox”…

Immunotherapy of Cancer( “Our last hope”…)

In vivo tumor seems to be protected:

T-killer

T-killer

T-killer

T-killer

The “Hellstrom” Paradox”, Nature, 1968;

?

Anti-tumor T cells destroy tumor cells in vitro:

T-killerT-killer

T-killer

The “Hellstrom-Schreiber” Paradox: -“Equilibrium lesions”(Nature, 2007)

The Motivation: 1974, Moscow University

Hypoxictumor

Adenosine

Adenosine

Adenosine

Adenosine

Adenosine

Adenosine

T-killerT-killerT-killerT-killerT-killerT-killerT-killer

Adenosine puts anti-tumor T killer cells to sleep …

The SolutionOhta and Sitkovsky, Nature 2001

• Moscow University: 1974-1981• Mass.Inst. of Technology: 1981-1984• National Institute of Health, Lab.Immunology: : 1984-

2004• New England Inflammation and Tissue Protection

Institute, NU: 2004-present :• Dana Farber Cancer Institute, Harvard Institutes of

Medicine: 2005-present• “Invisible “College” of Multiple Tough Reviewers:

Nature, J.Exp.Med., J. Biol. Chem; PNAS; J. Immunol ,..)

• “NewVac”: 2010-present

Where the study was done…

• Based on Solution of Hellstrom Paradox…

• RedoxTherapies and ChemRar: • Founders of “NewVac” in Skolkovo.• The IP-Creating and the IP-

attracting enterprise in Skolkovo

Tumor Defense CounterMeasures

Hypoxictumor

Adenosine

Adenosine

Adenosine

Adenosine

Adenosine

Adenosine

T-killerT-killerT-killerT-killerT-killerT-killerT-killer

Tumor Defense Countermeasures

Hypoxictumor

T-killerT-killerT-killerT-killerT-killerT-killerT-killer

Tumor Rejection

Survival

Anti-Tumor Hypoxia Drug

Competitive A2AR AntagonistTumor Hypoxia [O2]Low

Ecto-Enzymes [CD39]High

[CD73]High

ATP-->[Adenosine]High

Elimination or Blockade of CD73

Preclinical evidence of tumor rejection and immunological memory to rejected tumordue to the action of the A2AR antagonist in different animal models of cancer

The Anti-Tumor Hypoxia Drug enables anti-tumor T killer cells to reject lung tumors

21%

40%

60%

• If there is In Vivo Evidence No IP, No patents!• The decisive solution:• SITM • Skolkovo Institute of Translational

Medicine

The importance of animal models of diseases

• =SITM develops cutting edge novel ideas• =SITM makes great ideas patentable by

validating them in vivo• =SITM has Department of Animal Models of

Human Diseases• =“Humanized” and KO mice • =SITM coordinates clinical trials of Skolkovo

companies• Who can collaborate in launching SITM?

SITM

Skolkovo Institute of Translational Medicine

The Structure of Dana-FarberThe Structure of Dana-Farber

• Bone and Sarcoma

• Cancer Genetics

• Cutaneous and Mohs

Surgery

• Gastrointestinal

• Women’s Cancers

• Head and Neck

• Genitourinary

• Thoracic

• Hematology

• Neuro

• Experimental

therapeutics

• Psychosocial

DISEASE CENTERS

• Center for Cancer

Vaccines

• Center for Clinical

Translational Research

• Center for

Experimental Pathology

• Center for Cancer

Genomics

• Center for Cancer

Systems Biology

• Center for Applied

Cancer Science

INTEGRATIVE

RESEARCH CENTERS

• Proteomics

• Genomics

• Chemistry

• Computational

Biology

• ImagingTECHNOLOGIES

How Dana-Farber Cancer Institute at Harvard Organizes its 50:50 Balance of Clinical Care and Basic Research

An Innovative Model for Cancer

Research and Care

Some of the promising opportunities for Skolkovo

Specific Examples…

• For example, the NewVac in Skolkovo will have drug that may also improve the antibody-targeting therapies of breast cancer…

• Monoclonal Antibody Herceptin.• But How to get it to Skolkovo?

• DFCI, Harvard and U. Penn, Mark Greene. M.D.

• The Skolkovo may have chance to develop the most superior treatment using the next Generation Herceptin;

•

The answer #1: Recruiting the Discoverer of Herceptin

S22-Fc - a multi-specific binder to EGFR, Her3 and Her2/neu

MCF7 NE91

T6-17

S22-Fc

Binding to T6-17 (Her2) and NE91(EGFR) cells by S22-Fc

S22Fc

“Creation of a trivalent antibody like molecule with picomolar activity

against EGFr, HER2/neu and HER3”The molecule is already fully “human” …;

Has potential to help all HER+ breast cancer patients as compared with 25% for original herceptin Ab…

as compared with Zero with no “old” herceptin.

Is not it something that “everybody wants and nobody has”?

Drugs that are not novel, but are much needed…

and can be “novel again”…

• These drugs can be also very lucrative• Multi-$ Billion market• -The IP- is getting “old”…• But the international IP on them is still

possible!

Not “Cutting Edge” on the first look…

• But these actually ARE cutting edge technologies…

Fabrazyme Amevive

Xolair Bexxar Raptiva

Fabrazyme Amevive

Xolair Bexxar Raptiva

Chronology of Key Biotech Product Approvals 1982 - 2007

20031987 199819971995 19961988 1989 1990 1991 1992 1993 1994 1999 20012000

CBER (N=48)

CDER (N=14)

Activase

19861985

Nutropin

Glucagon

Thyrogen

Mylotarg

Ovidrel

NatrecorProtropin CerezymeCeredase

Follistim

Forteo

Epogen/ProcritEpogen/ProcritNeupogen

Leukine

Actimmune

Proleukin

Pulmozyme

Betaseron

ReoPro

Intron AAbatacept

Galsulfase

Abatacept

Galsulfase

Avonex

Retavase

Benefix

Infergen

Neumega

Rituxan

Zenapax Regranex

Simulect

Synagis

Remicade

Herceptin

Enbrel

NovoSeven

Ontak

Refacto

Zevalin

Elitek

Humira Rebif

Humulin R (1982)

Achieved $1 Billion Annually in International Sales

2002

Campath

Kineret

Xigris Aranesp

2004 2005 2006

Avastin

Erbitux

Tysabri

Lucentis

Myozyme

Elaprase

Vectibix

HumatropeHumatrope

IncrelexIncrelex

Products Most Likely Off Patent

by 2018

2007

2018

Why would you want to have a drug that is out of IP protection?

• Because it is proven to be safe…

• Because it works!

• It will bring you $$!

• And it did not cost you $$$$ to develop!

• Competition: China, India…

• But safety still must be proven..

Biosimilars in Skolkovo

• Our Chance?• New IP-based methods of inexpensive

evaluation of Innovative and “Biosimilars”…• “Evergreening” of drugs on the market…• -New combinations• -New delivery• -New formulations• E.g. ChemRar and Sanofi-Aventis..

“The Potential Skolkovo Enterprise:

• New IP-based Technologies to evaluate “Biosimilar” biotech products;

• Less expensive validation of BioSimilars• Also minimize the $$$ risk with innovative

drugs..• “Immunogenicity”… • -”scale-up”…. “omics” …• E. Reinherz, Harvard and Barry Karger, NU

GENERAL PRINCIPLE:Skolkovo must have strong requirement:

The IP-generating technological platform

• The Example:• Monoclonal antibody/ Proteomics based and• The disease-specific diagnostic or outcome-

predicting assays;

• If there is NO need in immunotherapy!• Early diagnosis!• Need in superior biomarkers.• Proteomics and bioinformatics platforms• Not just for immunotherapy!• For any disease!

What is even better than EFFECTIVE immunotherapy of

cancer?

“In Skolkovo” mAB proteomics technology

New IP to be created for every new disease

• ~10 000 mAB / experiments for proteome profiling

• Disease specific mAB libraries detect the natural form of the proteome

• Easy to translate

Immunogenpreparation

Hybridomageneration

ScreeningCloning

assay

Reagent characterization

Patent pending

proteome normalization (10,000 mABs / experiment)

No translation bottleneck

Record speed form bench

to market

Generation of the BSI mAb library against native human plasma proteins

using mAb proteomics (patent pending)

“In Skolkovo” created mAb/Proteomics diagnostics

• A test for early detection of lung cancer is in late development phase– Expectation is improvement of survival from

16% to 50%

• Serum from patients with other diseases…

• What e.g. about early bacterial infections?

• What about prostate cancer?

• What about heart disease?

• Targeting NOVEL targets by NOVEL small molecules and NOVEL biotech products:

• These are the most IP-rich technologies : • Must be based on “Breakthroughs in understanding

of molecular mechanisms of disease”.• Now is the good time to identify some of these

underfunded in USA/Europe breakthroughs.• Benefitting from failures of peer review at NIH..• Skolkovo has all to attract the top world

scientists!

The Recruitment of Top Talent to Skolkovo

• Yes: -Emotional to some…-Interesting to many..• =Bad times in the West…

- $$$ = is the “strongest chemo attractant!”• No: -1990s stories about “Russian Partners”…• -Yes: Skolkovo will dispel fears by excellent

examples of Russian Partners!• Thus Skolkovo will play yet another great role for

Russia by challenging the wrong image stereotype!

Will The Top World Scientists Come to Russia with their

Best to synergize with Russian scientists ?

What to Do?

• 1. Identifying top scientists with cutting-edge discoveries that have significant translational potential

• 2. =SITM:

• Skolkovo Institute of Translational Medicine

• Novel Treatments and drugs IP-Creating companies in Skolkovo

Contacts

[email protected]@neu.edu

USA numbers617-669-88-16 - works in Moscow617-800-52-65

Skolkovo is also uniquely qualified to catapult the medical care in Russia to the

much higher levels

• One can think about the MedTechSOP-Transfer enterprise in Skolkovo;

• The Medical Treatments, Standard Operating Procedures (SOP) and Technology transfer

• Top clinician-scientists of Dana Farber Cancer Institute, Harvard Institutes of Medicine,Harvard Medical School..

• A lot of people to persuade, but there is some initial interest..

Molecular Weight

IgG Antibody

~ 25,000 atoms

hGH

~ 3000 atoms

0 200,000 350,000250,00050,000 150,000100,000 300,000

Factor VIII

~ 55,000 atomsN

eed

for

Tri

als

Biosimilars – Complexity leads to unknowns - If you don’t run trials – you won’t know the safety or efficacy

Aspirin

21 atoms

COOH

OCOCH3

Complexity of biotech products

Drug Discovery from Uncultur-able before Microorganisms

● 99% of all species of microorganisms on the planet do not grow in the lab

● Millions of new species, an enormous untapped resource for drug discovery

● A general method to grow uncultured microorganisms developed based on

cultivation in situ in diffusion chamber and subsequent “domestication” for

growth in the lab

● Growth factors for many uncultured species identified, an additional tool for

growing them in the lab

Patent: US 7,011,957

Kaeberlein et al., Science 296:1127-1129.

Schumacher et al., 2009. Science 323:396-401.

Dörr et al., PLoS Biol 8(2): e1000317.

Lewis, K. 2007. Nature Rev. Microbiol. 5:48-56.

D’Onofrio et al., 2010. Chem. & Biol. 17: 254–264.

IP-generating drug discovery in Russia

• “Fishing expeditions”….

• But fishing expeditions DO catch fish!

• Some times…

Plasma

Collection

Plasma

Normalization

Patent pending

Shotgun

ImmunizationNascent library

generation

Library characterization

screening

HT Hybridoma

Cloning

mAb validation

ELISA

mAb

Production

mAb microarray

Production

Generation of the BSI mAb library against native human plasma proteins

using mAb proteomics (patent pending)

QuantiPlasma™

PlasmaScan™

Microarray

Libraries

>600 mABs

Characterization

mAb/epitope/protein ID

“10 000 mABs”

An Open Forum on the Scientific and Regulatory Issues

of Biosimilars and Follow-on Biologics

Boston, MA USA

Copley Marriott Hotel

Address by:

Senator Edward Kennedy

Chairman of the Senate Health,

Education, Labor and Pensions

Committee

Plenary by:

Dr. Randall Lutter

Acting Deputy Commissioner

for Policy, US FDA

Organizing Chair:

Prof. Barry Karger

Director, Barnett Institute, and

James L. Waters Chair,

Northeastern University

Hosted by:

A high level meeting of the international biotechnology and generics industries, together with government regulators and academic laboratories, for an open

forum and collegial debate on the scientific and regulatory issues in the introduction of generic complex biological drugs.

www.barnett.neu.edu/biogenerics/

For additional information or to receive updates, email [email protected]

BIOSYSTEMS INTERNATIONAL

The antibody technology company