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Peptide Pharmaceuticals: Development in Russia and Worldwide

Vladislav Deigin

“Peptos Pharma”Moscow, Russia

Shemyakin & Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences, Moscow, Russia

JV “Pharma Bio”

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GenomicProteomic

Peptidomic

Planet Galaxy

Universe

Peptides – universal bioregulatorsPeptides – universal bioregulators

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

OO-

NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

OO-

NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

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NH

N

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HC C

O

NH

CH

C

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H2C

+H2N

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O

C

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NH

N

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HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

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NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

OO-

NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

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NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

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NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

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NH

N

HN

HC C

O

NH

CH

C

HOO

HN

H2C

+H2N

CH

C

O

C

OO-

NH

N

HN

HC C

O

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Topics for discussion:

Peptide drugs: current landscape and perspectives;

Pipeline of peptide pharmaceuticals: contribution of Russian science;

Novel approach for next generation development of peptide pharmaceuticals

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Topics for discussion:

Peptide drugs: current landscape and perspectives;

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Total amount of registered API in USA and Europe

Non-peptide/protein drugs (over 5000)

Peptide/protein drugs (~60 synthetic peptides and ~15 proteins)

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Peptide pharmaceuticals – one of the fastest growing segments of the world market

Clinical indication for the peptide drugs. Publications related to synthetic peptide preparations

Sales volume for 10 the best selling peptide pharmaceuticals Number of peptide products in the development pipeline in 2008

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Topics for discussion:

Pipeline of peptide pharmaceuticals: contribution of Russian science: - Pharmaceuticals - Peptide vaccines - Oral delivery system

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Topics for discussion:

Pipeline of peptide pharmaceuticals: contribution of Russian science: - Pharmaceuticals

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There are 13 original branded peptide drugs developed and marketed in Russia

Peptide pharmaceuticals: Route of administration1 Dalargin (anti –ulcer) - IM

2 Thymogen (immunomodulator) - IM, Intranasal

3 Semax (neuroprotector, after stroke ) – Intranasal

4 Likopid (immunomodulator) - sublingual tablets

5 Immunofan (immunomodulator) - - Sq. injections

6 Thymodepressin (immunosupressor) – IM, Intranasal

7 Deltaran ( adaptation, neuroprotector) – IM

8 Gepon – (antiviral, immunomodulator) - Sq. injections

9 Sedatin (vet. market) - (stress – and anxiety protector)

- IM, Intranasal

10 Bestim – (immunomodulator) – IM

11 Allokin-alfa - Subq. injections

12 Noopept (nootropic) – oral tablets

13 Stemokine (Neogen) – (hemopoietic booster) – IM, Intranasal

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Latest survey of research areas in modern drug discovery field

Over 53% of most active researchers are dealing with immune-related drug - candidates

Research related to immune system

Published by Bioinformatics LLC

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Peptides affecting the immune system – the most advanced area of peptide pharmaceuticals approved in Russia

Immunoactive Peptide Pharmaceuticals:

Indications

1 Thymogen Immunomodulator, antiviral

2 Likopid Immunomodulator, antiviral

3 Immunofan Immunomodulator, antiviral

4 Thymodepressin Immunosupressor

5 Gepon Immunomodulator, antiviral

6 Bestim Immunomodulator

7 Allokin -alpha Immunomodulator, antiviral

8 Stemokine (Neogen) Hemopoietic booster, Immunomodulator

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Лекарственные препараты разработанные «Пептос Фарма»

Immunomodulators Immunosupressor

Hemostimulant

Approved peptide pharmaceuticals developed by IBCH RAS and “Peptos Pharma Ltd”

Thymogen for injections Nasal Spray Thymogen for injections Nasal Spray

Stemokine for injections

Likopid tablets

Neurotropic Neurotropic

pharmaceutical pharmaceutical

for treatment of for treatment of

neurotic neurotic

and stress related and stress related

disordersdisorders

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D-GLU –D-TRP

Thymogen

L-TRPD-

D-TRP

L-GLU

D-GLU

Thymodepressin

IMMUNOSTIMULATION IMMUNOSUPPRESSION

L-GLU –L-TRP

CHEMICAL AND OPTICAL STRUCTURES OF GLU –TRP ISOMERS

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T- cell

B-cell

L-L (natural)

D-D (synthetic antagonist)

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1. CONTROL 2. CYCLOSPORIN A (50 mg/kg) 3. THYMODEPRESSIN (10 µg/kg)

SU

PR

ES

SII

ON

IN

DE

XS

UP

RE

SS

IIO

N I

ND

EX

COMPARISON OF CYCLOSPORIN A AND THYMODEPRESSIN ON GVHD SUPRESSION

(MICE SPLENOMEGALY MODEL)

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* **

Ctrl titers

COMPARISON OF CYCLOSPORIN A AND THYMODEPRESSIN ON AUTOANTIBODY

SUPRESSION (Mercury inducing antibodies to fibrillarin, prophylactic mode)

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PASI 68 PASI 6

Patient B. before treatment

Patient B. after one month

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Patient C. before treatment by Thymodepressin

Patient C. after 4 month(one cycle of treatment)

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Neogen/Stemokine:Neogen/Stemokine: a new generation of immuno and hemo-stimulanta new generation of immuno and hemo-stimulant

Approved in Russia in 2009 Stimulates the immune system Stimulates regeneration of

hemopoiesis (hemopoietic stem cells) after irradiation or chemotherapy

Shows no side effects

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STEMOKINE (NEOGEN) AND G - CSF INFLUENCE ON REPOPULATION OF CFU-S AFTER 7 Gy IRRADIATION

0

500

1000

1500

2000

2500

3000

0 9 14 21сутки

CF

U-S

N

UM

BE

R

7 Gy

7 Gy+ G-CSF

7 Gy+NEOGEN

DAYS

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Likopid – a potent and safe immunomodulatorLikopid – a potent and safe immunomodulator

• Pronounced immunomodulatory Pronounced immunomodulatory effecteffect

• Minimal side effects, high Minimal side effects, high tolerancetolerance

• Convenient formulation Convenient formulation (1 or 10 mg tablets)(1 or 10 mg tablets)

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secretionsecretion

GMDPGMDP – – NOD2NOD2: : molecular mechanism of action molecular mechanism of action andand signal pathwayssignal pathways

NUCLEUSNUCLEUS

GMDPGMDP

key:key:

CARDCARDNODNODLRRLRRKinaseKinase

NOD2NOD2

GMDPGMDP

peptidoglycanpeptidoglycan

RIP2/RISCRIP2/RISC

1kB1kBNF-kBNF-kB IL-1IL-1proIL-1proIL-1

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INFLUENCE OF PEPTIDES ON HEMOPOIESIS

Suppression by ThymodepressinSuppression by Thymodepressin

Stimulation by NeogenStimulation by Neogen

Stimulation by LikopidStimulation by Likopid Stimulation by ThymogenStimulation by Thymogen

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Topics for discussion:

Pipeline of peptide pharmaceuticals: contribution of Russian science: - Peptide vaccines

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В-В-cellscellsFOOT AND MOUTH DISEASE VIRUS

EPITOPES FOR:

Т-Т-helpershelpers

SYNTHETIC PEPTIDE VACCINE

Site responsible for virus Site responsible for virus receptionreception

PATENTED SYNTHETIC FOOT AND MOUTH DISEASE VACCINE APPROVED FOR VETERINARIAN USE IN RUSSIA

Active principleActive principle - - syntheticsynthetic fragment of the VP1 viral protein acylated by palmitinic acid; fragment of the VP1 viral protein acylated by palmitinic acid;

AdjuvantAdjuvant – – synthetic polymethylsiloxane oil;synthetic polymethylsiloxane oil;

Duration of the protective immunityDuration of the protective immunity – – 1 1 year after single immunization;year after single immunization;

The vaccine is effective against the The vaccine is effective against the А А2222 viral strain in sheep.viral strain in sheep.

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Alzheimer’s disease (AD):Alzheimer’s disease (AD):

Vaccination with synthetic peptide fragment of α7-subunit of the AChR provides a new approach to

anti-AD drug development.

Our proposals:Our proposals:

1) Selected synthetic fragments of Аβ-α7

AChR-Receptor can be used for development of anti-Receptor antibodies

2) Antibodies directed against Receptor

will prevent the Receptor from binding to β-amyloid

3) Neurons will survive

4) Therapeutic vaccine will be developed

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The model of the extracellular N-terminal domain of α7-subunit of the AChR

Peptide I (1-23) 1GEFQRKLYKELVKNYNPLERPVA23

Peptide II (159-168)-(179-188) 159QMQEADISGY168-179IPGKRSERFY188

Peptide III (173-188) 173EWDLVGIPGKRSERFY188

Peptide IV (173-193) 173EWDLVGIPGKRSERFYECCKE193

Synthetic fragments of extracellular N-terminal domain of Synthetic fragments of extracellular N-terminal domain of αα77-subunit of the AChR-subunit of the AChR

EWDLVGIPGKRSERFYECCKE

CH2

HN

CH C

O

NH

CHC

O

C O

H2C

HN

CH C

CH2 OH

O

HN

CH2H2C

H2C

H2C NH2

Peptide IV (173-193) with “built-in” adjuvant

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The level of The level of ββ-amyloid in brain tissues of experimental AD -amyloid in brain tissues of experimental AD

– mice and control (Ct) mice– mice and control (Ct) mice

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Topics for discussion:

Pipeline of peptide pharmaceuticals: contribution of Russian science:

- Oral delivery system

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WHAT IS THE NEXT STEP IN PEPTIDE DEVELOPMENT?

Development of a new generation of small peptide-based pharmaceuticals with increased stability to digestive enzymes resulting in oral availability

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L-Glu-L-Trp - immunostimulant (Thymogen)

-D-Glu-D-Trp - immuno- and hemosuppresant

(Thymodepressin)

Chemical structure of peptide immunomodulatorsChemical structure of peptide immunomodulators

- high selectivity +

- minimal side effects +

- stability per os -

- solubility in aqueous media +

- low toxicity profile +

- non immunogenic +

- molecular mass below 500 D +

- high selectivity

- minimal side effects

- stability per os

- solubility in aqueous media

- low toxicity profile

- non immunogenic

- molecular mass below 500 D

Pfizer's “Ideal formula” :

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R

R

carrier

NH

CO

NH

CO

Linker 1

Linker 2

CH2

NH

Active molecule 1

o

NHCo

CH3

oCH3

Co

H

Active molecule 2

CycloTechnology Platform:

Multifunctional biologically active composition

Variable building blocks

Individual molecules chemically linked to a biocarrier

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CycloTechnology Platform: Biocarrier scaffold + Functional derivatives

Immunology Hematology Neuro-pharmacology

Chemo-pharmacology

- Immunostimulation

- Adjuvant activity

- Vaccination + adjuvant: Conventional vaccines Synthetic vaccines Cancer vaccines

- Hemostimulation

- Stem cell boosting

- Blood cell boosting and harvesting

- Immunosuppression

- Hemopoiesis suppression

- Autoimmune diseases

- Transplantation

- Neuroimmunology

- Drug addiction

- Psychopharmacology: Depression, Stress, Anxiety

Metabolic and

toxicity profile

improvements

for small molecules

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CycloTechnology platform:

New generation of peptide derivativesNew generation of peptide derivatives

- high selectivity +

- minimal side effects +

- stability per os +

- solubility in aqueous media +

- low toxicity profile +

- non immunogenic +

- molecular mass below 500 D +

- high selectivity

- minimal side effects

- stability per os

- solubility in aqueous media

- low toxicity profile

- non immunogenic

- molecular mass below 500 D

Pfizer's “Ideal Formula” :

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“Pharma Bio LLC” Development Plan for 2011-2013

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Set up of pilot GMP facility for peptide synthesis of API and nasal spray

Thymodepressin – clinical trials for new indications: RA, MS, Asthma

Stemokine – clinical trials for new indications : oncology, oncohematology, tuberculosis

Sedatin –Phase I –II clinical trials for the treatment of anxiety and stress

Opilong –Phase I –II clinical trials for the treatment of alcohol dependence

C12-OB – Preclinical development of new synthetic vaccine for the AD immunotherapy

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Layout of GMP pilot facility for peptide API and Nasal sprays

View of future GMP unit of “Pharma Bio”

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Peptide Pharmaceuticals: Development in Russia and Worldwide

JV “Pharma Bio”

Thank you!