Trends and Challenges in Technical and Manufacturing Collaboration

Alex Neverov Vaccine World MENA & CIS 2014

20 NOV 2014

Topics to Cover

Identifying Partners Who we are What do our partners share

Exploring BEVS Platform Technology Therapeutic focus

Flublok®, Panblok®, Ebola, Rabies

Geographic focus Host country – Japan case study

Exploring manufacturing partnerships Co-development Licensing

Pitfalls to avoid and summary

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The Company: Protein Sciences Manufacturing Vaccines for 30 Years

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Meriden, CT Pearl River, NY

Who we Are?

Proprietary Vaccines GeneXpress® and

Technology Licenses Research Antigens

BEVS Technology Platform

Company Business Overview

• Panblok® and FluNhanceTM

• SARS/MERS

• Rabies

• Ebola

Partners

• UMN/Astellas

• Laboratorios Liomont

$147 million BARDA contract funds work on Flublok and Panblok

• Boehringer Ingelheim Vetmedica - CircoFLEX®

• uniQure - Glybera®

• Merck

• Japan Tobacco

• Pfizer

• Wako (Takeda)

• Diamyd

• BioArctic

• Ebola

• Influenza

• HIV

• Diverse customer base

• Focus on quality

Profitable, cash flow positive business. Rapid growth: 40 to >130 in 2 years Privately held, common stock only – no debt

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A New Approach to Vaccine Manufacture

Traditional Modern: BEVS Grow pathogen (in eggs)

Inactivate pathogen

Purify antigen (i.e., the active ingredient)

Formulate vaccine

Produce antigen (in cell culture)

Use genetic code – no live pathogen

Purify antigen

Formulate vaccine

Fast Pure Pathogen- & Egg-free

TRADITIONAL METHOD

MODERN VACCINE

What Do Our Partners Share?

Right connections is a key Know how to deal with government

Regulatory Pricing and reimbursement for public market Local market specifics

Strictly follow highest international standards Ethical Technical Financial

Have manufacturing capacity in host country Ability to produce pandemic vaccine when needed BEVS advantage – low cost and ability to switch to other vaccine if needed

Willing to invest Meticulous in their execution In the game for a long term to reap full benefits of the platform

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Only need genetic code

Patented expresSF+® cells

Pure protein

Technology Platform – Baculovirus Expression Vector System (BEVS)

Engineer baculovirus with gene

Powerful promoter generates high yield

Proprietary baculovirus stable during scale-up

Seed insect cells in a bioreactor

Infect cells with baculovirus

Harvest cells

Purify protein

Formulate with PBS into vaccine

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Cell Line Qualification Summary

Extensive Cell Line Characterization

Traditional methods (FDA Guidance)

Specific tests for adventitious agents of concern (retroviruses)

Molecular methods (inch. degenerate primer PCR)

Biochemical methods

Cell culture based infectivity methods

Process yields good retroviral clearance

up to 16 log10 total clearance

Conclusion: Data indicates no evidence of adventitious agents in the expresSF+ cell line.

New cell lines will have to resolve new questions such as Rhabdoviruses – high barriers to entry for competitors!

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Manufacturing Advantages of BEVS

Safe eukaryotic expression system – no need to handle pathogens Speed – change virus vector insert, not cell line

Single qualified cell line for ALL products Single qualified master virus bank for ALL products Multiple genes may be co-expressed From gene to production in 21 days

Universal “Plug & Play” process Expression

High level protein expression Ability to express large proteins Biologically active

Processing Cleavage of signal peptides Post-translational processing (i.e., glycosylation) Correct folding

Scale-up – up to 21,000L with instant success Regulatory approval

US - PSC, Flublok Japan – UMN/Astellas, Flublok submitted, expected 2015 Worldvide – Boehriger Ingelheim, PCV2 EU – uniQure, Glybera Mexico – Laboratorios Liomont – expected 2015

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Favorable Economics of Production

Easy access to production capacity Cheap to built or lease

Possible to repurpose existing

Pearl River – converted in 60 days, 1% of full value/year

Low operating cost Simple media, standard US and DS processing

Flexible – one facility several products

Ideal for pandemic response if located in a host country Available when needed the most

Fast changeover for new threats response

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Therapeutic focus: Flublok® Influenza Vaccine

BREAKING NEWS 16 JAN 2013

FDA approves Flublok for the prevention of influenza in adults 18 - 49 years old

Extended to “18 and above” on 30 OCT 2014 “The Evolution, and Revolution, of Flu Vaccines” http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm336267.htm

World’s first recombinant influenza vaccine The pandemic solution

Only realistic pandemic vaccine Rapid development and manufacture Transfer manufacturing to other countries

THE GAME CHANGER – benefit or curse? New benefit: Jobs Act -7 years exclusivity

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Flublok: Product Attributes

Purified protein vaccine

3X the active ingredient vs. conventional

Strong immunogenicity in older adults

Exact match, conventional – adapted H3 -> egg adapted not protective

No egg protein

No influenza virus

No thimerosal

No antibiotics

No latex

No gelatin

Partnered in Japan and Mexico 12 12

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CDC Advisory Committee on Immunization Practices • Only Flublok preferential to be given to egg allergic

people, regardless of severity

New Developments • Quadrivalent formulation - in trials (9K outcome vs. competitor) • Prefilled syringes • Successful scale up to 21K Liters in Japan • New baculoviruses

• Four-fold yield increase – FDA approved and implemented • Ten-fold yield increase – applied for FDA approval

• Room temperature stable Flublok and Panblok • Applied for FDA approval, likely need small US clinical trial • Clinical trials in Japan completed successfully

Flublok: Product Attributes

Ebola Response

PSC resumed development of Ebola in 2014 Request by USG: BARDA and NIH Surface protein (GP) – protective PSC will provide protein for animal studies, results - Feb2015

Mice Guinea pigs Non-human primates (immunogenicity and challenge)

Production based on approved Flublok process Pure protein – likely will gain EUA status Clinical studies before completion of animal

Produced at 40L scale, developed purification scheme Ongoing efforts to produce at 600L scale in GMP run

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2009 H1N1 Pandemic Influenza Vaccine

Supply-Demand Gap

Adapted from R. Robinson’s presentation to FDA’s VRBPAC on February 29, 2012

Dem

and

fo

r H

ealt

hca

re

Serv

ices

Projected Availability of Recombinant Vaccines

12-16

weeks

22-24

weeks

Availability of Egg-Based Vaccines

Recombinant pandemic influenza vaccines are projected to be available much sooner than those produced with egg-based technology.

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Panblok Monovalent recombinant vaccine for pandemic influenza

First recombinant pandemic influenza vaccine

The pandemic solution Only pandemic vaccine that can be quickly manufactured and/or transferred

to and manufactured economically in other countries

We made the first pandemic vaccine in 1998

Contract issued by NIAID for vaccine against the Hong Kong “Bird

Flu”

Delivered over 1,700 doses of vaccine to NIH in only eight weeks

NIH and first responders vaccinated

We were the first to have an H1N1 vaccine available in 2009

Tested in Australia because of lack of USG support

Results as good as any other vaccine – no side effects

Other Projects in Development

Alternative Influenza vaccine (NA) SARS/MERS

SARS ready for clinical trial if needed MERS – Focus on veterinary

VLP vaccines (2 projects) >99% AND >95% purity, correct size and shape

Rabies Cheaper, cleaner Mice – protective Additional studies - early 2015

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Collaboration in Japan

UMN/Astellas – Large Companies

Initial technology transfer 3x600L

Build 2 x 21,000L capacity, could add more

First run contamination, all subsequent – success

Trained people in US

Sent our tech transfer team to Japan

Assisted in troubleshooting, QC testing

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Pitfalls to avoid and conclusions

Planning and evaluation are the keys

Understanding cost components

Risk/reward

Tech transfer is not easy. Be ready to help!

No manufacturing capacity in the country No vaccine when critically needed

Safe technology, no actual pathogen needed Only genetic information

Fast Technology. No need to wait for reassortant

Flexible. One facility – many products

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Closing remarks

This recombinant influenza vaccine became

a reality thanks to support of contract

HHSO100200900106C and perseverance of

the Protein Sciences team!

…. and as Benjamin Franklin Stated:

"Energy and persistence conquer all

things." 20

Thank You! Questions?

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