product development programmatic implementation · vaccines wide product portfolio s. no. vaccine...

Product Development

and

Programmatic Implementation

Bharat Biotech Confidential -Reference Document 2

Table of Contents

• Bharat Biotech Introduction

• Innovation @ Bharat Biotech

– Early Development

– Clinical Development

– India EPI – Introduction Experience

– Product Profile

• Conclusion

Bharat Biotech Confidential -Reference Document 3June 2018

June 2018Bharat Biotech Confidential -Reference Document 4

Bharat Biotech

Introduction

Introduction

Established : 1996

Promoters : Dr. Krishna & Ms. Suchitra Ella

Business Line : Vaccines and Bio-therapeutics

First Project : Hepatitis B Vaccine - US $ 3.5 Mn

Investment : Over US $ 250 Mn till date

Facility : One of the largest facilities in Asia

Personnel : ~1000

Accreditations : WHO PQ, PICS, Turkey, Ukraine, ANVISA..

Innovation : ~ 60 Global patents

Vision

Mission

To offer affordable, safeand effective healthcare solutions to combat mankind's most dreaded illnesses, and to thus eradicate or at least control their occurrence in the years to come.

Developing next-generation remedies through Genetic Engineering Technologies so as to create a healthier world.

Mission 7 Billion

Bharat Biotech - Introduction

5

Mission 7 Billion

Founder’s Profile

Dr. Krishna Ella

BSc / MSc, UAS Bangalore, India

Two time academic gold medallist

MSc Univ of Hawaii USA PhD Univ Wisconsin Madison USA

Rotary Foundation Scholar

Molecular biology / Signal transduction

Faculty : Medical University of South Carolina USA

Member : Prime Minister’s Scientific Advisory Council – India Member : Governing body CSIR - India Member : Technology Information, Forecasting and Assessment

CouncilDistinguished Alumni Award : University of Wisconsin


Today’s neglected diseases - Tomorrow’s global diseases

1 PLAGUE

2 HIV

3 INFLUENZA

4 MALARIA

1 DENGUE

2 CHIKUNGUNYA

3 TRYPANOSOMA

4 LEISHMANIA

5 FILARIA

6 ZIKA

• No DW manufacturers develop new vaccines• Most DW manufacturers are biogenerics players• DC manufacturers follow MNCs• Our Mission is to change that mindset

NEGLECTED DISEASES

GLOBAL DISEASES

Vaccine Manufacturer

Product Developer

7

Vaccines

Wide Product Portfolio

S. No. Vaccine Brand

1 DPT+ Hep B + Hib ComVac 5 ®

2 DPT+ Hep B ComVac 4-Hb ®

3 DPT; TT, DT ComVac 3 ™

4 Hep B Revac B+ ®

5 Hep B Revac B mcf ®

6 Hib BioHib ™

7 Typhoid TYPBAR ®

8 Typhoid Typbar TCV ™

9 OPV Bivalent BIOPOLIO B1/3 ®

10 OPV Monovalent Type-1 BIOPOLIO M1 ™

11 OPV Monovalent Type-3 BIOPOLIO M3 ™

13 JE JENVAC ®

14 Rotavirus ROTAVAC ®


1 Typhoid TYPBAR ®


3 Rabies INDIRAB ®

4 Influenza HN VAC ™

5 JE JENVAC ®


1 Typhoid TYPBAR ®


3 Influenza HN VAC ™

4 JE JENVAC ®

Children & Adult

Traveler

Children

Wide Product Portfolio

65 Countries

8

Product Pipeline

S. No. Vaccines Product Development

Preclinical Testing Phase I Phase II Phase III Commercial

License

1 Zika 2021

2 Chikungunya 2021

3 S. Paratyphi 2023

4 NTS Conjugate 2022

5 Human Papilloma Virus 2023

6 Acellular Pertussis 2023

7 Malaria PvRII 2023

8 Sabin IPV 2021

Therapeutics Product Development

Preclinical Testing Phase I Phase II Phase III Commercial

License

1 THR-100 2020

2 Lysostaphin Topical 2020

3 Lysostaphin IV 2020

•June 2018Bharat Biotech Confidential -Reference Document 9


Innovation

@

Bharat Biotech

Innovation @ Bharat Biotech

• Product development focus ….

– Developing world countries in Asia, Africa, South America

– Neglected Infectious diseases

– Ease of administration

– Halal

– Reduction in cold chain foot print

– Ease of distribution and delivery

– Antigen / Payload reduction

– Product pricing


BBV 121 : Zika Virus Vaccine

• Product Development from 2014

– Strains received Feb 2015

– Characterization and Vaccine Candidate Development

• Purified / Inactivated vaccine

• Phase I Clinical Trial : In Process : 2017

• Patent Priority date of July 2015


BBV 87 : Chikungunya Virus Vaccine

• Product Development – 2006 – Ongoing

– Strain isolation

– Strain characterization

– Vaccine candidate development

• Purified / Inactivated vaccine

• Phase I clinical trials : In Process – 2017


Malaria Vaccine Development

• Asexual blood stage vaccine candidates

– PfMSP-1; EBA-175; PvDBP

• Pre-erythrocytic vaccine candidates

– PfF2 ; PvRII

– PvRII : Phase I Clinical Trial

• Adjuvants Development

14June 2018Bharat Biotech Confidential -Reference Document

Products R&D Pipeline Projects RecognitionIssuesFast Facts

Vi Capsular Polysaccharide Tetanus Toxoid Conjugate Vaccine

World’s 1st Clinically Proven Typhoid Conjugate Vaccine

Dr. Christian Loucq - International Vaccine Institute Director-General launching

Typhoid Conjugate Vaccine in Hyderabad on 26th August, 2013

Launch

WHO

Prequalified

2017

WHO – SAGE Recommendation

• World Health Organization - Geneva

• Scientific Advisory Group of Experts (Immunization)

• Infants between 6 and 23 months of age

• Children between 2 and 15 years of age

Products R&D Pipeline Projects RecognitionIssuesFast Facts

TYPBAR-TCV WHO Prequalification

WHO

Prequalified

2017


Early Development

ROTAVAC® - Vaccine Development

Feb 2017Bharat Biotech Confidential -Reference Document 19

2009

Strains Isolated – AIIMS (116E)/IISc (I321)

Strains sent to NIH Indo-US VAP

DYNCORP Vaccine Seed

NIH to BBIL – vaccine seed

BBIL – Vero Adaptation

cGMP Manufacturing/Preclinical Tox

ORV116EVero Vaccine Candidate

ORV 116EPhase I/II clinical

ORV 116EPhase III clinical

India Licensure/Launch

Introduction into UIP

Phase I clinical – Adults, Children, Infants - USA

1986-88

2001

2011

2015

2016

ROTAVAC – Launch 2015

September 18Bharat Biotech Confidential -Reference Document 20

WHO

Prequalified

2018

Gene Origin of 116E Strain : nHRV

1

Gene

Segments

11

10

9

8

7

6

5

4

3

2

11

10

9

8

7

6

5

4

3

116E

BBIL

Human origin

Bovine origin

Strain isolated and characterized at AIIMS Delhi by Dr. M. K. Bhan, (1988)

Isolated from asymptomatic infants, with mild diarrhea, follow up/protection, 2 years

Characterized as G9 P[11], VP4 of bovine origin, and all other segments of human origin

Live naturally attenuated vaccinenHRV


116E STRAIN : nHRVCHARACTERIZATION - 1994


116E - Project Start : 1998 -2000


116E STRAIN : PUBLICATION - 2005

24

ORV 116E : GENOME SEQUENCE: 2010


ORV 116E: PCV TESTING - 2012


ROTAVAC® : Patents


• Filed - ~ 23 countries

• Granted - ~15 countries

• India, USA, EU, China, Australia, Russia, Mexico, UK, France,

Belgium, Germany, Japan, South Africa etc…..

• China : 3 Filed (2009,2012,2014) / 2 Granted (2015) / 1 in process

• 200780026055.8 / 201080031261.X / CN2013800330185

June 2018


Clinical Development

Clinical Stage Age

GroupNo. of

Subjects

Location Endpoint Status

Phase I: Adults18-45

yrs30 USA Safety

Completed

Phase I: Children 2-12 yrs 30 USA SafetyCompleted

Phase I: Adults 18-45 yrs 30 India Safety Completed

Phase I: Children 2-12 Yrs 30 India Safety Completed

Phase I: Infants 8-12 wks 90 India Safety / immunogenicity Completed

Phase Ib/IIa: Infants 8-20 wks 360 India Safety / immunogenicity Completed

Phase III: Infants 6-8 wks 6800 India Efficacy Completed

Phase IV: Infants 6-8 wks 900 India Immunogenicity/Safety

w & w/o buffer

Completed

ROTAVAC®

Clinical Development


ROTAVAC®

Clinical DevelopmentClinical Stage Age

GroupNo. of

Subjects


Phase III: Infants 6-8 wks 1356 India EPI Non-interference Completed

Phase IV-

Comparator-

Infants

6-8 wks 464 India Immunogenicity/Safety Completed

Phase IV - PMS 6-8 wks 15,000 India Safety Ongoing

Early

Implementation

6-8 wks ~100,000 India Safety Ongoing

Clinical Stage Age

GroupNo. of

Subjects


Phase III 6-8 wks 300 Vietnam Immunogenicity/Safety Ongoing

Phase IIb 6-8 wks 450 Zambia Design and Development


ORV 116E : STRAIN SELECTION STUDY - 2006


ORV 116E: DOSE ESCALATION STUDY - 2009


Phase III : Sites – Demographics

• 3 sites Across India

– Urban Slum : migrant labour

– Semi Urban : lower middle class

– Rural : farming / labour communities

• Aggressive management of diarrheal episodes

• Complete health care coverage during trial duration

– Mobile phones

– Ambulatory / Primary / Secondary / Tertiary


ROTAVAC: nHRV - Phase III Results

• Efficacy : Year 1 : 56.4 % / Year 2 : 48.9 % (Vesikari Score 11)1/2

– Significant in Developing countries

– Low vaccine coverage and high risk of reinfection

– Artificially reassorted vaccines show larger drop in efficacy

– Strong case for the requirement of the 3rd dose

Comparison with other Ph III efficacy trial conducted in India

– BRV PV / 3 doses : 2 Year efficacy : 39.5%

– Significant since trial conducted in similar sites / demographics / study design etc

1. Bhandari N, et al. Lancet. 2014 Jun 21;383(9935):2136-43. doi: 10.1016/S0140-6736(13)62630-6. Epub 2014 Mar 12.

2. Bhandari N, et al. Vaccine. 2014 Aug 11;32 Suppl 1:A110-6. doi: 10.1016/j.vaccine.2014.04.079.


ROTAVAC: nHRV - Phase III Results

• Safety : Intussusception cases

– Vaccine : first case - 112 days post 3rd dose

– Placebo : first case – 36 days post 3rd dose

• Cross Protection

– G2 : ~ 63 %

– G1 : ~ 42 %

– G12: ~ 69 %

– Others : ~ 67 %


Broad Heterotypic Protection

Rotavirus Strain Diversity

• Change is constant for Rotaviruses

• Change in serotypes based on seasonality, location, region, country, year, etc

• Same vaccine - same genotype :

– varying efficacy in different countries,

• Efficacy range from ~28% to 95%, depending on country, demographics, Vesikari score 11, etc


Impact of Co-infections

• Rationale:

– Quantitative molecular testing of stool samples for enteropathogensfrom diarrheal episodes from ROTAVAC’s phase III efficacy trial revealed high co-infection rates

• Aim:

– To asses the impact of co-infections on rotavirus vaccine efficacy estimates

– from ROTAVAC’s phase 3 trial / evaluate revised vaccine efficacy estimates

• Houpt and Kang Et al; 2018 (publication in process)June 2018Bharat Biotech Confidential -Reference Document 37

ROTAVAC (nHRV): Phase III Lancet, 2014


ROTAVAC (nHRV): Phase III Vaccine, 2014: 2nd Year Efficacy


GACVS – July 2014Safety Report

June 2018Bharat Biotech - Confidential 40

41

ROTAVAC®

EPI Interference Study

June 2018Bharat Biotech Confidential -Reference Document

Post Licensure : Safety Studies

• India : Safety : SAS – 3 States – India1

– Post marketing surveillance project

– Department of Biotechnology

– ~100,000 subjects / 3 states

– No reportable safety data available till date

• India: 28 Hospitals2

– Self-controlled series & Case-control approach

– Preliminary data: No signal detected

1 Das M, et al. Intussusception in Young Children: Protocol for Multisite Hospital Sentinel Surveillance in India,2018.2Reddy, et al. BMC Public Health. 2018; 18: 898


Post Licensure : Clinical Studies

• Vietnam : Safety and Immunogenicity

– Execution phase; all subjects enrolled

• Africa : Safety and Immunogenicity : PATH

– Design and Development phase

– Q4 2018 start


RVF – BBIL : PartnershipPost Licensure : Studies

• Rostropovich Vishnevskaya Foundation

• To introduce ROTAVAC® in Palestine

• BBIL donation of 150K doses

• To study epidemiology

• To study health economics

• RVF also working in Armenia, Azerbeijan, Georgia, Kyrgyzstan, Russia, Tajikistan, West Bank and Gaza,


ROTAVAC® : Birth Dose Study

• ROTAVAC® birth dose:

– To evaluate ROTAVAC® seroconversion

– Neonatal / Infant schedule

– 0,6,10,14 weeks / 6,10,14 weeks

– seroconversion post doses 3 and 4



India Introduction

June 2018

ROTAVAC® India – EPI Introduction

• Review and strengthening of existing cold chain system

– Electronic data base (NCCMIS data)

– Electronic Vaccine Intelligence Network (eVIN)

– 3300 (CCPs) in Phase I / 4200 CCPs in Phase II

• Training and development

– Easier : Similar to OPV - administration and supply chain management

– 5 drops / dose

– Assured delivery of antigen payload / minimal or no spit ups,

• RVV introduction in India..

– Example of how new vaccine introduction can be an

opportunity to strengthen the routine immunization system


ROTAVAC® India – EPI Introduction

• MOH India / UNICEF

• Procurement : ~ 50 Million doses 2016 – 2018

• States Introduced : 2016 - 4 / 2017- 5 / 2018 - 1

• Additional States : 2018 and beyond

• Strong surveillance network

– Intussusception : Sentinel / Retrospective / Prospective

– Disease burden : 2005 – ongoing



Product Profile

50

Cold chain capacity : Developing countries

Developing Countries~ 5000 doses

Developed Countries~500 doses

Cold Chain Management


Product Cold chain volume / course cm3

% increase compared to ROTAVAC

Shipping Costs Cold Chain Management Costs

BRV-PV 254 2554% ++++++++++++++ ++++++++++++++

RV5 139 1348% ++++++++++ ++++++++++

RV1 34 254% +++ +++

ROTAVAC 10D/5D

9.6 / 12.6 - + +

Shipping Costs : UNICEF / Country

Cold Chain Management Costs: Country

•Cold storage facilities, maintenance, power, power back up,

in country distribution,

•Cold chain space Impact on other vaccines at 2-8℃

ROTAVAC® - Product Profile

• Product development

– For the developing world by the developing world

– Developed and rejected : RT stable Lyophilized formulation, requiring reconstitution at point of administration

• Cold chain foot print

– Miniaturization of dose – 0.5 ml / dose (ready to use / no reconstitution required)

– Multi dose presentation - 10 D / 5 D

– Reduction in cold / supply chain foot print / Management – 300 doses / carton

• Ease of Administration

– Similar to OPV

– 5 drops / dose

– Better compliance / assured delivery of full dose / no spit ups

• VVM2

• Product PricingBharat Biotech Confidential -Reference Document 52

53June 2018

ROTAVAC®

Buffering Agent Study

ROTAVAC® - Product Presentation

54

#Presentation Vials / Carton Doses /Carton

Volume /Dose

(cm3)

1 5 dose 25 125 4.2

2 10 dose 30 300 3.2

Shelf life 60 months at -20º C;

As per VVM2 at 50 C ± 30 C at any time during shelf-life

ROTAVAC® – Administration



Manufacturing

Manufacturing FacilitiesGenome Valley - Hyderabad - India


Manufacturing Facilities


ROTAVAC – Manufacturing Facilities200 million doses



Conclusion

Conclusion : ROTAVAC®

• India Licensure : 2015

• Global Registrations : ~ 30 countries (in process)

• WHO Prequalified : 2018

• 5 patents filed / 3 Patents granted in ~ 15 countries

– USA, India, EU, China, Russia, Australia, Mexico……

• ~12 Publications ( 3 in process)



• Product Profile:

– 0.5 ml / dose

– 10D / 5D presentations; 3.2 - 4.2 cm3 / dose

– Reduction in cold / supply chain foot print (~300% reduction)

– ~ 300 doses / carton with VVM2

• Administration

– Similar to OPV

– 5 drops / dose

– Better compliance / assured delivery of full dose / no spit ups

• Product pricing to provide global access



• Efficacy : year 1: 56.4% / year 2: 48.9%

– Vesikari score 11

– 2nd year efficacy Important for developing countries with low immunization coverage

• ~20% proven reduction in all cause GE

• Safety : no vaccine attributable cases of ISS

– 1st case of ISS – 112 days after 3rd vaccine dose

• Broad heterotypic protection



• Programmatic Implementation : – ~ 50 million doses in India / UNICEF / Palestine

– ~ 200 million dose manufacturing capacity

– ~ 120 days supply timeline

• Controlled Clinical Trials :

– ~ 15,000 subjects

• Post Marketing Studies :

– ~ 115,000 subjects (ongoing)


Partners

Major Donor : Bill and Melinda Gates Foundation


http://www.cmch-vellore.edu/Default.aspx

http://www.cmch-vellore.edu/Default.aspx

“Our mission is to address the health care needs of emerging markets, drive innovation, be a front runner in research and development of

new vaccines and bio-therapeutics”

Mission 7 Billion

Dr. Krishna M. EllaChairman & Managing Director

67 Bharat Biotech Confidential -Reference Document

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