Post on 18-Jul-2020
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
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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
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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 ®
S. No. Vaccine Brand
1 Typhoid TYPBAR ®
2 Typhoid Typbar TCV ™
3 Rabies INDIRAB ®
4 Influenza HN VAC ™
5 JE JENVAC ®
S. No. Vaccine Brand
1 Typhoid TYPBAR ®
2 Typhoid Typbar TCV ™
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
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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
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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
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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
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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
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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
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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
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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
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116E STRAIN : nHRVCHARACTERIZATION - 1994
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116E - Project Start : 1998 -2000
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116E STRAIN : PUBLICATION - 2005
24
ORV 116E : GENOME SEQUENCE: 2010
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ORV 116E: PCV TESTING - 2012
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ROTAVAC® : Patents
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• 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
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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
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ROTAVAC®
Clinical DevelopmentClinical Stage Age
GroupNo. of
Subjects
Location Endpoint Status
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
Location Endpoint Status
Phase III 6-8 wks 300 Vietnam Immunogenicity/Safety Ongoing
Phase IIb 6-8 wks 450 Zambia Design and Development
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ORV 116E : STRAIN SELECTION STUDY - 2006
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ORV 116E: DOSE ESCALATION STUDY - 2009
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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
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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.
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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 %
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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
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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
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ROTAVAC (nHRV): Phase III Vaccine, 2014: 2nd Year Efficacy
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GACVS – July 2014Safety Report
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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
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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
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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,
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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
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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
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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
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Product Profile
50
Cold chain capacity : Developing countries
Developing Countries~ 5000 doses
Developed Countries~500 doses
Cold Chain Management
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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
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Manufacturing
Manufacturing FacilitiesGenome Valley - Hyderabad - India
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Manufacturing FacilitiesGenome Valley - Hyderabad - India
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Manufacturing Facilities
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ROTAVAC – Manufacturing Facilities200 million doses
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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)
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Conclusion : ROTAVAC®
• 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
Bharat Biotech Confidential -Reference Document 63
Conclusion : ROTAVAC®
• 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
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Conclusion : ROTAVAC®
• 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)
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Partners
Major Donor : Bill and Melinda Gates Foundation
Bharat Biotech Confidential -Reference Document 66
“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