Animation Best Viewed in PPT format. Clinical Approval and Development Pipeline of the GSK product CERVARIX

1. Rebecca Milburn
Dominic Smith
Priyesh Waghmare
Dhaval Mehta
Arjun Amirapu
Rodrigo Gutierrez

2. • Clinical Indications of Cervarix
• Where and when it has been approved
• Summary Gantt Chart
• Regulatory steps
• Clinical trials
• Product pipeline & Gaps
• Patents
• Competition and future of GSK & HPV
• Conclusions

3. Under Biologics License Application (BLA) #125259
CERVARIX is a vaccine indicated for the prevention
of the following diseases caused by oncogenic
human papillomavirus (HPV) types 16 and 18:
– cervical cancer
– cervical intraepithelial neoplasia (CIN) grade 1, 2 or
worse and adenocarcinoma in situ
– CERVARIX is approved for use in females 10 through
25 years of age.

4. • It was approved in the EU on 24th, Sep, 2007
• It was approved by the FDA on 15th, Oct, 2009
• It is now approved in >100 countries worldwide
• Sales in 2010 was $ 790m
• Component Quantity
Cervarix is available in 0.5-mL single-dose vials and
HPV 16 L1 protein 20 mcg
prefilled TIP-LOK syringes
HPV 18 L1 protein 20 mcg
• Intramuscular injection scheduled 0, 1, and 6 months
Aluminum hydroxide 500 mcg
3-O-desacyl-4’-monophosphoryl lipid A
50 mcg
(MPL)
sodium dihydrogen phosphate dihydrate as
0.624 mg
buffer

5. • MedImmune holds the patent for the VLP technology of the HPV Vaccine
• GSK and Merck in 2005 entered into a cross-licensing agreement to settle
patent disputes over the HPV Vaccine from MedImmune.
• GSK licensed the HPV Vaccine from MedImmune to produce CERVARIX in
2007
• MedImmune receives royalties from the sales of both products.
• AstraZeneca bought MedImmune entirely in April 2007
• The ongoing contracts with MedImmune are still active even after the
acquisition

6. Phase III (Europe)
September, 1998
Phase III (Asia, Europe, N&S America)
(26-55 yr old females)
•Original IND submission by Medimmune
Phase III (Europe) (15-55 yr old females)
Complete
•The 1998
Phase III (Asia, Australia, Europe) (10-14 Submission of CBER
July, females)application must contain information in threeCRmeeting toCR letter
IND Second labelling sent andto
Meeting with
First Labelling response
BLALetter
commentsdiscussion with
yr VRBPAC sent to of safety
GSK – Meeting
Pre-BLA proposal for final
broad areasIII (Europe)
Phase
and CBER BLA
discuss Cervarix GSK –
Approval ofand
Meeting
GSK
End ofefficacy
discussion
•Animal Pharmacology(IND)discuss
•Investigational New Drug
VRBPAC meeting
and Toxicology Studies
to
2009
:AS04 and MPL
15th,•Chemistry and ManufacturingtheEndmeeting 2
Phase III (costa rica)
•discussed safety issues related totrials proper
Oct, 2009 Information
Endpoints for of phase
phase 3
May,•Clinical strength, quality, purity, or potency of the
Phase III (Asia, Europe, N&SProtocols and Investigator Information
2006
identification, America)
14th, Dec, permitted 07
•The FDA IIb (extention) with in Phase of licensure
9investigational drug, entryrespect to1CMC information
Data submitted to the BLA to support clinical trials
th Sept, 2009
Phase
•identified potential clinicalmeetings is to discuss filing and
The purpose of pre-BLA hold issues
At the time Phase IIb12/13 that theBLA submission, Aefficacy of
VRBPAC animalthe original data supported the nominal
TheNovember, 2001studies votedof
in vitro and
format issues
CERVARIX to events and Related Biological cervical cancer and
imbalance (dose prevent of potential neuroinflammatory etiology
Phase IIa in ranging)
• The Vaccines INDHPV 16/18 related three in the pooled
13 clinical studies involving >30,000 females
six in the HPVAS04 group and Products Advisory
wasnonoted:AIOH3,AS04) CIN in females 15-25 years of age
Original
Phase precancerous lesions
I/IIa ( adjuvant,
Typically theSubmission also includes a discussion to identify
Committee. Meeting meeting
control group September 1998Pre-IND complete response letter was sent to the
A
Phaseproblems that 1998
In consultationJune can cause a refuse-to-file trialsthat the
I/IIa (includes non-niave) the VRPBAC, CBER concluded
sponsor • Primary with efficacy endpoint for phase 3 recommendation
was the
safetyhinder the review support the licensure of CERVARIX for
or and efficacyI data process.
Phase
prevention of CIN 2/3 associated with the relevant vaccine
the stated indication.
HPV type for which the subject was naïve at baseline
2001
1999
2000
2002
2003
2004
2005
2006
2007
2008
2009

8. Gap CERVARIX in 2007
9 filed patents
Pre-clinical Clinical trials MA
4 Approved Patents

9. • WO2004056389 – Use of composition comprising HPV -16 and 18 VLPs
• WO2005123125 –Addition of atleast one other HPV cancer type
GSK
• WO2006114312 – Vaccine comprising an L1 protein or immunogenic
fragment
• WO2004084831
• WO2005032586 Synthetic DNA molecules encoding the HPV 31,45, 52
Merck
• WO2005047315 and 58 L1 proteins, wherein said polynucleotides are
codon-optimized for high level expression in a yeast cell
• WO2005097821
• WO2009088256 – Improved vaccine efficacy by use of recombinant
Univ. Konkuk
baculovius
Univ. Cape Town • EP1506222 – Method for producing a chimeric HPV-16 L1 polypeptide with
HPV L2 peptide
Loyola University
Chicago • US7754430 – Vaccine formulations comprising viral capsomeres comprising
a HPV L1 protein
Indian
Immunologicals • WO2005123762 - Novel nucleic acid sequence encoding antigen HPV-16 L1
with improved immunogenicity.

10. • Multivalent vaccines
• Current GSK patent applications
– Genetic multivalent HPV vaccine sequences
• Potentially providing protection for all 15 high risk HPV
types
– Combined vaccine comprising HIV and HPV antigens
• Early development
– Combined vaccine comprising HPV 16 & 18 combined
with hepatitis B viral antigens
– Therapeutic vaccine initiating killer T-cell immune
response against HPV proteins E1 and E2

11. MERCK - Gardasil
• Merck introduced Gardasil in the same markets as GSK –
strong competitor
Indian Competitors
• Serum Institute from India released a pentavalent vaccine
for £ 1.5. This is the cheapest vaccine in the world and one
of its treatment targets is cervical cancer.
• By 2015, projected cost per dose by Indian manufacturers
is £2 or 3 per dose while GSK provides it for approx £60

12. • A new vaccine called Nine-Valent is in pre-clinical
trials at the Medical College of Georgia (2007).
• It prevents infection from 9 types of HPV
compared to 4 offered by Gardasil and 2 by
Cervarix.
• A Dutch company called ISA Pharmaceuticals is
developing several HPV vaccines.
• The cervical Cancer drug is in Phase I of clinical
trials.
Source: http://www.isa-pharma.com/pipeline/pipelinechart.php

13. • GSK’s current HPV vaccine technology cannot
compete with Merck’s in terms immune protection.
• Indian companies can produce HPV vaccines for
approx. 1/10 the cost.
• GSK may be considering acquisitions

14. Should be inexpensive to produce
• Patented codon optimisation techniques
• Edible vaccines
• DNA based vaccines
Mosaic preventative and therapeutic efficacies
Should have both
VLP
Future multivalent vaccines
• Early patents for chimeric vaccines encoding L1 and E6 or E7
•Comprising L1 proteins from each type of
• DNA vaccines ideal for this
•All
HPVtypes of HPV prolonged with next gen vaccines
Prophylactic protection should beas well as other virus
•Broad spectrum prevention of all high risk
antigens
• More effective adjuvants
• Nanoparticle based delivery systems
HPV types
Painless needle free immunisation
• Liquid/particle jet injector
• Micro needle
• Inhaler/oral sprays
• New vaccine formulations

15. • Submissions to begin clinical trials began in 1998
• CERVARIX was approved by the FDA on
15th, Oct, 2009 from data from 13 clinical studies
involving >30,000 females
• A >10 year ‘Gap’ exists in the development pipeline
for GSK’s HPV vaccine
• GSK may be considering various strategies to ‘Fill in
the Gap’

16. • Agosti JM, Goldie SJ. N Engl J Med. 2007 May 10; Introducing HPV vaccine
in developing countries--key challenges and issues. 356(19):1908-10.
• Miller, N. Roberts, J. (2009) MEMORANDUM DEPARTMENT OF HEALTH
AND HUMAN SERVICES UNITED STATES PUBLIC HEALTH SERVICE FOOD
AND DRUG ADMINISTRATION CENTER FOR BIOLOGICS EVALUATION AND
RESEARCH[online] Accessed from
:www.fda.gov/downloads/BiologicsBloodVaccines/.../UCM260030.pdf
[Accessed on July 14 2011].
• Pharma Deals (2007) Review: Deal making commentary and analysis, Issue
84: 6-7.
• IIPM (2011) http://iipmbschool.wordpress.com/2011/06/07/indian-firms-
push-down-global-vaccine-prices/
• Science Daily (2007)
http://www.sciencedaily.com/releases/2007/11/071119113902.htm
• www.gsk.com

18. ??HPV Vaccines
• HPV is the main factor associated with the
development of cervical cancer
• Cervarix HPV 16 & 18 – Does not protect against all
types
• Gardasil HPV 6, 11, 16 and 18
• Technology developing towards broad spectrum HPV
protection and therapeutics
• Among HPV genotypes, 15 are classified as high risk
types – 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56
58, 59, 68, 73, and 82
• Type 16 and 18 associated with 70% of all cervical
cancers

19. ??The Future of HPV Vaccines
• After the first two HPV vaccines entered the
market substantial advances in HPV vaccine
technologies have been made
• Several HPV vaccines are currently in clinical
and preclinical trials and many others are at
other investigational stages.
• These next gen HPV vaccines will overcome
the limitations of the previous gen