Clinical Approval and Development Pipeline of the GSK product

CERVARIX

Group 6Rebecca MilburnDominic SmithPriyesh WaghmareDhaval MehtaArjun AmirapuRodrigo Gutierrez

Outline

• 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

Clinical Indications of CERVARIXUnder 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.

Background of CERVARIX

• 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 • Cervarix is available in 0.5-mL single-dose vials and

prefilled TIP-LOK syringes• Intramuscular injection scheduled 0, 1, and 6 months

Component Quantity

HPV 16 L1 protein 20 mcg

HPV 18 L1 protein 20 mcg

Aluminum hydroxide 500 mcg

3-O-desacyl-4’-monophosphoryl lipid A (MPL) 50 mcg

sodium dihydrogen phosphate dihydrate as buffer 0.624 mg

Licensing• 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

Phase I

Phase I/IIa (includes non-niave)

Phase I/IIa ( no adjuvant, AIOH3,AS04)

Phase IIa (dose ranging)

Phase IIb

Phase IIb (extention)

Phase III (Asia, Europe, N&S America)

Phase III (costa rica)

Phase III (Europe)

Phase III (Asia, Australia, Europe) (10-14 yr females)

Phase III (Europe) (15-55 yr old females)

Phase III (Asia, Europe, N&S America) (26-55 yr old females)

Phase III (Europe)

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

CR Letter sentComplete

response to CR letter

Meeting with CBER and GSK – discussion of safety

and proposal for final efficacy

Meeting with CBER and GSK – discussion :AS0

4 and MPL

Approval of BLAEnd of 2009

VRBPAC meeting to discuss Cervarix

Second labelling comments sent to

GSK

First Labelling comments sent to

GSK

Original IND Submission

September 1998

VRBPAC meeting to discuss

Endpoints for phase 3 trials

End of phase 2 meeting

Pre-BLA Meeting

Pre-IND MeetingJune 1998

Submission of BLAJuly, 1998

•Investigational New Drug (IND)•discussed safety issues related to the proper identification, strength, quality, purity, or potency of the investigational drug, with respect to CMC information•identified potential clinical hold issues

September, 1998

•Original IND submission by Medimmune•The IND application must contain information in three broad areas• Animal Pharmacology and Toxicology Studies • Chemistry and Manufacturing Information • Clinical Protocols and Investigator Information

•The FDA permitted entry to Phase 1 clinical trials

November, 2001• The Vaccines and Related Biological Products Advisory

Committee.• Primary efficacy endpoint for phase 3 trials was the

prevention of CIN 2/3 associated with the relevant vaccine HPV type for which the subject was naïve at baseline

May, 2006

The purpose of pre-BLA meetings is to discuss filing and format issues

Typically the meeting also includes a discussion to identify problems that can cause a refuse-to-file recommendation or hinder the review process.

14th, Dec, 07

At the time of the original BLA submission, A nominal imbalance in events of potential neuroinflammatory etiology was noted: six in the HPVAS04 group and three in the pooled control group A complete response letter was sent to the sponsor

9th Sept, 2009

The VRBPAC voted 12/13 that the data supported the efficacy of CERVARIX to prevent HPV 16/18 related cervical cancer and precancerous lesions CIN in females 15-25 years of age

15th, Oct, 2009

Data submitted to the BLA in support of licensure

in vitro and animal studies13 clinical studies involving >30,000 females

In consultation with the VRPBAC, CBER concluded that the safety and efficacy data support the licensure of CERVARIX for the stated indication.

GSK Development Pipeline:Cervical cancer

GSK Development Pipeline for HPV vaccine

Clinical trials

CERVARIX in 2007

4 Approved Patents

9 filed patents

Pre-clinical MA

Gap

Competition

•WO2004056389 – Use of composition comprising HPV -16 and 18 VLPs

•WO2005123125 –Addition of atleast one other HPV cancer type

•WO2006114312 – Vaccine comprising an L1 protein or immunogenic fragment

GSK

•WO2004084831

•WO2005032586

•WO2005047315

•WO2005097821

Merck

•WO2009088256 – Improved vaccine efficacy by use of recombinant baculovius

Univ. Konkuk

•EP1506222 – Method for producing a chimeric HPV-16 L1 polypeptide with HPV L2 peptide

Univ. Cape Town

•US7754430 – Vaccine formulations comprising viral capsomeres comprising a HPV L1 protein

Loyola University Chicago

•WO2005123762 - Novel nucleic acid sequence encoding antigen HPV-16 L1 with improved immunogenicity.

Indian Immunologicals

Synthetic DNA molecules encoding the HPV 31,45, 52 and 58 L1 proteins, wherein said polynucleotides are codon-optimized for high level expression in a yeast cell

GSK – HPV Vaccine Pipeline• 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

Competition on the Market

• Merck introduced Gardasil in the same markets as GSK – strong competitor

MERCK - Gardasil

• 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

Indian Competitors

Future Competition

• 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

Our opinion- What’s with the ‘Gap’?

• 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

Next Generation of HPV Vaccine

Mosaic VLP

• Comprising L1 proteins from each type of HPV• Broad spectrum prevention of all high risk

HPV types

Future multivalent vaccines

• All types of HPV as well as other virus antigens

Should be inexpensive to produce• Patented codon optimisation techniques• Edible vaccines• DNA based vaccines

Should have both preventative and therapeutic efficacies • Early patents for chimeric vaccines encoding L1 and E6 or E7• DNA vaccines ideal for this

Prophylactic protection should be prolonged with next gen vaccines• More effective adjuvants • Nanoparticle based delivery systems

Painless needle free immunisation• Liquid/particle jet injector• Micro needle• Inhaler/oral sprays• New vaccine formulations

Conclusion

• 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’

References• 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

???

??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

??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