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Clinical Approval and Development Pipeline of the GSK product CERVARIX

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  • (technology ownership, expiry)
  • , the sponsor, GlaxoSmithKline Biologicals (GSK), agreed to the following indication: Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body
  • Each 0.5 mL dose of the vaccine contains: 20 mcg of human papillomavirus (HPV) 16 L1 protein 20 mcg of HPV 18 L1 protein 500 mcg aluminum hydroxide 50 mcg 3-O-desacyl-4’-monophosphoryl lipid A (MPL) 0.624 mg sodium dihydrogen phosphate dihydrate as buffer
  • , the sponsor, GlaxoSmithKline Biologicals (GSK), agreed to the following indication: Merck licensed the HPV Vaccine from MedImmune to produce Gardasil in 2006Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body
  • HPV proteins E1 and E2 both involved in viral DNA replication

    1. 1. Rebecca MilburnDominic SmithPriyesh WaghmareDhaval MehtaArjun AmirapuRodrigo Gutierrez
    2. 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. 3. Under Biologics License Application (BLA) #125259CERVARIX is a vaccine indicated for the preventionof the following diseases caused by oncogenichuman 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. 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 andHPV 16 L1 protein 20 mcg prefilled TIP-LOK syringesHPV 18 L1 protein 20 mcg • Intramuscular injection scheduled 0, 1, and 6 monthsAluminum hydroxide 500 mcg3-O-desacyl-4’-monophosphoryl lipid A 50 mcg(MPL)sodium dihydrogen phosphate dihydrate as 0.624 mgbuffer
    5. 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. 6. Phase III (Europe) September, 1998 Phase III (Asia, Europe, N&S America) (26-55 yr old females) •Original IND submission by MedimmunePhase III (Europe) (15-55 yr old females) Complete •The 1998Phase 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
    7. 7. Gap CERVARIX in 20079 filed patents Pre-clinical Clinical trials MA4 Approved Patents
    8. 8. • 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 baculoviusUniv. Cape Town • EP1506222 – Method for producing a chimeric HPV-16 L1 polypeptide with HPV L2 peptideLoyola University Chicago • US7754430 – Vaccine formulations comprising viral capsomeres comprising a HPV L1 protein IndianImmunologicals • WO2005123762 - Novel nucleic acid sequence encoding antigen HPV-16 L1 with improved immunogenicity.
    9. 9. • 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
    10. 10. MERCK - Gardasil• Merck introduced Gardasil in the same markets as GSK – strong competitorIndian 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
    11. 11. • 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
    12. 12. • 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
    13. 13. Should be inexpensive to produce • Patented codon optimisation techniques • Edible vaccines • DNA based vaccines Mosaic preventative and therapeutic efficaciesShould 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 vaccinesProphylactic protection should beas well as other virus •Broad spectrum prevention of all high risk antigens • More effective adjuvants • Nanoparticle based delivery systems HPV typesPainless needle free immunisation • Liquid/particle jet injector • Micro needle • Inhaler/oral sprays • New vaccine formulations
    14. 14. • 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’
    15. 15. • 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
    16. 16. ??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
    17. 17. ??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