Cervarix; HPV-16/18 L1 AS04 vaccine; human papilloma virus (HPV) types 16 and 18 L1 virus-like particles, recombinant with 3-deacylated monophosphoryl lipid A (MPL) plus aluminum [AS(04)] adjuvant

Status: BLA approved in Oct. 2009; approved in EU in Sept. 2007

Organizations involved:

GlaxoSmithKline Biologicals S.A. – Manuf.; R&D; Tech.

GlaxoSmithKline, Inc. – USA mark.

GlaxoSmithKline plc – Intl. mark.; Parent

MedImmune, Inc. – R&D; Tech.

AstraZeneca plc – Parent

Corixa Corp. – Manuf. other; R&D; Tech.

Ribi ImmunoChem Res., Inc. – R&D; Tech.; Former

University of Rochester – R&D; Tech.

Georgetown University – R&D

University of California – R&D

Pennsylvania State University. – R&D

Boyce Thompson Inst. for Plant Research – Tech.

University of Colorado – Tech.

Deutsches Krebsforschungszentrum – Tech.

Texas A&M University – Tech.

Merck & Co., Inc. – Tech.

CSL Ltd. – Tech.

University of Queensland – Tech.

UniQuest Ltd. – Tech.

Cross ref.: See the entries for Human Papillomavirus (HPV) Vaccines, and recently-approved, Gardasil, from Merck. See the entry for Monophosphoryl Lipid A (MPL) concerning the novel adjuvant used in Cervarix.

Description: Cervarix is an aqueous bivalent (two antigen) formulation of recombinant C-terminally truncated major capsid L1 proteins of human papillomavirus (HPV) types 11 and 16 L1 expressed as virus-like particles (VLPs) in insect cells (the cabbage looper Trichopulsia ni High Five cell line; BTI-TN5B1-4) using a baculovirus expression system, with AS(04) [SBAS04] adjuvant composed of 3-deacylated monophosphoryl lipid A (MPL; 3-O-desacyl-4.-monophosphoryl lipid A; derived from Salmonella minnesota R595 strain) plus aluminium hydroxide, hydrated [Al(OH)3]. As with Gardasil from Merck & Co., Cervarix contains recombinant HPV types 11 and 16 L1 VLPs that together cause about 70% of worldwide cases of cervical cancer. However, Cervarix does not contain HPV types 6 and 18 L1 VLPs (included in Gardasil) that together cause about 90% of cases of genital warts, i.e., this vaccine is targeted solely to cervical cancer, with no significant efficacy expected for prevention of most genital warts.

Cervarix is the first therapeutic to receive approval in a major market that is expressed by transformed insect cells and using baculovirus vectors.

Each dose of Cervarix contains 20g of HPV-16 L1 and 20g of HPV-18 L1 proteins adjuvanted with 50 µg AS04 adsorbed onto 0.5 mg (500 µg) of aluminium hydroxide, hydrated. Excipients in the formulation are sodium chloride (NaCl), sodium dihydrogen phosphate dihydrate (NaH2PO4.2 H2O) and Water for injection. The product is a sterile turbid liquid suspension for injection, filled as a 0.5mL monodose in either syringes or vials stored at 2-8°C. The shelf life of 3 years, with vaccine stored at 2-8˚C (refrigerated). The vaccine contains no antimicrobial preservatives.

Early baculovirus-expressed versions of this vaccine from MedImmune, including MEDI-501, MEDI-503 and MEDI-504 used in early trials, were formulated with alum adjuvant (no MPL).

Biological: HPV, L1 protein virus-like particles (VLPs), and related diseases are discussed in the Human Papillomavirus (HPV) Vaccines entry. Recombinant HPV L1 protein, the major protein of the HPV capsid (the component structures of the capsomere, the virus’s outer coating structure), self-assembles in solution to form immunogenic HPV capsomer-like structures about with a molecular mass of ~20 million Dalton (20,000 kDa) and size of ~55 nm.

In 1995, using a model VLP vaccine composed of recombinant canine oral papillomavirus (COPV) major capsid protein (L1), MedImmune reported the first demonstration that a recombinant subunit papillomavirus vaccine administered systemically can provide protection against mucosal infection with a papillomavirus. As little as 50 nanograms of the vaccine provided complete protection against mucosal COPV challenge in beagle dogs. Serum from vaccinated animals protected non-vaccinated animals against COPV. This was reported in the Proceedings of the National Academy of Sciences, Dec. 1995, 553-7.

Nomenclature: HPV vaccine, rDNA/GSK [BIO]; Cervarix [TR]; Papillomavirus (human types 16, 18) [INN]; human papilloma virus (HPV) vaccine type 16 and 19 L1 proteins, recombinant [SY]; MEDI-501, MEDI-503 and MEDI-504 [SY for early versions]

Companies: Precursors of Cervarix (MEDI-501, MEDI-503 and MEDI-504) were initially developed by MedImmune, Inc., which has collaborated in HPV vaccine R&D with (and/or licensed technologies from) a number of organizations. MedImmune collaborated with organizations including Georgetown University; University of California (Davis, CA); and Pennsylvania State University. As discussed in the Tech. transfer section, MedImmune has also licensed technologies from many organizations, and likely collaborated with some of these. MedImmune was acquired by AstraZeneca plc in April 2007.

In Dec. 1997, MedImmune concluded an agreement with SmithKline Beecham Corp. (SKB; now GlaxoSmithKine/GSK) for development and commercialization of HPV vaccines for prevention of cervical cancer and genital warts. SKB received exclusive rights to MedImmune’s HPV vaccine technologies, including those it licensed from other organizations. In return, MedImmune received an up-front payment; and receives future funding and developmental and sales milestone payments which together could total over $85 million. Medimmune also receives a 7% royalty on product sales (and 5% on sales of Gardasil by Merck; see related entry below). SKB/GSK is responsible for further product development, regulatory approvals, manufacturing and marketing. At the time, MedImmune was conducting a Phase I trial with MEDI-501. GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617, completed development and manufactures Cervarix.

In Feb. 2005, related to the settlement of patent disputes between GSK and Merck (see Tech. transfer section below) by cross-licensing, MedImmune amended its agreement with GSK. This involved MedImmune receiving certain milestone payments and royalties on sales of Gardasil, Merck’s HPV vaccine.

GSK, in its effort to develop Cervarix and attempt to catch up to Gardasil, which was originally about two years ahead in development, instituted the “one roof” management technique originally developed by Renault. By plucking experts from various disciplines across the company and putting them “under one roof”—that is, full time on one project, in one location, reporting to a single leader—GSK was able to significantly cut Cervarix’s development time. Before switching to “one roof,” 80% of the staff working on Cervarix spent only about 20% of their time on it, with management able to provide same-day decisions.

The vaccine is manufactured by GlaxoSmithKline Biologicals S.A. in Belgium.

JSC Binnopharm markets Cervarix in Russia.

Manufacture: The baculovirus expression vector system (BEVS) offers the advantage that a large percentage of cells can be induced to express protein due to the use of infection rather than transfection techniques. Baculovirus is an insect virus and grows in insect cells (e.g., the Trichopulsia ni High Five or Spodoptera frugiperda SF9 cell lines). These cells retain many eukaryotic mechanisms for processing of proteins, including glycosylation and phosphorylation.

HPV L1 proteins expressed in eukaryotic cells spontaneously assemble to form VLPs, as discussed in the Human Papillomavirus (HPV) Vaccines entry. However, most protein purification procedures have been designed to purify proteins much smaller than the about 20 million Dalton (20,000 kDa), 55 nm, size of HPV L1 VLPs. As discussed in the Tech. transfer section, MedImmune has licensed and/or developed methods for disassembly of L1 proteins into capsomeres, with this facilitating purification, and reassembly into capsid-like VLPs.

The L1 proteins of HPV-16 and HPV-18 are separately produced using a recombinant baculovirus expression system and the insect cell line Hi-5 Rix4446 (High Five cell line; BTI-TN5B1-4) derived from Trichoplusia ni (cabbage looper). First, recombinant baculovirus inocula of each serotype are prepared by amplification of the respective working seeds in the Hi-5 insect cell cultures. Next, these inocula are used for the infection of Hi-5 production cell cultures. L1 protein is released from the cells by osmotic shock and subsequently assembled into (VLP) closely resembling the configuration of native HPV virus particles, purified by a series of chromatographic columns, a nanometric filtration, an ultrafiltration and a final sterile filtration to generate the L1 VLP purified bulks. HPV-16 L1 VLP and HPV-18 L1 VLP as well as the liquid MPL are first individually adsorbed to Al(OH)3 to generate adsorbed bulks. The purified HPV-16 L1 VLP and HPV-18 L1 VLP protein bulks are stored in stainless steel vessels dedicated to the adsorption of aluminum adjuvant for up to 3 days at 2°C-8°C or at room temperature. The final bulk vaccine is produced by mixing defined amounts of adsorbed bulks and adding buffer solutions and Al(OH)3 to reach the intended final formulation.

The three intermediates used during manufacture are HPV-16 and HPV-18 adsorbed monovalent bulks (AMBs); MPL liquid bulk (MLB); and MPL adsorbed bulk (MAB). No process controls are applied for AMBs and MABs production. The process control of MLB production is tested by measuring the MPL particle size during the microfluidization procedure and before the final sterile filtration. The bioburden before sterile filtration is monitored. The QC testing established for AMBs addresses identity of the L1 protein, sterility, protein content and completeness of adsorption. The EU application included specifications and results of analysis for four HPV-16 L1 VLP and five HPV-18 L1 VLP AMB batches. The final bulk vaccine is tested for sterility. Final containers are subjected to tests for identity, sterility, general safety, in vitro relative potency, pH, volume, protein content, aluminium content, MPL content and completeness of adsorption for MPL, HPV-16 L1 VLP and HPV-18 L1 VLP proteins.

The manufacturing of the HPV-16 L1 VLP and HPV-18 L1 VLP makes use of an established two tiered cell bank system of the Hi-5 Rix4446 cell line (Master and Working Cell Banks (MCB and WCB)) and an established two-tiered baculovirus Seed Lot system set up for the HPV-16 L1 and HPV-18 L1 gene-encoding recombinant baculoviruses (HPV-16 or HPV-18 Master and Working Seeds (MS and WS)).

The comparability of HPV-16/18 L1 VLP antigen purified bulks prepared during the Phase IIb and Phase III development, including the final process purified bulks, was assessed by subjecting each to a series of physico-chemical analyses and by evaluation of the immunogenic properties. The results demonstrated satisfactory comparability. Preclinical comparison of the immunogenicity induced by the different process development stages' vaccine lots showed that all lots were able to elicit humoral and cellular immune responses which were consistent and comparable.

Potential impurities expected in drug substance purified bulks are host cell proteins (HCP), DNA, and infectious recombinant baculoviruses. These are efficiently removed by the purification process very efficiently. Other impurities, such as lipids or carbohydrates, are present only in negligible trace amounts.

No materials of animal origin are used in the current routine production process of the vaccine, except casamino-acids that are used in the preparation of the MPL immunostimulant and for which the source is compliant (in the EU) with the current CPMP Note for Guidance (EMEA/CPMP/410/01).

FDA class: Biologic BLA

Approvals: Date = 20091016; BLA (BL 125259/98)

Date = 20100902; BLA supplement (in addition to the full BLA); Indication = add lymphadenopathy to the Adverse Reactions, Postmarketing Experience section of the full prescribing information

indications: [Full text of the "INDICATIONS AND USAGE" section of U.S. product insert/labeling]:

1.1 Indications

CERVARIX® is indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18 [see Clinical Studies (14)]:

• cervical cancer,

• cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and

• cervical intraepithelial neoplasia (CIN) grade 1.

CERVARIX is approved for use in females 10 through 25 years of age.

1.2 Limitations of Use and Effectiveness

CERVARIX does not provide protection against disease due to all HPV types [see Clinical Studies (14.3)].

CERVARIX has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity [see Clinical Studies (14.2)].

Females should continue to adhere to recommended cervical cancer screening procedures [see Patient Counseling Information (17)].

Vaccination with CERVARIX may not result in protection in all vaccine recipients.

indications: [Full text of the "Therapeutic indications" section of the EU Summary of Product Characteristics]:

CERVARIX is indicated for the prevention of high-grade cervical intraepithelial neoplasia (CIN grades 2 and 3) and cervical cancer causally related to Human Papillomavirus (HPV) types 16 and 18. The indication is based on demonstration of efficacy in women aged 15-25 years following vaccination with Cervarix and on the immunogenicity of the vaccine in girls and women aged 10-25 years. See section 5.1 for information on the evidence that supports the efficacy of Cervarix in prevention of CIN grades 2 and 3 associated with HPV-16 and/or HPV-18. The use of Cervarix should be in accordance with official recommendations.

[The EU SPC also states, "The need for a booster dose has not been established"].

Status: Large-scale Phase III efficacy trials enrolling over 10,000 women are well underway, but are not expected to be complete until 2008. However, interim results could support approvals prior to trials’ completion.

In March 2006, GSK filed a MAA for Europe Union (EU) approval of Cervarix. In March 2007, the GSK CEO reported that the EU MAA for Cervarix was taking longer than the nine-month review for Merck’s Gardasil, because GSK’s data file was incomplete when it was submitted. However, he noted that despite this, the company’s timetable for expected approval remained on track.

On March 29, 2007, GSK filed a BLA seeking FDA approval of Cervarix for the prevention of cervical cancer and precancerous lesions associated with the most common cancer-causing human papillomavirus types, particularly types 16 and 18. On May 31, 2007, FDA declined a GSK request to grant fast track review to Cervarix (apparently viewing approval of a second HPV vaccine as not a high priority). The BLA will receive standard 10, rather than 6, month review.

In March 2007, besides the U.S. and EU, applications were pending in Australia, Canada, and major countries in Asia and Latin America.

On May 21, 2007, GSK received approval in Australia, its first approval in a major market country.

On July 19, 2007, the CMHP, EMEA, European Union, issued support for approval of Cervarix.

On Sept. 24, 2007, EMEA/EU granted approval to Cervarix, which will competed in the EU market against Gardasil marketed by Sanofi Pasteur. The EU had previously evaluated the AS(04) adjuvant system as part of the application for Fendrix (see related entry). As part of EU approval, GSK agreed to performing the studies and additional pharmacovigilance activities detailed in its Pharmacovigilance Plan, as agreed in version 2 of the Risk Management Plan.

In Oct. 2007, after receiving EU approval, GSK filed and application with theWorld Health Organization (WHO) to have Cervarix prequalified for distribution in developing nations. Prequalification by WHO is essentially accepted as constituting approval in many lesser-developed countries lacking sophisticated regulatory systems. The WHO prequalification program is intended to provide developing nations access to medicines that have been approved by recognized national health authorities. United Nations agencies and mass-vaccination programs can provide the products to poor countries once they are prequalified.

On July 11, 2008, GSK submitted its response to questions raised by the FDA in a "Complete Response Letter," dated Dec. 17, 2007. Also, with final data from GSK's Phase III pivotal efficacy study, HPV-008, expected to be available later in 2008, GSK decided it would wait and augment its application with these data to ensure they are included in the U.S. label. GSK anticipated submitting these data in the first half of 2009, with this likely delaying approval into 2nd half or late 2009.

On March 30, 2009, GSK completed the BLA for Cervarix for prevention of cervical cancer and cervical pre-cancer related to human papillomavirus types 16 and 18, with FDA response expected (PDUFA date) in six months.

On Sept, 9/10, 2009, the V accines and Related Biological Products Advisory Committee (VRBPAC), FDA, voted that clinical data support both the efficacy and safety of

Cervarix for use in in girls and young women for the prevention of cervical pre-cancers and cervical cancer related to HPV types 16 and 18.

On Sept. 29, 2009, FDA reported it would be delaying its expected decision regaring Cervarix approval.

On Oct. 16, 2009, FDA approved the BLA for Cervarix. Within a week, the Advisory Committee on Immunization Practices (ACIP) included it in its HPV vaccination recommendations (make the vaccine eligible for CDC purchase for distribution ot pediatric and public health programs). In an 11-1 vote, Cervarix was concluded to appear safe despite miscarriages reported around the time of vaccination and a small number of autoimmune problems such as rheumatoid arthritis and lupus. Panelists urged monitoring for those issues after approval to see if there was any link to the vaccine.

Also on Oct. 16, 2009, Cervarix received approval in Japan.

In Oct. 2009, Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), backed routine administration of Cervarix for 11-12-year-old girls to protect against cervical pre-cancersand cervical cancer associated with HPS types 16 and 18. This included a catch up for girls and young women who have not previously been vaccinated, which for the approved age range for Cervarix includes 13-25 year old girls and young women. ACIP also unanimously recommended to provide funding for Cervarix from the Vaccines for Children (VFC), CDC, program which provides vaccines at no cost to children up to 18 years of age who might not otherwise be vaccinated because of inability to pay.

On Aug. 25, 2010, EMEA/EU approved an amendment to the labeling for Cervarix to better reflect the scope of protection it offers. Marketing authorisation was adjusted to show that its efficacy goes beyond the HPV 16 and 18 strains to provide protection against 80% of all cervical cancers. The amendment was based on data from the PATRICIA study that demonstrated Cervarix is effective against HPV strains 16, 18, 31, 33 and 45 (not included in its original indication). The summary of product characteristics for Cervarix was also updated to include the prevention of precancerous lesions and cervical cancer causally related to certain strains of HPV.

Tech. transfer: MedImmune (now part of AstraZeneca) has assembled a large portfolio of licensed technologies for its HPV vaccines, including licenses with Boyce Thompson Institute, Georgetown University, University of Rochester, the Deutsches Krebsforschungszentrum, National Institutes of Health (NIH), as well as collaborations with the University of California (Davis, CA) and Pennsylvania State University that may have involved patent or technology licensing.

MedImmune (and/or GSK) has licensed patents from the National Cancer Institute (NCI), National Institutes of Health (NIH), concerning recombinant baculovirus expressed self-assembling HPV VLP vaccines. These patents by D.R. Lowy, J.T. Schiller and coworkers include U.S. 5,985,610; 5,871,998; 5,756,284; 5,744,142; 5,716,620; and 5,709,996, each entitled, “Self-assembling recombinant papillomavirus capsid proteins. These concern recombinant baculovirus and yeast expression of HPV type 16 L1 capsomer polypeptides capable of self-assembly into immunogenic VLPs. These patents cover aspects of both baculovirus-expressed Cervarix and yeast-expressed Gardasil. NCI had previously collaborated with Novavax, Inc. for the manufacture and development of baculovirus-expressed HPV VLP vaccines, which it tested in early-phase trials. Large-scale NCI were planned to start in 2000 or soon after, but never got underway.

MedImmune has received its own patents concerning HPV L1 VLP vaccines. This includes 6,416,945 and 6,261,765, “In vitro method for disassembly/reassembly of papillomavirus virus-like particles (VLPs),” providing improved methods for disassembly/reassembly of papillomavirus VLPs. VLPs are reacted with sulfhydryl reducing agent(s), e.g., glutathione, 1,4-dithiothreitol (1,4-dimercapto-2,3-butanediol), beta-mercaptoethanol, dithioerythritol and cysteine, with at least 70% of VLPs disassembling into smaller, correctly-folded L1 protein molecules, with reassembly induced by concentration by dialysis, diafiltration or column chromatography, or oxidation of the sulfhydryl reducing agent(s). The resulting reassembled VLPs are much more homogenous in particle size than the original VLP starting material.

In Aug. 1995, MedImmune exclusively licensed the High Five insect (Trichoplusia ni- or cabbage looper-derived) cell line from the Boyce Thompson Institute for Plant Research (Ithaca, NY), affiliated with Cornell University, for baculovirus production of recombinant HPV VLP vaccines. [Note, also reported as nonexclusive licensing]. This included U.S. 5,298,418, “Cell line isolated from larval midgut tissue of Trichoplusia ni” and U.S. 5,300,435, “Tricho-plusia ni Cell Line which Supports Replication of Baculoviruses,” concerning high production cell lines of Trichoplusia ni (cabbage looper), ATCC CRL 10859 and 10860; and 6,403,375, “Establishment of Trichoplusia ni cell lines in serum-free medium for recombinant protein and baculovirus production,” concerning cell lines from Trichoplusia ni eggs that may be cultured in commercial serum-free medium. High Five host cells provide up to 25-times more HPV vaccine antigen than standard Sf9 (Spodoptera frugiperda) baculovirus host cells, and may be cultured in serum-free media. Boyce Thomson has received other baculovirus expression patents, including 6,090,379.

In fall 1995, MedImmune exclusively licensed human HPV vaccine patents from the University of Rochester. These include U.S. 6,165,471 (and WO9901557), “Homogeneous human papillomavirus capsomere containing compositions, methods for manufacture, and use thereof as diagnostic, prophylactic or therapeutic agents,” coassigned to the University of Colorado, MedImmune, and University of Rochester. This concerns generation of recombinant HPV L1 capsomeres (components of the viral capsid) which are substantially incapable of assembly into virus-like particles. Capsomeres, because of their smaller size (vs. capsids), facilitate purification, and can be later reformed into capsid-like VLPs. A related University of Rochester patent is WO9420137, “Production of Human Papillomavirus Capsid Protein and Virus-Like Particles.”

MedImmune presumably had taken a manufacturing license for basic baculovirus expression vector system (BEVS) technology originally assigned to and marketed by Texas A&M University, the original developers of baculovirus expression systems. This includes U.S. 4,879,236 and 4,745,051 (both apparently now expired), both entitled “Method for producing a recombinant baculovirus expression vector,” covering aspects of baculovirus transfer vector construction and use in transient cell lines (with the virus infection killing the cells), by G.E. Smith and M.D. Summers; and/or U.S. 5,077,214, “Use of Baculovirus Early Promoters for Expression of Foreign Genes in Stably Transformed Insect Cells,” including promoters from Autographa californica nuclear polyhedrosis virus and a stably-transformed insect cell line, e.g., Sf9 of Spodoptera frugiperda or High Five of Trichoplusia ni, and vectors capable of continuous expression of a selected gene product, so the baculoviruses do not kill the host cells (apparently expiring in 2006).

In June 1999, MicroGeneSys, Inc., now Proteins Sciences, Inc., and Texas A&M University combined their intellectual property regarding baculovirus expression systems. Protein Sciences was exclusively authorized to sublicense the combined BEVS technologies to third parties. However, Protein Sciences reported that neither MedImmune nor GSK are current licensees, although they may have been licensees through Texas A&M University or their license may have lapsed with patent expirations.

In mid-1996, the German Cancer Research Center (Deutsches Krebsforschungszentrum or DKFZ; Heidelberg, Germany) granted MedImmune exclusive worldwide rights to patents concerning HPV vaccines involving sequences and vector constructs for expression of L1. This apparently includes U.S. 6,589,532; 6,562,597; 6,555,345; 6,368,832; and/or 6,322,795.

In Feb. 2005, Merck (developer of Cervarix, another HPV L1 VLP vaccine) and GlaxoSmithKline (GSK; collaborating with MedImmune) settled HPV-related patent disputes. The companies agreed to cross-license their respective patent portfolios (including those licensed from third parties). GSK (and MedImmune) was the prevailing party (i.e., won the dispute), apparently due to the strength and diversity of patents licensed by MedImmune. GSK received an upfront payment and will receive royalties from Merck based on sales of Gardasil. Thus, all of the patents held by GSK and MedImmune may be considered as also being licensed to Merck.

GSK has likely licensed recombinant recombinant HPV vaccine technology from Georgetown University. Dr. Schlegel and coworkers at the university began research in the late 1980s. Patents that may be licensed include U.S. 6,485,728, “ Formalin-Inactivated human papillomavirus L1 protein vaccine;” and 6,887,478, “Formalin-treated human papillomavirus L1 protein vaccine.”

The MPL component of GSK’s AS04 adjuvant used in Cervarix was originally developed by Ribi ImmunoChem Research Inc., which was acquired in mid-1999 by Corixa Corp., which was acquired by GlaxoSmithKline plc in April 2005. In Dec.1992, Ribi co-exclusively licensed MPL for adjuvant use in various pediatric and other vaccines to SmithKline Beecham (SKB; now GSK) and Lederle Praxis Biologicals (now Wyeth). As discussed in the Monophosphoryl Lipid A entry, in July 2004, Corixa entered into a manufacturing agreement with GSK to provide MPL through 2012; and Corixa (now owned by GSK) was to receive unspecified royalties on sales of vaccines containing MPL.

Trials: MedImmune began Phase I trials with MEDI-501 (HPV type 11 VLP with alum adjuvant) in early 1997.

Results from a Phase III trial with bivalent vaccine, Cervarix, were reported in the Nov. 13, 2004 issue of Lancet. This randomized, double-blind, controlled trial assessed the efficacy, safety, and immunogenicity of bivalent HPV-16/18 L1 VLP vaccine for the prevention of incident and persistent infection with these two HPV types, associated cervical cytological abnormalities, and precancerous lesions. Incident cervical infection was defined as having at least one positive polymerase chain reaction (PCR) assay for HPV-16 or HPV-18 DNA during the trial. Persistent cervical infection was defined as at least two positive assays at least six months apart for the same viral genotype. The trial enrolled 1,113 women in U.S., Canada and Brazil between 15-25 years of age who received three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0, 1, and 6 month schedule. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. In protocol-specified analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0%) against incident infection and 100% against persistent infection (47.0-100%) with HPV-16/18. In intention-to-treat analyses, vaccine efficacy was 95.1% (95% CI 63.5-99.3%) against persistent cervical infection with HPV-16/18 and 92.9% (95% CI 70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was highly immunogenic and induced levels of antibody protection against HPV-16 and HPV-18 that were 100 times and 80 times greater, respectively, than those induced by natural infection. At 18 months, vaccination-induced antibody titers remained 10 to 16 times higher than those naturally induced. Longer and larger-scale trials will be needed to prove clinical efficacy, i.e., prevention of cervical cancer, which takes decades to develop.

In May 2005, results were reported from ongoing trials with Cervarix indicating that the vaccine is effective for preventing cervical cancer from HPV types 31, 45 and 52, which together account for 12% of cases of cervical cancer. This has been interpreted to mean that the vaccine is/will be 82% effective for prevention of cervical cancer, by addition with the protective efficacy already demonstrated against types 16 and 18, which account for 70% of cases. Many analysts reported that they expect this apparent increased efficacy to differentiate Cervarix from Gardasil, with some claiming Cervarix is/will be superior to Gardasil (although Gardasil has more HPV type antigens than Cervarix). GSK more conservatively noted, “If these data are confirmed by ongoing research, it would mean that GSK’s vaccine might provide protection against more cervical cancer causing HPV types than originally estimated.”

Two large Phase III trials enrolling approximately 25,000 women began in 2004.

In Dec. 2005, GSK reported results from a double-blind, Phase III trial in conducted in Europe and Russia in 616 females showing that Cervarix induced at least 2-fold higher antibody levels against HPV 16 and 18 in 10-14 year old adolescent girls than in women 15-25 years old. The improved immune responses in younger girls suggest that use in this younger group might be associated with a longer persistence of antibodies. The trial involved 158 healthy girls aged 10-14 and 458 women aged 15-25 who received three doses of the vaccine over a six-month period. Cervarix was well tolerated and induced antibodies in 100% of volunteers in both age groups 1 month after completion of the course. The study indicates Cervarix provides the strongest and most-prolonged protection if given to girls at young ages, long before they are likely to encounter the sexually transmitted virus. The trial was not designed to confirm actual effectiveness of the vaccine, because few girls ages 10-14 are sexually active.

In early April 2006, follow-up data were published in Lancet from the double-blind, placebo-controlled, U.S., Canadian and Brazilian Phase III trial in 776 evaluable patients. Cervarix was 100% effective over 4.5 years against precancerous lesions associated with HPV-16 and HPV-18. Antibodies to HPV-16 and HPV-18 were detected in over 98% of women for up to 4.5 years. Patients also had effective antibody levels against HPV types 45 and 31. Cervarix was safe and well tolerated.

In Jan. 2007, GSK took the brave or foolish (depending on the outcome) step of initiating a 1,000-subject trial comparing the immunogenicity (efficacy) of Cervarix and Gardasil (see related entry). Results from the first studies to directly compare the two vaccines were reported in the July 2006 issue of Vaccine. Cervarix with its AS04 adjuvant provided immune response (antibody levels) that were consistently stronger and more sustained, including numbers of HPV 16/18-specific memory B cells, at every evaluated time-point, vs. Gardasil. The results were maintained for at least 3.5 years post-vaccination. The new trial is comparing immune responses to HPV types 16 and 18 in women aged 18-26. Secondary goals will assess immunogenicity in those aged 27-35 and 36-45. GSK hopes/presumes the MPL adjuvant in Cervarix will increase its immunogenicity vs. Gardasil, which uses a conventional aluminum salt adjuvant. The study will also look at immune responses to other cancer-causing HPV types, such as 45 and 31 which, together with types 16 and 18, cause more that 80% of cervical cancers. First results are expected around 12 months after enrollment is completed. This trial is not directed to the primary market of prepubescent females, but claims of superiority in adults could boost market share in this market at the expense of Gardasil. This trial is directed towards unvaccinated adult women, for which catch-up vaccination campaigns may be appropriate.

The March 2007 BLA filing included data from clinical trials in almost 30,000 females 10-55 years of age, reflecting an ethnically diverse population. The submission also contained data from the largest Phase III cervical cancer vaccine efficacy trial to date, conducted worldwide in more than 18,000 females 15-25 years of age.

In April 2007, results from an extended follow-up trial were reported showing that Cervarix exhibited 100% protection against precancerous lesions due to oncogenic HPV types 16 & 18 for for up to 5.5 years. This was an extended follow-up (EFU) analysis of women who participated in the initial efficacy study of Cervarix (a double-blind, controlled trial of 1,113 young women between 15-25 years of age, randomized to receive three doses of Cervarix, or three doses of placebo on a 0, 1 and 6 month schedule). The study looked at 776 women from the same cohort for a period of up to 67 months. Women were evaluated for the presence of HPV DNA by PCR using cervical samples and annual cervical cytology evaluations. This trial showed the longest duration of protection seen in any cervical cancer vaccine trial reported to date. Cervarix induced a strong immune response in virtually 100% of women in the study, which was maintained over 5.5 years for both virus types 16 and 18. At the end of the 5.5 year period, the average level of antibodies against both virus types 16 and 18 was at least 11 times greater than antibody levels associated with natural infection with the virus. Cervarix also showed 68% vaccine efficacy against precancerous lesions (CIN2+) and 38% vaccine efficacy against abnormal Pap smears, regardless of the type of cancer-causing virus detected, i.e., Cervarix has some efficacy against HPV types not included in the vaccine. The study confirmed cross-protection against incident infection with cancer-causing virus types 45 and 31 that also extended up to 5.5 years after vaccination.

In the June 27, 2007, issue of The Lancet, results from an interim analysis of an ongoing pivotal randomized Phase III study showed that Cervarix provided up to 100% protection against advanced precancerous lesions caused by the most common types of HPV, types 16 and 18. The primary objective of the interim analysis was to evaluate vaccine efficacy against precancerous lesions associated with cancer-causing virus types 16 and 18 among women who were DNA-negative and seronegative for the corresponding vaccine type at study entry. Secondary objectives included efficacy against 6- and 12-month persistent infection with virus types 16, 18 or other cancer-causing virus types, immunogenicity and safety. This study involved 18,644 women aged 15 to 25 from 14 countries across Europe, Asia-Pacific and Latin and North America, making it the single largest cervical cancer vaccine efficacy trial to date. This interim analysis showed results over an average follow-up time of 15 months after first vaccination, in which a proportion of the women enrolled already had a HPV infection or abnormal cytology (abnormal Pap smears) at study entry. The study also supported earlier preliminary evidence that the vaccine provides significant protection against infection with additional cancer-causing virus types. The vaccine showed significant cross-protection against 6-month persistent infection caused by virus types 45, 31 and 52. Together with virus types 16 and 18, these types are collectively responsible for more than 80% of cervical cancer cases globally. The vaccine with AS04 adjuvant produced a robust immune response for both virus types 16 and 18. As in prior studies conducted over five years and involving over 40,000 women, the candidate vaccine was shown to be generally well-tolerated.

Regarding this pivotal study, GSK noted that the majority of precancerous lesions included in prior primary analyses had multiple cancer-causing virus types detected, making it difficult to determine which virus type was the cause of the lesion. The observation of such a high number of lesions with multiple virus types was not expected based on published data. This necessitated additional analyses to determine which virus type was the cause of the lesion. In these analyses, causality was determined by confirming the presence of the virus in both the lesion and in previous Pap smear samples. According to GSK, “When using the pre-specified analyses which only required detection of virus in the lesion, and not taking previous samples into account, vaccine efficacy in women with virus type 16 and/or 18 in the lesion was 90 percent. When considering the virus type present in both the lesion and previous samples, the vaccine was 100% effective in preventing precancerous lesions caused by virus types 16 and/or 18.”

In March 2008, GSK reported new data showing that Cervarix provides significant protection for women against the four most common cancer- causing human papillomavirus types for nearly 6.5 years, the longest duration of protection reported to date. This was from an extended follow-up (EFU) analysis of 776 women who participated in the initial efficacy study of the vaccine. Over this time, Cervarix showed 100% efficacy in preventing precancerous lesions due to cancer-causing virus types 16 and 18 and also provided substantial protection against infection caused by virus types 31 and 45. Virtually 100% of women in the study, 15-25 years of age, maintained high levels of antibodies against both virus types 16 and 18 at every time point for nearly 6.5 years, the longest duration of consistently high antibody levels shown by a cervical cancer vaccine. The vaccine showed 78% efficacy in preventing incident infection caused by virus type 45, and 60% efficacy in preventing incident infection caused by virus type 31 Antibody levels remained several times higher than natural infection levels over the extended period of time.

In 2008, a Phase III pivotal efficacy study, HPV-008 (NCT00122681), in 18,000 pateints continued, with data from this expected to be filed in late 2008 as part of the pending BLA application. The trial is being conducted at 178 centers in 14 countries, using hepatitis A vaccine (Havrix) as the control.

On June 25, 2008, Merck spun some bad news for its HPV vaccine Gardasil into worse news for Cervarix. Merck reported receiving a “complete response” rejection from FDA on a supplemental application for Gardasil for older patients (women 27-45). FDA stated that one of the claims that it did not accept was the idea that Gardasil could protect against HPV strains beyond the four specifically included in the vaccine (6,11,16, 18). With only two strains covered by Cervarix, GSK has been relying on acceptance of a cross-protection claim to make its bivalent match up to Merck’s quadravalent product. Merck’s bad news may well be another reason why GSK took a more measured approach to Cervarix approval, waiting for full results from HPV-008 to be filed in late 2008.

The BLA for Cervarix included safety, efficacy and immune response data from clinical trials in nearly 30,000 females and reflects an ethnically diverse population.

Data from HPV-008 were submitted to FDA as part of completion of GSK's BLA filing. HPV-008 wa a Phase III clinical study of more than 18,600 women between 15-25 years of age, from 14 countries across Europe, Asia-Pacific and Latin and North America. The primary objective was to assess vaccine efficacy in the prevention of high-grade pre-cancerous cervical lesions (CIN2+) caused by human papillomavirus types 16 or 18. Secondary objectives included evaluation of vaccine efficacy in the prevention of pre-cancerous cervical lesions (CIN1+) and infections caused by virus types 16 or 18 or other cancer-causing virus types, as well as immune response and safety.

In May 2009, with competition already heating up with Gardasil, even before Cervarix received approval, GSK reported results from a study showing that Cervarix apparently induces a higher immune response than Gardasil. The head-to-head trial included more than 1,100 women aged 18 to 45. The two vaccines were given in three inoculations over six months. The women who received Cervarix had higher levels of neutralizing antibodies than those receiving Gardasil one month after the last dose. For one HPV type, the levels induced by Cervarix were more than twice as high as Gardasil and for another type they were more than six times higher. Both vaccines had "acceptable" safety profiles, but rates of "injection-site reactions," which can include inflammation and rashes, were higher among Cervarix users.

In July 2009, the final analysis of t HPV-008, the largest efficacy trial of a cervical cancer vaccine, was published today in The Lancet. The study, involving 18,644 women, confirmed Cervarix is highly effective at protecting against the two most common cervical cancer-causing human papillomavirus (HPV) types, 16 and 18. The study also showed that the vaccine provides cross-protection against HPV types 31, 33 and 45, the three most common cancer-causing virus types beyond 16 and 18. Among women who complied with the trial protocol procedures (87% of the total sample), the vaccine provided 92.9% protection against cervical pre-cancers (cervical intraepithelial neoplasia 2+ or CIN 2+) associated with HPV 16 or 18. A further analysis of the same cohort, which excluded lesions not likely to be caused by HPV 16 and 18, revealed that the vaccine was 98.1% effective against cervical pre-cancers (CIN 2+) caused by these two types.1

On Dec. 4, 2009, GSK published in The Lancet results from a study showing that ervarix protects against cervical cancer (due to HPV 16/18) for more than six years without the need for a booster. Among 776 females aged 15 to 25, 393 of whom received Cervarix, after 6.4 years vaccine efficacy against incident infection with HPV 16/18 was 95.3%, and 100% against 12-month persistent infection. Cervarix also protected women against incident infection with HPV-31 and HPV-45, which are among the types most frequently associated with cervical cancer after HPV 16/18, and are responsible for 10% of all cervical cancer cases.

Medical: Cervarix involves three vaccinations, a primary intramuscular injection and two boosters at one and six months.

Market: First-half 2013 sales were reported to be $285. Based on this, estimated 2012 sales were about $20 million.

- Total 2009 sales of Cervarix were $290 million (about 1/6th that of Gardasil). Total 2008 sales of Cervarix, primarily in Europe by Sanofi Pasteur, were $231 million. Total 2007 sales of Cervarix, primarily in Europe by Sanofi Pasteur, had been reported to be less than 10% of that of Gardasil, which had €342 (~$500 million in Aug. 2008) million in European sales in 2007, with about 3 million courses sold. Thus, total 2007 Cervarix sales were on the order of ≤$50 million.

Upon FDA approval, GSK set price of $128.66/dose or $399/course of three injections, slightly lower than Gardasil ($399).

In Oct. 2007, Cervarix was launched in the U.K. with pricing comparable to that of Gardasil from Merck. Both vaccines have a private prescription price of £80 ($162.50) per dose, or £240 ($490.46) for a course of three shots. However, the great majority of U.K. citizens receive medical care, including vaccines, through the National Health Service (NHS).

In Sept. 2009, the UK pharmacy chain Boots began selling an over-the-counter, three-injection course of Cervarix, at 134 of its 2,500 UK stores, charging £135/dose for a total cost of £405.

Sales of prophylactic HPV vaccines are expected to be in the range of $1-4 billion annually. See the Human Papillomavirus (HPV) Vaccines entry for discussion of the market potential for HPV vaccines.

In June 2005, GSK estimated that cumulatively, up to 80 million women could be candidates for HPV vaccination by 2010; and that the cervical cancer vaccine market could achieve a value of £2-4 billion ($4-7 billion) per year by 2010. GSK expects the primary market for Gardasil to be in the U.S. In a 3rd quarter 2004 presentation to analysts, GSK had projected a £1 billion ($1.9 billion in 4/2005) potential market for Cervarix.

Analysts with Friedman, Billings and Ramsey (FBR) in Nov. 2006 projected worldwide sales of Cervarix to be $150 million in 2007, $500 million in 2008, $650 million in 2009, and $700 million in 2010, with Cervarix slightly topping sales of Gardasil in the two later years.

The Oct. 2009 approval for use against strains beyond HPV 16 and 18, i.e, HPV 31, theoretically provided Cervarix with a marketing advantage relative to Gardasil. Although not included as an approved indication, the insert/labeling clinical trial discussion specifically mentions efficacy (determined by ad hoc analyses) against pre-cancerous conditions tied to HPV-31 infections: 89.4% against CIN2/3 and 100% against adenocarcinoma in situ. In contrast, Gardasil labeling then stated that "cross-protective efficacy was not demonstrated against disease caused by non-vaccine HPV types in the combined database" from two major pre-approval trials. GSK had previously estimated that HPV-31 is the cause of 4.6% of cervical cancers in the U.S.

GSK has reportedly been undercutting prices of Gardasil, inorder to capture market share, upon approval pricing vaccine at $386 a three-course dose, compared with $399 for Gardasil, and undercutting Merck in contract bids.

In Oct. 2010, GSK reduced the price for Cervarix in Canada by ~30%, reducng the price to $90/dose from $134.95. This was done to increase sales and market penetration. Market research had shown that the "relatively high price" of cervical cancer vaccines was one reason why nine of 10 Canadian women (90%) aged 18 to 25 had not been vaccinated against HPV. That's quite an uptake gap, considering that Cervarix has been available since Feb. 2010 and Gardasil since 2006. Half of the young women surveyed and 61% of mothers said cost was a deterrent.

GSK may have to consider other price reductions, similar to that in Canada, to expand or maintain sales in the face of competition from Gardasil, with Merck claiming its vaccine is better, i.e., provides coverage against more HPV strains and shows better results in head-to-head trials.