Cervarix on top in head-to-head, but how meaningful?

The first comparative study of the two licensed human papillomavirus (HPV) vaccines, Cervarix and Gardasil (HPV types 6, 11, 16, 18 recombinant vaccine), has shown that the former generated a significantly higher immune response as measured by neutralising antibodies (Abs) and memory B-cells.

Although GlaxoSmithKline has touted these results as highly positive, others have hit back claiming that the trial is meaningless as it did not look at which vaccine was more effective at preventing actual cases of cervical cancer or precancerous lesions. This would require a longer and larger trial, which GSK has said it has no plans to conduct. Instead, the company hopes that the head-to-head study will boost the profile of Cervarix, which is yet to be launched in the US and is trailing Sanofi Pasteur MSD's (sanofi-aventis and Merck & Co joint venture) Gardasil in global markets.

Meanwhile, recent data on Gardasil have shown that the vaccine offers protection from certain HPV strains for up to 9.5 years; previously, data only showed its effects for five years. In another study, Gardasil reduced the number of abnormal Pap tests and cervical procedures. However, with Gardasil's US sales falling and Cervarix not even on the market yet in that territory, can the comparative trial data make a difference in revenues for GSK?

Gardasil, which was first to market, and launched in the US and Europe in 2006, generated sales of US$1.4 billion in 2008, while Cervarix brought in just US$231 million. Cervarix is still awaiting US marketing approval, and has only been adopted as the vaccine in national immunisation programmes for two European countries, the UK and the Netherlands. The FDA refused to approve Cervarix until GSK provided more clinical information, but the company expects approval to come later this year.

So what of the new comparative data? The presence of Abs is a first indication of the body's ability to protect itself against disease, but this does not necessarily mean Cervarix could prevent more infections than Gardasil. The study showed that Cervarix provided significantly higher neutralising Ab levels than Gardasil: more than two-times higher for HPV type 16 and more than six-times higher for HPV 18. For both virus strains, Cervarix also induced 2.7-times more memory B-cells, another important element of the immune system.

According to GSK, the study "offers the first evidence that these two vaccines do not generate the same immune response against HPV types 16 and 18, the two most common cancer-causing virus types". Its competitor was dismissive of the data, with Bennett Lee, Medical Director for Gardasil at Sanofi Pasteur MSD commenting: "We see no clinical relevance in the results of this study ... and we don't see the point of doing such a comparison. If you want to compare vaccines, you compare clinical efficacy". However, the final word will come from doctors and patients when, and if, Cervarix is licensed in the US later this year.

Matthew Dennis - Editor, Cancer Drug News

Review confirms Gardasil's safety; predicted sales hit

Based on the review of available information, the FDA and the Centers for Disease Control and Prevention (CDC) have reaffirmed that Gardasil (quadrivalent human papillomavirus [HPV] types 6, 11, 16, 18 recombinant vaccine) continues to be safe and effective, and its benefits continue to outweigh its risks.

To date, the manufacturer, Merck & Co has distributed over 16 million doses of Gardasil in the US and as of 30th June, there have been 9,749 reports of adverse events following vaccination. Of these, 94 per cent were classified as reports of non-serious events, and 6 per cent as serious events. The non-serious events include syncope, pain at the injection site, headache, nausea and fever.

However, concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of 30th June, 20 deaths had been reported, although there was not a common pattern that would suggest they were caused by the vaccine. According to the review, in cases where autopsy, death certificate and medical records were available, the cause of death was explained by factors other than the vaccine.

Guillain-Barré syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. The FDA and CDC have reviewed the reports and, to date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. Thromboembolic disorders have also been reported in people who have received Gardasil. Most of these individuals had risk factors for blood clots, such as use of oral contraceptives, which are known to increase the risk of clotting. Thromboembolic disorders as well as other medical events are being studied through the Vaccine Safety Datalink Project in previously-planned, controlled studies. Merck has also committed to conduct a large post-marketing study to further assess the vaccine's safety.

The vaccine is one of Merck's flagship products but its sales have been under pressure. The company has recently predicted 2008 Gardasil sales of between US$1.4 billion and US$1.6 billion, down from prior estimates of US$1.9 billion to US$2.1 billion. The lower forecast is due, in part, to Merck's failure earlier in the year to receive US approval to market the vaccine to older women aged 27 to 45 years, as well as to extend its indication to include HPV types not included in the vaccine.

Gardasil is approved in the US for use in girls and women aged nine through 26 years to prevents infection with the types of HPV that cause most cases of cervical cancer and genital warts. The CDC's Advisory Committee on Immunization Practices recommended routine three-dose vaccination of girls aged 11 and 12 years. The vaccine is also recommended for girls and women aged 13 through 26 years who have not yet been vaccinated or who have not received all three doses.

Gardasil is marketed by sanofi pasteur MSD (sanofi-aventis’ joint venture [JV] with Merck) in EU countries covered by the JV and several other European countries. In the remaining European countries, located in Central and Eastern Europe, the vaccine is marketed by Merck Sharp & Dohme under the tradename, Silgard.

Matthew Dennis - Editor, Cancer Drug News

UK chooses Cervarix over Gardasil

The Department of Health (DoH), UK, has awarded the contract to provide the vaccine against human papillomavirus (HPV) to GlaxoSmithKline for its product, Cervarix. The contract is to supply the vaccine that protects against cervical cancer (CC) and precancerous cell changes in the cervix caused by HPV. The vaccine will guard against the two HPV strains that cause 70 per cent of cases of CC, types 16 and 18. The vaccine will be made available to girls aged 12 to 13 years from September, while a year later it will also be administered to girls up to 18 years of age in a two-year, catch-up programme.

GSK's CC vaccine is approved in 64 countries worldwide, but this was the first major national tender for which the company had bid. According to Eddie Gray, President of Pharmaceuticals Europe for GSK: "This is great news for girls and women across the UK and reflects the growing confidence in Cervarix, which provides cervical cancer protection with a strong and sustained immune response."

The UK's Joint Committee on Vaccination and Immunisation, which provides independent expert advice to ministers on vaccination, examined a wide range of evidence before recommending in June 2007 that an HPV vaccination programme be routinely introduced for 12 to 13 year old girls. However, this left the DoH to choose between Cervarix and its competitor, sanofi pasteur MSD's (sanofi-aventis and Merck & Co joint venture) Gardasil (quadrivalent HPV types 6, 11, 16, 18, recombinant vaccine), which are both licensed in the EU.

An adjudication was carried out to examine the vaccines offered against a wide range of criteria, such as their scientific qualities and cost effectiveness. The criteria used for the adjudication had been shared in advance with the companies which tendered. Following this process, the DoH selected Cervarix, going against the decision of many EU countries who have opted for Gardasil and the wider protection it offers. Commenting on this, Dr Nicholas Kitchin, UK Medical Director, sanofi pasteur MSD, stated: "We regret that school girls in the UK, unlike most of their peers in Western Europe, the USA, Australia, New Zealand and Canada, will not benefit from the unmatched cervical cancer protection and additional benefits provided by the world's leading HPV vaccine, Gardasil."

Cervarix uses GSK's proprietary AS04 adjuvant as its main differentiating point, which may enhance the immunogenicity of the vaccine, therefore potentially reducing the need for booster shots. However, the long-term efficacy of the two vaccines is believed to be similar.

The key reason for the DoH choosing Cervarix is likely to be price. With a list price for a full course of Gardasil as high as US$375 per person in the US, HPV vaccine costs are a key issue. Although the cost of Cervarix is commercially confidential, it can presently be administered through private clinics at a cost of £130.00 per injection (the immunisation course consists of three injections). GSK may have offered a heavily discounted price, relative to Gardasil, making the DoH’s decision easier. Another factor that must not be forgotten is the fact that GSK is, after all, a British company.

Matthew Dennis - Editor, Cancer Drug News