Vaccines for the world

By Julia Puppe, Editor

Looking at the world’s vaccine market, GlaxoSmithKline is amongst the top players. The company’s vision is to challenge the world of vaccines with vaccines for the world. What’s the strategy behind the concept? Julia Puppe asked Jean Stéphenne, President of GSK Biologicals.

GSK currently supplies one quarter of the world’s vaccines and distributes more than 35 doses of vaccine every second. By the end of February 2008, the pharma giant had 24 vaccines in clinical development. The latest vaccine to win approval from the European authorities was bivalent Cervarix, which stops infections from the human papilloma virus that cause about 70 percent of cervical cancers.

While the industry is seeking inspiration across the pond, where California is quickly becoming the Biotech Capitol of the world, it is in the Belgian village of Rixensart where GSK Biological’s success stories are made. It is expected that the enterprise, which holds 25 percent of the world vaccines market and employs about 9000 people worldwide, will generate revenues of around €2 billion this year.

Founded in 1945 under the name RIT (Recherche et Industrie Thérapeutiques), the company started as a pioneer in the production of antibiotics before finding its vocation in vaccine research, development and production in the 1950s. This vocation has remained strong throughout the series of different acquisitions and mergers, Smith-Kline-RIT (1969), SmithKline Beecham Biologicals (1989) and finally, GlaxoSmithKline Biologicals (2000).

Cancer vaccine
In 1974, Jean Stéphenne joined Smith-Kline-RIT, which then employed 50 people and made €1.9 million, mainly from the company’s polio vaccine. Today, he is the President of GSK Biologicals.

Sat in his Rixensart office, the 58-year-old is in good spirits when I meet him. He has just had news that after initially rejecting it, the Pharmaceutical Benefit Advisory Committee of Australia has finally agreed that Cervarix is cost effective, and recommended the vaccine to be included in their national immunization programme.

No surprise, believes Stéphenne. “Cervarix is the best cancer vaccine,” he says. “It offers up to 100 percent protection against pre-cancerous lesions caused by HPV 16 and 18, which together are responsible for over 70 percent of cervical cancer globally. In addition,” he continues, “it offers protection against HPV 45. HPV16, 18 and 45 together represent 90 percent of cases of cervical adenocarcinoma, and adenocarcinomas represent 15-25 percent of cancer cases, which are more difficult to detect by pap smears. This is why we believe that protection against HPV 45 is critical. In terms of genotype, HPV 18 and 45 are closely related, so a higher response against HPV 18 means better protection against HPV 45.”

Cervarix is formulated with the proprietary innovative adjuvant AS04, selected to ensure that the vaccine confers strong and sustained antibody levels in women. “When you vaccinate a girl of 12 or 14 years,” Stéphenne explains, “it is critical to guarantee protection 10 or 20 years later.”

Awareness
When GSK started the marketing preparations for Cervarix, Stéphenne and his team found that there was not a lot of awareness about the cause of cervical cancer; worse, there were a lot of false believes. “What we also realised was that the epidemiology of the disease was not known. Cervical cancer is the second most common cancer among woman after breast cancer.”

The Cervarix launch was built on the distinctive black and white disease awareness campaign with an added new call to action: ‘Help X-out cervical cancer’. “When testing our disease message during focus groups, we found that women spontaneously crossed their arms in a protective manner when discussing cervical cancer. From this instinctive gesture, the X-attitude was born. Also, we wanted to say that there is a way to cross out cervical cancer, because the HPV vaccine can make it disappear, both in the developed or developing country,” stresses Stéphenne.

GSK filed for FDA approval of Cervarix in March 2007 but wasn’t granted priority review because of rival Gardasil, which has been on the market since June 2006. GSK is currently working on providing answers to the FDA’s further inquiries into the Cervarix file. “I think we are still in the normal time for review of this new product,” Stéphenne comments, adding: “I cannot speculate on the timing of our approval, but we will continue discussions with FDA regarding the application. The agency is asking to have further access to our study data, which is standard practice. This whole process can take several  months.”

In Europe, too, Cervarix was launched after Gardasil, which was approved in September 2006. Now the race is on between the two vaccines as they battle it out to win a more than €125 million annual supply contract with the UK Department of Health. In October 2007, UK Health Secretary Alan Johnson announced the introduction of an HPV immunisation programme to routinely vaccinate girls aged 12-13 years against cervical cancer, starting from September 2008. So far, no decision has been made on which of the two vaccines will be used.

Concern
Not everyone, however, approves of making the vaccine available to under-aged girls. Critics are concerned that this might signal that sexual activity is acceptable or protected to girls at an early age. “Vaccination of adolescents”, Stéphenne admits, “is new but it is starting. If you take the meningitis vaccine Menactra for the prevention of meningococcal disease in the US, for example, it is used in adolescents. Booster vaccines for whooping cough can also be used in the US and in Europe. These are examples where vaccines are routinely used for adolescent.”

Cervarix, Stéphenne emphasizes, is not a vaccine against sexually transmitted diseases; it is a vaccine that protects against cancer. In addition, while promoting the vaccine, GSK is also stressing the importance of screening. “Together, they are the two best methods to control cervical cancer,” he asserts.

Cervarix is already registered in more than 50 countries, and Stéphenne is confident that the vaccine will become the leading brand for the lifelong protection against cervical cancer in the developed as well as the developing world. In October 2007, GSK applied for prequalification for Cervarix from the World Health Organisation (WHO) to facilitate faster delivery to developing nations. “This is because I believe that people in developing countries should have rapid access to life-saving vaccines once they are approved,” says Stéphenne.

The pipeline
With over 30 vaccines marketed worldwide, and 24 in development, there are other GSK projects worth mentioning. In addition to Cervarix, GSK also has two more products under review by the FDA: Kinrix against diphtheria, tetanus, pertussis and polio; and Rotarix, a rotavirus-induced gastroenteritis prophylaxis.

Over here, the streptococcus pneumoniae vaccine Synflorix was accepted for review by the European Medicines Agency (EMEA) in January 2008. The 10-valent vaccine, designed to protect children against both invasive pneumococcal disease (IPD) and bacterial respiratory infections, will follow Wyeth’s Prevnar, which has surpassed €1.5 billion in annual sales.

Another important product for GSK is the flu vaccine H5N1. Stéphenne expects approval within the next view months. In 2007, GSK sold it to the Swiss government and the government of Luxembourg.  In February 2008, the Finnish government announced that it had bought it, too, and GSK is in discussion with many other governments around the world.

The company is also looking into novel cancer immunotherapeutics. Last year, MAGE-A3 ASCI was shown to increase survival of lung cancer after chemotherapy by 27 percent. Currently in phase III, the programme will be a major medical breakthrough if the expected outcomes can be achieved.

In phase II is GSK’s recombinant malaria prophylaxis Mosquirix, which has been in development since 1983. It has been shown to reduce cases of severe malaria by 49 percent, and all clinical cases by 35 percent, in a group of Mozambican children treated in 2003. Further trials are needed to confirm the vaccine efficacy and safety before a file can be submitted to regulatory authorities, but the scientists at GSK are hopeful this will happen by 2011.

A successful model
GSK’s success, says Stéphenne, is down to two strategies. “First, we use new adjuvants to generate new vaccines. Two thirds of our pipeline contains an adjuvant system because we believe that science has progressed, and it’s important to use new tools to create new vaccines.

“Secondly, we have a global model, which means that we want to provide our vaccines to the world. We always say that we challenge the world of vaccines with vaccines for the world. That’s really our mission, reaching everybody no matter where they are.”

It’s not an easy task, Stéphenne adds. Amongst the challenges his industry is facing today is the increasing complexity of the market, he says; and associated with it, the growing amount of euros research-focused companies have to invest in it. “We have to invest more because of the ever increasing safety scrutiny, which means you need a large safety database. In addition, because we produce biological products, capital investments are higher. For newcomers, this makes it very, very difficult, but even for the companies that have established themselves in the vaccine industry, investment levels are daunting.”

When people think about vaccines, Stéphenne continues to say, they want them to be as cheap as possible. A modern vaccine, however, is complex. “You must have a return on investment, which means we need to convince and educate the medical community that vaccines are an investment and not a cost. We still need to do a lot of education. The population is aware of the huge impact vaccines against cervical cancer, malaria or flu can have; but we need to have the value recognized by society. That’s critical.”

Reaching the end of our interview, Stéphenne closes with his thoughts on Cervarix’ prospects. Shortly, he says, the company will publish study data after six and a half years of follow-up, aiming to demonstrate the long-term protection the vaccine offers.

He also hopes that Cervarix will show benefits over Gardasil. To this end, GSK began a head-to-head study in January 2007, with the primary objective to compare immune responses to HPV types 16 and 18 in 18-26-year-old women. Secondary objectives include evaluating the immune responses to HPV 16 and 18 in women 27-35, and 36-45 years old. The study will also compare immune responses to other cancer-causing HPV types.

“We will publish the results in the second part of 2008, and I hope we will show Cervarix’ superiority. If you induce the best immune response, you will demonstrate the best protection in the long-term. I come back to this because some people argue that it’s not important to induce a strong immune response. But after being in the industry over 33 years, I can safely say that it is critical for any vaccine that you induce the best biological activity in terms of immune response to guarantee the best quality.”

Stéphenne is confident that Cervarix will have a stronger immune response and broader protection than Gardasil. In response, officials at Merck point out that the study is limited to only immunogenicity, which cannot reveal the true efficacy in prevention of disease.

Irrespective of the study outcome, however, there is one sure victory to be gained over Gardasil: cheaper pricing. Merck’s vaccine is the most expensive on the list of recommended childhood vaccines released by the US Centers for Disease Control and Prevention. GSK, Stéphenne stresses, will give its best price – anywhere in the world. “And if tomorrow, the Global Alliance for Vaccine and Immunisation (GAVI) decides to include the HPV vaccine in its programme, the poorest countries will benefit at the lowest price,” he concludes.

Jean Stéphenne, who joined GlaxoSmithKline in 1974, is President of the Biologicals Division. Based in Rixensart, Belgium, Stéphenne has transformed GSK’s vaccine subsidiary from a small company with a 20 year-old polio vaccine and €1.9 million in revenues into a €1.9 billion giant. With 1.2 billion doses a year, GSK Bio now holds 25 percent of the world vaccines market.