CSL plots its future course with R&D

To no one's surprise, CSL has become the dominant force in the Australian biotechnology sector. Graeme O'Neill learns from CSL's chief scientist, Andrew Cuthbertson, about the solid research that will drive the company in the next few years.

Only 20 years ago, the idea of a vaccine that would be 100 per cent effective in preventing a common and potentially deadly cancer, might have been considered science fiction.

It took 15 years, but it's now science fact. Last December, Australian biotechnology company CSL (ASX:CSL) and its big pharma partner Merck announced that phase III trials data of their new Gardasil recombinant vaccine against human papilloma virus (HPV) had confirmed it is 100 cent effective in protecting females against the two major HPV strains that trigger cervical cancer, plus the two that cause genital warts.

CSL's scientific officer, Dr Andrew Cuthbertson, said CSL was "thrilled" with the trial data. "Vaccines are usually between 70 and 80 per cent effective. Merck's data show that Gardasil is 100 per cent effective in preventing early, pre-cancerous lesions caused by HPV16 and HPV18, which account for more than 70 per cent of cervical cancers," he said.

The recombinant vaccine comprises recombinant L1 proteins from four HPV strains: 18, 16, 6 and 11. The latter two are responsible for causing genital warts and can trigger abnormal PAP screening results.

Cuthbertson said the main pathogenic serotypes of the virus provide little cross-protection against each other, but collectively, they provide "remarkably robust" protection against genital warts and pre-cancerous lesions.

The vaccine is designed for prophylactic use, and not for treating established HPV infections. It is not yet clear whether a booster dose will be required some years after the primary course of three vaccinations. Cuthbertson said Merck's published immunogenicity and histology data for 16 to 25-year old women, which now extends over four years, is "very strong".

Merck has also published data from girls in the 9 to 15 age range, but it is limited to immunogenicity data, because of the problems associated with conducting invasive gynaecological examinations on young girls. But Cuthbertson said immune responses in younger women appear even more robust than in the older group.

"Immunocompetence typically declines from age 18, and Merck is now doing studies in mature women and men. But given the 100 per cent protection rate so far, and the antibody titres being reported, people in the field are confident the data will support a very strong public health benefit."

Validation

Cuthbertson said the vaccine was the culmination of 15 years' work that began in the early 1990s with a close collaboration between CSL and Prof Ian Frazer, of the University of Queensland. Frazer was named Australian of the Year on Australia Day, in recognition of his achievement and its potential contribution to public health.

After CSL and Frazer established a strong IP position, CSL partnered with Merck a decade ago. "Merck has done a fabulous job of driving a very large product and clinical development program, involving 25,000 subjects, culminating in publication of the phase III trial data late last year.

"We have had a very good experience with this high-quality collaboration between CSL and an Australian research group, and this exemplifies how long it takes," he said. "It validates our faith that we can do international standard biotechnology research in Australia."

Merck has applied to register the new vaccine in Europe, the US and Australia. CSL will market the vaccine in Australia.

Suggestions that the vaccine might be given to girls as young as nine have political puritans in Australia and the US reaching for their flintlocks, claiming the vaccine will encourage promiscuity. "The debate is about to begin," said Cuthbertson, but to deliver maximum benefit, he said the vaccine should be widely given to girls in their adolescent years, and he predicts many will express a great desire to ensure the vaccine is publicly funded, and nationally available.

He predicts that when the vaccine is widely available, it will have a "tremendously positive public health impact, particularly on women's health, and protection against cervical cancer".

CSL has not yet established a price for the three-dose vaccine.

"This is a state-of-the-art biotech vaccine, and a highly effective vaccine that prevents cancer," Cuthbertson said. "It has taken a huge R&D investment to bring it to this stage, and it's not unreasonable that the companies involved in its development would want to get a commercial benefit from its investment.

"But there's also a great desire to see it widely used. I'm sure the desire will be to price it to provide benefit to the investing companies, but to ensure pricing doesn't inhibit its widespread use."

But the vaccine's greatest benefit will be in developing nations, which account for about 80 per cent of the estimated 470,000 new cases of cervical cancer around the world.

Bird flu vaccine

CSL is also developing a vaccine to protect against a possible pandemic of H5N1 influenza -- the so-called 'bird flu'.

"We're the only influenza vaccine manufacturer in the southern hemisphere, and we've upgraded, modernised and expanded our facilities," Cuthbertson said. "We have an obvious responsibility to explore the development of a vaccine that could be protective in the event of a global pandemic.

"We're actually conducting a study to ask a basic medical research question: what do you have to do to stimulate the human immune system to generate a protective immune response against a bird virus?"

The fact that H5N1 is a bird virus means that all humans are immunologically naive to the new virus, and Cuthbertson said a concern is that this bird viruses may elicit a relatively weak response from the human immune system.

"We're asking: 'What is the dose of antigen we need to give in an H5N1 flu vaccine to get a protective human immune response?'. We're conducting human trials at two sites -- one in Adelaide, the other in Melbourne -- testing doses of 7.5 and 15 micrograms of antigen, delivered as one or two doses.

"And we're asking whether we need to add a traditional aluminium-based adjuvant to the formulation to boost the immune response."

Conventional influenza vaccines have been formulated without an adjuvant, and elicit only antibody-mediated immunity. Sanofi-Aventis has already reported "intriguing" early-stage data from its own influenza vaccine trials, suggesting that as much as 30mg of antigen, delivered in two doses, produces adequate protection against H5N1. "Assuming that's true, and we still need to see the data, it's very positive, because it means it's possible to make a vaccine against the bird 'flu. But the dosage is rather high," Cuthbertson said.

Among the world's major flu vaccine manufacturers, GlaxoSmithKline and Chiron are trialling vaccines, but have yet to release H5N1 dosage and immunogenicity data. CSL was next to report, but Cuthbertson said CSL will not know what dose of its own vaccine will be required to generate protective immunity until the data are available.

"The vaccine has to generate an appropriate immune response at the lowest dose possible, because the world's antigen production capacity is very constrained," he said. "If we require twice the standard dose, it will take us twice as long to produce adequate supplies of the vaccine. In a crisis, the dosage question becomes absolutely critical."

CSL has been in close discussions with Australia's chief medical officer, Dr John Horvath, and with other federal and state officials, on the H5N1 vaccine issue.

"We may have a candidate vaccine in the formulations we are testing, and if it is producing the right type of immune response, and is approved by the TGA, we would roll forward and test it in younger and older people, and file for registration of the first prototype pandemic vaccine later this year," Cuthbertson said. "But if we don't get an adequate immune response, we'll have no choice but to test higher doses in the clinic."

The most likely outcome, he said, is that some, but not all subjects involved in the trial will respond. "We'll then have discussions with advisers, our regulatory agency and the World Health Organisation to try to determine the best way forward.

"One question being debated is whether we should establish a stockpile of vaccine in Australia, like the US and UK are doing, or some would say we should go forward and vaccinate on the understanding that it will benefit the population, by converting them from being immunologically naive to having an immunological memory."

Iscomatrix

In the longer term, CSL is considering adding its proprietary Iscomatrix adjuvant to an H5N1 flu vaccine because the adjuvant has exhibited a substantial dose-sparing effect in animal studies. This has also been suggested in preliminary human trials.

In a pandemic, Iscomatrix could potentially extend supplies of the available antigen, protecting the Australian population and perhaps those of regional neighbours. But Cuthbertson said it could take several years to confirm the immunogenicity of a low-dose, Iscomatrix-boosted vaccine.

"The federal government has announced it has budgeted $16 million to create a vaccine stockpile, but it's not yet clear how and when it should be spent," he said.

One obstacle to developing an H5N1 vaccine has been that the wild-type virus kills the embryonated chicken eggs in which vaccine strains traditionally cultured. Overseas researchers have also found that antigen yields from the H5N1 virus are around 50 per cent lower than for non-pandemic strains.

Cuthbertson said CSL is working with an isolate from a Vietnamese patient that was imported into Australia after molecular geneticists in the UK rendered it safe, by removing sequences involved in pathogenicity. "We've made a manufacturing seed in our high-containment facility that grows well in embryonated eggs," he said.

CSL is using its tried and tested manufacturing protocols. "Over the years, we've acquired great experience manufacturing flu viruses in eggs. In our initial clinical studies we are also testing a well-tried adjuvant, aluminium phosphate.

"We take a strong view that, in a crisis, you don't want to be trying out new and interesting techniques." Cuthbertson said that, after creating a seed strain, the company could move into manufacture within six weeks. Assuming the 15 microgram antigen dose is optimal, and two doses are required for full protection, it could make up to 350,000 doses a day after reaching maximum production.

However, if the dose required is larger, and the manufacturing yields are lower than usual, production of large numbers of doses of vaccine will obviously take longer.

But the newly 'tamed' H5N1 virus strain may not be the one that eventually causes a pandemic -- it could turn out to be an H7 or H9 strain, necessitating an urgent switch in the manufacturing process.

"Logically, we should be working on the most likely pandemic strain, but we can't predict which one it will be," Cuthbertson said. "The only rational thing to do is what we're doing now -- prepare a prototype vaccine that provides the best chance of protection against the most likely threat.

"The way regulatory agencies are treating it, we will submit a dossier on a prototype pandemic vaccine to the TGA, and they have agreed that if the product is approved, and a different pandemic strain emerges, we would be able to more rapidly move forward with the new strain, so we're not starting from scratch."

Prototype

There are two reasons for applying the Iscomatrix adjuvant technology to making a better pandemic flu vaccine. Cuthbertson said the fact that the Iscomatrix adjuvant can generate cellular immune responses to influenza antigens raises the possibility of developing a vaccine that might offer cross-protection against different strains, instead of the traditional process of having to match the antigen sets in new vaccines to extant strains of the virus. Second, there is the dose-sparing effect on the amount of antigen needed.

"The higher the antigen dose required, the more compelling becomes the public health case for adjuvanting with Iscomatrix technology," he said. "One way or the other, we've got to develop a prototype vaccine. We're genuine leaders in this field -- CSL is among the three or four companies in the world doing this kind of work.

"We have the capability to develop a vaccine ourselves, but we would not be consumed by hubris if someone else had something we genuinely needed."

He said an adjuvanted influenza vaccine might provide an additional benefit. Every influenza season, the elderly are advised to have a protective vaccination, yet it is the elderly who are least likely to respond to vaccination because the immune response diminishes with age.

Cuthbertson believes an Iscomatrix-adjuvanted vaccine, by generating a stronger immune response, might also better protect the elderly, but said it is a complex issue, requiring research.

On the seemingly imminent threat of a pandemic, he said, "These things [pandemics] tend to happen every 30 years or so, based on historic data, but nobody can say whether it will happen today or in three to five years' time.

"But I would be much more comfortable about the ability of the world to respond if we had a prototype vaccine, we knew the dosage, the number of doses required, and we had a powerful adjuvant.

"We are having some very important assays done in a specialised laboratory in the UK. They're complex, but they have to be done properly, however long it takes."

New opportunities

Cuthbertson said CSL currently employs around 270 scientists round Melbourne, including a core group that is focused on longer-term, high-risk, high-reward projects. "We currently spend around $100 million a year on near-term, low-risk research activities in the longer term, and around $50 million on longer-term, high-risk biotech activity. We have the capacity to increase our spend assuming we find valuable new opportunities," he said.

"We're not withdrawing investment from short-to-medium term research, but we're trying to push more into recombinant antibody and other biotech areas, to develop higher-margin, breakthrough products in the future."