"Fever Pitch: Why the US
rejected Australia's wonder-drug"
for those interested, here's an article on Biota from the weekend Australian Financial Review
By Peter Roberts
History was hanging heavy on Dr Hugh Niall's shoulders as he walked into the Holiday Inn at Gaithersburg, Maryland, on February 24 to attend a hearing organised by the United States Food and Drug Administration (FDA).
At stake was the future of the anti-influenza medication Relenza, probably the most important drug ever developed in Australia and potentially one of those rare blockbusters that change the course of medicine and reap sales of $1 billion or more a year.
The prospects for Relenza, the first pharmaceutical to be discovered locally and brought to world markets under Australian control, were good.
It had already been shown to alleviate influenza in trials in Europe and Australia, and the drug's Australian developer, Biota Holdings, and its UK-based marketing partner, Glaxo Wellcome, were about to present a third, US study to the FDA's powerful advisory committee on antiviral drugs.
But Niall, a distinguished scientist and CEO of Biota, had not banked on an aggressive young FDA statistician, Dr Michael Elashoff, who almost single-handedly demolished the US study, leading to Relenza's rejection by the committee.
Instead of elation, Niall found himself walking out of the Holiday Inn a few hours later with a sick feeling in the pit of his stomach.
"It was an absolute shock to me; an unprecedented attack," says Niall. "It was equally a shock to Glaxo. They had been warned just 30 minutes before the meeting that the statistician was going to take the tack he did."
Even as he went into an emergency conference with Glaxo Wellcome, Biota's shares, which had risen as the meeting opened, were in free-fall on the Australian Stock Exchange, plunging from $9.10 to as low as $3 before recovering to end the day at $4.35. The storm clouds that rolled across the blue sky of a cure to influenza slashed the company's value from $664 million to $320 million in less than 24 hours.
Glaxo Wellcome's reputation for guiding new drugs through the FDA was in tatters, while the FDA's bona fides in dealing with drug applications were also under question.
"The drug had such a fantastic run through the development process that we thought it would just sail right through [the FDA]," says Dr Peter Colman, one of Relenza's inventors. "At a personal level, this is very disappointing indeed."
Disappointment has been tempered by the fact that Relenza will go on sale in Australia this winter and, almost certainly, in Sweden and throughout the large European Union market by Christmas. Formulation and packaging is under way at Glaxo Wellcome's Boronia plant in eastern Melbourne.
With the FDA announcing on Wednesday that it had extended its review period for Relenza by three months, expectations are rising that the drug might be approved in the US at least for "at risk" patients such as the old or the immune-suppressed and could even be more generally available in time for the northern hemisphere winter.
With further trials or a re-presentation of Glaxo Wellcome's data, Relenza will ultimately be approved for general sale in the US, which makes up half the likely market, but the body-blow to Australia's technological ego is still being felt.
The story of how Relenza came to symbolise the hope that Australia could mix it in an age when intellectual property (IP), and not natural resources, are the key wealth creators can be traced to the growth of a group of medical research institutions around the Melbourne suburb of Parkville.
Beginning with research into the immune system by Nobel prize- winner the late Sir Macfarlane Burnet, biological sciences have become one of the few areas -- perhaps the only area -- where Australian science has the critical mass to make a broad impact internationally.
"This is really important for Australia," says Dr Geoff Brooke, the director of the Rothschild Bioscience Unit. "So many people are looking to this as an example of Australia being able to create products from scratch that can make a difference in worldwide markets."
In the past, new medicines were the result of the laborious screening for their potential health benefits of thousands of chemicals isolated from nature or synthesised in the laboratory. Relenza, by contrast, is one of the first new drugs to come of rational drug design, in which scientists design a new compound to fit into a particular site in the body or in an invading organism such as a virus.
In 1996 three scientists were honoured with the Australia Prize for their part in developing Relenza: Dr Graeme Laver, Dr Peter Colman and Professor Mark von Itzstein. Together they tackled a virus which affects millions annually and which kills more than 10,000 -- largely elderly -- people in the US alone each year. There are occasional pandemics such as in 1918, when 20 million died from a virulent form of the virus. Scientists warn that another pandemic is overdue.
Until now influenza has defied medical science because the proteins that cover its surface mutate constantly to create new variants. Once inside a human cell, influenza reproduces at a fantastic rate, with thousands of new viruses breaking out of the infected cell to spread throughout the body.
Three scientific steps were needed to defeat it.
Dr Laver, of the Australian National University, succeeded in making crystals of neuraminidase, a protein on the surface of the virus which allows it to cut its way out of the cell.
Dr Colman, of CSIRO, used X-ray crystallography to image the shape of the crystals, and after four years discovered and imaged a small pocket on the surface that did not vary in shape between different strains of the virus. This, and developing an understanding of the workings of sialic acid, the natural compound that fits into the pocket, was the world-beating step.
Finally, Professor von Itzstein of Monash University used computer modelling techniques to modify sialic acid into Relenza, a compound which lodges permanently in the pocket, inhibiting the virus's ability to break out from infected cells.
"We now had something that acted right at the cutting action of the virus," Dr Colman says. "The virus just couldn't get away from the cell. It was fantastic."
But such scientific elation has brought little monetary return to Australia in the past. One recent example of excellent science at Melbourne's Hall and Ludwig institutes led to the development of two so-called colony-stimulating factors, or CSFs, now widely used to boost the body's immune defences. The Hall didn't patent its work and the Ludwig receives modest royalties -- while billions of dollars worth of G-CSF and GM-CSF are sold annually.
Relenza, by contrast, was one of four research projects behind the $4 million float in 1985 of Biota by entrepreneur Mark Crosling. Despite raising $74 million from the public and from product licences, Australian-owned Biota does not have deep enough pockets to bankroll a new drug from discovery through the minefield of clinical trials and regulatory hurdles to reach the market. In return for a generous 6 per cent royalty on sales, Biota hung onto the ownership of the intellectual property, but signed most overseas marketing rights for the drug to Glaxo Wellcome, which has since spent an estimated $20 million to $40 million developing the drug.
While $20 million does not seem out of reach for an Australian company, there are so many failures along the path to drug development that the average cost of bringing a new drug to market is more like $200 million.
"The problem with our industry is not that it is lacking money and not that it is lacking technology," says Dr Brooke of Rothschild.
"It is lacking the competent managers who know about commercialising technology. This is the same problem in all Australia's IP-based industries."
Biota seemed to solve that problem when it attracted the experienced Niall, a former vice-president for research and discovery at US biotechnologist Genentech to be chief executive officer with carriage of the all-important relationship with Glaxo Wellcome. Forcing the pace was the emergence of a competitor drug, a second neuraminidase inhibitor developed by US start-up business Gilead Sciences and being commercialised by Swiss-based Hoffman-La Roche.
Relenza is inhaled as a fine powder into the lungs through a Ventalin-like inhaler called a DiskHaler, a method Biota and Glaxo believe delivers the drug directly to the site of infection but which critics claim is difficult to use. Gilead's drug is a tablet, normally a more acceptable form of medication to the general public, but one which is likely to have more side-effects.
Roche plans to seek approval for its drug from the FDA this month.
"It is going to be a hell of a battle," says Dr Lisa Springer, analyst for Bell Securities. "It depends on whether Glaxo gets there [to the US market] at the same time or a bit after Roche. There is going to be a first-to-market advantage."
Relenza easily passed Phase 1 clinical trials, which test a compound's toxicity, and proved its antiviral credentials in Phase 2 trials, which test effectiveness and possible side effects on volunteers deliberately infected with the disease. Glaxo decided to conduct separate Phase 3 trials, which test for effectiveness in normal clinical situations in Europe, Australia and the US.
The Australian trial tested Relenza's effectiveness if taken within 36 hours of the onset of symptoms such as aches and pains and high temperature. An increasingly confident Glaxo Wellcome decided to test for effectiveness if taken within 48 hours in the US and European trials -- a tougher test but one which would give it a clear marketing edge over Roche.
"As you pass through [from Phase 1 to Phase 3 testing], your degree of confidence goes up and the value of the product goes up," says Niall. "The failure rate is lower, but the cost of failure is higher."
Relenza showed clear, positive results in the Phase 3 trials on 598 people in Europe and Australia, reducing the duration of influenza by 1.5 days in Australia and 2.5 days in Europe. Crucially, these results were statistically significant.
"There is a theatrical component to FDA committee meetings -- they really can be high drama," says Niall. "The set-up of the meeting is deliberately adversarial. It is reminiscent of the television legal shows that are so popular, like LA Law, that sort of stuff. But then we were expecting that." What Niall was not aware of as he entered the Holiday Inn was the results of the US study of 990 people. It was news to the Australian delegation that Glaxo Wellcome's US trial showed a one-day reduction in influenza symptoms, but that the reduction was not statistically significant.
Niall became uneasy, but comforted himself with the fact that two significant trials are normally enough for the FDA to allow marketing in the US.
He also knew that the methodology and "primary end point" -- the aim, or desired effect -- of the trials that would satisfy US health authorities that Relenza worked had been decided, as is normal, in conjunction with the FDA. The trials, to be successful, would have to show a one-day reduction in the duration of influenza symptoms. Symptoms that lingered or recurred after that alleviation were ignored.
But things began to unravel for Biota and Glaxo when the FDA's Dr Elashoff rose to attack the previously agreed end point.
"The primary end point . . . did not really do justice [to testing the efficacy of Relenza] through the course of their disease," he told the committee. "[Until now] . . . there was no real data to suggest a better way of quantifying efficacy."
It is not credible that Elashoff is merely some sort of rogue statistician or that the FDA did not expect and plan his attack, as has been claimed by some observers. This was deliberate FDA strategy, with Elashoff perhaps taking the "bad cop" role in undermining the agreed end point to take the heat off the official FDA.
With the benefit of Glaxo Wellcome's work and the benefit of hindsight, Elashoff criticised the reduction in the duration of influenza symptoms in the Phase 3 trials. He argued they should have counted the number of days in a 14-day period that patients had influenza symptoms and those days on which their symptoms were alleviated.
When the data was looked at from this point of view, Elashoff admitted the drug was still effective in the Australian and European trials, but less so, but that the US trials went nowhere near proving efficacy.
"The largest treatment effect was seen in the smallest study, while the smallest treatment effect was seen in the largest study," Elashoff said. "Secondly, it was the North American study, arguably the most relevant study for us, that was the one with the smallest treatment effect."
Such a devastating and un- heralded criticism of an agreed end point is extraordinary for an FDA employee, and brings into question the FDA approach to negotiating the trialling and approval of new drugs. With millions of dollars and market access at stake, companies need to be sure that the FDA agrees with trial methodologies.
Colin Armit, Glaxo Wellcome's Australian managing director, says: "It is an internal problem within the FDA. We have a problem because of that."
Niall was another outraged that the end point was not honoured by the FDA.
"This was a statistician taking an idiosyncratic view of the design of the trials," says Niall. "I couldn't believe it. He was re-opening an issue that had been discussed with and agreed by the FDA years earlier."
But this raises the question of why Glaxo Wellcome, a global giant with a good track record for getting new drugs through the FDA, did not see Elashoff's critique coming. Several members of the antiviral committee were openly critical of Glaxo Wellcome's submission, presentation and answers to questions.
New York analyst Richard van den Broek says that if Glaxo Wellcome had proved efficacy in its US trials, the committee meeting would have been short and ended in "hugs all round".
"They just didn't show it worked in the US," says van den Broek. "It has nothing to do with home-court advantage, bad statisticians or a provincial attitude against foreigners. They just ran, through bad luck or bad design, a bad trial."
In any case, Elashoff made an even broader attack on neuraminidase inhibitors such as Relenza, suggesting that on one reading of Glaxo Wellcome's data, Relenza caused only a small difference in actual symptoms over time.
"A difference of, say, seven days versus five days [in the duration of influenza] in the European study sounds impressive, like two days less of flu," Elashoff told the committee. "But the reality, even in the best study, was one of continued gradual improvement."
Niall, sitting impotently among 300 spectators in the committee room, watched as Elashoff's criticisms were echoed by a majority of the 17 voting members of the committee. Most were not FDA staffers like Elashoff, but outside specialists in virology, public health and respiratory disease which the FDA relies on to make an independent assessment. The FDA then makes its own decision and is not bound by the committee recommendation.
"There is absolutely no doubt that this compound is an antiviral," Dr Colman says. "It doesn't treat the symptoms, it treats the cause. There were two highly statistically significant studies done which showed it does reduce symptoms. The problem is simply that trials that rely on people feeling better are likely to have their ups and downs."
While much has been made of the weight the committee put on the US trial above the significant European and Australian results, there were complicating factors which worked against the committee accepting foreign data. The US patients used twice as many medications such as pain-killers and cough syrups -- which clearly reduce symptoms -- than either Europeans or Australians.
The studies in effect support such co-medication, prompting scepticism from committee member Dr Sharilyn Stanley that Relenza was useful in the general US population in reducing influenza symptoms. She suggested Glaxo Wellcome focus on at-risk groups.
Relenza had its friends at the meeting, including Dr John Hamilton of Duke University, who commented: "I believe [Glaxo Wellcome] have demonstrated sufficient efficacy to support their application."
Questions were also raised of the FDA over the use of recurrence of, say, a headache some days after influenza appeared to have been alleviated to condemn Relenza.
Dr Henry Masur, the chief of critical-care medicine at the National Institutes of Health, said: "I am impressed at the entire package of the drug discovery program and the drug development."
But the committee came down 13 to four against Relenza. While no significant safety questions were raised, the advisory committee simply found that Glaxo Wellcome had not shown the drug to be effective for the treatment of influenza.
Four of the committee members noted that they voted against Relenza reluctantly.
"I was reluctant in voting no," said Dr Brian Wong of Virginia-Connecticut Health Care Systems. "I believe that the data we saw . . . shows that it is a very promising antiviral, and I think that just a little bit more prospective analysis . . . will nail the case."
Glaxo Wellcome is in intense negotiation with the FDA and now has up to three months extra to argue its case. The FDA could do anything between approving the drug for sale in the US or rejecting it outright.
It could, for example, deem Relenza approvable pending the presentation of evidence in a new form or the conduct of new trials. Evidence gathered in the real-life use of Relenza in Australia this winter could be crucial.
Some independent observers are not concerned at the rejection as there is general agreement that it is only a matter of time before Relenza will be approved in the US.
"This is happenning all the time," says Rothschild's Brooke. "It is not such a big deal to get knocked back the first time round."
But meanwhile, Biota's value has been slashed, with the company's shares trading around $5. Burdett Buckeridge Young analyst Michael Carmody values the company at $5.70 based on the value of European and Australian sales and a likely delay -- until 2002 in his worst-case scenario -- in Relenza's entrance onto the US market.
"The market is a little gun-shy of biotechnology stocks at the moment," says Carmody. "They have been reminded that there are risks involved in R&D. Even at Phase 3, there are still risks."
Carmody estimates Biota's revenues from Relenza will peak at $60 million in 2007-8. Biota's value is also boosted by other new products in the drug development pipeline and by its development of a rapid test kit for influenza designed to be used by general practitioners in their surgeries.
"This is not the end of the story, nor is it true to say that in some way Australian science is lacking," says Glaxo Wellcome's Armit. "It has nothing to do with the quality of Australian science. It has got everything to do with a regulatory process and how an agency manages itself."
With Joanne Gray, Washington.
afr.com.au |
