Interview: the antisense evangelist

Persistence has paid off for Stanley Crooke and his company Isis Pharmaceuticals.

After nearly 10 years of pioneering work in the field of antisense technology, the company finally put the world's first antisense drug - Vitravene for CMV retinitis - on the market in 1998, and currently has 13 drugs in development, including two in Phase III trials and seven in Phase II trials.

But Crooke will be the first to tell you that Isis has never been a Wall Street favourite. Over the years the company has raised a whopping $US1.2 billion from the equity market, corporate partners and the government. But, Crooke said, "we have yet to return meaningful value to our shareholders."

However, according to Crooke, Phase III trial results with Isis' Affinitac compound for the treatment of non-small cell lung cancer could be significant enough to create a resurgence in the global biotech industry later this year. $1 billion R&D spend

Over the last 13 years, Isis has spent $US1 billion on R&D. Antisense technology has been through its ups and downs as a potential therapeutic, but Crooke has always believed in its merits. Essentially, the technology relies upon using a small RNA oligonucleotide to bind to a specific mRNA target. This inhibits production of the protein product either by disabling the mRNA or by recruiting RNAse enzymes to degrade the resulting double-stranded RNA complex.

"We can make an antisense inhibitor to any gene," said Crooke. By contrast, he explained, most proteins were not druggable. "It is the epitome of rational drug design."

An important aspect from a drug development point of view is that the antisense drugs are all essentially the same, no matter what the target. They have the same pharmacogenetic properties and the same mode of action.

Isis is in the position now where it has overcome many of the chemistry issues with antisense compounds with its second generation products. Key stability issues have been resolved with once-a-month dosing now possible, rather than every other day.

Antisense drugs can all be delivered in a variety of ways, including intravenously, subcutaneously, intradermally, intramuscularly, via aerosols, and topically. Crooke said the company is also making great progress in developing an orally available form, something he thought they would never achieve.

"This offers tremendous benefits at the development level. In traditional drugs, you lose 75 per cent before efficacy can be shown," he said.

In the long process of developing the new chemistry platform technology of antisense drugs, Isis has corned the market on antisense patents, and will be issued its 1000th patent soon, according to Crooke. Business magazine Inc recently named Isis the most innovative small company in the US.

Isis has had plenty of partnerships and collaborations in its lifetime, but has never given away its core technology, always keeping tight control of its patents, said Crooke. A lot of the partnerships have been discontinued over the years, as pharmaceutical company directions have changed. "Many companies paid for development, then gave the drug back. Isis either continued development itself, or sold them on to another company.

"Every single partnership achieved its goal. Despite the fact that we achieved all our goals, our partners did not take advantage of it," said Crooke.

Aussie connection One of Isis' current partners is Melbourne start-up Antisense Therapeutics (ATL), part of the Circadian group. It's an unusual teaming, in that most of Isis' partnerships to date have been with large pharmaceutical companies.

"The relationship with Antisense Therapeutics is part of a real strategy. It begins with a platform that can generate 50-100 drugs very easily. Our strategy is to get as many drugs out there as possible," Crooke said. Isis will provide ATL with five compounds based on targets selected by ATL and ATL will conduct pre-clinical and clinical trials with these compounds. The failure rate in pre-clinical and Phase I and II trials is lower than with traditional and small molecule drugs because antisense drugs all have the same properties with the same basic chemistry.

Crooke said that the partnership with ATL gave the small company an opportunity to access the Isis pipeline, with a drug for multiple sclerosis that Isis had not developed. A key factor in the partnership was ATL's relationship with the Murdoch Children's Research Institute.

Isis provides exclusive access to their technical expertise as well as manufacturing capabilities, and in return owns 14 per cent of ATL, Crooke said.

"This is not something we do every day. So far we are pleased with how it is progressing," said Crooke. "There's a challenge ahead in raising capital, but we're encouraged that raising money should be possible."

Additional reporting by Mark Pachacz

Dealing with the downturn

At an investor briefing in Sydney after the AusBiotech conference, Crooke offered his views on the pharma and biotech sectors in the US.

"This is the worst environment I've ever seen for the pharmaceutical sector," he said. "The FDA is in a shambles. Mergers are reducing productivity. The immediate and direct impact is that money is tighter, and there's a desperation to license Phase II and Phase III drugs.

"In biotech, it looks like we've hit bottom. Our stock is better than some, but it should have been a lot better because we've put out nothing but good news this year."

Meanwhile, he said, big biotechs like Millennium Pharmaceuticals were burning $US400m a year: "and I don't think that's sustainable.

"On the other hand, this is the first downturn I've seen where no one is questioning whether biotech will exist... hopefully we won't go through the same period of insane valuations we had with genomics."

-- Iain Scott