By Randall Osborne

Editor

Stephen King, in his 1991 novel "Needful Things," renders excruciatingly well the struggle of protagonist Polly, as she endures the advance of rheumatoid arthritis (RA).

Polly, in bed, turns to hang up the phone.

"A monstrous bolt of pain broke through the thin web the painkiller had stretched over her nerves and raced all the way up to her shoulder," he writes. "She had to bite down on her lips to stifle a cry . . . The pain was fully awake again, awake and raving, turning her hands especially the one she had bumped into fever-pits. She lay on her bed, looking up at the ceiling through her blurry eyes, and wept.

"Oh, I would give anything to be free of this, she thought. I would give anything, anything, anything at all."

As King would have it, Polly goes on to make a pact with a dark figure named Mr. Gaunt who provides her with a pain-erasing necklace, in return for which she must surrender her soul, and the reader finds himself well outside the bounds of medical writing.

But it's appropriate that the suffering of RA would be so keenly described by a writer of horror stories. For as many as 2.5 million people in the U.S. with rheumatoid arthritis, the condition is making a true tale of horrific woe. "Joint pain," for them, has nothing to do with marijuana for use as therapy.

Many instead have found relief with Immunex Corp.'s Enbrel (etanercept), a clear leader in the RA market, and Remicade (infliximab), from Centocor Inc., both of which work by inhibiting tumor necrosis factor, Remicade having been approved about a year after Enbrel.

Both are biologics that represent an advance beyond corticosteroids by neutralizing the TNF cytokine, with fewer side effects than other forms of treatment and with benefits that last longer.

Nobody knows what causes RA, which may come about through some devilish combination of environmental and genetic factors, along with a viral infection. Known as an immune system disorder, it comes in two forms: the more rare Type 1, which lasts less than a few months and brings no disability; and the frightful Type 2, which hangs on for years, or for life.

The synovium, which surrounds joints with a protective cushion, or sac, is continuously inflamed, steadily wrecking the collagen in cartilage, damaging the bones. Even worse, RA can spread to the rest of the body, harming other organs.

It's a disease against which just about everything has been tried, from aspirin to gold salts to remedies with daunting acronyms such as non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). On this field of battle, Enbrel and Remicade seem like weapons almost as magical as Polly's necklace.

That's the good news. The bad news is, they're expensive not the cost of a soul but still a punishing amount, especially if insurance fails to chip in. A key drawback: Both treatments are injected, which means a mode of administration that is inconvenient and uncomfortable. If there's one thing RA patients don't want, it's more pain.

"For any patient, a pill is preferable to a needle," said Michael Partridge, associate director of corporate communications for Vertex Pharmaceuticals Inc., and RA patients ideally are treated in the earlier stage of the disease, when they are more likely to be as squeamish about punctures as anyone else.

Now, at least two firms have significantly advanced oral TNF inhibitors, which they say are engineered to be more specific, hence more effective, and easier to take: Vertex, which began a Phase II trial of its compound, VX-745, in January; and Scios Inc., which in April offered favorable data from a Phase Ib trial, and said it plans to begin a Phase II study shortly.

Vertex is "leading the field," Partridge told BioWorld Financial Watch, adding that Scios "likes to talk a lot about its program," and others are working quietly in the same space.

"It's very competitive, and it's not limited to those companies," he said. "The target is of high interest, and has been for a long time. Other companies are not being vocal about it, but it may be a reflection of their desire for secrecy."

John Sonnier, an analyst with Prudential Securities, said "there are a number of people, big pharma and in biotech, that are pursuing TNF inhibition through alternative routes, but it remains to be determined how large the ultimate market for TNF inhibitors can be. It's implicated as a bad actor in a number of diseases."

Vertex made headlines a year ago with its potential $800 million pre-market deal with Novartis Pharma AG. The research program is focused on using the chemogenomics approach devised by Vertex to discover eight small-molecule drugs, or kinase inhibitors, which Novartis would then develop and market. Excluded from the collaboration is VX-745, an inhibitor of the p38 kinase.

Partridge said the companies are "principally going after all kinases, but a handful are excluded," namely those on which either Vertex or Novartis "had made substantial progress previously."

The p38 kinase is a stimulatory modulator of pro-inflammatory factors that include TNF-alpha as well as interleukin-1 and cyclooxygenase-2, all implicated in RA.

Scios was in the news more recently, having won an FDA panel's blessing for Natrecor (nasiritide) to treat acute congestive heart failure. After a somewhat difficult history, Scios is hot, and shortly after the committee's recommendation of approval for Natrecor, the company said it plans to raise about $115.8 million through a shelf registration filed in January. The Scios compound, SCIO-469, also targets the p38 kinase.

"It's a program that has moved very fast," Sonnier told BioWorld Financial Watch. "The compound was discovered in house, and they moved into the clinic, I believe, earlier this year."

Partridge noted that others with oral p38 kinase inhibitors in development include GlaxoSmithKline plc and Johnson & Johnson, both with drugs in Phase I trials.

"SmithKline Beecham was the first to discover the target, in the early 1990s, and that spurred a lot of interest in it," he said.

Another player in the oral RA drug arena is DuPont Pharmaceuticals Inc., which has begun Phase II trials with a TNF-alpha converting enzyme inhibitor, or TACE a protease, as opposed to a kinase, Partridge noted.

"At a molecular level, they couldn't be more different," he said. "It's difficult to know how to judge [the quality of] these targets, but a number of people have gone after TACE as well. My perspective, which is limited, is that there are more companies going after p38."

At the end of King's novel, Polly forsakes Mr. Gaunt and throws away the necklace, taking back her agony. The strictly science-minded, who find this fictional story hard to swallow, are holding out hope that RA patients will find a new therapeutic pill easier to get down and that those patients' stories will reach happier, pain-free endings.

And everybody else involved will make a lot of money. Enbrel sales last year totaled $652.4 million, and developers of oral RA drugs are eager to get at least a slice of that. It looks possible, Partridge said.

"Enbrel and Remicade have not only proven that inhibiting TNF-alpha can exert a powerful therapeutic effect but, more importantly, physicians are clearly comfortable with the idea of anti-cytokine approaches," he said.

Added Sonnier: "It'll be interesting to see where they ultimately go. [RA] is obviously the natural first step, but there could be a number of indications."

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