Parkinson's disease and restless leg syndrome (RLS) made news in two very different ways last week, as the Italian firm Newron Pharmaceuticals SpA started its second Phase III study with safinamide - just as the firm kicked off an initial public offering in Switzerland to raise as much as CHF349 million (US$289 million) - and Neurogen Corp. bought rights to Phase II-ready aplindore from Wyeth Pharmaceuticals Inc. for $3 million up front.

Big money, small money. IPO, conventional deal. Dopamine uptake inhibitor (safinamide), partial dopamine D2 receptor agonist (aplindore).

"Newron's compound is very different from ours," Thomas Pitler, vice president of business development for Neurogen, told BioWorld Financial Watch, adding that the drug is "mainly classified as a monoamine oxidase-B inhibitor," though Newron pointed out that safinamide works without an affect on MAO-A, and provides sodium channel blocking activity and calcium channel modulation.

Before Neurogen took aplindore, Wyeth tried the compound against schizophrenia but found the necessary doses too high. Even though the compound only partially hits the D2 receptor, raising the dose risks the odious side effects of a full agonist, such as nausea and hypertension.

But the pharma company noted good levels of brain receptor occupancy at lower doses, and due-diligence research by Neurogen discovered benefit against Parkinson's disease in mammalian models when used as a stand-alone therapy or when given with levodopa, a common approach with late-stage patients.

Stephen Davis, chief operating officer for Neurogen, called the discovery important, since it "suggested we may have the full Parkinson's commercial opportunity available" and provided insight that "other interested parties would not have had."

That commercial opportunity is growing, with about 1.5 million people living with Parkinson's and 60,000 new cases diagnosed each year. Typically, the disease develops after age 65 (only 15 percent of those diagnosed are younger than 50) and so, as baby boomers live longer, the market will expand.

Neurogen plans to try doses of controlled-release aplindore (as developed by Wyeth) fivefold to 10-fold lower than those used in other trials. The aim is to improve on such full-agonist therapies as GlaxoSmithKline plc's Requip (ropinirole), which is doing well despite its long titration period: seven weeks for Parkinson's, and four weeks for RLS, a dopaminergic deficiency that is less understood than Parkinson's.

"Parkinson's is truly a neurodegenerative disease," said William Koster, president and CEO of Neurogen. "It's not clear what exactly is going on with regard to RLS."

Requip sales rose more than 70 percent last year, as of September. Another marketed Parkinson's/RLS drug is Boehringer Ingelheim GmbH's Mirapex (pramiprexole), which sold $575 million last year.

Koster was involved in the development of aripiprazole, a compound that generated much buzz about partial dopamine agonism. Bristol-Myers Squibb Co. markets aripiprazole - a dopamine D2 receptor with partial agonist activity at serotonin 5HT1A receptors, and antagonist activity at 5HT2A receptors - as Abilify for schizophrenia and bipolar disorder.

Newron tested safinamide in early and later-stage Parkinson's. "It could certainly be used in conjunction with a compound like ours," Pitler said, adding that dopamine agonists steadily are becoming the first-line treatment of choice.

An approved drug that may hold added promise, Pitler said, is Teva Pharmaceutical Industries Ltd.'s Azilect (rasagiline), which inhibits MAO-B, but may or may not affect MAO-A. An ongoing trial with the compound, partnered with H. Lundbeck A/S is testing whether Azilect slows disease progression.

"Even dopamine agonists may [do that], but it hasn't been shown," he said, noting that most Parkinson's patients stay on dopamine agonists throughout their disease. "You keep adding on more and more compounds. The pill burden for these patients is phenomenal."

Also making news last week in the Parkinson's arena was Antipodean Pharmaceuticals Inc., which completed enrollment in a Phase II study to evaluate MitoQ (mitoquinone).

The trial is designed to randomize 128 patients into one of three treatment arms to compare MitoQ, administered at 40 mg or 80 mg once daily, to placebo, with the primary endpoint of disease progression according to the Unified Parkinson's Disease Rating Scale.

Thomson Scientific, in a report published this summer, called MitoQ one of the five most promising drugs to enter Phase II. The drug blocks mitochondrial oxidative damage, one of the key underlying mechanisms of Parkinson's, Thomson noted, and Antipodean is exploring MitoQ's potential for treating retinal degeneration, Alzheimer's disease, Friedreich's ataxia (a progressive disorder of the nervous system and muscles) and cardiac ischemia.

Pitler said it's too early to tell how much Neurogen might be able to improve the titration period with aplindore over existing therapies. "Wyeth has done a fair amount of work, pushing the titration pretty hard," he said. "But anti-psychotics are not typically titrated."

Davis said most therapies in the works have been proved to offer only symptomatic relief, and aplindore finds itself in the same boat - but if the quality of life can be improved by cutting back side effects, that would be considered an advance, in Parkinson's and RLS, which is sometimes underplayed.

Another firm with efforts under way in the RLS space is XenoPort Inc., which has XP13512 in Phase III trials. XenoPort's technology deploys transporter proteins as molecular "targets," and uses medicinal chemistry techniques to transform drugs into substrates for the transporters. XP13512 is described as a Transported Prodrug of gabapentin, a generic compound primarily used to treat neuropathic pain.

Having RLS - a disorder characterized by an urge to move one's legs, often accompanied by sensations of burning, creeping, tugging or tingling - is bad enough, Davis said; to endure the problems that come as a result of trying to treat the condition worsens the whole picture, as researchers find in their contacts with the afflicted.

"You really develop an appreciation that this is a debilitating disorder in severe patients," he said.