West Coast Editor
Neurogen Corp.'s buyout of rights to Phase II-ready aplindore from Wyeth Pharmaceuticals Inc. gives the firm a potential foot in the door to the growing market for D2 dopamine receptor agonists against Parkinson's disease and restless leg syndrome - even if Wall Street wasn't jumping up and down about the deal.
Shares of Neurogen (NASDAQ:NRGN) closed Tuesday at $5.16, down 13 cents, as investors may have taken a wait-and-see approach to aplindore, which didn't work out for Madison, N.J.-based Wyeth against schizophrenia because of the high doses needed. Neurogen agreed to provide $3 million up front plus "very much back-end loaded" milestone payments for the compound, said Stephen Davis, chief operating officer for the Branford, Conn.-based firm.
Stephen Uden, Neurogen's head of research and development, said the company expects to test dosing "five- to 10-fold lower than those used in previous trials," which should improve the side effect profile while keeping efficacy.
"Our expectation is to use controlled release, which will also hopefully smooth out the activity of this compound and help us reach appropriate doses quickly, but at the same time, sustain those levels," he said, allowing that "inevitably, if you push the doses hard enough, you're going to start to see dopamine-type side effects," such as nausea and hypertension.
Wyeth developed the controlled-release form after noticing that food blunted the side effects, but decided not to go ahead with a Parkinson's program because the market wasn't big enough.
As a partial agonist of the D2 dopamine receptor, aplindore could have an edge over marketed, full-agonist therapies (which need a much longer titration period - seven weeks for Parkinson's, four weeks for RLS), such as GlaxoSmithKline plc's Requip (ropinirole).
Sales of Requip have jumped more than 70 percent over last year, as of September. Another, similar drug in the game is Boehringer Ingelheim GmbH's Mirapex (pramiprexole), which sold $575 million last year.
Phase I and Phase II trials with aplindore by Wyeth have shown that, even in low amounts, the drug achieved what Neurogen called "excellent" brain receptor occupancy and pharmacologic activity, and thus could prove worthy in Parkinson's and ALS, said William Koster, president and CEO of Neurogen, during a conference call.
"In the 1990s, I was involved in aripiprazole, and clearly there was a great deal of interest in partial [dopamine] agonism at that time," he said. 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.
When Neurogen starts aplindore trials late next year, the firm will have three programs in Phase II, including NG2-73 for insomnia and MK-2295 for postoperative pain.
NG2-73, designed to selectively modulate receptors of the gamma-aminobutyric acid neurotransmitter system, started a Phase II trial in chronic insomnia patients at the end of October, with the aim of measuring a reduction in time to onset of persistent sleep and sleep maintenance across a range of doses and formulations during two weeks of treatment. The study is expected to enroll up to 240 patients. In May, Neurogen said top-line results from a 369-patient Phase II trial in transient insomnia showed the drug significantly reduced time to onset of persistent sleep vs. placebo at all doses tested.
Earlier this month, Neurogen's partner with MK-2295, Whitehouse Station, N.J.-based Merck & Co. Inc. started a Phase II proof-of-concept trial in postoperative dental pain, triggering a $3 million milestone payment to Neurogen.
MK-2295 is part of the companies' vanilloid receptor-1 alliance signed in 2003, which gave Neurogen a $15 million license fee, $15 million in equity and $12 million in research funding during the first two years, as well as up to $118 million in milestone payments for one therapeutic indication. (See BioWorld Today, Dec. 2, 2003.)
Davis said partnering of aplindore will depend on clinical data, and will be different for each indication.
"RLS is primarily a primary care physician type of market, and we would likely look for a marketing partner," he said. Parkinson's, on the other hand, is split, with about half the prescriptions written by primary-care doctors and half by neurologists, which means "an opportunity for us to build a commercial sales force ourselves" for the specialty-care half, Davis said.