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Psyadon Initiates Phase III in Lesch-Nyhan Disorder

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By Marie Powers
Staff Writer

Small biotech Psyadon Pharmaceuticals made a big clinical move by initiating a Phase III study of ecopipam – its only asset – for the treatment of self-injurious behaviors in the ultra-rare orphan disease Lesch-Nyhan disorder.

The global study will investigate whether the drug, which has demonstrated efficacy in Tourette syndrome, can control the devastating symptoms of Lesch-Nyhan, which often prompts children to be restrained so they don't harm themselves.

Advancing ecopipam into a pivotal study was a victory of sorts for Richard Chipkin, the Germantown, Md.-based company's president and CEO, who has seen the asset progress through nearly 20 years of clinical development. Chipkin founded Psyadon in 2008 around the license for ecopipam, a selective antagonist of the D1 dopamine receptor, but his history with the drug dates back much farther.

Chipkin was a research scientist at Schering-Plough Corp. when he first identified and oversaw clinical development of ecopipam, initially in schizophrenia. The drug failed in that indication, and Chipkin moved to Schering-Plough's business development group and later to the biotech industry, where he landed at start-up Psychiatric Genomics and, later, at Ruxton Pharmaceuticals Inc.

He kept tabs on ecopipam, however, through friends at Schering. In 2008, Chipkin learned the compound was available for licensing after Schering decided not to advance it in a second indication, obesity, due to psychiatric side effects. Although the drug was never sent to a regulatory authority for comment, never reviewed and never submitted in a new drug application (NDA), "if you look at the side effects of the newer [obesity] drugs, ecopipam actually looks pretty good," Chipkin said.

Ecopipam came with a wealth of preclinical findings and a safety database of more than 2,000 patients treated in clinical studies – a boon for a potential orphan drug. In addition, the first-in-class molecule had a differentiated approach by selectively blocking dopamine only at the D1 receptor, in contrast to more common D2 receptor antagonists.

Based on his knowledge of the compound, Chipkin began searching for an appropriate central nervous system (CNS) indication to test the drug. A Phase I dose-ranging study in Lesch-Nyhan, a rare genetic disorder characterized by a mutation in a single gene, was launched within two years.

The syndrome is characterized by high uric acid levels, causing gout-like swelling in joints and other metabolic consequences in mostly male patients. If detected early, the metabolic symptoms can be treated and kidney failure averted, Chipkin explained. Although many patients now survive for decades, they continue to suffer from horrifying CNS effects.

"These are two independent events, probably from the same mutation," Chipkin told BioWorld Today. "There is a dysfunction in dopamine systems in the brains of these patients leading to motor problems," including dystonia and self-injurious behavior, in which patients have been known to bite off their own fingertips, lips and tongues. Many are restrained in wheelchairs and forced to wear mouth guards for their own protection.

"We don't pretend that we're going to cure the disease," Chipkin said. "We are treating the symptoms."

The multicenter, double-blind, randomized, three-way crossover Phase III is the largest and most rigorously controlled intervention ever attempted in the disorder. The trial is designed to assess the efficacy and safety of ecopipam in pediatric patients with moderate to severe self-injurious behaviors. Patients will take ecopipam (50 mg/day or 100 mg/day, based on body weight) or placebo once daily over an 18-week treatment period with self-injurious behavior frequency and severity rated using the Behavior Problems Inventory.

The trial plans to enroll 20 patients across two centers in the U.S., multiple centers in Europe and a possible site in South America. Pediatrician William Nyhan, who discovered the disorder, is serving as the clinical investigator at the University of California at San Diego site.

Tourette Syndrome a Second Indication

Because ecopipam's previous safety data were collected from adult patients, Psyadon tested the Phase III doses in an open-label study in a small subset of Lesch-Nyhan patients, confirming the compound was well tolerated with no unexpected side effects. The company shared those data with the FDA in an end-of-Phase II meeting, and the agency provided guidance in the Phase III design. Ecopipam has orphan drug designation from the FDA and the European Medicines Agency (EMA) in the disorder.

The trial is expected to complete enrollment and dosing by year-end, with top-line data expected in the second quarter of 2014.

Chipkin has high hopes for the study, since the company last year halted a Phase II trial of ecopipam in Tourette syndrome early when a planned interim analysis showed a highly statistically significant reduction in the severity of tic symptoms. That decision was supported by the independent drug safety and monitoring committee and the research committee formed through Psyadon's partnership with the Tourette Syndrome Association, which provided some funding for the study. The open-label, nonrandomized trial evaluated ecopipam over an eight-week period at 50 mg per day for two weeks and 100 mg per day for the remaining six weeks, with change in Yale Global Tic Severity Score as its primary efficacy endpoint.

Psyadon hopes to move the drug to the next stage of development in the Tourette indication, too, but first the company needs to secure additional funding. In 2008, Psyadon raised $8 million in a private financing from New Enterprise Associates Inc., which remains its only outside investor. Chipkin is currently meeting with potential investors to raise a $15 million to $20 million venture round that would see the company through the next three years, including completion of the Lesch-Nyhan trial and regulatory filings in the indication as well as the initiation of a randomized, placebo-controlled, double-blind study of the drug in pediatric Tourette patients.

Although Chipkin is the company's only full-time employee, he works with approximately a dozen consultants – many of them former Schering executives who became independent contractors when the pharma merged with Merck & Co. Inc. in 2009.

"Even though the company is young, the corporate history of the drug is unparalleled," Chipkin said.

Psyadon is keeping long-term business development options open. With fewer than 2,000 Lesch-Nyhan patients in the U.S. and Europe, "we could put together a sales force and target pediatric neurologists," Chipkin observed. "But we are open to discussions on mergers and acquisitions. That's the exit strategy for most biotechs nowadays."