Disappointing results in a Phase IIa proof-of-concept study with NPS 1776 has prompted NPS Pharmaceuticals Inc. to change gears and move the drug forward in an indication other than migraine.
Results of the study in patients with moderate to severe migraine headaches were inconclusive, the company said.
"The study was designed to show a significant difference between the treatment groups and the placebo groups," said David Clark, the company's vice president of corporate affairs, "and the placebo response was much higher than we had anticipated."
NPS 1776 (isovaleramide), a small organic molecule compound, failed to meet the primary endpoint, a significant reduction in headache pain two hours after administration of drug compared to placebo. The trial enrolled 189 people with moderate to severe migraine. They were randomly assigned to receive either a high dose of 800 mg or a low dose of 400 mg of drug, or placebo. Researchers noted a positive response in 60 percent of patients receiving the high dose, 64 percent of patients receiving the low dose and 56 percent of those receiving placebo.
Study results also showed no serious adverse events in any of the subjects. Adverse events were infrequent and evenly distributed between the study groups. The pharmacokinetic profile of NPS 1776 showed that peak blood concentrations were achieved 30 minutes after dosing.
"The compound has a very interesting profile in many different preclinical models in CNS disorders," Clark told BioWorld Today. "And so we're not discouraged about the molecule itself. Even in this trial, while we're not able to demonstrate a reduction in migraine pain relative to placebo, we did show a very favorable pharmacokinetic profile and a very favorable safety profile."
Salt Lake City-based NPS intends to complete its evaluation of data from the study, and will continue to explore the development of NPS 1776 in other central nervous system disorders to be determined later, Clark said. It is unlikely that the compound will move forward in the migraine indication.
The double-blind, placebo-controlled Phase IIa trial was assessing the effectiveness of the drug in relieving migraine pain and associated symptoms, such as nausea and sensitivity to light or sound. NPS initially focused on the migraine indication because isovaleramide is somewhat chemically related to valproic acid, which is used in migraine prophylaxis, Clark said.
"In the preclinical trials that had been done before, the drug showed very good indications of efficacy in models of epilepsy and spasticity," he said.
Several Phase I trials showed the drug was safe and well tolerated. NPS is initiating additional trials to evaluate new formulations, including a controlled-release formulation.
At the end of the second quarter, NPS had incurred total costs of about $8.3 million on isovaleramide. The company owns 100 percent of the rights.
Ahead of isovaleramide, NPS has one product on the market and two others in late-stage clinical trials. Sensipar (cinacalcet), partnered with Thousand Oaks, Calif.-based Amgen Inc., was approved in March for hyperparathyroidism in patients with chronic kidney disease on dialysis and for hypercalcemia in those with parathyroid carcinoma. (See BioWorld Today, March 10, 2004.)
Next in line for NPS is the osteoporosis drug Preos, which has finished pivotal Phase III trials. The company hopes to file a new drug application with the FDA by the end of this year. NPS is partnered with Roskilde, Denmark-based Nycomed Group for the European rights to Preos. The company released the positive Phase III data in March. (See BioWorld Today, March 31, 2004.)
In April, NPS started a Phase III trial of its third product, teduglutide, for short-bowel syndrome. The product also is in Phase II testing for Crohn's disease. Teduglutide is an analogue of glucagon-like peptide-2, a naturally occurring hormone that regulates proliferation of the cells lining the small intestine.
NPS also is working with London-based AstraZeneca plc to find compounds that act on targets in the central nervous system called metabotropic glutamate receptors, or mGluRs. AstraZeneca has exclusive rights to commercialize mGluR subtype-selective compounds, and NPS will pay an equal share of the preclinical research costs through March 2006. The companies entered the deal in March 2001.
NPS' stock (NASDAQ:NPSP) lost $1.66 of its value on Tuesday, closing at $18.93.