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Predix Pharmaceuticals Obtains Special Protocol Assessment for PRX-00023 Pivotal Study in Anxiety; Predix Also Initiates Phase Ib Clinical Trial for PRX-08066 in Pulmonary Arterial Hypertension

Posted on: Wednesday, 30 November 2005, 09:00 CST

Predix Pharmaceuticals, a drug discovery and development company, announced today that under the Special Protocol Assessment process, it has reached final agreement with the United States Food and Drug Administration (FDA) on the design and statistical analysis plan of its first pivotal study for PRX-00023, its 5-HT1A agonist and lead product candidate, to treat generalized anxiety disorder (GAD). In addition, Predix announced continued progress on its pipeline of internally discovered product candidates with the initiation of a Phase Ib clinical trial of PRX-08066, the company's novel small-molecule 5-HT2B antagonist, in conditioned athletic adults with transient pulmonary artery hypertension induced by a low oxygen environment.

"We are very pleased to have reached final agreement with the FDA on the Special Protocol Assessment for our Phase III clinical trial of PRX-00023 in generalized anxiety disorder. With three of our internally discovered product candidates currently in clinical trials and an extensive pipeline of novel compounds in preclinical development, we believe that our targeted drug discovery technology and approach will enable us to continue to bring at least one new product candidate into the clinic annually," said Michael Kauffman, M.D., Ph.D., president and CEO of Predix.

Dr. Kauffman further commented, "The proof-of-concept trial of PRX-08066 is an exciting event for Predix, as we believe there is a significant need for improved treatment of pulmonary arterial hypertension (PAH), a serious and often fatal cardiovascular disease. Because of its selectivity - in preclinical models PRX-08066 reduces only pulmonary and not systemic blood pressure - we believe that this product candidate may lack the systemic blood pressure effects of currently approved therapies for the disease."

PRX-00023 Phase III Study Design for GAD

Predix and the FDA had previously agreed upon the design and primary and secondary endpoints for this Phase III trial, which was initiated in August. The trial is an eight-week, double-blind, placebo-controlled, multi-center study. The trial includes approximately 20 sites in the United States and is expected to enroll up to 310 patients with moderate-to-severe GAD who will be randomized into one of two arms, consisting of approximately 155 patients each: a placebo arm, or a PRX-00023 treatment arm, in which patients receive a dose of 40 mg administered over a three-day period followed by a dose of 80 mg once daily for the remainder of the study. The primary objectives in this trial are to evaluate the efficacy of PRX-00023 in GAD as measured by the change from baseline in the HAM-A scale, and to assess the safety and tolerability of PRX-00023 during treatment of patients with GAD. The HAM-A scale is the only FDA accepted standard for the evaluation of anti-anxiety activity, and has been used in all pivotal trials of drug candidates for the treatment of GAD. This trial will be the first of at least two pivotal trials with PRX-00023 for the treatment of GAD.

About PRX-00023

PRX-00023 is Predix's lead product candidate and represents a novel, highly selective , non-azapirone class of 5-HT1A agonists discovered using PREDICT(TM), the company's proprietary G-Protein Coupled Receptors (GPCR) modeling, screening and lead optimization technology. Buspirone is currently the only 5-HT1A agonist approved in the United States for GAD but is generally taken three times a day, requires approximately three weeks of dose adjustment to reach therapeutic levels, and may cause lightheadedness and nausea. Several other 5-HT1A agonists have shown efficacy in Phase II and III clinical trials in depression. However, most of these drugs belong to a chemical class of drugs called azapirones and their development has been hindered by poor tolerability at therapeutic doses, rapid metabolism, resulting in a short half-life and, therefore, requiring multiple daily dosing, and the requirement of slow dose escalation to effective doses because of nausea and lightheadedness, which are thought to be caused by their binding to off-target G-Protein Coupled Receptors (GPCRs).

In contrast, PRX-00023 is designed to have minimal affinity for the GPCRs associated with the side effects of 5-HT1A agonists that are in the azapirone chemical class, and to have a more convenient dosing profile than azapirones.

PRX-08066 in PAH

PRX-08066 is a novel, highly selective, oral 5-HT2B antagonist being developed for PAH. Over the past decade, the 5-HT2B receptor has been shown to be linked to the development and progression of PAH, including cases associated with the use of certain diet drugs in humans. PRX-08066 is the first 5-HT2B antagonist being developed for PAH and has completed two Phase I clinical trials in healthy volunteers. The first Phase I clinical trial was a randomized, placebo-controlled, double-blind, single-dose escalation study with 24 subjects. Over a dose range from 25 mg to 800 mg, PRX-08066 was well-tolerated and there were no serious adverse events or liver toxicity issues associated with treatment. A separate 14-day, multiple-dose Phase I clinical trial in healthy volunteers showed that PRX-08066 was well-tolerated. Preliminary pharmacokinetic data from these two Phase I studies is consistent with once or twice daily oral dosing.

Phase Ib Study Design in PAH

The Phase Ib clinical trial will study the pharmacodynamics and tolerability of PRX-08066 in approximately 12 adults conditioned to exercise at high altitudes, with elevated pulmonary artery pressures induced by low oxygen levels (hypoxia). The trial will explore the effects of PRX-08066 on pulmonary blood pressure and exercise capacity.

This Phase Ib study features a randomized, double-blind, three-period crossover design, where each subject receives drug or placebo twice daily for 3 days in three separate periods, with an interval of 1-2 weeks between visits. Pharmacodynamics of PRX-08066 will be characterized by the noninvasive measurement of pulmonary artery blood pressure, right atrial pressure, cardiac index (i.e., cardiac output indexed to body size) and exercise capacity.

The trial is expected to be completed in mid- to late-2006, and if the results are favorable, the initiation of a Phase II clinical trial is anticipated in the second half of 2006.

About PRX-08066

PRX-08066 is Predix's third of three product candidates currently in the clinic, all of which were internally discovered utilizing computer-based G-Protein Coupled Receptor (GPCR) models and optimized with integrated computational-medicinal chemistry. PRX-08066 is a highly selective, small-molecule 5-HT2B antagonist being developed for the treatment of PAH and other pulmonary disorders. PRX-08066 was designed to provide both symptomatic improvement, through selective dilation of diseased pulmonary blood vessels, and to slow disease progression, by inhibiting the thickening of the pulmonary arteries that occurs as PAH worsens.

PRX-08066 has demonstrated selective dilation of pulmonary blood vessels in both acute and chronic pre-clinical models of PAH, as well as disease-modifying effects in vivo and in in vitro signal transduction pathway studies.

About Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a serious and often fatal cardiovascular disease affecting nearly 50,000 Americans and 50,000 Europeans. The disease is characterized by the elevation of pulmonary artery blood pressure and progressive thickening and narrowing of the blood vessels to the lungs, which can lead to heart failure. Symptoms of PAH include fatigue after minimal exertion, dizzy spells, chest pain, shortness of breath and fainting. The global market for PAH drugs is growing rapidly, from approximately $600 million in 2004 to an estimated $1 billion in 2010, as more patients with PAH are diagnosed and initiated on drug therapy.

PAH results from the accelerated proliferation of blood-vessel-associated smooth muscle cells that lead to the constriction of pulmonary arteries. Blood supply to the lungs is mediated by contraction of the right ventricle in the heart, which can accommodate normal pulmonary blood pressures but is poorly suited to tolerate the increased pulmonary pressures associated with the arterial constriction that occurs in PAH. Over time, as the right ventricle loses the ability to pump blood into the hypertensive pulmonary system, the right ventricle heart muscle weakens and becomes enlarged and dilated, eventually leading to heart failure in many cases.

About Predix

Predix Pharmaceuticals Holdings, Inc. is a pharmaceutical company focused on the discovery and development of novel, highly selective, small-molecule drugs that target G-Protein Coupled Receptors (GPCRs) and ion channels. Using its proprietary drug discovery technology and approach, Predix has advanced three product candidates into clinical trials and has six additional programs in preclinical development and discovery. Predix initiated the first of at least two pivotal Phase III clinical trials for generalized anxiety disorder for its lead drug candidate, PRX-00023, in August 2005, and is conducting this Phase III study under a Special Protocol Assessment agreed to with the FDA in November 2005. Predix has two other clinical-stage drug candidates: PRX-03140 for the treatment of Alzheimer's disease, entering Phase II, and PRX-08066 for the treatment of pulmonary arterial hypertension, now in Phase Ib.

Source: Business Wire

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