Chelsea initiates NORTHERA Phase III trial for symptomatic NOH associated with PD

Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced the initiation of Study 306, a pivotal Phase III trial evaluating the efficacy of NORTHERA™, an oral synthetic precursor of norepinephrine, for the treatment of symptomatic neurogenic orthostatic hypotension (NOH) associated with Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in America. As a result of decreased levels of norepinephrine associated with PD, approximately 20% of PD patients may experience symptomatic NOH. NOH is a neurogenic disorder resulting from deficient release of norepinephrine, the neurotransmitter used by sympathetic autonomic nerves to send signals to the blood vessels and the heart to regulate blood pressure. This deficiency results in decreased blood pressure when a person assumes a standing position and is characterized by lightheadedness, dizziness, and falls. Symptoms of chronic NOH can be incapacitating, not only putting patients at high risk for falls and generating significant health care costs, but also severely affecting the quality of life for patients and their loved ones.

Study 306 is a randomized, placebo-controlled, induction-design Phase III trial targeting the treatment of 84 patients with symptomatic NOH associated with Parkinson's disease. All centers participating in the trial are in the U.S. The trial is up to 12 weeks in duration and includes an initial, blinded dose titration period lasting up to two weeks, after which all patients will continue on to an 8-week double-blind treatment period. During the blinded titration period, patients randomized into the treatment arm will be titrated daily with up to 600 mg of Northera t.i.d. to achieve maximum therapeutic benefit while patients randomized to placebo will undergo the titration using placebo capsules.

The primary endpoint of the trial will be the relative mean change in the Orthostatic Hypotension Questionnaire (OHQ) composite score between Northera and placebo. The OHQ composite score is a single endpoint that reflects the average of the composite orthostatic hypotension symptom assessment (OHSA) score and the composite orthostatic hypotension daily activities scale (OHDAS) score. In addition to individual and composite OHSA and OHDAS scores, secondary outcome measures in the study include falls, Unified Parkinson's Disease Rating Scale (UPDRS), and Parkinson's Disease Questionnaire (PDQ-39).

Update on CH-4051 Phase II in Rheumatoid Arthritis

Following a conference call earlier this month with the U.S. Food and Drug Administration (FDA), Chelsea received written comments from the FDA detailing their information requests related to the company's Phase II trial of CH-4051 in rheumatoid arthritis (RA). As previously announced, the FDA is requesting additional detail from Chelsea's preclinical studies, notably histological reports from lower dose groups in the completed toxicology studies, to establish the no-observable-adverse-effect-level (NOAEL) in this animal model and support proposed Phase II doses.

"Given the known toxicities and side-effects of methotrexate, the most widely prescribed antifolate, we believe that the FDA is interested in fully characterizing the safety of our proposed Phase II doses of CH-4051," commented Dr. Simon Pedder. "It is, in part, why we believe there exists a significant need for both a safer and more effective antifolate treatment alternative. The purpose of the new proposed trial is to test if the safety and efficacy of CH-4051 will show improved tolerability and reduced hepatotoxicty as compared to the MTX."

Chelsea anticipates completion of the requested histology reports by late July. In the interim, the company continues to explore potential strategies for further mitigating any FDA concerns regarding dose while allowing for evaluation of the full dose range and minimizing potential program delays. Chelsea anticipates filing a response to the FDA in late July, at which time the agency will have 30 days to review and respond to the submission.