This week, the Food and Drug Administration (FDA) gave Chelsea Therapeutics some disappointing news regarding its orphan designated drug Northera ™ (droxidopa). In a written letter, the FDA told the pharmaceutical company that another clinical trial will be needed to properly determine the safety and efficacy of Northera. That is unfortunate for both Chelsea Therapeutics and patients with primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine-beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy who are suffering from neurogenic symptomatic orthostatic hypotension.
So what happened?
Back in September 2011, Chelsea Therapeutics submitted their application to the FDA.  In November, the FDA granted the drug a priority review which is given to any drug that may offer major advances in treatment or provide a treatment where no adequate therapy exists. All was good.
However, in March 2012, the FDA gave the company a complete response letter stating that more data was needed to ascertain the safety and efficacy of Northera over a longer period of time (i.e., 2-3 months).
While this was happening, Chelsea Therapeutics continued to work with the FDA and submitted preliminary data from another study (306B) to hopefully provide the FDA with sufficient information to approve the drug. Unfortunately, this week the FDA told the company that their additional study had a flawed design and that the study “is unlikely to provide sufficient confirmatory evidence to support a Northera™ (droxidopa) Capsules New Drug Application (NDA)”.
In a press release, Dr. William Schwieterman, Chief Medical Officer of Chelsea Therapeutics stated "Chelsea's clinical program in this orphan indication, having enrolled over 450 patients to date, represents the largest randomized controlled database ever assembled to assess patients with symptomatic neurogenic orthostatic hypotension."
The approval of Northera will likely not happen soon; disappointing patients with neurogenic orthostatic hypotension, as well as their caregivers. However, Dr. Schwieterman remains optimistic, stating, “This experience affords us unique insights into the challenges associated with conducting clinical trials in this small and diverse patient population. Applying both our experience and robust body of clinical evidence, we believe we can continue to demonstrate the efficacy of droxidopa and submit compelling data supporting our application for U.S. marketing approval.”
On a positive note, Chelsea Therapeutics appears highly committed to getting Northera to its intended patients. As of July 1, 2012, all corporate officers and members of its Board of Directors volunteered to a 25% reduction in compensation until data from its ongoing Phase III study of Northera™ (droxidopa) becomes available (likely early 2013). Let’s hope the company can achieve its goal.
Neurogenic Orthostatic Hypotension and Droxidopa
Orthostatic hypotension is a fairly common condition in the elderly and can be due to cardiovascular, endocrine, and/or neurological impairments. Orthostatic hypotension is a sudden and prolonged drop in blood pressure when a person stands, leading to symptoms of dizziness, lightheadedness, blurred vision, fatique, and/or poor concentration.
Symptomatic neurogenic orthostatic hypotension is a subtype of orthostatic hypotension that occurs from a diminished norepinephrine response to standing. Neurogenic orthostatic hypotension can occur in patients with Parkinson’s disease, multiple system atrophy, pure autonomic failure, non-diabetic autonomic neuropathy and dopamine beta hydroxylase deficiency.  While the number of people with neurogenic orthostatic hypotension is unknown, Chelsea Therapeutics has stated that approximately 180,000 suffer from it (although those estimates have not been confirmed).
Droxidopa is a synthetic dopamine and norepinephrine precursor. Unlike L-dopa, the natural precursor to dopamine and norepinephrine, droxidopa does not require dopamine beta hydroxlase to form norepinephrine, thereby allowing the drug to be converted to norepinephrine faster in patients with their catecholamine systems compromised.