FDA
15th January 2014

FDA Advisory Committee Strongly Supports Northera for Approval

Chelsea Therapeutics’ Northera (droxidopa capsules) received strong support from the Cardiovascular and Renal Drugs Advisory Panel of the U.S. Food and Drug Administration with a vote of 16-1 for the treatment of symptomatic neurogenic orthostatic hypotension in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, or pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy.

FDA Advisory Committee Strongly Supports Northera for Approval

Chelsea Therapeutics’ Northera (droxidopa capsules) received strong support from the Cardiovascular and Renal Drugs Advisory Panel of the U.S. Food and Drug Administration with a vote of 16-1 for the treatment of symptomatic neurogenic orthostatic hypotension in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, or pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy.  

Droxidopa is a prodrug for norepinephrine, converted both peripherally and centrally as it crosses the blood-brain barrier. It therefore acts as a vasoconstrictor which, at least in theory, should help patients retain adequate blood pressure when they stand up from sitting or supine positions.

Orthostatic hypotension is a common complication of Parkinson’s disease and certain other neurodegenerative conditions that affect autonomic function. These include multiple system atrophy, primary autonomic failure, and nondiabetic autonomic neuropathy.

In March of 2012, The FDA had narrowly accepted Northera for this indication, but then withheld its approval, asking Chelsea to provide more efficacy data on the medication. It accepted the resubmitted application last year, which included results from a new phase III trial called Study 306B.

The 174-patient trial essentially confirmed findings in earlier studies; namely, that droxidopa was better than placebo in improving patients’ perceptions of dizziness, lightheadedness, and imminent loss of consciousness after 1 week of treatment. However, as in the earlier studies, the drug showed no clear benefit at later time points.

Most committee members said the lack of evidence of treatment benefit beyond 1 week was a major drawback. Several said it could be addressed in postmarketing studies, but others worried that, without such data, neither the FDA nor Chelsea could offer evidence-based dosing instructions in the product’s label.

In briefing documents and in an oral presentation, FDA staff raised questions about the integrity of study 306B. Its primary endpoint had been changed twice (Chelsea had set fall rates as the primary endpoint in the 306B trial, but then changed the protocol) and treatment assignments were accidentally made available to study investigators for a few weeks part way through. In addition, panelists raised the peculiarity that stemmed from one of the earlier studies which was performed on both sides of the Atlantic. This study showed far more dramatic and uniform responses to droxidopa at one site in the Ukraine than anywhere else.

But separate, intensive audits of the Ukraine site by the FDA and by an independent consultant hired by Chelsea — in which handwriting styles and ink colors were examined and blood pressure measurements were observed — found nothing wrong.

On the positive side for Chelsea, the committee found no major safety problems, and there was relatively little discussion of the drug’s adverse effects. The one that appeared most concerning was hypertension, and one panel member commented that increased blood pressure would be a benefit in many patients, not an adverse effect.

Furthermore, Chelsea has recently commenced yet another phase III trial of droxidopa for neurogenic orthostatic hypotension with a planned enrollment of 450 patients and lasting for 17 weeks — by far the largest and longest such trial conducted in the condition. Its principal aim is to evaluate the durability of the drug’s treatment effect which is something the FDA had mentioned would be beneficial.

Northera was previously granted orphan-drug designation and received fast-track status from the FDA.

The FDA is not bound by the CRDAC’s decision but normally follows its recommendation.

ISS has over a decade of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact info@innovativescience.net.

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