FDA approvals

FDA panel recommends approval of Northera for hypotension treatment

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 16-1 to recommend approval of droxidopa for the treatment of hypotension in patients with primary autonomic failure.

The panel made its recommendation despite reservations from FDA staff, who expressed concerns about safety and efficacy data as well as the design of studies conducted by the sponsor, Chelsea Therapeutics, to make the case for droxidopa, which would be marketed under the name Northera if approved.

According to an FDA briefing document, droxidopa is a pro-drug converted into norepinephrine and is believed to help prevent neurogenic orthostatic hypotension in patients with a primary autonomic failure condition such as Parkinson’s disease when they rise from a supine to a standing position.

Lower standard of proof

Panel members said that they were willing to allow the drug on the market based on a lower standard of proof than usual because droxidopa is an orphan drug, and patients with primary autonomic failure have no alternatives to treat their neurogenic orthostatic hypotension.

“If there were other available treatments out there, I might have used a higher standard,” panel member Michael Proschan, PhD, MS, of the NIH, said while explaining his vote to recommend approval.

Darren K. McGuire, MD, MHSc, FAHA, FACC, of University of Texas Southwestern Medical Center, Dallas, agreed, noting that while the studies had “notable limitations,” “the threshold of proof for an orphan indication is not the same as it is for a regular application. The company followed the FDA’s advice as best it could, and found some significant endpoints.”

Some panelists qualified their “yes” votes with a desire for the findings to be confirmed in postmarketing studies, especially in terms of durability.

In the document, FDA staff members noted that in the original application by Chelsea Therapeutics, rejected by the agency in 2012, only one of three submitted studies supported the efficacy of droxidopa, and then for only 1 week, despite the intention for the drug to treat a chronic condition. The FDA briefing also noted that the strength of the evidence does not meet the standards for approval, a lack of placebo groups in the studies, safety signals raised during the studies for which the drug could not be excluded, and that BP was collected with the patient’s head tilted at 30 degrees instead of lying supine.

One trial, Study 301 (n=162), met the primary endpoint of improvement to score on a questionnaire pertaining to core symptoms, the Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 (P<.001). The effect size was 1.3 on a scale of 1 to 10, where the average baseline reading was between 5 and 6. The trial also provided evidence that droxidopa raised systolic BP by a mean of 7.3 mm Hg for 1 week (P<.001) and provided 1 week of benefit according to the Orthostatic Hypotension Questionnaire (OHQ). Another trial, Study 302 (n=101), missed the primary efficacy endpoint (OSHA Item 1) and showed no effect for droxidopa on systolic BP, but documented an improvement in OHQ. A third trial, Study 303 (n=102), showed no effect on OSHA Item 1 or OHQ, a decrease in systolic BP in the droxidopa group, and data that refute “several of the Study 301 findings,” according to the briefing document.

More positive findings

The firm subsequently submitted results from another trial, Study 306B, according to the briefing document. While droxidopa met the primary endpoint of 1-week improvement in OSHA Item 1 (P=.028) and showed favorable trends for other endpoints, “the results do not meet the criteria as a ‘robust’ or ‘strongly positive’ single study to support a symptom benefit” and continue to offer no evidence that the treatment works beyond 1 week, according to the briefing document.

Many panelists who voted to recommend approval said they did so because Study 306B confirmed the findings of Study 301. However, the lone dissenter, Scott Emerson, MD, PhD, of the University of Washington, said he voted “no” because he was not convinced by the data from Study 306B. “There are probably patients out there who benefit from this drug, but I am not sure we know who they are,” he said.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does.

For more information:

CRDAC Clinical Briefing Document. NDA 203202.