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SILVER SPRING, Md. -- Droxidopa (Northera) is getting a second look by an FDA advisory committee for the treatment of orthostatic hypotension stemming from neurological disorders like Parkinson's disease, but an agency review doesn't look promising for approval.
In of the FDA's Cardiovascular and Renal Drugs Advisory Committee, the reviewers recommended against approving the drug, primarily due to "the lack of sufficient evidence of efficacy" and concerns about the durability of its effect.
The reviewers also pointed to a few safety concerns, including hypertensive episodes that may have contributed to deaths of some patients. But these took a back seat to the reviewers' disdain for the efficacy data.
One of them, Shari Targum, MD, stated bluntly that the FDA should issue a complete response letter to the sponsor, Chelsea Therapeutics, "because of inadequate evidence of effectiveness."
In March 2012, the FDA had turned down an earlier application from Chelsea for similar reasons.
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.
, a neurologist at the Mayo Clinic in Rochester, Minn., told 鶹ý in an email that a new treatment for neurogenic orthostatic hypotension would be welcome.
"We have VERY limited options for orthostatic hypotension," she wrote. "Only midodrine [is] approved for it. Success is only partial in more severe cases, and new drugs are needed."
Sandroni said droxidopa's mechanism was appealing because it not only is converted to norepinephrine "but is also taken up into adrenergic terminals ... and released only on baroreflex unloading, so [it is] acting like a smart drug."
After an FDA advisory committee narrowly recommended droxidopa's approval for the indication in February 2012, the agency -- telling Chelsea that it needed to submit data from an additional trial.
Chelsea last year with . However, the data may not be enough to change the FDA's mind on the drug.
One of the objections FDA staff had raised at the earlier advisory committee meeting was a lack of evidence that droxidopa's benefits lasted beyond 4 weeks of treatment. The new "306B" trial had a primary endpoint of improvement relative to placebo in dizziness and lightheadedness after just 1 week of treatment. It was met, according to Chelsea, but improvements in this measure and in standing blood pressure at later time points were not statistically significant.
Targum listed several other problems with the 306B study:
Its primary endpoint was changed twice; first when it was split off from an initial study after an interim analysis showed that it would fail to meet its primary endpoint of improvement on a composite symptom score after 8 weeks, and then switching from patient-reported falls to dizziness and lightheadedness at 1 week.
Evaluator blinding may have been compromised during these protocol changes.
The improvement in the final primary outcome measure with droxidopa was clinically minimal, though statistically significant.
Targum also noted that two of the other three studies performed by Chelsea failed to meet their primary endpoints.
Another group of FDA reviewers also noted the relatively small clinical improvement in study 306B "when compared with intra-subject variability." Their conclusion was that the small benefit and apparent lack of durability "made it questionable whether droxidopa has any long-term treatment effect."
Sandroni, however, told 鶹ý that neurogenic orthostatic hypotension is progressive, such that the loss of droxidopa's efficacy over time may be "due to worsening of the primary conditions."
Perhaps hedging its bets, Chelsea has 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.
Advisory committee members will be asked to comment on the adequacy of the 306B study data and whether there are specific patient populations that may benefit more than others. The single voting question on the draft agenda is whether the drug should be approved.
From the American Heart Association: