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FDA's Next Northera Demand? We Chelsea; Phase III Hits Goal

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By Randy Osborne
Staff Writer

Chelsea Therapeutics Inc.'s primary endpoint-hitting Phase III news about Northera (droxidopa) sent the stock south, as Wall Street reacted to word that effects on dizziness – the main goal of the trial – did not last as long as the FDA may want for approval.

Shares (NASDAQ:CHTP) closed Wednesday at $1.14, down 65 cents, or 36 percent, after trading as low as 98 cents.

The drug, a catecholamine that converts directly to norepinephrine (NE) via decarboxylation to boost levels of NE in the nervous system, targets symptomatic neurogenic orthostatic hypotension (NOH) associated with Parkinson's disease (PD).

Although the Phase III trial met the primary endpoint of reduction in dizziness and/or lightheadedness at the first week (-1.0 relative to placebo; p=0.018), Northera showed only a trend toward working through the fourth and eighth weeks.

The reduced efficacy over time already has come up in talks with the FDA and "is likely a key factor for approval," wrote Alan Carr, analyst with Needham & Co.

"It is not yet clear, however, to what standard the FDA will hold the drug," added Carr, noting that a trend may be enough, given the unmet need in NOH. "We await detailed results and more insight into the FDA disposition," Carr wrote.

Charlotte, N.C.-based Chelsea, meanwhile, sought to explain the results to investors. Robert Hauser, from the University of South Florida, served as lead investigator in the trial, known as 306B.

"That [1.0] amplitude of improvement is considered in the clinically relevant range, so I was very pleased to see that, and I think that is the most important result in the study," he said during a conference call. "And that was backed up by improvement in standing systolic blood pressure. To see that supportive information, I think, is quite powerful, as well."

Adverse events turned out "really quite similar" in the placebo and Northera groups, with a discontinuation rate about 6 percent higher in the Northera group, which Hauser called "pretty darn good." Slightly higher instances of headache, dizziness and nausea in the active drug arm were "to be expected" as well, he said.

Especially "intriguing," in Hauser's view, are the data regarding fewer falls by PD patients on Northera. Falls make up a major cause of hospitalization, and their incidence was the primary endpoint of the trial as first designed. "This [outcome regarding falls] really deserves careful explanation and exploration," Hauser said.

Asked by analyst Robin Karnauskas, of Deutsche Bank, what the data might suggest about "the big picture" – i.e., Northera's chances for approval – officials said the results must be offered to the agency before anything definite is known. But the company has been given some clues.

William Schwieterman, Chelsea's chief medical officer, said regulators "have appeared, at least in some instances, to be open to the idea of shorter-term studies with trends supporting long-term benefit. At least, that was some of the early discussions at some of our meetings in the spring. We just can't say exactly how the FDA is going to view this" until the full data set is in hand. Needham's Carr noted that the agency already has said 306B will not stand as a confirmatory trial because of "numerous changes" and "concerns over maintaining the blind."

Schwieterman praised the "consistency of effect" seen with Northera, across endpoints in the current trial and when the results are laid alongside another study, 306A, both originally part of a study called 306.

After an interim analysis, 306 was divided into A and B. The former enrolled 51 patients, and the latter enrolled 174, making it the largest randomized, placebo-controlled Phase III trial ever conducted in NOH. Patients, all in the U.S., were treated for up to 10 weeks, including an initial blinded dosage titration period that lasted up to two weeks.

Joseph Oliveto, interim CEO, defended the endpoint switch, saying that it was part of the plan to "try to reposition us to support the NOH claim. The FDA's view on falls is that obviously they are a very clinically important endpoint," but the agency officials "didn't necessarily associate falls with NOH," Oliveto said.

"They view this as a very important study," he added, and Chelsea aims to "see if we can learn from these data relative to what an ideal plan would be."

In March, after Northera squeaked past the Cardiovascular and Renal Drugs Advisory Committee, the FDA nixed its approval. The complete response letter wanted data from another trial, as briefing documents released ahead of the panel meeting hinted might happen. Chelsea's other bad luck this year included a Phase II miss with CH-4051, its candidate for rheumatoid arthritis, which was dropped so that the company could put more effort into Northera. (See BioWorld Today, June 1, 2012, March 30, 2012, and Feb. 14, 2012.)