Despite winning a reluctant yea vote from the Cardiovascular and Renal Drugs Advisory Committee last month, Chelsea Therapeutics International Inc.'s neurogenic orthostatic hypotension (NOH) candidate Northera (droxidopa) failed to win FDA approval, sending shares of the Charlotte, N.C.-based firm falling 28.6 percent.

The stock (NASDAQ:CHTP) closed Thursday at $2.62, down $1.05.

Unsurprisingly, the FDA's complete response letter (CRL) requested data from an additional positive trial before it would consider approving Northera in NOH patients with primary autonomic failure due to conditions such as Parkinson's disease, multiple system atrophy and pure autonomic failure, dopamine beta hydroxylase deficiency and nondiabetic autonomic neuropathy. That same request had been expressed by FDA reviewers in briefing documents disclosed ahead of the advisory panel. (See BioWorld Today, Feb. 14, 2012.)

And the possibility of an additional trial was further discussed by the panel members during the Feb. 23 advisory meeting, though the 7-4 vote ultimately came down to the positive data from the Phase III 301 study and the lack of existing treatment options for NOH patients. (See BioWorld Today, Feb. 24, 2012.)

Northera, an orally active synthetic precursor of norepinephrine, has followed a bumpy development path in the U.S., though the active ingredient, droxidopa, has been marketed for more than 20 years in Japan for NOH, an orphan condition characterized by a sudden decrease in blood pressure when a person assumes a standing position, resulting in dizziness, blurred vision and fainting, which can lead to serious falls and injuries.

The only drug currently approved by the FDA for NOH is ProAmatine (midodrine, Shire plc), though another drug, corticosteroid Florinef (fludrocortisone) sometimes is used off label.

Results from Study 301, which was conducted under a special protocol assessment, were promising enough for the agency to consider granting approval based on a single positive efficacy trial, but the FDA noted that some subgroups – women, older patients, Parkinson's patients and U.S. patients – yielded "less persuasive results," Chelsea's CEO, Simon Pedder, told investors on a Thursday morning conference call.

Those data "undercut" overall results from the 301 study, he added, and the agency has asked for data from a new study designed to show durability of the drug's effect, ideally over a two- or three-month period.

To date, Chelsea has completed two Phase III studies (301 and 302). The 301 trial demonstrated statistically significant improvements in eight of 10 NOH symptoms, but higher-than-expected placebo results derailed the 302 study. The placebo effect struck again in another Phase III trial, Study 306, but the company responded by changing the primary endpoint after noting the dramatic decrease in the number of falls in Parkinson's patients. Data from that study are expected late this year, and Chelsea is hoping those results might satisfy the FDA. (See BioWorld Today, Sept. 25, 2009, Sept. 21, 2010, and Feb. 3, 2011.)

While the rate of falls is the primary endpoint, the 306 trial also is designed to measure benefits using the orthostatic hypotension symptom assessment scale, namely the item related to dizziness, and the composite score based on the orthostatic hypotension questionnaire.

Since the CRL did not mention the 306 study, Chelsea execs will have to meet with the FDA to determine whether data from that trial might be suitable, Pedder said.

Roth Capital analyst Scott Henry wondered on the call, however, whether the firm might be better off starting a new trial from scratch that was designed to meet all the FDA's requirements, rather than relying on data from an ongoing trial that might not be designed to the agency's specifications.

Pedder responded that the path for NOH drugs was hardly well trodden. "We're really kind of pioneering this space," he said, pointing out that ProAmatine went through seven trials before gaining approval.

Plus, Northera has clearly shown symptomatic benefit in NOH – the first drug to do so – so that's "a big win for us," he added.

On the plus side, the CRL indicated no outstanding safety issues, despite concerns raised in last month's briefing documents. But the FDA did recommend including a black-box warning related to supine hypertension, though that could be avoided if the company is able to produce data showing no or limited effect of the drug on supine hypertension.

Even if Northera ends up saddled with a warning, it would still be competitive to ProAmatine, which also carries a black-box warning, Pedder noted.

The CRL also asked for additional bioequivalence work.

Chelsea, which expects to end March with more than $50 million in cash, already is taking steps to reduce cash burn, said Nick Riehle, the company's chief financial officer. After looking at the "various scenarios for acquiring the data the FDA is requesting," Chelsea anticipates cash on hand to be "more than adequate to get us out to such data and somewhat beyond that," he added.

Besides the registrational trials, Chelsea also has conducted two long-term open-label extension studies (303 and 304), a dedicated QTc study (102) and a 24-hour ambulatory blood pressure monitoring safety study (305).

An estimated 80,000 patients in the U.S. would fall under Chelsea's proposed indications for Northera.