FDA Sends Hypotension Drug Droxidopa for More Study

Allison Shelley

March 30, 2012

March 30, 2012 — The US Food and Drug Administration (FDA) would like to see more evidence for droxidopa in the treatment of neurogenic orthostatic hypotension in patients with primary autonomic failure before it considers approving the product, Chelsea Therapeutics has announced.

In a complete response letter, the agency has requested a second positive study supporting the drug's efficacy.

Primary autonomic failure occurs in Parkinson's disease, multiple-system atrophy, and pure autonomic failure, as well as dopamine beta-hydroxylase deficiency and nondiabetic autonomic neuropathy.

This is not the first time the FDA has raised concerns about the product the company would like to market as Northera. In a damning regulatory review, the agency raised concerns that the beneficial effect of the drug did not last long enough — particularly in light of worrisome safety signals during the open-label phases of the trials. These included deaths, strokes, myocardial infarction, progression of underlying disease, and hypertensive crisis.

Five clinical trials were submitted in this new drug application — studies 301 to 305. The first 3 address efficacy and safety and the other 2 address safety only. Study 301 is the only trial to meet its primary endpoint, change on the Orthostatic Hypotension Questionnaire, which is essentially a composite endpoint because it includes 10 separate questions.

Rough Regulatory Road

At an FDA advisory committee meeting last month, reviewer Melanie Blank, MD, complained the safety database of this development program is not robust. The total patient exposure in the Chelsea program was 535 patients. Only 341 patients were exposed for 6 weeks or more, and just 83 patients tried the maximum dose of 600 mg.

"This low extent of long-term exposure makes it difficult to properly evaluate the long-term safety of droxidopa," Dr. Blank said. "My regulatory recommendation is that we should not grant approval for droxidopa at this time."

But as previously reported by Medscape Medical News, despite this recommendation, the advisory committee surprised many by voting in favor of approval. In a close vote of 7 to 4, many panelists acknowledged it was a difficult decision but were moved by the litany of patients testifying about the debilitating nature of their symptoms and the life-changing effect the drug has had. Chelsea Therapeutics paid for the travel expenses of most of the patients and their families attending the meeting.

There was 1 abstention in the final vote, and another member declined to comment either way because of a lack of evidence, he said.

The rare and often disabling symptoms of neurogenic orthostatic hypotension include dizziness, weakness, fainting, and falls. Patients often become confined to a wheelchair or are bedridden and suffer from many comorbid conditions, such as infection and fracture. Many people develop secondary autonomic failure from other conditions, such as diabetic neuropathy or advanced age. This raises the possibility of a wide off-label market for droxidopa.

Unmet Medical Need

"We believe there continues to be an important unmet medical need in addressing the symptoms associated with [neurogenic orthostatic hypotension] and remain committed to working with the FDA to determine the appropriate next steps required to bring a much needed new therapy to the market as quickly as possible," Simon Pedder, president and chief executive officer of Chelsea Therapeutics, said in a news release.

The drug is already available in Japan for the same indication, but it is marketed at lower doses of 100 to 300 mg, compared with the maximum dose of 600 mg proposed for the United States.

In the United States, there is currently only 1 other approved drug for these symptoms, Shire's midodrine, marketed under the brand names Amatine, ProAmatine, and Gutron. The FDA is considering withdrawal of this drug because the manufacturer has reportedly failed to complete required postmarketing studies confirming efficacy.

Droxidopa is an orally administered, synthetic amino catecholamine acid prodrug that is converted mostly peripherally, but it is also converted centrally into norepinephrine as it passes through the blood-brain barrier. It is thought that patients with hypotension lack the ability to autoregulate their blood pressure through vasoconstriction when they rise from a lying to a standing position. Therefore, it is thought that vasoconstrictors can offer therapeutic benefit.

In a news release, Chelsea Therapeutics said that although the FDA did not refer to its ongoing study 306, a 10-week double-blind, placebo-controlled trial, it hopes that data from this study could potentially meet the criteria for clinical efficacy and durability of effect identified in the complete response letter.

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