Surprise FDA Panel Vote Favors Hypotension Drug Droxidopa

Allison Shelley

February 24, 2012

February 24, 2012 — In a close vote, a US Food and Drug Administration (FDA) committee has recommended approval for the hypotension drug droxidopa.

After a damning regulatory review, the odds were against Chelsea Therapeutics convincing the panel of the merit of the new drug they would like to market as Northera.

"It was a difficult decision," many of the committee members said as they stated their vote for the record. The panel voted 7 to 4 in favor of approval of the new option for neurogenic orthostatic hypotension. There was 1 abstention, and another member declined to vote (because of a lack of evidence, he said).

The indication is for patients with primary autonomic failure, including Parkinson's disease, multiple system atrophy, and pure autonomic failure, as well as dopamine beta-hydroxylase deficiency and nondiabetic autonomic neuropathy.

The rare and often disabling symptoms 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.

Already Available in Japan

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 Japan, 9 cases of neuroleptic malignant syndrome have been reported in patients taking droxidopa.

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.

Midodrine received accelerated approval in 1996 for its effects on raising systolic blood pressure, which was considered at the time to be a surrogate marker of effectiveness for hypotension.

Other options are used off-label, but most of these drugs have serious safety concerns. At this time, patients with neurogenic orthostatic hypotension have few therapeutic alternatives.

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 standing position. Therefore, it is thought that vasoconstrictors can offer therapeutic benefit.

However, droxidopa has faced a rough regulatory road. An FDA review raised concerns that the beneficial effect of the drug did not last long enough for patients — 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.

The manufacturer's stock has lost more than half its value since February 13, when the company first disclosed the FDA's position. Chelsea shares closed Wednesday trading at $2.41, and trading was halted Thursday for the committee meeting. Shares are selling today at $3.75.

Damaging Review

Five clinical trials were submitted in this new drug application (study 301 to 305). The first 3 address efficacy and safety and the final 2 address safety only.

Study 301 is the only trial to meet its primary endpoint, the Orthostatic Hypotension Questionnaire, which is essentially a composite endpoint because it includes 10 separate questions.

Speaking at the meeting, FDA reviewer Melanie Blank, MD, said 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."

Committee members echoed these concerns, but many were moved by the litany of patients testifying about the debilitating nature of their symptoms and the life-changing effect the drug has had on their lives. Chelsea Therapeutics paid for the travel expenses of most of the patients and their families attending the meeting.

Narrow Vote

"There is no question droxidopa is effective in a subset of patients," committee chair Michael Lincoff, MD, from Cleveland Clinic in Ohio, said at the meeting, "and the risks are not unpredictable," he pointed out after voting in favor of the drug.

Vasilios Papademetriou, MD, from the Veterans Affairs Medical Center in Washington, DC, said he reluctantly voted yes and, despite the limitations of the trials, was swayed by patient testimonials, including examples of people once wheelchair-bound who can now walk. "This is a devastating problem and we don't have effective therapies. This won't help all patients, but it will help some of them and I could not in good conscience deprive them."

Sanjay Kaul, MD, from the Cedars-Sinai Heart Institute in Los Angeles, California, said he disagrees and voted no. Dr. Kaul says the paltry data are reminiscent of those for midodrine, which may soon be withdrawn from the market because of a lack of efficacy. "We have an opportunity here to learn from the lessons of the past," Dr. Kaul said. "I cannot as a scientist and clinician recommend we move forward without evidence of efficacy, durability, and safety."

Jeffrey Cohen, MD, from the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, said he voted yes, even though the arguments on the other side were very compelling.

"As a neurologist on a predominantly cardiology panel, I have to say you live in a world that is much more black and white than the world I live in. Unfortunately this is neurology and the majority of illnesses I treat have no clear outcomes. I understand all too well the limitations of the studies, but I can tell you that this drug will be useful for a subset of my patients."

The FDA now has a difficult decision to make — to continue pursuing the concerns outlined by its reviewer or follow the recommendation of its advisory panel and move to approval.

Chelsea Therapeutics has proposed a postmarketing registry of 200 to 300 patients over 4 to 5 years to obtain more data on droxidopa exposure and long-term safety.

Some committee members have recommended a new clinical trial, ideally with midodrine as the comparator. Many anticipate the agency will move forward with droxidopa, but with additional study and labeling restrictions.

The FDA decision is expected by March 28.

Cardiovascular and Renal Drugs Advisory Committee Meeting, February 23, 2012, Silver Spring, Maryland.


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