FDA Panel Endorses Droxidopa to Treat Neurogenic Orthostatic Hypotension

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.