Droxidopa

[Lenna]

I know that some institutions are doing clinical trials of droxidopa for POTS. Beth Israel in Boston in one of them. Here is an "interesting" article about the drug. I've copied the entire article here because I don't think the link will give you the full text if you're not a subscribed member.

http://www.medpageto...mail.com&mu_id=

FDA Skeptical of Hypotension Drug

By John Gever, Senior Editor, MedPage Today

Published: February 22, 2012

An FDA staff review of droxidopa (Northera) for treating neurogenic orthostatic hypotension in patients with certain neurological diseases has recommended against its approval, according to documents released Tuesday.

The review, released in advance of a Thursday meeting of the agency's Cardiovascular and Renal Drugs Advisory Committee, cited lack of evidence that droxidopa is effective for longer than four weeks and "worrisome safety signals" seen in clinical trials.

The latter included deaths, strokes, heart attacks, hypertensive crises, and underlying disease progression that occurred during the open-label phases of the trials.

Droxidopa is being developed by Chelsea Therapeutics for treating symptomatic, neurogenic orthostatic hypotension in patients with primary autonomic failure -- which can be associated with Parkinson's disease and multiple system atrophy -- dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Currently, the only drug specifically approved for this indication is midodrine, and the FDA may soon pull it from the market because it has never been shown to be effective in rigorous trials.

Eight other drugs are used off-label, according to the FDA review, including indomethacin, desmopressin, and octeotide. Most have multiple contraindications and all have significant side effects, the review noted.

Droxidopa is a prodrug for norepinephrine, converted both peripherally and centrally as it crosses the blood-brain barrier. It therefore acts as a vasoconstrictor which, at least in theory, should help patients retain adequate blood pressure when they stand up from sitting or supine positions.

Chelsea's marketing application is based on three safety-and-efficacy trials and two that examined only safety. A total of 535 patients were treated in the company's clinical program, with only 341 receiving the drug for more than six weeks, the FDA reviewers noted.

Moreover, only 83 ever received the maximum dose of 600 mg three times a day.

As a result, the FDA staff review said, "the safety database of this development program was not robust."

It also asserted that the available safety data were "not so clean."

According to the review, "during the longer term open-label experience with droxidopa, there were several deaths, SAEs [serious adverse events], discontinuations for AEs, and events of hypertensive crisis, strokes, and myocardial infarction."

Reviewers continued, "Of utmost concern are reports of neuroleptic malignant syndrome from Japan that aren't clearly explained. During a 10-year reporting period, there were nine cases of neuroleptic malignant syndrome while patients were taking droxidopa."

Although some of those cases could have arisen from other drugs patients were taking, there were several that "appeared to have no likely etiology" other than droxidopa exposure, the staff review indicated.

In addition, the reviewers questioned the study's efficacy even in the short-term trial data. One of the two randomized trials failed to meet its primary endpoint, which was a statistically significant improvement in scores on the first item in the Orthostatic Hypotension Symptom Analysis scale.

But the review also noted points in the drug's favor.

The other main study, also a randomized trial, documented improvements in hypotension symptoms of 0.9 and 1.3 points on two scales in which baseline scores were in the range of five to six, and which lasted at least one week. The same trial also showed that droxidopa increased standing systolic pressure for at least a week.

And, the trial that failed in its primary endpoint did show a significant benefit on a secondary efficacy endpoint, scores on the Orthostatic Hypotension Questionnaire.

The advisory committee will be asked to discuss the drug's efficacy and safety record in the trial data, and will vote on whether it should be approved.

The FDA is not required to follow advisory committee recommendations, but it usually does.

[issie]

All they had to do was ask me about this one. When I was wrongly diagnosed with Parkinson's I was given sineament. It made me so much worse. I can agree that it makes the illness progress. Now, there are studies indicating that instead of a LACK of dopamine - there may actually be an INCREASE of dopamine peripherally. I hope someone can find that reference and post it. I remember reading it. And, in my case - that maybe was proven true - by the wrong experiment with the wrong drug - for the wrong illness. Don't you just love being a guinea pig. But, that's how it is with this illness. We just have to keep trying things and hopefully one day, something is going to work. One thing it lets you know - when it doesn't work. It puts another piece of the puzzle together for you. You can rule out things that your body IS and ISN"T doing.

Issie

[Chaos]

Maybe this will be helpful in keeping midodrine on the market since one of the arguements the docs were making to the FDA was that this was the only drug available for OH.

It's interesting that they say this is a vasoconstrictor and crosses the blood/brain barrier. If they've shown cerebral HYPOperfusion (Stewart et al) then it would seem you wouldn't want a vasoconstrictor crossing the blodd/brain barrier and causing further vasoconstriction in the brain.

I think in past discussions about this drug, it was thought that it wouldn't be an option for "hyper" type presenting patients because they already have too high levels of norepi and would therefore not be useful to a large number of the members on here.

Thanks for posting this Lenna. My neuro was already talking about having me try it when it became available but this report doesn't make it look like something I'd be too interested in taking.

[ramakentesh]

its actually just the pro drug for norepinephrine and many research groups have resisted using it in POTs because they think it would make the condition worse rather than better. Although most current research would suggest that it would be helpful at least in some.

Nearly all the trials have been for NMH and what I had heard was all positive rather than negative, especially in Australia.

High NE in the brain doesnt vasoconstrict, it actually reduces sympathetic outflow in most cases.

[Lenna]

UPDATE:

Split FDA Panel Favors Droxidopa for Hypotension

By John Gever, Senior Editor, MedPage Today

Published: February 23, 2012

An FDA advisory committee voted narrowly in favor of droxidopa (Northera) for neurogenic orthostatic hypotension in patients with certain neurological disorders.

By a 7-4 vote, with one abstention and one member not voting, the agency's Cardiovascular and Renal Drugs Advisory Committee recommended on Thursday that the drug be approved.