Article: 2012 - the Year Ahead Pt II: ME/CFS Efforts Expand

Comments

Thanks for this great summary of 2012 research, Cort. Nice to see lots of intriguing work going on. 'Knowledge Base to Biomarker' sounds fascinating. Do you know any more about it?

Glad to see more EEG research too (as well as all the other stuff of course).
 
This gives me hope for the community. Thanks, Cort.
 
Yes, great article again and very hopeful.
What about Dr. Benjamin Natelson studies of the brain of ME/CFS patients at his Pain and Fatigue Center in Beth Israel Medical Center in NYC?
 
Thanks for this great summary of 2012 research, Cort. Nice to see lots of intriguing work going on. 'Knowledge Base to Biomarker' sounds fascinating. Do you know any more about it?

Glad to see more EEG research too (as well as all the other stuff of course).
Thanks Astrocyte. I'm going to try and find out more about the Knowledge Base To Biomarker study with Dr. Vernon. That is intriguing is it not? This is the kind of 'out of the box' cutting edge stuff that Dr. Vernon loves I think.
 
This gives me hope for the community. Thanks, Cort.
Thanks Merry, the CAA is going to announce their grants tomorrow - so we should have 4 or 5 more research studies to look at tomorrow :). There's something about ME/CFS experts funding ME/CFS research that adds an extra edge to me - you don't get the hostile review panels who are quirky about CFS - you just get people who dearly want to succeed. ;)
 
Yes, great article again and very hopeful.
What about Dr. Benjamin Natelson studies of the brain of ME/CFS patients at his Pain and Fatigue Center in Beth Israel Medical Center in NYC?
Missed it! ......I knew about Natelson and I love his work but I didn't know about the Pain and Fatigue Center in Beth Isreal Medical Center. (I was hoping that a few CFS research centers would pop up that I didn't know about). I will see if I can get some info on that. I'm pretty sure that he's doing an followup spinal fluid study...

Thanks!
 
Thanks, Cort, lots of hope in that article!

I hadn't previously heard of Droxidopa - any info on what advantages it might have over other drugs used for OI?
 
Missed it! ......I knew about Natelson and I love his work but I didn't know about the Pain and Fatigue Center in Beth Isreal Medical Center. (I was hoping that a few CFS research centers would pop up that I didn't know about). I will see if I can get some info on that. I'm pretty sure that he's doing an followup spinal fluid study...

Thanks!
Hi Cort,

Isn't it great that there are even more?:cool:
His wesite that shows the studies is here: http://www.painandfatigue.com/new_research_studies.html
 
Got me excited about a possible ritux study by PHANU, i was hoping something like this would happen.

cheers!!!
 
Got me excited about a possible ritux study by PHANU, i was hoping something like this would happen.

cheers!!!
Yep....They're not the only ones...the Open Medicine Institute is trying to get a study going as does Dr. Enlander.
 
Thanks, Cort, lots of hope in that article!

I hadn't previously heard of Droxidopa - any info on what advantages it might have over other drugs used for OI?
Here some more info on Droxidopa from the study

droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the International non-proprietary name (INN) for a synthetic amino acid precursor of norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited, Japan. It has been approved for use in Japan since 1989.
Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure, and Parkinson's disease. There are four stereoisomers of DOPS; however, only the L-threo-enantiomer (droxidopa) is biologically active.

The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been precisely defined; however, its NE replenishing properties with concomitant recovery of decreased noradrenergic activity are considered to be of major importance.

Droxidopa has been marketed in Japan since 1989. Data from clinical studies and post-marketing surveillance programs conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In clinical studies, the prevalence and severity of droxidopa adverse effects appear to be similar to those reported by the placebo control arm.
 
Thanks, Cort - I've been avoiding drug treatment for my OI because of concerns about supine hypertension, BP spikes, etc. so Droxidopa sounds interesting if patients have no more adverse effects than those on placebo.
 
The Lapp website says the trial is continuing, the clinicaltrials.gov site said it was terminated for lack of interest from the patients - not sure what is going on but the company that makes the drug is trying to get it into the US market. Hopefully they will succeed.
 
Thanks Astrocyte. I'm going to try and find out more about the Knowledge Base To Biomarker study with Dr. Vernon. That is intriguing is it not? This is the kind of 'out of the box' cutting edge stuff that Dr. Vernon loves I think.
This project is creating a huge database that will continue to grow and grow as more studies become available. The CAA envisions it (and all their projects) as being 'open source' and available to all researchers at some point. I believe it will be done later this year.
 
Droxidopa and FDA

Thanks, Cort - I've been avoiding drug treatment for my OI because of concerns about supine hypertension, BP spikes, etc. so Droxidopa sounds interesting if patients have no more adverse effects than those on placebo.
Ouch - so much for benign side effects; FDA panel recommends not approving droxidopa

FDA Skeptical of Hypotension Drug
By John Gever, Senior Editor, MedPage Today
Published: February 22, 2012

http://www.medpagetoday.com/Neurology/GeneralNeurology/31305?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g161002d0r&userid=161002&email=jwhy@earthlink.net&mu_id=

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.
Be the first to leave a comment
 
FDA Panel Votes FOR Droxidopa for Hypotension

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.

An FDA staff review released before the meeting had recommended against approval, citing lack of evidence that the drug 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. Also, nine cases of neuroleptic malignant syndrome had been seen in Japanese patients taking the drug.

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. A variety of other drugs are used off-label, all of which have significant side effects and/or contraindications.

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 was based largely on two randomized trials and an open-label extension to one of them. One of the randomized studies failed to meet its primary efficacy endpoint, which the FDA staff review noted among the drug's negatives.

The FDA usually, but not always, follows recommendations from its advisory committees.
Be the first to leave a comment
 
Thanks for another helpful and comprehensive round up. I agree that things are on the up.

One point - I've no idea why WPI are following up Kerr's work, given his own failure to replicate the earlier findings in a 2011 PLos One paper:
We conclude many of the previously identified reporter genes are study-specific and thus cannot be used as a broad CFS diagnostic.
Not many people seem to know about this study.
 
Thanks for another helpful and comprehensive round up. I agree that things are on the up.

One point - I've no idea why WPI are following up Kerr's work, given his own failure to replicate the earlier findings in a 2011 PLos One paper:Not many people seem to know about this study.
Thanks OceamBlue - Yes, I completely missed that.. how I did I don't know. How unfortunate that was. Gene expression has been problematic to say the least in ME/CFS...Here's another section from the paper:

However, when assessed on a new, blinded 128 sample test set only 58% of samples were predicted correctly. Importantly, a high number of false-positive predictions were made, with 31% of CFS-positive predictions being from healthy volunteers. In addition, a high number of false negative predictions were made, 57% of the CFS samples being predicted as healthy controls. Therefore, with the methods used here we cannot predict CFS disease based on the analysis of expression of 44 classifier genes in the peripheral blood.