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"Hemispherx Biopharma Research Team Identifies Characteristics...predictive of response to Ampligen"

Kyla

ᴀɴɴɪᴇ ɢꜱᴀᴍᴩᴇʟ
Messages
721
Location
Canada
http://globenewswire.com/news-relea...dictive-of-Improved-Response-to-Ampligen.html


PHILADELPHIA, Sept. 21, 2015 (GLOBE NEWSWIRE) -- Hemispherx Biopharma (NYSE MKT:HEB) announces the publication of an online peer reviewed research article of an analysis of clinical data on its investigational therapeutic, Ampligen, entitled, "Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME); Characteristics of Responders to Rintatolimod" in the current issue of Journal of Drug Research and Development. The team of authors is composed of Hemispherx staff, consultants and leading independent clinical experts in CFS/ME in the United States.

Data from a previous Phase III clinical trial of Ampligen in patients with CFS/ME were retrospectively analyzed to determine whether baseline exercise tolerance (ET) could be used to predict responses to Ampligen (rintatolimod) vs. placebo. A modified Bruce ET treadmill test was used because of the severe physical exercise intolerance of CFS patients.

Analysis of significant improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using a baseline exercise threshold ET of greater than 9 minutes. For this subset of patients with baseline ET >9 minutes, 33% of patients on Ampligen®, an experimental therapeutic, vs. 12% of patients on placebo improved ET duration by ≥ 25% (p=0.004) while 23% of Ampligen® treated patients improved by ≥ 50% compared to 4.5% placebo patients (p=0.003).

A continuous responder analysis provided further support for a significant clinical enhancement in the ET effect in the Ampligen® cohorts as compared to placebo.

The Karnofsky Performance Score (KPS) and Vitality (SF-36 subscale) quality of life secondary endpoint also demonstrated similar clinically significant improvements for the cohort of study subjects with baseline ET > 9 minutes, as a function of the same ET parameters. Importantly, these improvements, the 10 point increase in KPS and 14.6 point increase in vitality scores, are both considered by the authors to reflect clinically significant changes that represent objective improvement in the quality of life. Ampligen®, an experimental therapeutic, also reduced deterioration in ET compared to placebo in patients who failed to improve physically.

Taken in context with the recent peer reviewed publication pointing to reduced NK function in CFS/ME patients, (entitled "Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity" in which 17 studies were reviewed that evaluated NK cell cytotoxicity (NKCC) data and the relationship to different CFS case definitions and CFS disease severity, Journal of Clinical and Cellular Immunology (Strayer D, et al, J Clin Cell Immunol 2015;6:4 http://doi.org/10.4172/2155-9899.1000348), a new set of evidence based criteria have now been identified which may assist in selection of CFS/ME patients who may derive significant benefit clinically from therapeutic intervention with selective TLR-3-dsRNA activators. "In context, this clear statistical improvement corroborates our independent clinical experts, who indicate that they have also identified criteria predictive of responsiveness to our experimental drug Ampligen®", states Tom Equels, President of Hemispherx.



- See more at: http://globenewswire.com/news-relea...esponse-to-Ampligen.html#sthash.BJi2UlGo.dpuf
 

Riley

Senior Member
Messages
178
I don't really understand what this study is saying. How is an exercise test predictive of response?
 

SOC

Senior Member
Messages
7,849
Some big names
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod
David R Strayer1 Bruce C Stouch2 Staci R Stevens3 Lucinda Bateman4 Charles W Lapp5 Daniel L Peterson6 William A Carter1 William M Mitchell7*

The inclusion and exclusion criteria for study enrollment is detailed in Supplemental Table S1 and meets both the original [1] and revised [2] CDC clinical definitions of CFS.
I can't find the Supplemental Tables :oops: so I can't figure out what these patients actually looked like. The CDC clinical definitions of CFS are not impressive, but the researchers also say these are "severe CFS/ME" patients, so it could be a decent cohort anyway. Maybe someone with better cognitive function than I have atm can figure that out.
Conclusions
A modified Bruce ET protocol allowed clear identification of a rintatolimod responder subset in patients with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes exercise. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.
Am I reading this correctly that Ampligen works better with less severe patients (or less severe severe patients o_O)? That's a bit disappointing for the worst among us, but the somewhat positive news is that the more severe patients had less deterioration if they were taking Ampligen than those who weren't.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Maybe this is helping to prepare the ground for the big (expensive) study that Hemisperx is supposed to be publishing soon? They need to identify some sort of patient-subgroup that responds to Ampligen with a statistically significant effect size, so they can get the drug FDA approved. I don't particularly like this way of identifying a subgroup, but if it gets it approved and onto the market, then job done, and it will be available to our community. I thought Hemispherx might have found a biomarker in relation to NK cell function, that helps identify a cohort that responds to treatment - and perhaps they have - perhaps they have two markers now. It's supposed to be a big (expensive) study that they are publishing, if I've understood things correctly.
 

Riley

Senior Member
Messages
178
This "study" is just a post hoc rehashing of the old phase 3 data. I don't think it in any way demonstrates an ability to identify responders.

Having Lapp, Peterson, and Bateman on the study doesn't really mean much other than they all have been principal investigators in the ampligen trials and are therefore responsible for the data collection.

Also, I have responded well to ampligen and was 100% bedridden in a dark room when I started. I obviously did not do an exercise test then, nor would I do one now out of fear of relapse.

This contradicts the hypothesis that a nine minute treadmill test predicts greater response.

I think this is just a PR effort by Hemispherex.
 

SOC

Senior Member
Messages
7,849
Also, I have responded well to ampligen and was 100% bedridden in a dark room when I started. I obviously did not do an exercise test then, nor would I do one now out of fear of relapse.

This contradicts the hypothesis that a nine minute treadmill test predicts greater response.
One person/data point doesn't contradict anything, especially since you didn't do the exercise test so we don't know for certain how you would have done on it. They are not claiming their conclusion applies 100% of the time with 100% of the patients. It's a statistical conclusion.

I'm very pleased to hear that you were severely affected and responded well to Ampligen. That is encouraging for our more severe patient population.
 

Forbin

Senior Member
Messages
966
In a recent video, Dr. Peterson said that 1 in ~7 ME patients in his practice (~15%) meet the entrance criteria for Ampligen. Of those treated, he said that 70% experience about 80% improvement (a "dramatic response").

The link to that unlisted Dr. Peterson youtube video can be found here at the facebook page of the MEFM Society of BC.
...
https://www.facebook.com/permalink.php?story_fbid=967783493267674&id=191475807565117

Since it is unlisted, I thought it might be best not to post the link directly on PR.

Dr. Peterson's comments on Ampligen begin at about 51:50 into the youtube video.
 

SOC

Senior Member
Messages
7,849
In a recent video, Dr. Peterson said that 1 in ~7 ME patients in his practice (~15%) meet the entrance criteria for Ampligen.
I assume this means they meet the entrance criteria for Ampligen research studies which could be quite stringent -- no other treatments, for example. That isn't necessarily an indication of what percentage of patients would be suitable candidates for Ampligen treatment once (if) it's available to the public.

Of those treated, he said that 70% experience about 80% improvement (a "dramatic response")
That's good news, even if only a fraction of us are suitable candidates for Ampligen.

My guess is that substantially more than 15% of us would be suitable candidates for Ampligen, but that a smaller percentage of that larger group would see a dramatic response. It's probable that Hemispherix selected their research entrance criteria to select the group most likely to respond dramatically. That doesn't mean it wouldn't benefit others, even if to a lesser degree.
 

Jill

Senior Member
Messages
209
Location
Auckland, NZ
What I want figured out is how two drugs with different actions can both be 'working ' in ME. I v much favour the rituxan work and like the vascular auto antibody theory. I wonder if ampligen mode of action in some way could also be affecting B cells . Anyone any thoughts.
 

alkt

Senior Member
Messages
339
Location
uk
I assume this means they meet the entrance criteria for Ampligen research studies which could be quite stringent -- no other treatments, for example. That isn't necessarily an indication of what percentage of patients would be suitable candidates for Ampligen treatment once (if) it's available to the public.


That's good news, even if only a fraction of us are suitable candidates for Ampligen.

My guess is that substantially more than 15% of us would be suitable candidates for Ampligen, but that a smaller percentage of that larger group would see a dramatic response. It's probable that Hemispherix selected their research entrance criteria to select the group most likely to respond dramatically. That doesn't mean it wouldn't benefit others, even if to a lesser degree.
that would depend on various government and insurance people thinking that some undefinable improvement in pwme is worth the cost . i do not think nice in england are going to approve funding for someone who only gains a partial improvement to their overall quality of life. after all if its not going to benefit the taxman by significantly reducing the bill for disability benefits the been counters would veto this treatment.
 

nandixon

Senior Member
Messages
1,092
What I want figured out is how two drugs with different actions can both be 'working ' in ME. I v much favour the rituxan work and like the vascular auto antibody theory. I wonder if ampligen mode of action in some way could also be affecting B cells . Anyone any thoughts.
It doesn't seem to me that autoimmunity is very likely in the patients who have a significant response to Ampligen, given that that drug is an immunostimulant.

Unless, the autoimmunity is itself of an immunosuppresive nature (e.g., autoantibodies that somehow increase the activity of Tregs, as one example), which would be a novel finding, I think.

Note that rituximab (and also cyclophosphamide) can be either immunosuppressive (good for autoimmune diseases) OR immunostimulatory (good for states of immune suppression, like in cancers) depending on the context of the disease. (Cyclophosphamide can also be either an immunostimulant or an immunosuppressant depending on the size of its dose, i.e., the newer "metronomic" low dosing versus the older cytotoxic high dosing.)

And we don't know what the context of the disease is for ME/CFS.

I think the weight of evidence (e.g., the Lights' series of papers; Montoya's gene expression work and the SIRS analogy; increased Treg activity; increased IL-10 levels post-exertionally, etc.) suggests ME/CFS is more likely to be a state of immune suppression rather than autoimmunity.

But it may be one thing in one subset of patients and the other in another subset. (And might even be a sort of hybrid autoimmunity-induced immune suppression, as mentioned.)

The autoimmune theory really has no weight of evidence at all, that I'm aware of, with the sole exception of the time lag for response to rituximab. But that time lag could correspond to the death of several cell types other than just alleged autoantibody-producing plasma cells.

In other words, the B cells being depleted by rituximab may merely be mediating (passing along) a bad signal that is arising elsewhere, rather than actually being inherently bad (i.e., autoantibody-generating) themselves.

I think the Ampligen success stories, if indeed true, are yet more evidence for some type of immunosuppressive state in ME/CFS. But I'm mainly just putting out some ideas for researchers to think about.
 

Forbin

Senior Member
Messages
966
Late night speculation...

Could a failure in one element of the immune system dealing with a chronic pathogen lead to a general chronic activation in response to that failure (perhaps by chronically trying to stimulate the defective element)? You'd could have both specific under-performance in one element of the system and a more general chronic activation as a result of that failure. A drug that specifically stimulated the under-performing element might then have the counter-intuitive effect of quieting the more general chronic activation (which might be the main cause of the symptoms)..
 
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JohnnyD

Senior Member
Messages
206
@SOC , I agree completely with your last post. this was a study of severe CFS patients. Even though they could not include patients in the analysis that could not make baseline ET, they still saw improvement in those patients.

Doing a survey of 17 pas NK cell function papers and doing this retrospective really confirms what Peterson has known for some time. Peterson is the clinician with the most ampligen experience, by far. re: from a 2011 Phoenix Rising article:
http://phoenixrising.me/archives/6103

"The Key Test


Dr. Peterson distinguishes what he believes to be an archetypal ME/CFS patient from the others primarily by using one test – the natural killer (NK) cell functioning test. The International Consensus Criteria for ME considers post-exertional neuroimmune exhaustion or PENE to be the hallmark of ME and Dr. Hyde focuses on SPECT scans, but Peterson has found the NK cell functioning test to be the most definitive."

The study correlated severity of disease with NK cell function and then looked at ampligen improving NK Cell function and correlating that with improved ET and other life function testing. With the P Values quoted, p=.002 and p=.003, the role that chance played a part can be dismissed. The positive effect was due to ampligen. Peterson now has the stats to back him up. IMO, they have identified a bio-marker for severe CFS patients and a sub-group that responds to ampligen. To understand the significance of this and to put it in perspective, re-read the June 5, 17 experts letter to the FDA and their call for conditional approval of ampligen. This puts increasing pressure on the FDA to do something about ampligen and treatment for this devastating disease.

http://www.cortjohnson.org/treating...experts-request-major-ampligen-review-at-fda/
 

A.B.

Senior Member
Messages
3,780
I don't think there is necessarily a conflict between the autoimmune and immune deficiency hypotheses. We all agree that B cell depletion and Ampligen don't work for everyone. The spectrum of CFS and probably also ME is so wide that there is room for many different diseases processes.
 

msf

Senior Member
Messages
3,650
I would like to see Nandixon, Forbin and Prof. Edwards debate this, while I sit back and chant ´fight, fight, fight!´
 

nandixon

Senior Member
Messages
1,092
I would like to see Nandixon, Forbin and Prof. Edwards debate this, while I sit back and chant ´fight, fight, fight!´
I actually think it's a pretty close call between whether a majority of patients with ME/CFS are suffering from some form of immune suppression versus some form of autoimmunity (or a hybrid of both). Maybe like a 55% chance the former and 45% the latter. And there are almost certainly subsets of both, anyway.

One interesting thing is how well that immune suppression fits with respect to PEM. When athletes, for example, overexert themselves - say running a marathon, this causes immune suppression. In ME/CFS, it might be that some of the same affected pathways are exaggerated upon merely minimal exertion. That is, in ME/CFS, minimal exertion might be interpreted by the body as over exertion.

On the other hand, I don't see any predominant signs of PEM in any autoimmune diseases - although granted ME/CFS might be the first. There is plenty of fatigue in autoimmune diseases (this is actually the number one most disabling symptom across all autoimmune diseases), but not PEM, I don't think.