Mitchell: Efficacy of rintatolimod [Ampligen] in the treatment of CFS/ME

[mango]

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me).

Mitchell WM1.

Author information
1a Department of Pathology, Microbiology & Immunology , Vanderbilt University.

Expert Rev Clin Pharmacol. 2016 Apr 5. [Epub ahead of print]

Abstract
Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms.

The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA).

Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2'-5' adenylate synthetase, protein kinase R).

Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe.

The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.

Keywords:
Ampligen; Chronic Fatigue/Myalgic Encephalomyelitis; TLR3 agonist; clinical efficacy; clinical safety; clinical trials; dsRNA; primate/non-primate disassociation of toxicity; rintatolimod

http://www.ncbi.nlm.nih.gov/pubmed/27045557

 

[*GG*]

Can you add in the title that this is about Rintatolimod=Ampligen?

GG

 

[mango]

Can you add in the title that this is about Rintatolimod=Ampligen

great suggestion! thank you

 

[sdmcvicar]

That's one heck of a paywall. I don't have access to the complete article through my normal routes as part of the U of Texas Medical Branch. Will try to hunt down a copy tonight.

 

[M Paine]

Is it correct that this is a review paper, and we probably won't see new data about Ampligen in this paper?

Does this seem like something Hemispherix might be involved in, to further the goal of gaining approval for this drug?

Hopefully this paper is one step closer to seeing this as a treatment option for patients.

 

[halcyon]

That's one heck of a paywall. I don't have access to the complete article through my normal routes as part of the U of Texas Medical Branch. Will try to hunt down a copy tonight.

https://sci-hub.io/10.1586/17512433.2016.1172960

 

[Janice Hargreaves]

That's really great to be able to see the full paper. Thank you for posting. More hope then?

 

[sdmcvicar]

Thanks halcyon!

Actually a good comprehensive review.

 

[M Paine]

Not to suggest that anything untoward is occurring here, but it's interesting to see how the wheels turn so to speak

"Declaration of Interest: WM Mitchell is an independent member of the Board of Directors of the public company Hemispherx Biopharma with stock and option ownership."

 

[joshualevy]

Also note that the author specifically thanks two people for critiquing the paper: one is a co-worker at the author's university and the other is the medical director of Hemispherx. The author also acknowledges getting access to Hemispherx's FDA files. So this paper was clearly an inside job. But much more importantly (to me) there is no new information here. After decades of noise, Hemispherx has (at best) one phase-II trial and one phase-III trial completed. Everyone knows that you need two phase-III trials to get approval under normal rules.

I say "at best" because my memory is that the FDA reviewers did not agree with Hemispherx's conclusions about their phase-III trial. So from the FDA's point of view (the only one that matters), there might only be a single phase-II trial, when two phase-III trials are needed. And this has been true for years. If Hemispherx was serious about this drug, and the drug showed promise, they would run another phase-III trial (or two more). Partnering with another pharma company if needed. If the drug were promising, companies would be lining up to invest in the first drug for a large unmet need.

But it is clear the drug is not promising, and republishing old data is not going to make it so.

 

[halcyon]

But it is clear the drug is not promising, and republishing old data is not going to make it so.

What's sad is that it could be promising for a subgroup of patients. We know there are patients that basically go back to normal on the drug. The fact that statistically it didn't work on a heterogeneous group of CFS patients is no surprise. You'd think by now they'd be able to characterize the responders to the drug and set up a more targeted trial but I guess not.

 

[Kati]

Also note that the author specifically thanks two people for critiquing the paper: one is a co-worker at the author's university and the other is the medical director of Hemispherx. The author also acknowledges getting access to Hemispherx's FDA files. So this paper was clearly an inside job. But much more importantly (to me) there is no new information here. After decades of noise, Hemispherx has (at best) one phase-II trial and one phase-III trial completed. Everyone knows that you need two phase-III trials to get approval under normal rules.

I say "at best" because my memory is that the FDA reviewers did not agree with Hemispherx's conclusions about their phase-III trial. So from the FDA's point of view (the only one that matters), there might only be a single phase-II trial, when two phase-III trials are needed. And this has been true for years. If Hemispherx was serious about this drug, and the drug showed promise, they would run another phase-III trial (or two more). Partnering with another pharma company if needed. If the drug were promising, companies would be lining up to invest in the first drug for a large unmet need.

But it is clear the drug is not promising, and republishing old data is not going to make it so.

Thanks for this comment @joshualevy. To your knowledge has there been 2 different pharma companies joining forces and investment in order to put a drug on the market? Is this common occurence?

 

[joshualevy]

The fact that statistically it didn't work on a heterogeneous group of CFS patients is no surprise.

I have never understood this reasoning. The basic argument, used by you and many others is this: since CFS patients are heterogeneous, it is OK to ignore trial results that we don't like, because the failure is somehow caused by this heterogeneity.

But, in fact, the opposite is true. Imagine a heterogeneous disease, where only 20% of the people have the "real" disease, and 80% have something else (or many other things). You give them all a drug which only works on the "real" disease. The 20% get noticeably better. Nothing happens to the other 80%. You score an immediate double win: first the drug shows overall improvement: 20% improve a lot, the rest don't change so you end up with overall improvement. Second, you get a powerful clue to help you separate out the "real" disease from everyone else. In the past, something very similar has been done with some cancers; they are classified based on which drugs they react to.

So even in a heterogeneous disease, a drug that works will have a successful clinical trial unless (a) it hurts people who don't have the "real" disease as much or more as it helps people who do have it, which is very bad luck. Or (b) the "real" disease is so rare within the heterogeneous group, that the results are statistically insignificant, which is also very bad luck. And neither case is likely to be true here.

You'd think by now they'd be able to characterize the responders to the drug and set up a more targeted trial but I guess not.

Exactly! The obvious conclusion is this: Some ME/CFS patients get better and some get worse. It is the random fluctuations of the disease. If you give them the drug, then some get better and some get worse. It is the random fluctuations of the disease and the drug has no effect. There are no "responders" you are just measuring random fluctuations. That is why they can not be characterized, and have not been characterized even with many years of research.

 

[joshualevy]

To your knowledge has there been 2 different pharma companies joining forces and investment in order to put a drug on the market? Is this common occurence?

Absolutely! Phase-III trials are too expensive for most small pharma companies to fund themselves (and Hemispherix is very much "small pharma"). It is normal for a bigger pharma company and a smaller pharma company to cut a deal to fund phase-III trials. (The bigger company supplies the money and ends up owning part of the new drug or partial marketing rights to the new drug, if it is successful in testing.) I don't have time to write a good posting on this right now, but maybe in a couple of days. But the answer to your question is that it very common.

 

[M Paine]

For those of us unfamiliar about the contention surrounding the Phase III trial data, does anyone have a link to more information about that?

 

[LaurelW]

I say "at best" because my memory is that the FDA reviewers did not agree with Hemispherx's conclusions about their phase-III trial.

I was there at the FDA meeting where they voted against the approval of Ampligen. I testified along with many other people. It was really disheartening because most of the people voting didn't know anything about ME/CFS. They also didn't allow Hemispherx to answer any of their questions and concerns, even though they were ready to do so. I heard later that more than one person said that if they knew more at the time, they would have voted in favor. So the worthiness of their decision shouldn't be considered an expert opinion.

That being said, Hemispherx has always operated on the edge financially and really needs to do another Phase III trial. A lot has been learned about the disease since then.

Having been in two Ampligen trials myself, I can tell you that their are people who are really good responders, some who respond but with much less dramatic effect, and some who don't respond at all. Finding a way to tease out which ones will respond would be a huge boon to the drug company, the doctors, and the patients. As far as the duration of the treadmill test being a predicter, I'm skeptical.

 

[M Paine]

Great insight, thanks @LaurelW

 

[joshualevy]

For those of us unfamiliar about the contention surrounding the Phase III trial data, does anyone have a link to more information about that?

Sure. Here is some information:
http://simmaronresearch.com/simmaro...-which-way-ampligen-the-fda-advisory-meeting/

Here are the low-lights (there are no high lights):

1. The first study (AMP-502) did not show positive results until Hemispherx tossed out 7 patients. Only then was it successful. Here is the quote: "After finding that the original exercise protocol was too difficult, however, Hemispherx changed the protocol and eliminated the first seven patients from the analysis. ( If those patients are included in the analysis the significantly positive effects disappeared. )".

2. The second study (AMP-516) was also unsuccessful as originally run. Exact quote: "failed to show significant increases in self-reported functioning or ETT." The success later claimed by the company involved post-hoc re analysis of the data.

 

[panckage]

The only drug in advanced clinical development is rintatolimod

This statement also is a bit of a red flag. Surely they know rituximab is in stage 3 trials now. To completely ignore this is odd. And isn't ampligen the drug that only makes oneself like 10% better. Too bad you have to waste 15% of energy going to the doctor all the time to get the drug administered