What lessons can Berlin Cures learn from Ampligen?

[Paraprosdokian]

Hi,

I am thinking of writing a letter to Berlin Cures, Dr Bettina Hohburger and Professor Carmen Scheibenbogen to assist them with experimental design. I am hoping to gather more ideas from people on PR who have a longer memory about Ampligen.

I am not a scientist, but it occurred to me that Berlin Cures is likely to be unaware of Ampligen and could learn lessons from the failure of Ampligen to get approved.

Ampligen was a drug that anecdotally cured or significantly improved the lives of many ME/CFS patients, but which ultimately failed to convince the FDA of its efficacy and safety.

We dont have access to the FDA rejection letter, but it is described in a press release from Ampligen's creator, HemisphereX:

The Agency stated that the submitted data do not provide substantial evidence of efficacy of Ampligen® for the treatment of CFS and that the data do not provide sufficient information to determine whether the product is safe for use in CFS due to the limited size of the safety database and multiple discrepancies within the submitted data.

It seems the FDA's calculation shows they did not show statistical significance for efficacy, but HemispherX did. The question of safety seems to be related to some patients who became worse while on Ampligen. In later presentations, HemispherX insists the number of adverse events in the drug and placebo cohorts were identical.

The experimental design of the Ampligen trial is described here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917909/#!po=23.6842

What lessons can we gather here? I was going to suggest the following lessons:

• Suggest that they speak with Dr Peterson and Dr Lapp about their proposed experimental design. The doctors might be able to share lessons or provide tips without disclosing confidential information about the Ampligen trial.
• The phase 3 Ampligen trial measured improvement based on exercise tolerance using a treadmill. Both the placebo and Ampligen arms improved their exercise tolerance, but the improvement in the Ampligen arms was statistically significantly larger than the placebo arm based on the company's calculations.
• The safety profile featured severe adverse events in both arms. That is likely because ME/CFS patients experience severe crashes. Berlin cures will need to design their experiment design with this fact in mind.
• Suggest they use an objective primary endpoint, such as improvement in microcirculation in the eyes rather than attempting to use

So any tips on experimental design for Berlin Cures? You guys read a lot of ME/CFS papers. What is the best way to measure improvement in performance? Ampligens phase 2 trial used Karnovsky scores which are a subjective measure. Step counts seem to be a flawed measure as well.

 

[Pyrrhus]

Interesting ideas, thanks for sharing!

I know that a number of people have asked what Berlin Cures can learn from the Rituximab trial, but I hadn't thought of the Ampligen trial...

 

[halcyon]

I believe that muscle testing is likely to be one of the best objective markers to use in ME research. A couple papers I linked in another thread (Jammes & Retornaz, 2020; Jäkel et al., 2021) discuss the use of handgrip strength testing as a possibility. An older study also used strength testing (using leg muscles) with a 2-day protocol to good effect (Paul et al., 1999).

Now, it may be that while these methods work OK for diagnostic purposes, they may work less well for measuring improvement in clinical trials, perhaps due to high variability or training effect or other reasons I can't think of. Also, I don't have a good sense of whether muscle testing would be better or worse than repeat CPET testing in terms of danger to the patient. I have to imagine, especially the handgrip test, would be much less strenuous, but I don't know for sure. I just feel like repeat CPET has built-in selection bias and it's not a good measure to use because it automatically excludes more severe patients from the cohort.

All I know is I'm sick to death of subjective outcome measures.

 

[heapsreal]

I believe that muscle testing is likely to be one of the best objective markers to use in ME research. A couple papers I linked in another thread (Jammes & Retornaz, 2020; Jäkel et al., 2021) discuss the use of handgrip strength testing as a possibility. An older study also used strength testing (using leg muscles) with a 2-day protocol to good effect (Paul et al., 1999).

Now, it may be that while these methods work OK for diagnostic purposes, they may work less well for measuring improvement in clinical trials, perhaps due to high variability or training effect or other reasons I can't think of. Also, I don't have a good sense of whether muscle testing would be better or worse than repeat CPET testing in terms of danger to the patient. I have to imagine, especially the handgrip test, would be much less strenuous, but I don't know for sure. I just feel like repeat CPET has built-in selection bias and it's not a good measure to use because it automatically excludes more severe patients from the cohort.

All I know is I'm sick to death of subjective outcome measures.

You heard from the health guru's that some of these diagnostic studies dont directly diagnose cfsme. Well my opinion of that is its bs. Use tests as biomarkers such as the 2 day exercise test, nk function test, cd8 T cell function test, different cytokine studies etc used in conjunction with the current diagnostic criteria. I dont understand whats so hard about it????

 

[SWAlexander]

AIM seeks FDA approval to study Ampligen for Covid-19
The two-arm, randomised trial will enrol 80 subjects with PCCD to evaluate Ampligen’s efficacy and safety.
https://www.pharmaceutical-technology.com/news/aim-study-ampligen-covid/

 

[Paraprosdokian]

I believe that muscle testing is likely to be one of the best objective markers to use in ME research. A couple papers I linked in another thread (Jammes & Retornaz, 2020; Jäkel et al., 2021) discuss the use of handgrip strength testing as a possibility. An older study also used strength testing (using leg muscles) with a 2-day protocol to good effect (Paul et al., 1999).

Are people with MECFS weaker than others? If not, why would a grip test grow stronger. Aside from deconditioning, I feel as strong as ever.

Scheinbenbogan's immunoadsorption test showed promising results in terms of step count and subjective reporting (against objective crtieria) but no improvement in grip strength. Not sure if thats a flaw in the measurement or proof that immunoadsorption doesnt work.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854315/

 

[halcyon]

Are people with MECFS weaker than others? If not, why would a grip test grow stronger. Aside from deconditioning, I feel as strong as ever.

It's more that in CFS patients are unable to reproduce maximum voluntary contractions (MVCs) upon repeat testing. In the Paul et al. study, this was evident both when repeated in the same session, as well as 24 hours later. It's recovery, rather than strength/endurance, that is abnormal in patients.

Not sure if thats a flaw in the measurement or proof that immunoadsorption doesnt work.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854315/

As far as I'm aware, the antibodies identified (using the CellTrend assay) have never been proven to be pathogenic. Also, the methodology used by that lab is known to produce false positives through a phenomenon called non-specific binding.

 

[Paraprosdokian]

Thanks for your help everyone! Ive incorporated your ideas into my email. Here is my draft email. Any comments or additions?


Lessons on experimental design for BC 007 from Ampligen failure


Dear Dr Hohburger and Dr Kräter


I am writing to draw your attention to a ME/CFS drug named Ampligen which failed to get FDA approval in the USA. I hope to draw out some lessons from that failure for how to design your phase 2 trial for BC 007 in ME/CFS and Long COVID. I apologise for writing in English.


I am not a scientist, but I have severe ME/CFS. I want to see BC 007 approved for treating ME/CFS. The FDA rejected Ampligen in 2009 and a decade later, there has been no progress in approving Ampligen. You may only get one shot at approving a drug, so I hope that you get it right the first time!


History of Ampligen


Ampligen is a drug with broad immunomodulatory and antiviral properties. Its manufacturer, AIM Immunotech (then named Hemispherx Biopharma), sought FDA approval for treating ME/CFS. Despite powerful anecdotal stories of people in wheelchairs walking again, the FDA rejected the drug because of sufficient evidence of safety and efficacy (see https://sec.report/Document/0001144204-13-006126/ for further information).


This document describes the experimental design of the Ampligen trials: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917909/#!po=23.6842


Some of the blame can be attributed to AIM which cut their trial from 48 weeks to 24 weeks and which had data collection issues. However, many issues arise from the subjective nature of ME/CFS. I outline some of these issues and potential solutions below.


Lesson 1 - Ask those who experienced the trial firsthand


I suggest that you speak with Dr Dan Peterson (his clinic can be contacted at xxx), Dr Charles Lapp (xxx), or Dr Lucinda Bateman (her clinic can be contacted at xxx). They are doctors who prescribed Ampligen and can tell you their experiences running a clinical trial for ME/CFS. They may be able to share lessons without breaching any confidentiality requirements.


I also suggest you speak with Dr Øystein Fluge (xxx) and Dr Olav Melle (xxx) who ran the Rituximab clinical trials


Lesson 2 - Use objective measurements


Many ME/CFS studies use self-reported measures of fatigue, which can make proving the efficacy of a drug very difficult. I suggest you use objective measures of improvement. For example, you could ask ME/CFS patients to measure their handgrip strength twice. (See https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02774-w for more details) or engage in a two day cardiopulmonary exercise test (https://me-pedia.org/wiki/Two-day_cardiopulmonary_exercise_test). I acknowledge the latter can be challenging.


You are also fortunate that you can measure decreases in autoantibody levels and improvements in eye microcirculation.


Lesson 3 - focus on improving individual symptoms


AIM is now focusing on proving that Ampligen can improve individual ME/CFS or Long COVID symptoms instead of improving ME/CFS or Long COVID universally. For example, their latest phase 2 clinical trial only aims to prove that Ampligen improves cognitive function in Long COVID.


Lesson 4 - patients will inevitably experience 'crashes'


One feature of ME/CFS is that overexertion can cause an increase in symptoms known colloquially as a 'crash'. If patients overexert too much, they can permanently decrease their capability. Many patients who are improving can try to do too much, causing a crash.


These crashes may be classified as Severe Adverse Events. They will occur in both the placebo and treatment arms. This can make it difficult to prove the safety of our drug.


I believe patients in the Ampligen trial experienced crashes. In a recent presentation, AIM emphasised that there were an equal number of Severe Adverse Events in both the Ampligen and placebo arms of their trials (https://d2ghdaxqb194v2.cloudfront.net/2265/185883.pdf).


You must advise your patients to continue pacing even if they feel stronger. They may still experience a crash if they attempt to do too much too quickly.


I hope you have found these lessons to be helpful. The entire ME/CFS community sends you their best wishes.


Kind regards

 

[mitoMAN]

It's more that in CFS patients are unable to reproduce maximum voluntary contractions (MVCs) upon repeat testing. In the Paul et al. study, this was evident both when repeated in the same session, as well as 24 hours later. It's recovery, rather than strength/endurance, that is abnormal in patients.

Yes the Charite Berlin uses the repeated handgrip test for diagnostic criteria of ME/CFS

 

[marcjf]

Does anyone know where exactly AIM sought approval? I always got the impression that they put all their chips on US, by seeking FDA approval. That did not seem to pay off. Evey country will review the drug individually. I am assuming that Berlin Cures will first seek approval within Europe. Not sure if that makes it harder or not.

For example, WinSanTor, the company who is trialing a new treatment for SFN, seems to have done their homework. They consulted with the FDA, and they said they will not be wasting time seeking approval with them. This is a stament from them about this: https://winsantor.com/phase-2-clinical-trial-update/

 

[Paraprosdokian]

Does anyone know where exactly AIM sought approval? I always got the impression that they put all their chips on US, by seeking FDA approval. That did not seem to pay off. Evey country will review the drug individually. I am assuming that Berlin Cures will first seek approval within Europe. Not sure if that makes it harder or not.

For example, WinSanTor, the company who is trialing a new treatment for SFN, seems to have done their homework. They consulted with the FDA, and they said they will not be wasting time seeking approval with them. This is a stament from them about this: https://winsantor.com/phase-2-clinical-trial-update/

AIM also tried in Australia Europe and Argentina. They got knocked back in two and succeeded in Argentina. They got approval for use in severe ME/CFS cases, but are awaiting final inspection by regulatory authorities before they can start commercial sales.

 

[marcjf]

AIM also tried in Australia Europe and Argentina. They got knocked back in two and succeeded in Argentina. They got approval for use in severe ME/CFS cases, but are awaiting final inspection by regulatory authorities before they can start commercial sales.

That is so random, nobody would be able to afford the medication in Argentina, at least at the current price point.

 

[Marylib]

I get your point about the expense involved in staying alive via Ampligen. But some have managed, or I guess we can all keep waiting until more of us get pancreatic cancer.
https://aimimmuno.com/press-release...-and-innovative-therapies-for-pancreatic-can/

 

[Paraprosdokian]

I get your point about the expense involved in staying alive via Ampligen. But some have managed, or I guess we can all keep waiting until more of us get pancreatic cancer.
https://aimimmuno.com/press-release...-and-innovative-therapies-for-pancreatic-can/

AIM is currently developing protocols for a phsse 3 study. Theyve missed their original target of filing their phase 3 study request by end 2021, but it could come any month now