GM604: Is it Ready For FDA Approval?

It is challenging for any scientist, clinician, or stakeholder to keep abreast of the peer-reviewed published observations in their respective field. ALS is no different. It is even more challenging and critical to filter through all the available daily content from additional sources and focus on the pivotal advances. The breakthroughs at any point in the drug development value chain that could lead to the “Ah ha” moment and eventually a treatment for ALS.

Looking back, it’s not very surprising how little mental energy I put into the announcement of Genervon successfully completing a phase IIA trial of GM604 in ALS back in October of 2014. After all it was only 12 patients and 12 weeks of exposure to GM604. Typically that would make it just the first check box in the long and arduous process of testing if a drug is safe and provides any measureable benefit to ALS patients or any other disease.

I remember going to ClinicalTrials.gov and looking at the design and outcomes and a doing a quick pubmed search of GM604. The summary on clinicaltrials.gov confirmed the design and suggested it was really just a safety trial. With so few patients, the clinical outcomes and biomarker arms looked too underpowered. When I say that something is underpowered, I mean that there were not enough people enrolled in the trial to truly tell whether the drug is being helpful or harmful. As far as the PubMed search, a search for GM604 returned very little. A couple of publications of a five amino acid fragment of Motorneuron trophic factor (MNTF) having some effect in preclinical models of ischemia.

ALS TDI covered the phase II results and our interpretation of the results on October 14 of 2014 publishing our conclusion on our website, several days after the announcement and I left it at that.

The one paragraph I should have noted in the Genervon announcement dated October 19th 2014 was as follows:

ALS Compassionate Use: An ALS patient was first diagnosed with the disease in Q1 2005 and by Q3 2008 was quadriplegic and on a ventilator. After a six-dose treatment of GM604 under an approved single patient compassionate-use IND, the patient’s swallowing volume increased in two weeks to 20cc from a baseline of 10cc. Five weeks after treatment, the patient consumed 240cc of water in 20-25cc bursts without leakage.”

Kind of like the Ice Bucket Challenge from the Summer of 2014, I don’t think anyone could have predicted what ensued. The ALS patient community became galvanized over the announcement, convinced that GM604 should have rapid approval by the FDA for all ALS patients. Everyone keyed in on the seemingly amazing results of the Phase IIA safety trial and perhaps even more so to the single patient compassionate use trial.

Everyone wanted access. And they wanted it now.

Genervon followed up in January with more detailed results of the compassionate use trial. Most doctors call observations from a single patient a clinical case study, but I guess Genervon preferred to call it a clinical trial. The tsunami of appeals from patients wanting access continued to escalate.

A petition was generated by an ALS patient Nicholas Grillo appealing to the FDA for accelerated approval of GM604 for all ALS patients based on the data from the 12 patients in the phase II safety study ALS.

Tens, no hundreds of thousands of people have signed the petition and most recently a peaceful rally at the FDA was held in Washington demanding that the FDA approve GM604 for accelerated approval.

Here I am today trying to understand why the community has rallied around GM604?

Why not NP001? It is a drug that went through a much larger clinical trial and showed efficacy!

Why not Tirasemtiv? A compound that went through several much larger trials in ALS and also showed some signs of efficacy…The data are certainly as good as those from GM604.

Why not Retigabine, Memantine, Rasagaline, TUDCA, NurOwn, or Ozanezumab? You get the picture.

Of course my scientific brain immediately took over trying to rationalize the situation and I asked the basic question…

Is there really aALS Heterogenityny way to justify all of the attention being given to GM604? Given the heterogeneity of disease onset and progression in ALS, how could one measure a drug effect in only a 12 patient study over 12 weeks?
Is there data out there that could support or refute the claims of the phase IIA results in any way?

The trial reported outcomes for ALS-FRS, Forced Vital Capacity (FVC), and the levels of several protein markers in cerebrospinal fluid. The raw data from these outcomes have not been published. However Genervon did provide some high level statistical data on median change from baseline as well as bounds (minimum and maximum change) for the FVC. So I chose to focus some effort here.

There is a data repository of ALS clinical data that should be able to shed some light on this issue. It’s called the PRO-ACT Database and it was designed and assembled by the non-profit Prize4Life and the Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital.

 

ForSpirometerced vital capacity or FVC is measured in the clinic with a spirometer. The device measures the amount of air a person can forcefully dispense from the lungs measured in liters. Often FVC from a subject is compared to a percentage of what a normal healthy subject of similar age and height would be.

In clinical trials the decline is often measured at set intervals and percent decline from trial initiation is calculated

The PRO-ACT database has clinical measurements from 8,600 subjects with ALS. The database contains 45,000 FVC measurements from 7,854 subjects. That’s a lot of data! The graph here shows all the measurements in the database and clearly demonstrates a correlation between days since diagnosis (x axis) and FVC measurements in liters (Y axis).

ProACT FVC scatter In order to statistically model FVC results from the Genervon phase II trial one must generate a study population that is similar to the population that was studied in the Genervon phase IIA trial.

Here are the enrollment characteristics and endpoint assessments for FVC from the Genervon trial:

 

 

Enrollment criteria

  • 24 months or less since symptom onset
  • FVC at baseline greater than 65%
  • 18 years or older 
  • Endpoint for FVC
    • FVC measured at baseline, 2, weeks, 6 weeks, and end of study 12 weeks

What I did here isn’t much different from what sports statisticians do when they use a computer to project outcomes of a game between two teams. They enter key attributes of the teams into the computer and ask the computer to predict who is most likely to win. Here, I entered key attributes of the patient population enrolled and asked about the predicted outcomes.

Specifically, to build this population group from the PRO-ACT database, I filtered out subjects who had presented with ALS symptoms for more than 24 months prior to enrollment in a trial and those who were less than 18 years of age and who had an FVC < 65% at baseline. Since this was a longitudinal study, I also filtered out subjects who had fewer than 3 FVC measurements including the baseline visit and those who had an FVC measurement out to at least 70 days to simulate a 12 week study.

The filtering reduced the number of “qualified subjects” to 777 subjects and reduced the total number of FVC measurements from 45,000 measurements to 5,439 measurements.

It was still an incredibly large sample set to build a model of FVC function and to compare the FVC measurements from the Genervon trial, especially when one considers that the entire Genervon phase IIA trial would only have 48 FVC measurements (12 subjects with 4 measurements).

Genervon reported the changes in FVC from the placebo groups and the group treated with GM604 as a percentage of change from the baseline measurement at time 0 to the endpoint time of 12 weeks.

I calculated a percent change in FVC of subjects from their baseline measurement at time 0 to the closest point to 84 days. No one included in the calculation had a duration shorter than 70 days and in some cases there were patients included with 120 days of data.

FVC DistributionA plot of the distribution of the percent change in FVC from this cohort shows an almost normal distribution. A normal distribution forms an inverted “U”. The Y axis in the distribution plot shows a count of the number of subjects in that bin and the X axis is the percent change from baseline into bins of 2% changes. The numbers above each bin are the numbers of subjects in that bin.

The distribution is slightly skewed to the left. Not surprising since patients with ALS do have decreased respiratory function over time and would be reflected in a decrease in FVC. It is interesting to note though that 50% of the subjects change less than 5% in a positive or negative direction in their FVC from baseline over 12 weeks. So with a bunch of patients, you see a hint of worsening, but most patients don’t change very much in this time frame.

So what does all of this statistical jargon mean in terms of the Genervon’s phase II results?

Here are their conclusions from their press release:

Controls                                  GM604

Mean FVC                   -22                                          -5.6

STD FVC                     15.6                                        7.7

Median FVC               -25                                          -8.9

Minimum FVC            -36                                          -14.9

Maximum FVC           -3.7                                         5.8

pValue from T-TEST                                     0.0359

pValue from Wilcoxon Sum Rank                0.0726

If we focus on the median decline in FVC that they reported in their two cohorts, they claim a dramatic therapeutic benefit because FVC declines by a median of 22% in the placebo group and only declines by 5.5% in the GM604 treatment group.

If we now go back and compare these numbers to our much larger sample population from the PRO-ACT database, let’s see what we might conclude.

We can calculate some general statistics from these data and calculate some confidence intervals to our distribution that is calculated in this table.

  • Maximum decline: -40.09%
  • Maximum improvement: 61%
  • Median change from baseline: -4.33%
  • Mean change from baseline: -4.02%
  • Standard deviation: 102
  • Sample size: 778
  • Sqrt sample size: 89
  • Standard error: 007
  • 95 confidence interval
  • -4.33 +/- 0.007 (shown as redline)

 

Ultimately we can FVC Median Change in PRoActshow that the median decline in FVC from this very large cohort of patients collected randomly from multiple trials over several years is a decline in FVC of only 4.33% over 12 weeks (Shown in red in the distribution curve).

 

Should we really believe that the placebo group from the Genervon trial, with its 22% decline over the same duration, can fairly represent the overall ALS patient population?
If we now color the median declines for the two cohorts in the Genervon trial onto our distribution you can see that the GM604 treated subjects are still several standard deviations below what one would predict could be possible in this study over this time (Shown in yellow in the distribution curve). More importantly the placebo group in this study are way out on the distribution many standard deviations away from the predicted value (Shown in magenta on the distribution curve).

Genervon Outlier Distribution

 

 

 

 

 

 

 

 

 

 

How can this happen?

So I can only conclude several possibilities.

One, the FVC data could have been collected improperly. Highly unlikely.

Two, fast progressing patients were enrolled in both cohorts and enriched for really REALLY fast progressing patients in the placebo cohort. The data could be very skewed by a couple of fast progressing patients in each cohort.

Or could there have been an issue with the prescreen FVC of 65% of greater?

Regardless, it makes me wonder whether any real conclusions can be drawn from such a small trial. Based on the modeling demonstrated here from a very large patient cohort it does not appear plausible that the cohort of patients enrolled in the Genervon trial would represent a “normal” cohort of ALS patients. Therefor based on the model I continue to be very skeptical that there is any way that GM604 could have provided any therapeutic benefit in this small of a trial with this short of an exposure.

I am sympathetic to the needs of the ALS patient community to have effective treatments for this disease.

I agree that patients should have access to promising treatments as soon as possible. I am a passionate supporter of providing hope to ALS patients. Of turning over any stone and determining if it could provide any level of benefit to slow down disease progression in ALS. These are not just words. Anyone who knows me will validate its backed up by actions.

However in the early stages of drug development these types of “false positive” read outs are all too common and we have seen them many times in the ALS community. Think no further back than lithium, ceftriaxone, dexepramipexole, creatine and we could go on. The only logical path forward with the current data is that GM604 did not have an acute safety issue and warrants further testing in larger scale clinical trials to continue to monitor safety and with a well designed and adequately powered trial hopefully a positive outcome on disease progression and life expectancy.

The ALS community may not appreciate this opinion but each and every patient should consider that GM604 has not been adequately tested in patients as of today. There is still evidence to be collected on long term safety. There is still data to collected on if it actually makes disease progression worse and does indeed provide therapeutic benefit. Each of these is a risk for every patient who chooses to demand and ultimately take an experimental treatment. In addition a patient taking an experimental treatment like GM604 could make that patient be excluded for the next clinical trial of a potential treatment. A potential treatment that might actually slow down disease in ALS.

194 thoughts on “GM604: Is it Ready For FDA Approval?

    1. Harmony William (MUST READ: HOW I GOT CURED FROM ALS DISEASE)
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      1. I contacted Harmony William (Isabella Alexis) and I asked her to show medical records that she actually had ALS and she was cured. that was the last time I heard from her, she did not reply. I would deduct this is a scam!

        1. recently i went to the website showing what dr what
          he asked me yo remit 1000 us dollarsto him i thnk is from south africa and that is regarding the herabal tea which he claimed can cure als
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          the case was closed I think is aCSAM

      2. I contacted Harmony William (Isabella Alexis) and I asked her to show medical records that she actually had ALS and she was cured. That was the last time I heard from her, she did not reply.

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  1. Yes, helpful stuff from Steve Perrin, though he’s breaking a butterfly upon a wheel here. It has been clear even to me (a patient) from the start that a 22% decline in FVC in the placebo group suggests atypically fast progressors. At that rate people would be outta here in a year.

    However, the post makes no mention of biomarkers, which are a more significant indicator than FVC, not being subject to placebo effect. Nor is there a discussion of GM604 regulating biomarkers in the direction of homeostasis, regardless of the stage. Nor is there a discussion of the plausible mechanism of action along multiple pathways. And I do not understand why GM604, if approved, would necessarily prevent one’s enrollment into another trial, as per Steve. An ibudilast trial actually insists on riluzole. So we cannot tell what exclusion criteria will be with regard to GM604.

    So, GM604 still seems like the best bet for monotherapy at the moment. Tirasemtiv does look interesting for LMN. NP001 does look interesting in the light of their recent “responder” findings based on LPS and IL-18. Neither is available. Broader access, including access to GM604, is still the best bet to try to save your neck, if you have ALS, and AAP is the way to go, IMHO.

    1. Thank you for your insights. I would love to ask Steve if he thinks the current population of PALS shoukd just give up and die so that business in terms of long clinical trials can continue? We have had it with business as usual. I think what has caught the FDA and the researchers off guard here is that suddenly ALS patients are showing their teeth. Their nice little complacent lab rats are storming the castle and we aten’t going to stop.

  2. The goal of the ALS patient population is to get promising treatments which are in trials out to the patients who need them much more quickly. There is an FDA program already in place since 1992 called Accelerated Approval. It’s actually a conditional approval for patients to get access trial drugs which have shown safety and a signal of efficacy. The pharmaceutical company MUST STILL CONTINUE WITH CLINICAL TRIALS to gather the data which FDA will use to determine full approval or revocation.

    Dr. Perrin hasn’t seen any of the clinical trial data so he is not competent to comment on that. His exercise in matching patients from PROACT is interesting but hardly convincing – especially given his earlier hostility toward GM604. However, FDA has *ALL* of the data from both the clinical trial and my own n=1 experience as the compassionate use patient. Let’s let FDA make the decision on the conditional approval.

    The warning about exclusion from other clinical trial is poppycock. A standard 30-day washout period (or, though less likely, 30 days of consistent dosing with GM6) would provide a stable environment for another clinical trial. Only participation in a stem cell trial, where cessation of dosing still leaves behind active treatment, would prevent enrollment in another clinical trial.

    As for NP001, we agree that it’s another perfect candidate for Accelerated Approval. If Neuraltus decided to apply for it we would provide immediate support. As for tirasemtiv, it doesn’t actually treat ALS but rather masks the effect of decline in phrenic nerve function. While it has a desired result, the possibility of cardiac or other muscular complication would make support more hesitant.

    This story is actually about patients advocating for themselves when the institutional advocacy has failed. We are patients with a serious life-threatening illness for which there is great unmet need. That is the bar set by FDA for the Accelerated Approval Program. It is applied to other diseases with considerably less-dire threat to life. We want it applied to ALS.

    1. I really enjoyed your comment. My husband has ALS and I am rallying around GM604 and most of all, The Right to Try. My husband is blessed with a slow progression, but ALS is marching on. Good luck and God Bless on your journey.

    2. My mom has ALSO and currently take Neroltus. No significant changes. She is on a feeding tube, C PAP and can barely speak anymore. Neroltus at times, seems to enable her to speak better, but it’s just brief and spoadic. I don’t believe this is the drug. However, I would like to get my hands on GL3 GAA and am in the process of doing so. I will keep yall posted throughout my journey. Prayers for my mom who is in her 9th year with ALS. Both her brothers passed from ALS after 10 yrs, her first cousin passed at 11yrs. Her sister was just diagnosed and comparing progression, my Aunt may only be able to make 3 or 4 years.

  3. I was one of the subjects who did receive GM-604 in the IIA trial at Mass. General. I appreciate all the efforts that ALSTDI undertake daily. I was fortunate enough to tour your company last year and was impressed. Unfortunately my financial and limited fund raising efforts are spoken for by my local clinic. Being a patient of two years I of course dream of the miracle cure, but being realistic I realize that I only I have a limited time to hope. Thank you for presenting your point of view on GM-604, I kind of took ownership of the drug because of my participation in the trial. Your presentation helped me to realize what I was already thinking, but didn’t really want to admit. Thank you.

    1. In rebuttal to my comments above, I have progressed to the point of this reality. Unfortunately reality is that I am dying. My comment above lets everyone off the hook, and I don’t like the word desperate, but I am feeling that way lately. When I went through the trial for GM-604 I felt a sense of hope that has since gone away. When I learned that I actually was given the drug it renewed my hope for a cure. Then this campaign began in support of GM-604 and I felt on top of the world. However over these past few months my hope has diminished and I have become very frustrated with “the process” . The only argument I have is, I felt great throughout the trial and for a few months after. Then it wasn’t long before my FVC dropped dramatically and my right leg started giving out. I am now having trouble talking, I use the bi-pap all night and half of the day. I can only walk a few steps with assistance. Not to mention the feeding tube I have had since last August. I am not saying that GM-604 is “the cure” . BUT, what would it hurt to find out ? I am willing as hell to experiment more with any drug that has shown some hope. And I know I am not alone . So if anyone with any influence reads this, please be aware that we need the hope. Thank you, Mike Britt

      1. Hi Mike, I’m sorry to hear about your decline. Hang in there, we’re doing everything we can to get any drug in the pipeline approved that shows signs of safety and efficacy. So it appears that GM604 did help you but because you couldn’t get the maintenance doses after the trial ended you began to slip again? Is that accurate?

        Jehad Majed
        HopeNowforALS.org
        jmajed@mac.com

    2. Hi Mike how are you? I hope you’re going well and still have motivation for the GM6. Your testimony was important for me. Thank you
      Moreno

  4. My husband has ALS. He is willing to take the risk with GM604, and it should be his right to take that risk.

    I have to tell you that the anger within the ALS community is palpable and growing by the day. We are done with business as usual. Where are the treatments???? Long clinical trials gets ALS patients nothing but death.

    This disease is a horror and the FDA is protecting people to death.

    1. I Have ALS for 7 mo. and you can bet if was one of their Family members of the FDA they would pass the Bill in a heart beat I need this Drug GM604 I will do the test I don’t care where it is I will be there If Obama needed it would pass

    2. Hello! My husband also has ALS and please know that I feel the very same way! I am tired of the endless clinical trials with no available treatment or cure!!!! Mr. Perrin stated that ALS is different for everyone which is so true – so how then do all these researchers think they will ever hope to find one drug that works for everyone!! Maybe GM604 WOULD HELP my husband!!! He and every other patient deserves THE RIGHT TO TRY!!!

    3. I have ALS and I agree totally with you on this. If there is any chance that GM604 will delay the disease or help it in any way it should be my right to take it if I chose to. These people that say they are protecting us are doing nothing but giving us a death sentence by doing nothing.

  5. Thank you for your very in depth commentary on Gm604.
    I am one of those desperate relatives of a person with ALS and have sent emails to everyone I know asking them to sign a petition to fast track the drug. I understand now something I had no way of knowing prior to your very informative and detailed description/conclusion above.
    The other “miracle” drug being touted is the stem cell injection from Israel. It seems they are setting up trials through Mass General. But we could go to Israel and receive the drug.
    Hearing what you’ve just said I want to be cautious. Can you tell me what you know , if anything, about that treatment?
    I am so glad I stumbled on your website in my desperate search. Please keep me informed. Is there any chance we can talk by phone? My cell is 847.902.4790. Thanks, Maggi

    1. so far maggie
      i think the brainstorm of israel has claimed that but the cost how much
      Tks maggie if u r rich may be u can try i m too poor for that tks
      don ng

    2. I wonder whether this drugs GM604 is it a pill for swallowing or an injection sorry i m a little confused tks

  6. Genervon’s official response to Dr. Perrin’s wrongful allegations in his blog and challenges him to post it against his first blog.

    First of all Dr. Perrin’s intentional deception to the public has some pretty graphs but has completely wrong assumptions as compare to Genervon’s trial design. What is evil about his deception is that he pretended he is comparing apple with apple and somehow his numbers are different from Genervon’s detailed data and analysis, therefore he alleged Genervon’s data is wrong. After all of these confusion he then allowed that may be Genervon has enrolled fast progressing definite ALS and FVC >65% patients. He knew from public record that is exactly how the Genervon trial was designed and data analyzed. He caused public confusion on purpose.

    Secondly Dr. Perrin needs to follow the basic ethic rule for researchers to declare full disclosure of funding sources and competitive project/product areas to avoid any possibility of conflict of interest.

    Thirdly Dr. Perrin seemed to have known that Genervon has already disclosed the data and the inclusion and exclusion criteria for enrolling definite ALS patients from whom our PIs get the FVC data and our special CRO did the data management and data analysis. Yet his deliberate effort to use wrong assumptions to mislead the public is puzzling.

    Fourthly based on Genervon’s Phase 2A data analysis,

    Clinical data #1:
    GM604 reduced the decline in ALL patients forced vital capacity (FVC) from screening to week 12 with statistical significance favoring GM604 treated group. FVC change from screening, p=0.0476. FVC % change from screening, p=0.0359. Any p value that is smaller than 0.05 is significant, any p value that is smaller than 0.01 is very significant.

    Clinical data #2:
    In a comparison between the treated and placebo groups of definite ALS patients in the trial with regards to disease progression before and after the start of treatment, GM604 treated group had a decrease in slope when compared to before treatment administration. GM604 in Phase 2A ALS trial achieved a positive trend of slowing down disease progression as measured by ALSFRS-R slope. A further analysis as specified in the FDA approved protocol by using historical data (placebo control in the Ceftriaxone trial) in ALSFRS-R for definite ALS patients as placebo data to compare with GM604 treated patient was performed and such comparison showed statistical significance, p=0.0047.

    Biomarker data #1-3:
    Excessive TDP43 and Tau are very bad proteins found in the brains of ALS and Alzheimer patients. GM604 decreased the expression of TDP43, Tau and SOD1 in the same trial with statistical significance and strong trend between the treated and placebo groups of ALS patients across 3 matrices of the same patients: TDP43 (p=0.0078), Tau (p=0.0369) and SOD1 (p=0.055). The Parkinson’s disease (PD) trial biomarker BDNF also achieved statistical significant increase by GM608, p=0.035.

    Finally FVC data analysis:
    Most ALS deaths are due to decline in pulmonary function resulting from respiratory muscle weakness. FVC (Forced Vital Capacity) is a measurement that assesses respiratory compromise in ALS patient. The value is expressed as a percentage of the expected value (of predicted capacity for age, height and gender). Genervon posted on Genervon’s website the Change and Percentage Change from Screening to Week 12 in FVC. The mean Change in FVC from Screening to Week 12 is -17.5 in placebo, but is -5.6 in GM604 treated group. The mean percentage Change (mean change divide by screening value) from screening is -22.61% in placebo, but is -5.6% in GM604 treated group. This is a total decline over 12 weeks. That is, the rate of decline in placebo group is -17.5 / 3 = -5.83% per month, but is -5.6/3 = -1.86% per month in GM604 treated group.

    In Genervon’s registration of GM604 trial for ALS inclinicaltrials.gov , it clearly stated that to participate in Genervon’s Phase 2A trial for ALS, patients symptom onset must be less than or equal to 24 month, and also meet the El Escorial criteria of definite criteria for a diagnosis of ALS, and also at screening must have a Forced Vital Capacity (FVC) >= 65% of predicted capacity for age, height and gender. ALS patients diagnosed as definite and are within 2 years onset usually have a faster disease progressing rate, and we expect the FVC decline rate will be faster than average ALS patients. We rely on the Principal Investigators to enroll definite ALS patients who are randomized to GM604 treatment or placebo in a 2:1 ratio.

    The FVC change in the published paper in a Phase 3 Minocycline trial for ALS showed placebo patients rate of decline is -3.01%/mo. See link http://www.ncbi.nlm.nih.gov/pubmed/17980667.

    The fast FVC decline rate (-5.83%/mo) in the placebo group of definite (fast progressing) ALS patient being faster than the historical 3%/mo is not surprising. The slower FVC decline rate (-1.86%/mo) in the GM604 treated group of definite (fast progressing) ALS patients is surprising. The difference between the GM604 treated group and the placebo group in the trial achieved statistical significance of p=0.0476, even though the sample size is small. In Genervon’s trial, all ALS patients are fast progressing in both the GM604 treated group and placebo group, randomized (cannot manipulate to enrich the “really really fast progressing patients” in the placebo group as Perrin insinuated in his blog).

    Dr. Perrin’s blog cited the wrong line item of percentage change of FVC. He should have instead cited the change of FVC table (-17.5 in placebo, but is -5.6 in GM604 treated group).

    Dr. Perrin’s analysis result from PRO-ACT database did not mention whether his data are from patients meeting the El Escorial criteria of definite criteria for ALS or whether it is from all ALS patients. He knows his comparison between PRO-ACT database and Genervon’s data are not based on ALS patients of same disease state.

    Knowing Genervon’s trial chosen patients with FVC >=65% at screening, Dr. Perrin chose to compare with patients whose FVC are < 65% at baseline, contrary to Genervon's inclusions/exclusion criteria. He said maybe because the ALS patients in Genervon's trial are fast progressing which he knew from public record that is exactly what Genervon has set up the trial to do. He did not say what kind of ALS population he chose which is probably not fast progressing. He is NOT comparing apple with apple.

  7. The real issue at hand is not whether the ALS community should support Genervon GM6, but rather should we support a new FDA approval paradigm. I completely agree that we need more data. The real questions at hand are what data are required, how much, and how best to collect it. A Phase 3 trial is an inferior process that yields
    inferior data when compared to conditional approval.

    Another clinical trial would suffer from the following weaknesses:

    1) Common trial design would limit patient inclusion to those
    diagnosed within 2-3 years of trial commencement and exhibiting a
    Forced Vital Capacity > 60%. This trial design attempts to include
    only those patients exhibiting “average” disease progression.

    1a) In ALS, with an unknown number of disease variants and
    pathogeneses, the notion of an “average” patient is scientifically
    invalid and indeterminable.

    1b) This gap in knowledge also precludes determining the number of
    patients to recruit to create a valid sample population.

    1c) This standard trial design yields no data on efficacy in late- or
    early-stages of disease.

    2) Conditional approval is a superior process to a Phase 3 trial, with
    or without compassionate use or expanded access. It would yield
    superior results sooner and at far lower cost.

    2a) Conditional approval gives supervised access that will yield more
    data sooner, across a broader spectrum of patient profile. A useful
    comparison is the experience of the patient-led trial of lithium
    carbonate, where patientslikeme.com was able to publish results more than a year in advance of traditional clinical trials. The traditional trials eventually confirmed the patient-led results. It is not
    inconceivable that conditional approval would yield data from 2000+
    patients, versus perhaps 400 in a Phase 3 trial plus compassionate
    use.

    2b) A Phase 3 trial unnecessarily burdens the regulatory and medical
    communities. Recruiting trial clinics, who must get approval from
    their Institutional Review Boards, then recruiting trial participants,
    takes thousands of person-hours without adding to patient safety.
    Compassionate use requests would result in tens of thousands of pages of paperwork for neurologists and the drug manufacturer. Costs to the drug manufacturer are estimated to be $30 million, draining funds from other research and development efforts.

    A Phase 3 trial would result in inferior science, more slowly, at
    higher cost. We are not asking to support the Genervon GM6 product, but to support the conditional approval process.

  8. April 20, 2015

    Just once, I would like to read an argument written by a respected member of the established ALS research community that puts forth compelling reasons why Accelerated Approval of GM604 should be denied while, at the same time, the author refrains from taking snarky, back-handed swipes at Genervon’s integrity. Plus, I would like for the author to do a modicum of homework before publishing.

    Unfortunately, this blog post seems to continue an all-too-familiar, unfortunate pattern of taking unwarranted jabs at Genervon, presumably in hopes that doing so will help drive home the author’s argument against Accelerated Approval for GM604. For me, such tactics have the exact opposite of the intended affect. I mean, there could be some persuasive information in this post. However, once the back-handed jabs and not-so-subtle implications that Genervon somehow “cooked the books” start spewing forth, I find it hard to take anything in the post seriously.

    Am I over reacting? Perhaps. But were the following things really warranted, and does one typically see such things in posts by respected scholars?

    • Regarding Genervon’s published results of the single patient Compassionate Use trial — “Most doctors call observations from a single patient a clinical case study, but I guess Genervon preferred to call it a clinical trial.”

    I honestly don’t give a wit what we call it. I am interested only in the credibility of the data and the patient. Taking a slap at Genervon for calling it a single-patient clinical trial seems absolutely pointless — unless of course the point was to try to subtly discredit Genervon. (“The company obviously does not even know the proper terminology, so how can the results be trusted?”)

    What *IS* important to me about this single-patient trial (or study) is the credibility of the patient from whom the results were obtained. For ethical and patient-privacy reasons, Genervon did not disclose the name of the Compassionate-Use patient, but fortunately we all know who he is anyway because the patient chose to come out publically and identify himself. He is Eric Valor, and you can read his self-identification as the patient for this trial at the following link:
    http://friends4eric.blogspot.com/2015/01/condition-green.html

    Eric Valor is well known and extremely well respected in the ALS patient community. He also happens to be an intelligent scientist himself who is concerned about what he perceives as a lack of intellectual honesty in posts by certain members of the ALS research community regarding GM604. You can read his well-argued response to such recent posts by the MND Association and the ALS Association here: http://friends4eric.blogspot.com/2015/03/scuttle-rebuttal.html

    • Regarding comparisons of GM604 to past failed treatments for ALS — “Think no further back than lithium…” Whoa. Please do not tell me that you just attempted to smear GM604 by grouping it with the outright fraud that was lithium. I haven’t been around the ALS community for very long and even I know that the false hope that surrounded lithium was due entirely to the fact that the researchers purposely selected slow-progressing patients for the lithium cohort, while they put the faster-progressing patients in the placebo cohort. With fraud like that, guess what happened? Lithium looked like a promising treatment — until the fraud was discovered. What was the reason for mentioning lithium and GM604 in the same breath if it wasn’t to sling completely unwarranted mud at Genervon at GM604?

    The fact is Genervon had nothing to do with the selection of patients in the clinical trial of GM604. If there are any questions concerning the randomization of the patients or the double-blind nature of the trial, those questions should be directed to the two highly-respected physicians who carried out the trial.

    • Regarding Accelerated Approval for other possible new treatments for ALS — “Why not NP001?… Why not Tirasemtiv?… Why not Retigabine, Memantine, Rasagaline, TUDCA, NurOwn, or Ozanezumab? You get the picture.”

    I certainly do get the picture! The picture is this: There may be several possible new treatments for ALS that show promising signs. However, to the best of my knowledge, the only one of these drugs for which Accelerated Approval has been requested from the FDA is GM604. Genervon actually wants to provide ALS patients early access to GM604. That is the picture. You want the ALS community to rally around one of the other new drugs? Ask the FDA for Accelerated Approval.

    As to the gist of this blog post — that the results of both cohorts in the GM604 clinical trial seem peculiar when compared to the historical median rate of decline of FVC in overall ALS patients — three hypotheses were put forth:

    (1) the FVC data may have been collected improperly in the GM604 clinical trial;

    (2) the reported FVC pre-screen threshold of >65% may have “an issue”;

    (3) fast-progressing patients were selected for both cohorts.

    The first two of these hypotheses go directly to the competence and the integrity of the physicians who conducted the clinical trial. I personally believe they are above reproach.

    The last of these hypotheses is spot-on correct! A person with just a casual interest in this subject, along with access to Google, can find that the Phase IIA clinical trial was purposely carried out with ONLY fast-progressing patients. (So this entire blog post seems to be about proving that the patients selected for the clinical trial were exactly the types of patients that the trial claimed them to be — fast progressing ALS patients). It follows then, that the median rate of FVC decline in such patients can be expected not to match at all that of the historical overall ALS patient database.

    I have no way of knowing whether this blog post was purposely disingenuous or was written before bothering to read the basic parameters of the GM604 clinical trial. I do know this: I find the pattern of these types of posts by members of the established ALS research community disturbing. And, frankly, such posts serve to discredit that community in my mind. I do wish I could draw a different conclusion. Sometimes, however, evidence is pretty compelling.

    Al Redux
    Atlanta, GA

    1. Thank you so much for your insightful response! My husband has ALS and he deserves THE RIGHT TO TRY!!! I requested a face to face meeting with Congressman Mark Sanford to try and have “Right to Try” legislation passed in South Carolina. His father passed from ALS so I hope he can help do something. I am terribly frustrated with the endless clinical trials and no treament or cure!!!!

    2. Hey Al, I was a patient in the phase 2a GM-604 trial at MGH. I can tell you how completely impressed I was by the professional, by the book treatment throughout the trial. And as I have compared my progression rate to other PALS that I have known, I feel as if my progression is quite slow. I can only speak for myself, but I have to disagree with your findings of only faster progressing people were chosen.
      Sincerely, Mike Britt

  9. Risk is not an issue to most of us 30000 with nothing else to try except GM604. You know as well as I , the odds of getting into a treatment trial are very low. Between few trials (less than ten US treatment trials currently enrolling according to your website,) strict inclusion criteria and geographical challenges, trials are not an option for most.

    I have been diagnosed for 18 months. I have tried unsuccessfully to get into 3 trials. I now want a choice and there are no other offers except GM604 .

    It’s time for true compassion. Give us the information and let us decide.

    Carolyn B Heath, RN

    1. Carolyn, try looking at healingals.com – there you will find the stories of nine people who have recovered from this dreadful illness through nutritional and emotional therapy. I have the illness too but am skeptical about one drug for all patients. This is a very complex condition. I wish you luck. Louise

      1. Sorry to hear you have ALS. I agree, ALS is a complex disease and there is probably not one drug for all. We must become well informed and decide for ourselves. Let’s all fight together for options, even if we might not personally choose to try it. I would like to try GM6 because even though the trial was small. ..it was performed by very reputable institutions, Massachusetts General and Cambridge and showed safety and promise for efficacy.

    2. hi carolyn
      understand that in japan there is a drug called RADICUT and is approved in korea and japan i wanted to try still waitingo may be u could try tk
      don n g

  10. Enough with the high-handed BS from our overlords dolling out crumbs as they see fit.
    Us living with ALS are doing tremendous amounts of research. Show us the data and credentials and we can decide on our own whether we want to take ANY DRUG that might prolong our lives.

    This is crap – and coming from the ALS-TDI no less?!

    1. 100% correct. We don’t want sci-lords to decide on behalf of us. It’s our fate, not theirs!

  11. Spot on, all of you. I’ve been fighting ALS for 12 years and am fed up with the patronizing attitude from the medical and regulatory institutions. We are intelligent people capable of making decisions regarding our medical care. The medical establishment should do more to unleash our talents and intelligence to accelerate the science instead of protecting us to death.

    1. Steve what type of exercise ,food and ext. are you doing to live with this for so long. we just found out my husband has ALS and I want to do anything and everything I can to help him to live a longer life.

  12. Ben S. IS spot on: “Show us the data and credentials and we can decide on our own whether we want to take ANY DRUG that might prolong our lives.”

    That is exactly what the FDA requested of Genervon — show everyone the data so that all parties (FDA, ALS clinicians, and most importantly PALS and CALS) can make informed decisions based upon all of the data rather than a series of press releases.

    1. If the FDA was actually saying what “J” claims, we wouldn’t be having this discussion.

      The FDA *is* asking Genervon to show everyone the data (the same data that the FDA already has). But the FDA most certainly is not making this request “so that all parties… can make informed decisions.” No, the FDA will still make all decisions for us. We don’t need to worry our pretty little heads about such matters.

    2. Unless and until the FDA grants the accelerated approval for GM604, release of all data will not serve any purpose other than stirring more confusing and time consuming debate among the sci-lords. If FDA grants accelerated approval now, we can look at all the data and make our informed decision.

  13. Thanks for the comments. I’d like to reply to some of the major themes I’m seeing.

    Hostility towards GM604 or Genervon- I would argue against comments that I have been hostile towards Genervon or GM604. I thought people were entitled to their own opinion! In both my blog and in my summary of the announcement back in October, I supported that GM604 passed acute safety assessment and should continue to work through the regulatory process to examine efficacy. My only point in my blog is that there is no way the FVC data demonstrates efficacy. It’s underpowered, too short, and the placebo group doesn’t represent a normal distribution of ALS patients.

    Endpoints in the trial not mentioned- I didn’t mention the change in biomarkers because they didn’t release enough statistical data. It takes hundreds, if not thousands, of samples replicated across multiple studies to develop biomarkers of drug response. These data are just too premature. I also didn’t mention ALS FRS because they didn’t release enough of even the high level statistics (median, maximum, minimum changes to model against other data.

    Accelerated Access Program- AAP is a legal and regulatory guideline only. It does not require the company, organization, or individual who applies for AAP to be able to deliver on the promise. With respect to GM604, does Genervon have all the drug for 1000 patients sitting in their home? Do they have the funds for the distribution of drug? Do they have the funds for the clinical follow up? I estimate this entire cost is about $100M. I think that before a company should be allowed to demand AAP for a drug, they should have to deposit these funds in an account governed by a 3rd party or else they are making a lot of noise and getting the hopes a patient population all excited for nothing.

    Comparison to Lithium- I wasn’t trying to taint GM604 by comparing it lithium with regards to data quality or trial design. Rather, I wanted to point out that the entire ALS patient community got behind lithium right after the phase II trial results came out, much like we have seen for GM604. These two comparisons are very accurate. It was premature with not enough data to get excited. There are dozens of other examples and I am sympathetic to all of them. The patient community wants hope and the right to choose. I am not opposed to either and advocate for both. But I do think it’s fair to try and share with the community interpretations of data in an unbiased fashion. And yes, I am unbiased and have ZERO conflicts of interest.

    1. Steve:

      I will grant you that the biomarker candidates are new and not yet “proven”, but FDA did allow them as endpoints in the Phase 2. They are not brand-new fabrications by Genervon and are backed by a lot of recent research by known researchers. And they were all quite uniform in response to GM6 while the placebo group all continued in the abnormal direction. In my n=1 case report the biomarker candidates sometimes went in the reverse direction, but ALWAYS TOWARD NORMAL LEVELS. This is a great indication that GM6 promotes neuronal homeostasis – the holy grail for ALS research.

      Granted the Phase 2 was only a very small population, and in ALS it’s unheard of to be able to collect reliable efficacy data in such a small cohort. However, what you fail to understand is that this trial was very different from previous trials. The effect registered was much larger than in previous such trials (especially dexpramipexole) and was backed up by multiple secondary measurements not subject to any placebo effect. The combination of surprisingly-large effect size and objective biological markers sets this aside from previous trials (which also used the ALSFRS almost exclusively). I won’t go into your erroneous though well-intentioned attempt to use the released FVC information as evidence of poor trial design (there was serious protocol deviation with one of the sites/subjects and you used a very inappropriate comparison population).

      I do have issues with two of your points in your last comment. First is the lithium debacle. The media reports came out which obviously created a lot of excitement within the patient community. Our first reaction was asking and pleading the research community to quickly follow up with more trials to confirm that study and the response from the research committee was absolute disinterest. Therefore the patient community took it upon themselves to create a verification study, which we did. We did *NOT* merely go out and start using lithium off-label. In fact, it was only after our trial data was being released that the research community decided to do a confirmation study. By then we had already demonstrated that lithium had no effect in ALS and begged the research community to not waste time and millions of dollars.

      But again, the research community ignored the patient community.

      Second, you are absolutely wrong about AAP not requiring the company to prove the drug is efficacious. You could have very easily looked on the FDA website. If you couldn’t find it there, you could Google “FDA accelerated approval” and the very first result is the FDA page explaining the program. AAP in fact requires further trials to confirm the judgment of FDA in granting the accelerated approval.

      Third, are you kidding about questioning Genervon’s ability to meet market demand in the case AAP is granted? Your analysis of GM6 production costs is based on what extensive knowledge of GM6 synthesis? Also, if AAP was granted, do you really think Genervon would have any trouble raising whatever additional capital might be necessary to ramp up to commercial production? Your entire point about needing some kind of escrow account or else “they are making a lot of noise and getting the hopes a patient population all excited for nothing” is irrelevant and just a weak attempt to sow fear, uncertainty, and doubt. I expected better from you.

      The movement here isn’t for GM6 to skip the regulatory process. It’s to get FDA to use its existing programs and Congressional mandate to provide potentially life-saving treatment to PALS. This is especially important now that truly-effective treatments are very near (including several from TDI’s excellent research programs). Caution is obviously warranted but ALS is a race against a clock that doesn’t care. More aggressive strategy is thus required which necessitates a little less caution and more courage.

      1. I guess I should start off by apologizing for not keeping the conversation going. Although I am concerned it will never end and we will never agree to agree or disagree.

        I am learning proper “blogging” etiquette if you will.

        ENV the second that you have now agreed with me that based on the FVC data there was a site enrollment problem it now means none of the data from this trial is interpretable. Not the FVC data, not the ALS FRS data and certainly not the biomarker data. It was very very very underpowered to begin with and now they don’t even have placebo controls.

        As far as the biomarker data specifically I agree there has been exploratory work done on these markers.

        But the fact that all move in the same direction in this study is meaningless due to the obvious flaws in the design. I am sorry but I was Director of Biomarker development at Biogen for both RNA and protein markers and similar role at Aventis prior to that. In order for a biomarker panel to be valid it needs highly powered and more importantly replicated studies. Hundreds of patients and controls in both studies.

        Just to show everyone how variable biomarkers can be here is a blood biomarker from 180 ALS patients and 48 healthy controls. It’s very statistically significant but look at the variability in the ALS group. Study power is key.

        If you can show me a publication in the literature for SOD1, tau, Cystatin-c and TDP43 levels in CSF in 2 separate studies with at least 100 patients per group I’ll fold on this one.

        Some of your other comments.
        I was using lithium as a high profile example and you know it. There have been dozens of other examples of PALS taking off label drugs with no proof or hint of efficacy and later finding out they don’t have effect and in some cases are deleterious and again you know it.

        And I was not wrong about my reading and interpretation of FDA guidelines for AAP. I did not say that that they wouldn’t have to demonstrate efficacy in a follow up study. I said that the FDA does not require that the company or group granted AAP have the drug manufactured in advance and does not require them to demonstrate ability to execute the trial or funds to distribute the product.

        The guidelines say that the FDA MAY want to be prepared for other aspects of drug development including manufacturing, pg 16 of the guidelines.

        So your final points about me not knowing production costs ect. of GM604. You are right I don’t know the exact production costs of GM604.

        But I do know that GMP manufacturing, packaging, distribution, trial monitoring will be millions of dollars.

        And no I don’t agree that any VC, Angel group, pharmaceutical company, or biotech would come into this one given how little data there is today. They are not that desperate to fail yet again in later stage trials for an ALS drug.

        In the last eight years at ALS TDI I have become friends with hundreds of PALS and their families. I have eaten at their homes. They have become my family. And I have gone to way too many funerals and shed tears.

        I always get behind what we at ALS TDI think are the best opportunities for PALS. And more often than not they are not ALS TDI compounds. I have had many I put my money where my mouth is on this topic and I get behind other companies compounds all the time with resources from our science team, our lab and our checkbook.

        I agree the process is not perfect on getting patients access to treatments sooner. But there has to be a balance between early access with poor quality data or premature data and the traditional and laborious clinical trial process.

        What we should be focusing on is the process to fix the system and not as much focus on one drug with so little data.

        1. So where is my husband’s access to any one of those other promising drugs you talk about and have been researching?!!! Every day I see a new drug advertised on T.V. for diabetes or COPD – the disclaimer says they may kill some people, but they were obviously approved by the FDA and must help a lot of people. So how do you propose getting one drug to market for all ALS patients??? I’m glad to know you support the right to try and that’s why you should be shouting from rooftops and helping to get GM604 (or one of the other drugs) into the hands of PALS if you truly believe the patient has the right to decide!!!! If I sound passionate – I am! I love my husband very much!!

        2. No worries about blogging skill. It takes significant time which I know you don’t easily have. Thanks for making time for it.

          I really fail to see how you go from issues with one data point of one measurement of one patient to disqualification of the entire program. That’s a logical fallacy the size of Texas. At the most, that patient’s data should be omitted (although it was also proper to just use the earlier screening data point, which is what ended up happening). Either way, the FVC data was the same. So that point is asked and answered.

          As biomarker expert you should recognize that uniform direction of movement in treatment patients is a significant signal. This is made moreso by the continued opposite (toward abnormal) movement in the placebo group. The fact that my individual late-term patient test showed movement the other way, from the opposite side, but also toward normal, is a strong indication of homeostasis. This is something which should draw your intrigue. The ability of a small population nevertheless showing significant effect is addressed in earlier Hope Now for ALS releases.

          Two studies on a particular biomarker candidate with over 100 patients each? You know as well as I how hard it is to get a trial population that large. Biogen had to go international to get a population like that for Dex. You also know as well as I the paucity in funding for ALS research, putting such populations outside the ability of any entity but perhaps ALSA with the IBC funds. Therefore your challenge is ludicrous. Maybe this is a good study target for TDI…

          I missed the link you presumably meant to post about the blood biomarker study. Without seeing and reading I cannot evaluate it.

          However, I can offer an absolutely iron-clad way to get biomarker study information on *thousands* of patients: Accelerated Approval. Get a demonstrably safe drug with some biomarker effect out in the population and learn very quickly what the correlation is with impact on disease.

          As for the lithium subject, I know that many patients have tried off-label and exotic drugs with zero data precisely because nothing else is available. Lithium data was deliberately manipulated to cause excitement. You and I also know that drugs in official trial can hasten progression. I was in the high-dose arm of the Ritonavir trial (supported in part by early TDI mouse data – well before the 2008 publication) which hastened my progression. That’s part of the process. But I had hope during. So your point again?

          You did imply FDA required a lot of reserve capital for manufacturing, etc. Perhaps it is a typo or some other misunderstanding. It’s not important enough to argue in this setting.

          I know you are sincere in the battle against ALS. You know I support TDI and have for longer than most. Funeral talk is irrelevant as we have both lost many friends. And this debate is indeed about ways to move forward. GM6 just happens to be the first horse we can ride into the battle for AAP. The old process doesn’t fit the requirements of patients. We need something to happen, FAST. Death is already on the table so the worst is irrelevant to the discussion. Let’s try something to fix the system.

          (ps. you know that AAP is already denied, so how about you offer dialogue with Hope Now for ALS on AAP? We welcome constructive input. I forwarded your offer of mouse runs to Genervon, but it would be better coming directly from you. CC me on that, and CC me on a discussion to info@hopenowforals.org).

  14. Placebo group don’t represent the normal population of PALS? Then what you want in a Phase III trial? That the group in placebo are 200 or more of PALS? What about if on the end of the trial the result is that the 40% of them died and on GM6 just the 10%? What you’ll say to them lover of thus on Placebo? That you need to conduct the trial like this and they died because of missing data?

    Biomarker in PALS populations are always similar or do they change (apart miracles)? The 8 PALS on GM6 had change on biomarker and this is a ‘enough statistical data’ I guess!

    Accelerated Access Program- AAP is right a guideline where you can also find the indication that describe exactly what need if FDA grant a procedure. This what you say is mentioned in the procedure of every ‘Expedited Programs’ and if the sponsor (Genervon) don’t show the ‘manufacturing development plan’ the FDA don’t grant to the GM6 the AA! So what you say about the funds, deposit ecc is irrelevant and already in the procedure itself. Please read the ‘Guidance Industry’ pag. 25, IX, ‘General consideration’ in particular ‘Manufacturing and Product Quality Considerations’ it describe everything. Maybe is better before to make ‘such statement’.

    Maybe PALS community, ALSA, AISLA, you and many more got behind the Lithium however doesn’t mean that this time with the GM6 is the same or that will not help patients with ALS right?

    By the way Almost important human discover is made by an ‘idea’ not by how many and what kind of academic degree the source had. Same is for the most important substance found! Just accidental discoveries like;
    Penicillin, Dynamit, Match, Mauveine, Cola, Steel etc etc. If you don’t see this then I guess that many great figures of humanity are turning in his grave right now!!

  15. Hi Moreno

    Thanks for the post.
    One thing I should point out on your comment is that you a re not referencing the requirements for AAP in your comment and you should understand that the FDA has 4 different programs for streamlining drug approvals. Page 24 section that you reference about manufacturing is NOT a guideline for AAP its a guideline to apply for Rapid Approval.
    The 4 programs to help companies move products through the regulatory process at the FDA are:
    1. Fast Track
    2. Breakthrough Therapy
    3. Accelerated Approval
    4. Priority Review Designation

    You reference guidelines for Priority Review Designation. There are no requirements for a company to be ready to manufacture, quality control, distribute, or monitor the follow trial. They do “require” a follow up trial but don’t offer requirements on having everything ready to go.

    Steve

    1. Thank you Dr. Perrin for the answer. I’m not mother speaking English (Italien) and maybe I’m wrong however the ‘guidelines for Priority Review Designation’ you referring is NOT an ‘Approval pathway’ but just a ‘Designation’. For this reason the descriptions for the productions I mean under the capitol IX of the ‘Guidance for Industry’ under ‘General Consideration’ and not in ‘Priority Review’, Capitol VII. It follows that the only program with Postmarketing product and an Approval pathway is the only ‘Accelerate Approval’. GM6 receive the ‘Fast Track’ on 2014, now is discussing with FDA about the possibility of the AA (General Consideration) and if become it off course the sponsor have to show FDA ‘Manufactory Development Program’ right? If the sponsor don’t go on market with own product and just with program like Fast Track, Priority Review ecc why have to make an MDP now if they need first in 5/8 years when done all Trials??
      I think that the Polemic if Genervon made or not the NDA was inapropiate. The guideline is very clear about that and at first say; ‘The sponsor should ordinarily discuss the possibility of accelerated approval with the review division during development, supporting, for example, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials, which should usually be already underway at the time of approval’
      Is exatly what Genervon did on 16 January, discuss about an AA and present the Phase IIa trial ‘data’. If FDA had already say ‘ok’ to the AA and Genervon didn’t react with an NDA I agree with the discussion but this wasn’t the case.
      Best regards
      Moreno

      1. Hi Moreno

        First of all your english is very good. Certainly better than my Italian. We are splitting hairs in the interpretation which you eloquently point out. The language the FDA uses in the guidelines is that they MAY require you to discuss the plan. But they do not say that you will be REQUIRED to have a drug manufacturing supply chain, distribution process, or ability to conduct the trial.

        Steve

        1. Thank you Dr. Perrin for the answer! I’ll teach you Italien’s language if you want..:))
          I understand this about the gudeline. However is good point but the most important is that like other hundreds of thousands PALS I just wish a chance to have a cure for this terrible disease that take you almost evrithing NOW.
          Moreno

    2. Something that is never mentioned on these forums is that the FDA has approved only 3 drugs for Accelerated Approval in 3 years since Congress passed the law forcing them to offer AA and the other paths mentioned by Steve. From what I can gather, Congress has done nothing to compel the FDA to speed up the process.

      1. Sorry this is a joke ok trying to Make all people haPPY
        THE HOLE IS THE WHOLE TROUBLE
        THE WHOLE TROUBLE IS THE HOLE TROUBLE
        WITHOUT THIS HOLE THERE IS NO WHOLE TROUBLE

  16. Mention is made of other trial treatment, but no mention of Neuralstem’s stem cell injection. Care to comment on the direction of that trial and the FDA?

    1. Hi Joe

      A discussion on Neuralstem is an entire other blog. High level comment. They are trailblazing new ground with the FDA on cell based therapies for ALS and doing a good job navigating new waters.

      Steve

  17. Steve, Thank you for your informative article. I understand your approach and agree with you, however, the petition is a sort of ‘backlash’ to the decades of no or little progress toward this disease. Finally, now there appear to be a few drug treatments that may actually be safe and work. Most of us think that a streamlined process should be applied to drugs that address fatal diseases. They should be given financial and testing priority. It’s unfortunate that there has been some friction lately, but as you well know time is definitely of the essence.

  18. I omitted in my last post FVC. From my own personal experience I can tell it’s not necessarily accurate. I’ve had 3, a 68, a 65 and the last one (most recent) was 75. My mouth muscles are weakened so I cannot make a tight seal around the cardboard tube. On my last 2 tests I used a mouthpiece which is better.

    1. Walter thank you for both posts.

      Yes FVC and ALS FRS are both tough readouts with variability at multiple levels. Clinic to clinic and even repetitive measurements as you describe

      Steve

  19. I would like to see this drug approved right away. It is hard on the patient, not knowing if I can walk, speak, breathe the next day. More difficult for me looking at my parents and husband eyes.( Filled with Tears ) please, someone help

  20. My names are Andrew Parker …ALS has been ongoing in my family for long..I lost
    both parents to ALS and it is so much pain have not been able to get over. As we all know medically,there
    is no solution or cure for ALS and the cost for Medication is very expensive..Someone introduced me to a Harbal
    man email:(droyekpenherbalhome@gmail.com)(Native Medical Practitioner)in oxford.. I showed the man all
    my Tests and Results and i told him have already diagnosed with ALS and have spent thousands of dollars
    on medication..I said i will like to try him cos someone introduced me to him..He asked me sorts of
    questions and i answered him correctly..To cut the story short,He gave me some medicinal soaps and some
    herbs(have forgot the name he called them) and he thought me how am gonna use them all..At first i was
    skeptical but i just gave it a try..I was on his Medication for 2 weeks and i used all the soaps and
    herbs according to his prescription.. that he will finish the rest himself..and i called him 3 days
    after, i arrived and i told him what is the next thing..he said,he has been expecting
    my call.. he told me to visit my doctor for another test..Honestly speaking,i never believe all
    he was saying until
    after the test when my doctor mention the statement that am, also negative and the doctor started
    asking me how do i get cure….Am telling this story to every one of you encase you also having
    same problem you can contact him on his via email address: droyekpenherbalhome@gmail.com .

    Kind Regards!
    Thanks…

  21. Funny how Dr. Perrin almost immediately responded to Moreno’s post glomming onto an error made by someone who is clearly challenged with the English language, yet no mention was made nor any response to the excellent points raised in ENV’s post. In my opinion, the absence of a reply to ENV tells the true story here. Dr. Perrin, if you want respect from the ALS patients, then engage in meaningful dialogue when someone challenges you, as ENV so eloquently did. Believe it or not some of us out here are smart enough to figure out what is accurate vs what is conjecture. Throwing bogus cost numbers out which you have no qualifications to make in the first place screams of a hidden agenda. All that said my question is relatively simple; if Genervon has been proven to be safe, then tell me what is the harm of allowing these patients access to the drug? What’s the downside??? WHAT IS THE WORST THAT CAN HAPPEN??? Will Genervon KILL THEM sooner than the disease itself??? Clearly, Genervon is not worried about that liability, so why are you?? Attempting to protect scientific protocols so that proper development of treatments for other diseases are done in a methodical fashion in the future is one thing but using it as an excuse to hamper a possible extension of life to those who are dying is quite another. One thing is sure; on the limited trial basis, several people with ALS benefited from this treatment – that may not be a scientific certainty but it IS a tangible fact. So if you scientists yielded your sacred ground and supported an effort to make Genervon to, say, 30,000 people, and the treatment ended up helping only 20 patients (who cares how it worked…), do you honestly think the other 29,980 patients that died anyway (because it didn’t work for them,) would wish anything but the best for those those who were fortunate enough to benefit from it??? Or do you think the families of those who passed away under that scenario would hold it against Genervon (or your association), because everybody didn’t survive? These people aren’t begging for a cure, they are begging for a reasonable chance – ANY CHANCE – to try something that has shown a glimmer of hope for their otherwise fatal train ride which they are doomed to take.

    1. “Funny how Dr. Perrin almost immediately responded to Moreno’s post glomming onto an error made by someone who is clearly challenged with the English language, yet no mention was made nor any response to the excellent points raised in ENV’s post.”

      My thoughts exactly when I read Dr. Perrin’s response.

      I would love to see a live discussion (debate?) so each claim by both sides could be responded to and analyzed. We need facts presented without disparaging remarks and innuendo.

      ALSA: Sponsoring and broadcasting this debate with a neutral moderator would be a real service to your community and would help clarify issues beyond just GM604. Knowledge empowers.

      1. I agree! That would be great to see that kind of presentation. In fact I’d like to see several originators present their products in such a debate. That way we could really get a sense of comparison between those newest cutting edge options.

  22. My names are Andrew Parker… ALS has been ongoing in my family for long..I lost both parents to ALS and it is so much pain have not been able to get over. As we all know medically,there is no solution or cure for ALS and the cost for Medication is very expensive..Someone introduced me to a Herbal man email:(droyekpenherbalhome@gmail.com)(Native Medical Practitioner)in oxford.. I showed the man all my Tests and Results and i told him have already diagnosed with ALS and have spent thousands of dollars on medication..I said i will like to try him cos someone introduced me to him..He asked me sorts of questions and i answered him correctly..To cut the story short,He gave me some medicinal
    soaps and some herbs(have forgot the name he called them) and he thought me how am gonna use them all..At first i was skeptical but i just gave it a try..I was on his Medication for 2 weeks and i used all the soaps and herbs according to his prescription.. that he will finish the rest himself..and i called him 3 days after, i arrived and i told him what is the next thing..he said,he has
    been expecting my call.. he told me to visit my doctor for another test..Honestly speaking,i never
    believe all he was saying until after the test when my doctor mention the statement that am, also negative and the doctor started asking me how do i get cure….Am telling this story to every one of you encase you also having same problem you can contact him on his via
    email address: droyekpenherbalhome@gmail.com .

    Kind Regards!
    Thanks…

  23. Right on Brother if was someone in their Family they would pass it in a Heart beat so pass the Drug what have you got to lose but our LIFE I have ALS.

  24. Mr Perrin is trying desperate to support his point of view and his big salary. He and all the CEO of FDA are living from us, people who will die soon and their families who will give anything to save the loved ones.
    As a scientist is a disgrace, a shame for neurologist people, he is trying to demerit Genervon’s GM604 trials in the ALS community.
    We all know there are more options available, but are not safe like GM604, and why FDA is not taking action for approval, well, sounds more of a conflict of interest, not being open to new drugs who can change the curse of medicine.
    Right now people are dying from these bureaucratic attitude from FDA and your support.
    We not only need new medicine capable of cure many diseases, We also need another FDA capable to help people with diseases, the main point why is was created.
    People around the world is waiting for this drug to be approved, many want to buy it as soon as come to the market. Time is running out for many and desperation is growing up every single day.
    My prayers for all are not longer fighting with us, and my prayers to see a miracle tomorrow “FDA approved GM604”

    1. Eliana thanks for your comments

      According to Hope Now for ALS the FDA did recently decline to approve the request for AAP to Genervon (http://hopenowforals.org/author/jehadmajed/). They did agree to assist Genervon in their clinical trial process moving forward in ALS.

      In that spirit ALS TDI will also offer to help Gernevon in this regard as well.

      If Genervon wants to send ALS TDI 1 gram of GM604 and explicit instructions on how to formulate and dose the drug in animals ALS TDI will run several survival and pharmacodynamics studies on biomarkers at ALS TDI for free.

      In exchange for this ALS TDI will have the right to publish the results of the study regardless if it is positive or negative in the spirit of collaboration.

  25. Who really knows how fast or slow ones individual progression might be. I don’t know if GM-604 stalled my spike in progression, but I sure would love to find out. That of course would mean we would have access to the drug. I do appreciate all the great energy you are all putting in to this campaign, but like I said earlier I am not letting myself get my hopes up anymore. Thanks for everything you are doing. Mike

  26. MUST READ: HOW I GOT CURED FROM ALS DISEASE)
    I am from Philadelphia, I was diagnosed of ALS disease (Lou Gehrig’s disease) in 2013 and I have tried all I can to get cured but all to no avail, my life was gradually coming to an end, until i saw a post in a health forum about a herbal doctor from Africa who prepares herbal cure to cure all kind of diseases including ALS, MND, Epilepsy, Leukemia, Asthma, Cancer, Ghonorhea etc, at first i doubted if it was real but decided to give it a try, when i contact this herbal doctor via his email, he prepared an ALS herbal portion and sent it to me via courier service, when i received this herbal portion, he gave me step by step instructions on how to apply it, when i applied it as instructed, i was cured of this deadly disease within 7 days, I could not walk or talk understandably before but after i took the herbal cure as he instructed i regained strength in my bones and i could talk properly unlike before, I am now free from the deadly disease, all thanks to Dralegbe. Contact this great herbal doctor via his email dralegbeherpsspelltemple@gmail.com

  27. MUST READ: HOW I GOT CURED FROM ALS DISEASE)
    I am from Philadelphia, I was diagnosed of ALS disease (Lou Gehrig’s disease) in 2013 and I have tried all I can to get cured but all to no avail, my life was gradually coming to an end, until i saw a post in a health forum about a herbal doctor from Africa who prepares herbal cure to cure all kind of diseases including ALS, MND, Epilepsy, Leukemia, Asthma, Cancer, Ghonorhea etc, at first i doubted if it was real but decided to give it a try, when i contact this herbal doctor via his email, he prepared an ALS herbal portion and sent it to me via courier service, when i received this herbal portion, he gave me step by step instructions on how to apply it, when i applied it as instructed, i was cured of this deadly disease within 7 days, I could not walk or talk understandably before but after i took the herbal cure as he instructed i regained strength in my bones and i could talk properly unlike before, I am now free from the deadly disease, all thanks to Dralegbe. Contact this great herbal doctor via his email dralegbeherpsspelltemple@gmail.com.

  28. (MUST READ: HOW I GOT CURED FROM ALS DISEASE)
    I am from U.S.A, I was diagnosed of ALS disease (Lou Gehrig’s disease) in 2012 and I have tried all I can to get cured but all to no avail, my life was gradually coming to an end, until i saw a post in a health forum about a herbal doctor from Africa who prepares herbal cure to cure HIV/ and all kind of diseases including ALS, MND, Epilepsy, Leukemia, Asthma, Cancer, Gonorrhea etc, at first i doubted if it was real but decided to give it a try, when i contact this herbal doctor via his email, he prepared an ALS herbal portion and sent it to me via courier service, when i received this herbal portion, he gave me step by step instructions on how to apply it, when i applied it as instructed, i was cured of this deadly disease within 7 days, I could not walk or talk understandably before but after i took the herbal cure as he instructed i regained strength in my bones and i could talk properly unlike before, I am now free from the deadly disease, all thanks to Dr CHIWAKA. Contact this great herbal doctor via his email chiwakaspelltemple@gmail.com

  29. Join me celebrate
    this day which my Lord God
    has made for using this great and
    powerful healer called Dr CHIWAKA that cured my ALS disease which has been
    eating me up for over 6years now without
    solutions, i tried looking for solutions on line, and through hospital, they
    keep on giving me orientations about drugs that can extend my years. now since
    Dr CHIWAKA has helped me to cure my disease with the use of herbal remedy and knowledge
    of his forefathers everything has been going well now, i owe you greatly for
    healing me so if anybody need is help or you also want to get cured you can also
    contact him on his email address: chiwakaspelltemple@gmail.com .

    Thank,
    Kind Regards…

  30. My names are Wendy Morrison … ALS has been ongoing in my family for long..I lost both parents to ALS and it is so much pain have not been able to get over. As we all know medically,there is no solution or cure for ALS and the cost for Medication is very expensive..Someone introduced me to a Herbal man email:(drcomfotherbalhealinghome@gmail.om)(Native Medical Practitioner)in oxford.. I showed
    the man all my Tests and Results and i told him have already diagnosed with ALS and have spent thousands of dollars on medication..I said i will like to try him cos someone introduced me to him..He asked me sorts of questions and i answered him correctly..To cut the story short,He gave me some medicinal
    soaps and some herbs(have forgot the name he called them) and he thought me how am gonna use them all..At first i was skeptical but i just gave it a try..I was on his Medication for 2 weeks and i used all the soaps and herbs according to his prescription.. that he will finish the rest himself..and i called him 3 days after, i arrived and i told him what is the next thing..he said,he has
    been expecting my call.. he told me to visit my doctor for another test..Honestly speaking,i never
    believe all he was saying until after the test when my doctor mention the statement that am, also negative
    and the doctor started asking me how do i get cure….Am telling this story to every one of you encase
    you also having same problem you can contact him on his via
    email address: drcomfotherbalhealinghome@gmail.com

    Kind Regards!
    Thanks…

  31. Join me celebrate
    this day which my Lord God
    has made for using this great and
    powerful healer called Dr alabi that cured my ALS disease which has been
    eating me up for over 6years now without
    solutions, i tried looking for solutions on line, and through hospital, they
    keep on giving me orientations about drugs that can extend my years. now since
    Dr alabi has helped me to cure my disease with the use of herbal remedy and knowledge
    of his forefathers everything has been going well now, i owe you greatly for
    healing me so if anybody need is help or you also want to get cured you can also
    contact him on his email address: alabispelltemple@gmail.com .or via

  32. It is now August 2015. there is still no drug from any company available to ALS patients. Forget using it on mice use it on us! Whether it’s GM 604 or something from ALS TDI or another company. We need and want something now! No more excuses, we are dying anyway. I want to take this risk now! Save a mouse test it on me!

  33. Still do not understand why people is dying every day from this disease when there is something available to save them. Why?

  34. I thought AAP was approved back in the nineties when HIV/AIDS Patients went after it.but they’re having only approved three drugs since then part is not so hard to believe!

  35. Dr. Perrin,

    I believe the lady has made you a challenge. Are you going to take her up on it? If you are prepared to test this drug yourself then why not test it on humans and see for yourself whether or not it works.

    1. Hi Pippit
      I offered to test it in animals which would be a typical first step for any drug before moving towards a patient population. ALS TDI can’t test it in humans for a couple of reasons. First it is not our drug it is owned by Genervon. I would hope they have their own strategic plans to move it further along in clinical development as fast as possible for ALS patients. In addition ALS TDI doesn’t have the financial resources to run a large clinical trial of GM604
      Steve

  36. I would think Genervon is probably planning more human trials, but it sure wouldn’t hurt to have two sources witness positive results!

    Maybe you could get their permission to do human trials. They might even offer to help with funding. Also, you might want to look into grants from The Muscular Dystrophy Association. I read their page recently regarding scientists they were funding and they had several working on ALS in addition to scientists working on many other diseases that were neuromuscular in nature.

    Clinical trials don’t need to be huge to receive FDA approval. I know that drugs like Remicaide (a biologic for rheumatoid Arthritis and other autoimmune conditions) were approved with several 5-person trials done at various locations in the US and in other countries. I read the raw data on those, and it was FDA approved (and a black box warning added soon after) even though several of those trials were called off early because of serious drug safety issues. The model they used with small studies done by different researchers made it much easier for the drug to meet FDA’s study requirements and each site didn’t have to invest a whole lot of money.

    This new ALS drug doesn’t appear to have the adverse events Remicaide had, so it should have an even easier time being approved as long as enough people help it happen.

    There’s more than one way to skin a cat. It would be to both parties’ advantage to work together and prove it works (not to mention to the advantage of all patients whose lives hang in the balance).

    I hope you’ll seriously consider approaching Genervon with a proposal to enter into some sort of joint venture with which to move this forward more quickly.

    Sincerely,

    Pippit

  37. Hello Dr. Steve Perrin! Do you remeber me? I think that you are maybe intresting to my last succesfull suite to get the GM6!? here the Translation:
    Porto Recanati (Macerata), September 21, 2015 – “The judge’s decision will change my life. I’ll be the first to use this medication, but I’m not afraid. ” Serrani Moreno Miranda, 47, a native of Treia and resident in Porto Recanati, is ill with ALS since 2009. He has two children but lives alone. To help in the house, two assistant by day and a night. Coexists with walking problems but also with a great strength of character that allows him to move on it head. Has a history of entrepreneurial success, he had established himself as a restaurateur and trader of new and used cars in Germany; He continued its second business in Porto Recanati until last year, and stops because of illness. September 10 changed his life: a court order of Macerata will allow him to be cured with an experimental drug from the United States of America, the GM 604, which promises to slow down or perhaps even stop his terrible disease.

    “The measure – said the lawyer Fabio Trapuzzano – arrived in two weeks from the hearing: the anxious waiting my client has turned into hope for him this is a real chance of survival and improvement of their status’ . Moreno Miranda Serrani returned to Italy when he started having the first symptoms of the disease. “I left for Germany when I was 26 – he says -. In 2012 I was forced to return because of my health. At first the doctors were wrong diagnosis thinking it was a stenosis of the medullary canal. Years earlier, I had a problem at vertebra due to an accident during a dive. They operated by inserting a prosthesis cervical vertebra five. For a few months I felt better. Then they returned fatigue, muscle weakness, lack of balance, walking insecure. Four years after I was diagnosed with ALS. Since then my therapy involves the use of the only drug approved: Riluzole. But it is a palliative. A year and a half ago I stopped walking. Fortunately my disease progresses slowly. ”

    The 47-year old continued to struggle day after day with great tenacity. “I have written to all the journals in the newspapers talking about the new drug GM 604 and the petition that another patient was taking to speed up the approval for use of the drug – says -. Then I contacted my lawyer who said, let’s try. And it went well. I want to say to anyone who is experiencing this situation to pull themselves together. ” The first judicial success in this field, of Trapuzzano dates back to 2002 when it achieved for its client the possibility of treatment with another investigational drug American. “At the time it was a national case – remember -. Out of 100 patients treated with the drug 30% benefited. The IGF1BP3 became untraceable: in 2009 the pharmaceutical company decided to stop selling the product to Italy: from there a void therapeutic absolute. Especially because the only registered drug for this disease prolongs life, according to the medical literature, only three months. ”

    “In our case – said the lawyer – there was great sensitivity by the court of Macerata and creates a precedent and a hope for all patients in the area. It is a victory more humane and judicially. It is not just a measure, but a real chance of survival for my client. ”

    Federica Andolfi
    here the link: http://www.ilrestodelcarlino.it/macerata/cura-sla-farmaco-sperimentale-usa-1.1322075

    1. Way to go! I’m glad to see someone has broken through the barrier! If legal action is what will move this forward then it is a victory and moves us that much closer to access and freedom of choice.

  38. Excellent!!!… let’s send it to court, is a civil right to decide for our lives, no one has the power to stop like the FDA is been doing it.

  39. Right Eliana! Here an idea that I have taken from the Judge order:
    what do you thinks about this?
    This is just an Idea token from the result of my suite. Off course is just a scheme, outline and a way that if you think could be helpful to go troughs.
    I would like to make a ‘warning’ and deposit a letter to a court, to the FDA, congress, HELP commission, health ministerial and health minister with the follow.
    · Premise that ALS is a degenerative and progressive disease.
    · Premise that for that reason for pALS is urge a helpful treatment to slow down, suspend or stop the symptoms.
    · Premise that that treatment or drug doesn’t exist.
    · Premise that I will covered in care act material by: I dispose of health insurance/my own/government/employer.
    · Premise that ‘smoke for the good right’ and ‘danger in delay’ can be apply in this case.
    · It found that in the pipeline are some promises drug to treat ALS in the Phase II Trials.
    · It found that (here can be many thinks like: trials take 10y, als is heterogenic disease, right to try, etc etc etc
    · It found that the FDA doesn’t use the AA program for disease like ALS.
    · It found that this behaviour preclude Pharma Company to invest resources to found a drug (or what’s so ever).
    · It found that could be in some of those trials in the pipeline an helpful als treatment impossible to establish in present time.
    I warning you
    · https://en.wikipedia.org/wiki/Periculum_in_mora
    · I reserve the right (Me or if I’ll be death my……) from requesting damages from you if it will be demonstrate that after the Phase III of one of those Drugs could improve my health condition or save my life however you didn’t approve/ grant the access to the AA program NOW.

    Periculum in mora – Wikipedia, the free encyclopedia
    Periculum in mora, Latin for “danger in delay”, is one of two conditions which must be asserted in actions aimed at obtaining a protective order or injunction to be granted the relief sought (the other condition being fumus boni iuris). The second condition is the c.d. Prima facie case. The burden o…
    EN.WIKIPEDIA.ORG

    1. Yes, all great points! If the FDA’s outdated standards are resulting in the unnecessary death of people with ALS then it should be treated as Gross Negligence and they should be held liable. It is clear that they are expecting innovators to meet too high a burden considering the consequences of acting too slowly, and therefore cannot be allowed to continue using such outdated guidelines in making their decisions.

      The court is a very good way to prove this point. In fact, maybe make it a Class Action Suit! That would be much stronger than any petition we could sign onto.

      The stakes are so high that the FDA or any other regulator agency for that matter cannot continue to expect clinical trials of 100s of patients in order to make new discoveries available to patients with no time to waste.

      I also wonder why they make allowances for other drugs, fast-tracking approval of drugs like Remicade after 5-person studies while they allow drugs for ALS to languish.

      Besides, with a disease so deadly one really has to re-evaluate whether requiring placebo-controlled trials is even ethical or humane given that those PALS receiving the placebo are losing precious time by not receiving the drug. I believe this outdated study design should be challenged in court too and asked that such a requirement be thrown out where it concerns fatal and life-shortening diseases.

  40. I always pointed that this fight is taking too long to benefit people with diseases.
    Why don’t take it to court? Is the only way to fight for our right to live, why they have to decide, every day people is dying without no hope for the rest, is cruel, inhumane, unfair for the whole family and FDA is letting us die in a slow agony. I think that will be the only way the world will know about us, no the ice bucket to fill everybody pockets and we all know, where is money, corruption rise.
    I like your points, I hope we can get this fight over and soon. I will start to do the same, too. God will help us.

  41. Legal action of this type is futile. Period. The very claims you make against FDA are legal activities for them and are indeed even mandated by law. The Judicial system has no authority to intervene. Any change must be by law passed by Congress. The President can order FDA to change certain aspects of how it carries out its duties. But any lawsuits as discussed here will be summarily dismissed on Day 1.

    1. Dear Eric I agree with you that is a lost suit however my is a suggestion argumentadet like this:

      I know that in US there isn’t the ‘right to healt’ like in Italy that is a fundamental right established by the Constitution Article 32. This stablish:
      ‘La Repubblica tutela la salute come fondamentale diritto dell’individuo e interesse della collettività, e garantisce cure gratuite agli indigenti.’…
      Google transleat did good job this time….:
      ‘The Republic protects health as a fundamental right of the individual and collective interest, and guarantees free medical care to the indigent.’

      For this reason my suggestion is to make something like a ‘warning’ a letter and deposit this letter in the central US court. A Preliminary injunction or some similar.

    2. OK, then let’s do it! I’ve already been in touch with the Committee on Health and Human Services about my situation. It seems that as a group we could make an even bigger impact to get these archaic laws/regulations changed. They clearly aren’t effective when applied to these types of diseases. When a method becomes outdated it needs to be thrown out sand replaced with something that truly serves the people.

      If an Act of Congress is what it will require then let’s go straight to them!

        1. Hi Eliana,

          I’m emailing you right now! I think we need to create a petition on one of those sites like Change.org and direct it straight to the Secretary of Health and Human Services. I’ll send you her address and also post it in a comment here.

          I think we should all write as individuals and also get all the ALS organizations to write official position letters too!

    3. By the way if I was living in the US the day after FDA reject the AAP for the GM6 I was making this! But of course this is me……..

  42. FDA is the one who is breaking the law, the order has been already placed but they just don’t follow them, this lawsuit is because FDA is killing and attempted to kill more and we have to do something before it is too late..

  43. Here is the address for the Secretary of Health and Human Services;

    Sylvia M. Burwell
    U.S. Department of Health & Human Services
    200 Independence Avenue, S.W.
    Washington, D.C. 20201

  44. Well it is November now and I am progressing (in a bad way). I would like to get into some clinical trials and I live near Emory, my doctor referred me to their ALS clinic which is supposedly one of the best in the country and I can’t even get them to schedule me because that neurologist is out of town and won’t allow his nurse to schedule people without his express permission. Unless he’s in Mongolia or the Australian outback I’m pretty sure his nurse could get permission by phone or internet. It’s not that hard! Excuse my French, but that’s just F’ed UP! Someone is going downhill fast, has been referred officially to them and they won’t even put them on the schedule??? I know that clinic gets funding from the ALS Association and also from MDA in addition to other private non-profits and it seems to me they should not be allowed to delay treatment to people when a proper referral has been made. It also seems unethical for a clinic of that type to cherry pick their patients.

    Apparently they are doing genetic mapping and that neuralstem research there at that location, and possibly other clinical trials, but what good is it if people in urgent need are being turned away?

    My GP felt powerless to do anything about t and I’ve been in contact with him several times today due to the urgent nature of my situation.

    I can really relate to Ben above who was said these people are “doling out crumbs are as they see fit”. Yup, that about sums it up.

    These “professionals” need to stop creating barriers. We have enough just dealing with this disease.

  45. I’ve written Secretary of HHS Burwell again. The way regulations are set up is allowing many of us to just die with no help. Everybody’s hands can’t be tied. Something must be done. I don’t want to go down like this and I know others feel the same urgency about their lives.

  46. I am not an ALS patient, I am a journalist living in South Africa. Can someone please inform me about GM604’s current status? I am specifically interested if it has been given to sufferers for compassionate reasons any where in the world? If so, would that be legal?

  47. Hallo Dr. Perrin what do you think about this?Since I get under my skin observed during the past seven years an inexorable decline of motor functions due to the motor neuron disease (ALS), I can testify that, after I started the treatment with the experimental drug GM604 I could feel a downturn of this trend. After some infusion and 20 days I, the physical therapist and my both caregivers, we saw some small improvements The symptoms, such as akinetic-rigid, dysarthria, the loss of strength, weakness, the spasms etc. etc. they are reduced. Decreased either the stiffness on the legs (feet, ankles, and toes included), that the pain during massage or stretching. Remarkable less myoclonic spasms, didn’t stir up as before, they are short and stoppable, allow me to sit with the feet folded. Almost absent the involuntary spasm on the day time, better also for the night ones. Little better the range of movement self- or assisted-motion on all limbs. My hand fingers, the wrist are better re-contracted. The voluntary movements that I’m still be able to do are now easier, fluidal, faster, less spastic and muscle strength is slightly improved on all muscles that aren’t atrophies, unchanged for those almost atrophic like deltoids or flexors of the feet. I feel less exhausted or I don’t gasping for breath like before. I’m sure the nerve conduction is better now.

  48. I am so happy for you. Wish you keep improving your health with GM604. I am pretty sure that FDA and partner Perrin, do not care for your health, they are focus in how much money they can get from Ice Bucket Challenge and other campaigns they are running now. Hope your good news will be soon in the news around the world and Genervon has one more case to support GM604.
    Keep us updated in your progress, please. We need to hear good news all the times.
    God bless you,
    Eli.

  49. Wow, Moreno! That is excellent! I can’t remember if you said you got to take it after the trial was over now on an ongoing basis after you’d finished the trial. Is that the case?

    You know what you should do; go to as many news shows or talk shows you can get to have you on and speak about this publicly. Media moves mountains. I truly believe this is the way things will change for the better. There’s no doubt in my mind that the makers of this drug are onto something. It seems that several people have had marked improvement from it and this can’t be brushed aside.

    Also, if you can get on the speakers list for any conferences, do it! Tell your story to the people who truly are looking to improve things in this specialty, and don’t stop telling it until you find the right people with the power to give this drug the spotlight it deserves!

  50. Let’s see if that holds or improves over 6 months. Then you can claim success. It appears that Genervon is only in it for the money since they refuse to move forward with real investigation and instead want to market GM6 via email for nearly $100,000 for a few weeks of drug. Instead of doing real studies they rely on very selective anecdotes from patients to whom they have sold GM6 and cobble together “press releases” to keep up the fervor.

    GM6 is not very expensive or time-consuming to make. It’s 6 basic peptides put together in a chain. The order of the pattern is public knowledge. I urge all PALS to save their money. And DO NOT sign any non-disclosure agreements with Genervon.

    1. I don’t have a crystal ball to say what’s will be in 6 or 12 month and you either Eric, so let’s speak about fact and not about oracle preview. A fact is that I was 3 week ago worst that today and this is never happened to me since 7 years from the first symptom. For the rest is a discussion that isn’t my business however if I have to sign an ‘non-disclosure agreements’ I do it especially if it helps me to get what’s so ever Drug that helps.

    2. Where can I obtain this public knowledge of this peptide chains. I would like to get hold of the formula and compound it myself if it’s cheap and easy!

  51. If you didn’t read the complete story of Mr. Moreno, he won a trial in Italy, to get access to GM604, that was the only way Genervon was able to provide him the drug.
    It is not as far as I know, Genervon is looking for this kind of profit. I think you are wrong.

  52. I am not wrong. Genervon is actively marketing GM6 to PALS in many countries outside the USA. I know Moreno and he is not doing a clinical trial but rather an open-label individual use without rigorous data control. I did the same thing earlier this year. You should look up who I am.

    1. env I’ve not heard of it being sold anywhere, but positions in other countries are getting it for patience I don’t know if there’s a price tag on it or not. Env what is your opinion of GM 604 did it help you or not? would you take it again if you had the chance?

    1. Off course I’m not!
      I don’t have a crystal ball to say what’s will be in 6 or 12 month and you either Eric, so let’s speak about fact and not about oracle preview. A fact is that I was 3 week ago worst that today and this is never happened to me since 7 years from the first symptom. For the rest is a discussion that isn’t my business however if I have to sign an ‘non-disclosure agreements’ I do it especially if it helps me to get what’s so ever Drug that helps.

  53. Mr Perrin I have not seen GM 604 on sale anywhere at any price. If it is as simple as 6 peptides chained together then why the hell doesn’t your company do it? And if this is public knowledge where do I find this public knowledge? I will compound the stuff myself! And you claim Genervon is in it for the money?

  54. I am trying to search in South America who is selling GM604 as per ENV said, so far, nobody, nada, none.. ENV do you know where I can get it?

  55. You can do a Google patent search for the filings or you can find the links to the documents in my blog http://www.ericvalor.org/carpe-fragments. GM6 is under patent protection so no other company can make and sell it. You can only get it directly from Genervon.

    Moreno, you and I have talked about plateaus and placebo effect. Due to the nature of ALS you cannot claim effect until it has endured for about 6 months on average. ALS can also suddenly stop progression by itself without any treatment, so this phenomenon can be (and frequently is) mistaken for treatment effect.

    GM6 is an interesting drug being horribly mismanaged by Genervon. Tell them to accelerate trials because FDA has said an absolute NO to advanced approval without more data.

    1. Eric off course I know about the placebo effect, I also know that I lost ca 2 point on ALSFRS-R and 5% on FVC each year. That’s mean today I have 23/44 and 64/100%, about the EMG I did one 3 Year Ago and one 1 YA. In 6/12 month I’ll let you know all thous result then and only then we can speak about resoult because for now we have only perception however I don’t speak about result I say just ‘some small improvements’.

      1. Mr Moreno, if the Italian government are paying genervon for their medicine, does that mean my brother in ireland is entitled to it also under European Union law?
        Next time you are on here can you also get confirmation /endorsement from your neurologist that this very expensive drug works.
        Thank you
        A concerned bystander.

  56. Mr Eric, there is a feeling that nothing is been done to solve the cure of ALS, a very complicated disease, not the same in everyone and I think that depends of the strength of the recipient of the disease. More delays in those trials that doesn’t show advance or progress like GM604. It may be not for everyone who has ALS but at least will be a relief for many and that chance is being take it away. FDA approves medicine irrelevant without the protocol imposed to Genervon, medicine who harms instead of cure or save lives. Tell me why there is no equal opportunity to feel better if Genervon has at least one solution for many, why is people dying without help.

  57. Whether the hold-up is coming from Genervon, the government, or both press coverage and patients who participated in the trial speaking in front of conferences about its benefits to them is what is needed to exert the pressure to make whomever has the power to move forward budge on this.

    Come with documents in hand about your improvements. If any tests were done that back you up, bring those reports and show them. Even TV shows like 20/20; investigative reporting shows are good places to get some interviews. They can look at what was done and try to quantify the results independently. You just never knoew who may be watching and take an interest in the findings.

  58. Here’s an analogy that I hope will make sense. I’m just a scientist who knows people who have the disease has been following this whole story since 2012 because, well, I want ALS to be fixed.

    We all know that the GSK Phase II trial of ozanezumab failed in 2015 after showing zero effect. Let’s pretend some small, previously unknown company owned ozanezumab back in 2012/2013 and ran the first small safety trial that GSK published here in open access for all to read (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026380/#pone.0097803.s005). It was larger than the GM604 study, yet still, they could only scientifically say that the drug appeared tolerable. (we won’t get into the fact that the mouse data was actually published too rather than just press released as awesome)

    Looking at the data from that trial, you will see that in the repeat dose 15 mg/kg, ALSFRS-R slope was nearly halved (-0.77 vs. -1.48) with 9 patients (keep in mind GM6 had 6). A similar effect was also seen in the muscle testing (MMT). Note despite the large effects, the underpowered study meant it was not mathematically possible to say this was significant.
    drug placebo
    RD 15 mg/kg* 9 -0.77 9 -1.48 0.71 (0.69) -0.67, 2.09

    The drug was well tolerated for the most part.

    Now, let’s say that small company (not GSK), back in 2013, decides to put out a press release (or several) saying the MMT and ALSFRS-R slopes of decline are halved with this new drug and it’s safe to take. They don’t publish the rest of the data or submit any of it for peer-review and they don’t present any of the data at ALS meetings. No building of goodwill in the scientific and clinical community by backing up the claims with the data, just press releases telling the public about that big effect. And the company pushes for people with ALS and their families to get the FDA to give Accelerated Approval and not show all of the data from that PLoS One paper to everyone.

    We now know if that had happened, people would have been very excited and petitioning over access to a drug that actually doesn’t slow ALS progression. The company could make money selling a drug that we now know doesn’t work and investing nothing to trials where the cost is on them and drug access is free to participants. There would be no way to know at that point if it worked or not based on such a small (still bigger than GM604) study so of course people would want the right to try it. The kicker is, if that had happened, two years after that theoretical “ozanezumab is awesome” press release, people would still be trying to get this drug (that ended up being ineffective) in the same way they are trying to get GM604 now.

    Instead, ozanezumab was handled a company who put it through the right process, risked a lot of money (many millions) that they will now not get back, had 150 people taking their drug for free on trial soon after and if somehow there was a 50% slowing of disease seen last spring when the results were announced, there would probably be a very good case for accelerated approval with the FDA right now, or at least a large trial with a lot of people on the drug.

    I hope that analogy helps direct the energy in the right place.

  59. Here’s the difference, Anonymous; here on this very forum we have people who have posted that GM604 worked for them personally and these were not just people blindly following the “hype”, as you suggested about the other drug in your analogy.

    When I think about what to take for myself I would rather look at real live examples rather than just statistics. People are not going to put themselves out there like that if a particular treatment didn’t work for them, and they wouldn’t continue to take it or continue to try to maintain access to it after a trial is over if it didn’t really help them.

    I’d say for a 6 person study GM604 has a pretty good track record!

  60. Hi Giftbearer,
    Your 100% correct in your thinking.
    The only part I dont get is the logic in how this drug is distributed. With Moreno is appears to be a case of Im alright jack whilst the rest die. If other countries are prepared to pay and administer for it, why isn’t it more freely available to everyone if it had the potential to save lives. Granted genervon would appear to be get rich quick merchants they may have the elixir that saves lives. There is something seriously wrong in this whole world if terminally ill people are being denied access to a potential life line. What is happening to mankind.
    We dispare but yet live in hope

  61. I think it has more to do with the particular government of each country. The US and some other countries have regulations and laws that cut off options for patients and make it overly difficult to get treatments that could save our lives or at least extend them.

    Those making these restrictive laws and regulations can never understand because they aren’t sick, but sooner or later everyone gets something they can’t recover from, so I hope those in power in the FDA and Health and Human Services, as well as those agencies causing similar obstructions in other countries will stop and really think about what they would do it it were they, their wives, their mothers, or their children whose lives hung in the balance.

  62. Hear hear. Well said Giftbearer. Yes its only when pals and close relatives are involved in this fight for life against this dreadful horrible disease, that you realise how cruel the world can be.

  63. s try it please let mme knoe tks and appreibhapdythat recenmtl ytjere is adrug form japan called RADICUT I wonder any

  64. sorry understand that there is a drug from japan is called RADICUT treatment for ALS and by approved by JAPAN
    Wonder anybody has tried it tks
    does anyone know the cost many thanks

  65. to be frank
    i m now trying the chinese medicine from china hunan
    and shall infor you all for the outcome once is good
    will tell you all more about it
    tks
    don ng

  66. Just a gentle reminder to inform all ALS patient that dont trust the website too much
    recently i had a bad experience about the herb from south africa or nigeria
    They informed me that the medicine cost so much later after bargaining the medicine was reduced to a very good prices upon that when i transfer the money to them about 100US dolars
    they said that is only for the medicine hiw about the air frieght The air freight company is charging around US 400,00 i said i cant afford
    ANYWAY i think is really a SCAM
    so becareful all ALS PATIENT
    DONT be a fool again tell yourself is this herb is really that good
    they are the instant millionaire right now dont ever like me so stupid to get fooled again

  67. My names are Michael Brennan… ALS has been ongoing in my family for long..I lost both parents to
    ALS and it is so much pain have not been able to get over. As we all know medically,there is
    no solution or cure for ALS and the cost for Medication is very expensive..Someone introduced me
    to a Herbal man email:(dr.sabiherbscure@gmail.com)(Native Medical Practitioner)in oxford.. I showed
    the man all my Tests and Results and i told him have already diagnosed with ALS and have spent thousands of dollars
    on medication..I said i will like to try him cos someone introduced me to him..He asked me
    sorts of questions and i answered him correctly..To cut the story short,He gave me some medicinal
    soaps and some herbs(have forgot the name he called them) and he thought me how am gonna use them
    all..At first i was skeptical but i just gave it a try..I was on his Medication for 2 weeks and i used all the soaps and herbs according to his prescription.. that he will finish the rest
    himself..and i called him 3 days after, i arrived and i told him what is the next thing..he said,he has
    been expecting my call.. he told me to visit my doctor for another test..Honestly speaking,i never
    believe all he was saying until after the test when my doctor mention the statement that am, also negative
    and the doctor started asking me how do i get cure….Am telling this story to every one of you encase
    you also having same problem you can contact him on his via
    email address: dr.sabiherbscure@gmail.com or call/Whatsapp +2348167257144.

  68. HOW I GOT CURED FROM ALS DISEASE

    My name is Amily willian from U.k, I was diagnosed of ALS disease (Lou
    Gehrig’s disease) in 2014 and I have tried all I can to get cured but all
    to no avail, my life was gradually coming to an end, until i saw a post in
    a health forum about a herbal doctor from Africa call DR OKIJAIKE who
    prepares herbal cure to cure ALS/ and all kind of diseases including HIV,
    MND, Epilepsy, Leukemia, Asthma, Cancer, Gonorrhea etc, at first i doubted
    if it was real but decided to give it a try, when i contact this herbal
    doctor via his email, he prepared an ALS herbal portion and sent it to me
    via courier service, when i received this herbal portion, he gave me step
    by step instructions on how to apply it, when i applied it as instructed, i
    was cured of this deadly disease within 7 days, I could not walk or talk
    understandably before but after i took the herbal cure as he instructed i
    regained strength in my bones and i could talk properly unlike before, I am
    now free from the deadly disease, all thanks to Dr.OKIJAIKE Contact this
    great herbal doctor via his email okijaike@gmail.com

  69. I was beyond desperate. I had ALS disease in June 2010, I fortunately had the treatment immediately with antibiotics which seemed to clear it up and after having been very ill and lost about 2 stone in weight i thought id fully recovered. Following this major illness in 2010, I believe I have never been right since- i tire more easily and seem to have a weakened immune system. More concerning is the fact that in the last 1 year from March 2015 (where I have developed eustaian tube disorder in the middle ear which the problems are now ongoing for over a year) through to present (May 2016). I am also getting other illnesses that are odd/unusual and within a close space of each other and at least once a month falls nearly on the same week each month. For example: Labrynthitis for two weeks, then two weeks later flu and deafness/ear disorder flared up, then two weeks later i now have chicken pox. In between all these more serious illnesses i have had vomiting bugs also but relatively normal type bugs. My GP has put the illnesses down to a change in my environment as i started a new job in september 2015, but i feel it is much more serious than that and others around me in my office are not getting any of the illnesses i am experiencing. I am desperate and at the point of suicide with my health,before i meet Dr Adam who help me with a cure that i used now i’m so happy thank God for Dr.Adam and if you have lost hope in your life there is hope now contact Dr.Adam at
    dr.adamsaisha@gmail.com .He can also cure Cancer of any type Zika, Hiv just name it there is a cure .

  70. Hello my name is Joy let me testify to the general public how i got cured by DR.Hansan for healing spell from (ALS), I have been diagnosed of (ALS) for good 8 years and I was almost going to the end of my life due to the constant pain, especially in my knees.all I have in my mind is let me just give up because life was no longer interested to me any more but I just pray for God every day to accept my soul when ever I die, luckily to me my kid sister ran to me that he found a doctor in the internet who can cure (Trichomoniasis,CANCER, And HIV/AIDS )he helped me out on everything, the great Dr Hassan, only ask for my picture, so he can cast a spell on me from his temple.. after two days I started getting more stronger my blood started flowing normally i started experiencing changes all over me as the great Dr Hassan assured me that i have been cured,after some time i went to my doctor to confirmed if i have be finally healed behold it was TRUE, if you have HAPATITIS B HERPES CANCER HIV/AIDS any kind of and he also do love spell, and kind of spell you can think of or any illness i advice you all to contact him on dr.adamsaisha@gmail.com. Good luck

  71. Hi
    in the US MARKET i think that there are many drugs like iplex, NP001 GM 604 Tirasemtiv all are for ALS How come all is not approre yet They have done so many trial s
    Please help us fDA
    WE NEED THE DRUGS TO SURVIVE TKS
    DON NG

  72. They should be on their 3rd or 4th clinical trial on humans already. We tried to get the FDA to pass it last year and they wouldn’t. It doesn’t make since the FDA can be that cold hearted and not pass a drug due to possible side effects when the patient only has a short period to live anyway. There has to be something more to it that we are not aware of. If not, whom ever has authority at the FDA needs to be figuring out how not to go to hell for not giving ALS patients the right to try because it will be worse than ALS.
    My email is tdanyelcares@yahoo.com

  73. This is a very interesting blog.
    Below is how i got a cure for my wife who suffered from ALS (Lou Gehrig’s disease).
    I lost my dad to ALS 5 years ago , he suffered from the dreaded disease for 6 years with his doctor telling us he can’t be cured and all the therapies and life support machines could not save him and 3 years later my wife was also diagnosed of the same disease and i was devastated she fainted when the doctor read the diagnosis because she knew how deadly the disease was. In a year her condition worsened and she was unable to move and she was confined to the bed, the doctors told me all her muscles were dead, she was able to eat via a machine because she could not swallow anything. I searches and tried different neurologist and different medicines none worked and i was so scared to lose my wife. While running up and down seeking for a solution i met my friend from third grade saw me all worked up, we got talking and in the process of discussion i told him all i am facing. He felt sad and told me about Dr. Joseph who was able to cure his cousin. I was interested and he gave me his contact. I contacted him and he came down to where my wife was and started to treat her with his medicine and in a space of 3-4 months she was up on her feet again and in 6 months she recovered fully. She can do normal things like walking, eating, without any assistance whatsoever. I am so amazed at the potency and effectiveness of his medicine. I decided to share my story for you not to lose hope or feel your world has ended you too can be okay like my wife. Simply contact him on his mail (josephalberteo @ gmail. com) for more information about his treatment. I hope this helps someone out there.

  74. i want to share a story with anyone else going through a genital herpes infection. I was embarrassed about my condition, After dating a guy back in 2009, i discovered what i thought was a case of the flu, but my doctor told me I had contacted Herpes Simplex. My boyfriend also had it, and had transmitted the infection to me, He claimed to be clueless about it. I developed a rash around my genital area, and then i later split up with him, now ex-boyfriend. After getting over the breakup, i became more objective about my condition, and started looking for a cure to rid it of this infection. I became disaffected with conventional treatments, in that you have to take some large pills every day, or large doses of antiviral medicine every time you feel another rash is developing. This is an awkward and ineffective way to rid an infection.i was about given up on my condition when a friend introduce me to a herbal remedy home for treatment, i give thanks to God for using this great man to bring me back to life.All thanks to Dr ejeke for his wonderful spiritual help. You can contact him via email : ejekeogumenhealinghome@gmail. com if you have similar problem, or any solution you may need,Good Luck.

  75. ALL THANKS TO DR WILLIAMS FOR GETTING MY WIFE OUT OF FIBROID WITH HIS HERB One of the greatest moments in this world is when you see your own wife put to bed, this awesome moments makes you a man and not just a man a real man. My wife suffered from Fibroid which made her unable to get pregnant and give us a child for almost 18 years with multiple surgeries done and none seemed to help the situation. I almost gave up but due to the love i had for her because i married her a virgin i had to find a way to help her. I told a member of my church who recommended Dr. williams to me, i contacted him and he sent me a medicine and this medicine shrinked it naturally in a weeks it was like magic but it’s science. I am happy writing this because he delivered a baby girl. Do not loose hope too soon contact him on drwilliams098765@gmail.com and i am confident she will help you too.

  76. ALL THANKS TO DR WILLIAMS FOR THE GREAT DEED HE HAVE DON FOR MY DAUGHTER?
    My daughter suffered from a terrible tinnitus for more than 23 years which started after she turned 5 we all thought it will end but got even worse as days went by. We tried all several treatments and therapy prescribed by various doctors we met but to no avail, she lost total concentration and screamed most times. She usually tells me she hears hissing and ringing noises. This were steady noise that disrupted her entire life, even at night she screams even more because the sounds become louder because everywhere is quiet and she slept less because of this.It was during a casual conversation with a friend that i learned about dr Williams herbal medicine I was able to contact him on his email address. and give him all the necessary information that he needed,few day later he sent me the herbal portion and his medicine was able to restore her back to normal and she is very okay now without any side effects whatsoever. If you have Tinnitus, do not hesitate to contact him on drwilliams098765@gmail.com for advice and for his product. I hope this also helps someone out there.

  77. ALL THANKS TO DR WILLIAMS My daughter suffered from a terrible tinnintus for more than 23 years which started after she turned 5 we all thought it will end but got even worse as days went by. We tried all several treatments and therapy prescribed by various doctors we met but to no avail, she lost total consentration and screamed most times. She usually tells me she hears hissing and ringing noises. This were steady noise that disrupted her entire life, even at night she screams even more because the sounds become louder because everywhere is quiet and she slept less because of this. I was able to contact Dr.williams. on the matter and his medicine was able to restore her back to normal and she is very okay now without any side effects whatsoever. If you have Tinnitus, do not hesitate to contact him on drwilliams098765@gmail.com for advice and for his product. I hope this helps someone out there.

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