Tag Archives: FDA

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Disaster and Development

Hello and welcome back to the Cripple Command Center podcast. My name is Eric Valor and I will be your host for this episode. It’s my podcast so I get to hog up all of the miniscule glory from an obscure blog about a very niche subject. I promise I won’t let it go to the wig. On tap for this episode are: An update on the latest Neuraltus NP001 confirmatory Phase 2 trial, the new Brainstorm Phase 3, and a note about two decades’ worth of data on Oregon’s Death With Dignity Act.

But first, I would like to urge my readers and viewers to go to my friend Patrick O’Brien’s GoFundMe page and donate to his new independent film project. Patrick is a PALS like me, totally quadriplegic and on mechanical ventilation to live. Nevertheless, he continues on with his passion for independent filmmaking. His first project after he was diagnosed and became quadriplegic and vented, “Transfatty Lives”, won the TriBeCa Film Festival Audience Award and is available on Netflix and i-Tunes, among others. It’s amazing and I urge you all to watch it.

Please go, click, and donate. Patrick deserves the support to keep his work going.

Another urgent matter is regarding the ALS community in Puerto Rico. As you know, a severe hurricane devastated the island, effectively removing the communications infrastructure. This is especially dangerous for PALS by making it even more difficult for them to obtain the assistance they need. You have no doubt already heard of some patients dying in care facilities because the generators which powered ventilators ran out of fuel.

There are over 200 PALS in Puerto Rico who need assistance. Team Gleason, of which I am a board member, has committed at least $10,000.00 to this specific relief effort. I urge everybody watching, hearing, or reading this to donate. Your contributions will help us reach as many PALS as possible with supplies and equipment. With assistance from groups like Baton Rouge Emergency Aid Coalition, Cajun Airlift and networks of physicians in Puerto Rico and on the mainland, we will coordinate getting relief directly to those with ALS. Please consider donating to help PALS with little resources and little help on the horizon.

OK, to business. Neuraltus began their second Phase 2 trial of NP001 in February on 2017. The trial was to have 120 participants in 18 sites across North America and the 120th patient will have the final dose in December! Results are expected mid-2018. The previous trial “failed” but a post-hoc analysis found a responder group based on a set of inflammatory markers found in the blood and restricted this trial to patients fitting the responder profile. The results this time are expected to be much better.

Next item is the new Brainstorm Phase 3. This trial is the follow-up to the impressive Phase 2B which concluded in July of 2016. In the July 18, 2016 Update from Hope Now For ALS, HNFA issued its review of the Brainstorm data showed remarkable results in a group of patients classified as “Responders” (ALSFRS-R slope improved 100% after treatment compared to a 3-month lead-in observed slope of decline). “Responders” were almost half of the treated group. Their ALSFRS-R scores were significantly better than the placebo group and the surveilled biomarker candidates showed significant improvement. The Phase 3 is a multiple-dose trial where the Phase 2 was a single-dose. The results are expected to be even better, though ALS has shown itself to be quite elusive to hit when previous “slam dunk” treatments were thrown at it. Stay tuned here and to the HNFA website for news as soon as it’s released.


Now for a subject that is intensely personal and not a recommend topic for dinner conversation . It’s definitely a dating taboo. This subject is the Oregon Death With Dignity Act (DWDA) which was passed in 1997. The law, which went into effect in 1998, has strict restrictions on terminally-ill patients who would then request a prescription to end his/her own life on their own terms rather than the much more unpleasant terms dictated by terminal illnesses.

According to the Medscape article which prompted this segment of the podcast:

“To obtain a DWDA prescription, patients must be adults of sound mind, have Oregon residency status, and have a terminal illness diagnosis. In addition, two physicians must confirm the patient’s diagnosis and prognosis, the patient must be offered hospice care, and the patient must make one witnessed written request and two oral requests at least 15 days apart.”


It’s a very common-sense approach to ensure only those truly with a terminal illness have access to this program and that people requesting it are not in a state of undue stress or confusion. According to the 20 years of data compiled, the program is a total success. This is where we get into danger of ruining Thanksgiving dinner – especially when Drunk Uncle gets his inevitable too many beers and bourbons before the turkey is even out of the oven and resting.

The issue is being discussed in every individual state and on the federal level. There are many points of resistance, including religious groups and people who have had the cultural stigma of suicide ingrained in their lives. But is it really suicide if one ONLY has a medically-verified shortened life of suffering and loss of personal dignity? Isn’t it better to go out while you still have your human dignity, where family and friends can remember you whole and relatively hearty? These are questions which only the individual patients can answer for themselves.

I made my decision because I knew that I could suck the marrow from he bones of technology and life a full life full of triumph and tragedy, love and loss, creation and oblivion. I have done all that rather more intensely in my shortly over a decade of living with ALS than the previous nearly 4 decades of healthy living. But I feel that every citizen of the United States should have the right to make this decision for themselves. Adults of sound mind should be allowed to be the masters of their own lives. We do not have the luxury of any opinion about when, where, how, and by whom we are brought into this world. It’s the ultimate indignity to be denied the ability to choose our own terms of exit after tragic illness sets the date. However, this is an individual’s choice. I invite discussion on the Comments Section following each text transcript on my website.

I think 2018 is going to be a landmark year in the otherwise long and somber history of ALS. The previous clinical trials of Brainstorm’s Nurown and Neuraltus’ NP001 have had results that were much more remarkable than any in ALS history and, although history has been brutal with Phase 3 failures, there’s no reason to believe that these Phase 3s will be any different from their previous results. I believe this even more since sub-groups of PALS have been identified as very likely to respond to treatment, something not done in past clinical trials for other ALS treatments. We now have two “Real Deal” prospective treatment options going for registration (known to people not in the clinical trial business as approval) which should soon provide effective treatment for many PALS, finally extending lives in meaningful quantities. And for the unlucky among us, the Death With Dignity issue has become a national debate. With excellent data such as those coming from Oregon, hopefully it will become a nationally-recognized right for those of us unfortunate to contract a fatal disease to control our own destinies.

But like everything, PALS will need to go out and get these things for themselves. If Neuraltus and Brainstorm do decide to apply for registration, they will need our help by showing our support for approval and demanding FDA follow through. Likewise, we must also forcefully demand that lawmakers recognize our natural-born rights to control our own lives. Again, like how every gain PALS have made came from one or a few of us starting a small movement, with more joining in and staying active until the goal was achieved, we together can always achieve our goals. Not bad for a bunch of people confined to wheelchairs and beds who cannot physically speak. With a little clever use of technology we are still very potent advocates for ourselves.

A parting point is a political one. It has to do with the new Republican tax bill recently introduced in Congress. One particularly problematic issue with the bill, among multiple others, is the elimination of the Orphan Drug Tax Credit (ODTC). According to NORD, the National Organization for Rare Disorders:

“The ODTC allows drug manufacturers to claim a tax credit of 50 percent of the costs of clinical research and testing of orphan drugs. The ODTC is part of a package of provisions enacted in 1983 in the Orphan Drug Act (ODA) that provide incentives for drug companies to develop products for rare diseases. This legislation has been extremely successful, resulting in over 600 therapies for rare diseases coming to market in the last 35 years.

Without the Orphan Drug Tax Credit, approximately 33 percent fewer orphan therapies would have been developed, and 33 percent fewer orphan therapies will be developed going forward if the tax credit is repealed. This means that at least 10 fewer therapies would come to market for rare diseases each year, only exacerbating the stark need for rare disease treatments even further.”

This is a serious issue for developing treatments not only ALS but all other rare diseases. This is simply unacceptable for not just the patient community but all of America. Giving companies incentives to develop treatments for rare diseases creates jobs and innovation. And, when effective treatments are found, they create economic boosts from the sustained new jobs associated with the new treatment’s production and distribution. But primarily the patients could remain healthy and continue fully participating in the local and national economies. The ODTC is not a “loophole” and eliminating it is penny-wise but pound foolish, paying for tax cuts by eliminating excellent investments in the future of America.

Please help stop this by telling Congress that this is unacceptable. The ODTC is one of the only tax credits that actually saves lives. Tell your Senators and Representative to oppose repealing the Orphan Drug Tax Credit, and stand up for the 95 percent of rare disease patients still searching for a treatment.


I would be remiss if I did not remind my viewers, readers, and listeners that open enrollment for health insurance plans administered under the Affordable Care Act (ACA, also colloquially known as Obamacare) runs from November 1st to December 15th. Certain states are open longer – check your state exchange website for the dates you need to know. This is half the length of open enrollment in previous years because the Trump Administration cut it from 3 months to 6 weeks (a month and a half). Trump also decimated the advertising budget, so people needing coverage under the ACA might not be made sufficiently aware of the new shorter schedule. So, remember this year to get your enrollment completed before December 15th. Don’t wait until the last minute – take some time to take care of yourself today. December 15th is the deadline so make sure your enrollment is complete with plenty of time left. Log on to either your state exchange or the national website and make sure you’re covered by the plan of your choice before December 15th.

That’s this episode of the C-to-the-3 podcast on ericvalor.org. I have been and ever will be Eric N. Valor. Until next time, keep breathing easy.

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MAGIC Mitochondria (and more)

Audio Podcast (192kbps MP3 download)
(video at bottom of text)

Hello and welcome back to my podcast.

My name is Eric Valor and today I have a few different subjects to cover. I will cover the new ALS treatment recently approved by the FDA, the latest message from Hope Now For ALS, MAGIC in yeast cells, and trouble for stem cell therapies.

But first, I would like to make a personal announcement. Some of you may already know this, but I was recently accepted to the Academy of Neurology as a researcher. It’s not a huge deal but it’s nevertheless something I am proud to have on my CV.


Now, to business. My first item on the board is the first drug to be approved for ALS in 22 years.

In May of 2017, the FDA approved edaravone, also called Radicut or Radicava, for use in the United States. Edaravone was developed and originally approved for use in Japan in 2001 for protection from the effects of a type of stroke. Its MOA, or method of action, is as a scavenger of free radicals. These molecules have an unpaired electron in one of their atoms, making them extremely reactive with other molecules. The radicals at subject are called reactive oxygen species or ROS, produced as a byproduct of the mitochondria creating energy for the motor neurons. These molecules, when not properly controlled, cause significant damage to cellular structures. There have been many attempts to eliminate these ROSs as a treatment for ALS, but all previous attempts have failed.

There are some side effects resembling allergic reactions, from redness and itching up to anaphylaxis, which requires immediate emergency medical assistance or the person can perish). The incidence of serious adverse effects (SAEs) was low, with the most common, dysphagia or difficulty swallowing, occurring in 12% of patients. Milder adverse events occurred at the same rate as placebo.

Edaravone Adverse Events

The dosing regimen is 14 days of one infusion per day of 100 milliliters administered over one hour followed by 14 days with no infusions. Subsequent cycles are 10 days of infusions followed by 14 days without. Edaravone showed up to 33% slower progression in patients who were fewer than 2 years post-diagnosis, were still ambulatory, and could still feed, dress, and bathe themselves. Three out of four clinical trials of edaravone for ALS failed to meet clinical endpoints, but the fourth, when restricted to the PALS described previously, met its endpoints. What that means is that it seems effective only in people very early on in progression.

The second item on the agenda is the recent update which Hope NOW for ALS posted about its activity. On May 10, 2017, HNFA released a statement describing their May 1, 2017 meeting with key officials at FDA CDER. The statement also mentioned the approval of Radicava and how it is the first drug approved to treat ALS in 22 years. The main point of the HNFA statement was to indicate willingness by the FDA to consider updated clinical trial methods to make clinical trials more accurate and humane. It’s a hopeful message and indicates, along with the new approval of a treatment for ALS, that the FDA may be really changing how it sees and deals with life-threatening or fatal conditions.

ALZ Forum Logo

Third, the ALZ Forum has a nice article on mitochondria making MAGIC. In a study published in the March 1st edition of Nature, a team from Johns Hopkins University describe mitochondria in yeast cells untangling misfolded cellular proteins before tearing them apart for recycling the components. The process was termed “mitochondria as guardian in cytosol” or MAGIC. Aggregated or misfolded proteins which become tangled in each other are known to be torn apart in cellular machinery called proteasomes. Without mechanisms for breaking down these aggregated proteins they would clog the entire cell like the white of a boiled egg. You can see the same process happen as you fry your breakfast in the morning. That would be very bad for the cell and ultimately us.

In MAGIC, these same aggregated proteins are imported into the intermembrane area, a small space between the outer and inner membranes of the mitochondria. There the proteins are untangled from each other, then passed into the inner mitochondria where the individual proteins are chopped up. When heat shock proteins in the cytosol of the cell aren’t working properly this puts more stress on the mitochondria which are already very hard at work creating energy for the neuron. Think of it like hauling a heavy trailer up a mountain road in your car. Your engine strains under the load, getting hotter and pumping more smoke out of the tailpipe. The “smoke” from the mitochondria is the ROSs. The authors further reported that this process also happens in human cells. If those holds true then it would tie together two critical factors of neurodegenerative disease: protein aggregation and mitochondrial dysfunction. That’s would be an important finding as it would further elucidate the mystery of ALS, Alzheimer’s, and Parkinson’s.

In another story, again from the ALZ Forum, it appears that significant efficacy differences exist between clinical-grade stem cell lines and their research-grade counterparts. The differences may explain why some clinical trials fail. Two studies in the February 14 edition of Stem Cell Reports (study 1 and study 2) suggest that the outcomes could have been anticipated if the production lines were animal-tested the same way as in preclinical studies. The two subject studies looked at the unsuccessful trials by StemCells Inc. of spinal injury treatment using neural precursor cells. The company reported that the cells remyelination and motor recovery in mice with spinal injury.

But in two different trials with the same cells expanded using the Good Manufacturing Process (GMP) standard, required for production for use in humans, the cells failed to demonstrate efficacy. When the same lines were later tested in mice for the subject studies, they matured at about half the rate as the research-grade cells and largely remained as undifferentiated clumps. In one study about 4 percent of the grafted cells continued to divide and in some cases extended neurites into the surrounding tissue. Obviously injecting undifferentiated stem cells is a very bad idea and no two stem cell lines are identical. Together these studies provide strong evidence for preclinical testing of clinical-grade cells prior to use in humans.

Finally, another announcement: Beginning with this podcast (and retroactively back to the prior podcast) the video portion will be included at the bottom of the transcript. This will make viewing easier for my blog readers.

Thank you for reading and/or viewing. Leave a comment with your thoughts or any questions, and subscribe to get a notice in your email whenever a new episode is published. Until then, keep breathing easy!

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Reddit AMA Guest Appearance

Reddit Tag-Along


On Friday, November 18, 2016, I participated in a Reddit AMA as a co-guest in support of my friend, Jef Akst. Earlier this year she published a book titled Personal Trials: How Terminally Ill ALS Patients Took Medical Treatment Into Their Own Hands (available on amazon.com in both Kindle and paperback) about the Oral Sodium Chlorite Project I created along with Rob Tison and Ben Harris, and our journey through the DIY drug experience. Reddit asked her to do an AMA about the book and she asked me to tag along for the session to give the ALS patient perspective and as one of the subjects of the book.

It was my first time ever doing this and it was exhilarating. For two hours, Jef and I were furiously typing away trying to keep up with the deluge of questions. In fact, I am still going back and answering late questions right now. At first I was a little nervous about facing a bunch of trolls and kooks, as the Internet appears full of these days. But the questions were all quality and reflected a desire to actually learn something about the subject.

I am grateful to Jef for writing the book, telling the story of patients driven to find their own solutions to untreatable diseases. And I am extremely grateful to Reddit for giving us this opportunity to share a taste of the experience with others who may have never previously heard of ALS before today. And thank you again, Jef, for inviting me to help her tell the story.

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Neuraltus News!

Phase 2B Enrollment Open Now!

On Thursday, September 22, 2016, Neuraltus Pharmaceuticals announced the commencement of their long-anticipated Phase 2B for their lead candidate NP001. NP001 is a molecule that reverts macrophages (white blood cells) from an activated state where they hunt down and destroy pathogens and injured tissue to a calmer state where they nurture and protect other cells. I have blogged about NP001 extensively in the past. This trial follows up their Phase 2A trial which completed a few years ago. Unfortunately many of the participants in that trial are no longer with us, including my friends Rob Tison and Ben Harris with whom I launched the concurrent Oral Sodium Chlorite Project.

What It Is

This Phase 2B trial is to confirm the results of the post-hoc analysis of the responder class found in the Phase 2A. In that analysis, Neuraltus discovered that patients who were given the highest dose (2mg/kg body weight) and had elevated levels of pro-inflammatory proteins called IL-18 and C-reactive protein responded quite favorably to the drug. If this Phase 2B returns the expected results, NP001 would have a strong case for the same accelerated approval that FDA just granted for the Sarepta DMD drug eteplirsen. We could have the first new treatment since riluzole and the first truly effective one.

Sign Up Now!

I encourage all PALS to use the Clinical Trials tool on my website, provided by our friends at Antidote. It is very important that this trial is fully enrolled as soon as possible so that it is quickly completed and NP001 gets a shot at getting on the market. That is the best chance for it to get to ALL the PALS whose lives could be extended. We did it for the Phase 2A and can do it again for the Phase 2B.

This is a very exciting moment in the history of ALS.

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On Masitinib

I may have to revise my opinion of masitinib (which would not upset me in the slightest). Some of my readers may know that I have not been very optimistic about the probability of the drug being an effective treatment option for ALS. It’s been around for some time as a veterinary drug. But the company AB Science is developing it for ALS and other conditions.


Preclinical information appears encouraging, although the study has a few issues. The rat model is not like the mouse model and is not very suitable for a survival study. The survival data are also very difficult to interpret due to the curious use of different numbers of animals in each cohort. I will defer to the opinions of my more statistics-inclined members (please feel free to comment!). The cellular data have a similar issue because they were taken in vitro rather than vivo. Nevertheless, it’s encouraging and we can hope for quick human trials.

The press release.

The study (open access!).

And the first USA patient gets approval for Compassionate Use!

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ALS-New-Drug: New-Scam?

UPDATE – June 29, 2016: Apparently the site is back and whining that ALS Untangled is somehow responsible for them losing “charitable funding”. ALS Untangled had nothing to do with RCH4 except having asked me to take the lead in gathering information about it from the provider and from patients. My initial assessment was indeed made quickly but was based on all the information currently available, and was made based on my decades of expert professional experience in identifying Internet scams. There is currently zero scientific evidence for any of the claims made of that website and the provider has been given multiple ongoing opportunities to back up the claims with objective evidence. I never made any claim of “criminality” – rather I feel that something is not right and that PALS should avoid injecting themselves with a completely anonymous substance.

UPDATE – May 12, 2016: Apparently the domain owner, Michael Richards, pulled the site and folded up his tent. No idea what he told “his patients”. I have absolutely no guilt over this. If all it took was one person questioning the veracity of that RCH4 whateveritwas to make him pull up stakes, then there was nothing worth putting hope into in the first place.

UPDATE: If anyone has attempted to obtain this drug and have retained emails or postal letters, please contact me so I can investigate further.

BREAKING NEWS! (April 14, 2016)

I was just alerted to a website advertising a new treatment for ALS (http://als-new-drug.com – text provided for reference but no link for reader safety). The site purports to represent a “group of retired scientists and doctors” in Europe who “discovered a previously unknown protein … which promotes ALS” and “designed a drug which safely stops production of the problem protein”. The site provides no references for the protein and a web search of the name given provides no relevant returns. The same goes for the given name of the drug. Neither is any information given about exactly who comprises this group so that their qualifications may be examined.

Domain information is:
Registrar WHOIS Server: whois.publicdomainregistry.com
Registrar URL: Updated> Date: 2015-09-04T02:32:35Z
Creation Date: 2015-07-05T10:28:14Z
Registrar Registration Expiration Date: 2016-07-05T10:28:14Z
Registrar: PDR Ltd. d/b/a PublicDomainRegistry.com
Registrant Name: Michael Richards
Registrant Organization: Not Applicable
Registrant Street: 56, Amanda Close
Registrant City: Chigwell
Registrant State/Province: Essex
Registrant Postal Code: IG7 5JG
Registrant Country: GB
Registrant Phone: +7.981150350
Registrant Email: privacy@wzukltd.com

This raises a number of red flags and identifies it as a likely scam:

  1. There’s no identification of the “scientists” behind this
  2. There are no links to publications about the protein
  3. There are no links to publications about this new drug.
  4. The website is cheap, poorly-designed, and unprofessional.
  5. The website is registered to an individual in Great Britain with an obscured contact email address.
  6. The website is clearly designed to create anxiety in the reader about “missing out”, thereby making the reader immediately more amenable to the presumably eventual sales pitch for the “immensely expensive” drug.

Without any evidence of efficacy, safety, or even the ingredients of this substance, I would very very strongly urge everyone to ignore this website completely.

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Hope Now for ALS

There has been a lot of recent controversy surrounding the experimental treatment in clinical trials known as GM604. A lot of misinformation has been tossed around on both sides of the issue. I want to beg your attention for a little while to explain what’s really going on.

First, as many of you know, I was the single late-stage PALS who received GM6 in compassionate use. The intent behind this was to get a look at differences in biomarker candidate levels between earlier-stage and late-stage PALS. Any outward physical manifestation of improved condition noticed would be a bonus and, due to my advanced condition, no improvement in condition was expected. Nevertheless, Genervon and I came up with the idea to try to chart improvements in the tongue. The rationale is that since my tongue is only moderately affected, and because the hypoglossal nerve contains one of the shortest motor neurons in the body, any possible improvement would be noticed there first.

Because of my growing cooperative relationship with Genervon dating back to my first blog post on GM6, I was granted the only Expanded Access outside of trial. They were interested in getting a look at GM6 behavior in late-stage PALS and I had proven to them my organizational skills in preparing my own medical surveillance team and in communications by preparing the mechanism for data capture. Even a single Expanded Access Program can be a burden on such a small company not optimized for such work. My knowledge and experience gained over the past few years was of considerable help in filling out and transmitting (and following up on) my own paperwork.

Thousands of single Expanded Access requests would be overly burdensome and even if Genervon enlisted the help of the ALS Emergency Treatment Fund, the maximum number of patients who would be able to participate would be measured in the few hundreds. Not only would patients have to pay for drug but would also have to pay for their own medical surveillance team and at least one hospital visit for the first infusion (this alone represents several thousand dollars). If you are required to give biological samples, the cost tops $10,000.

Genervon shared with me much of the top-level data from the Phase 2 to compare against my own data. Even though the trial population was small, the data were stronger in separation between treatment/placebo cohorts than in any legitimate trial results I had seen before. And GM6 was demonstrated safe over a much larger group spread over three different neurological diseases (including ALS) plus a healthy safety group. For these reasons I suggested to and worked with Genervon on applying for the FDA Accelerated Approval Program in order to get GM6 to all PALS paid for by insurance and Medicare.

And thus began the shitstorm…

Researchers, neurologists, and leaders of certain advocacy organizations who believe in the FDA’s 60 year old regulatory formula – comprised of designing, completing, and analyzing Phase 1, 2, 3 trials over a period of 5-15 years – are failing in their proclaimed mission. They simply have to stop regarding patients as helpless victims willing to eat rat poison if someone said it cured ALS, Genervon as somehow the 19th Century snake oil salesman, and themselves as the White Knight riding to our rescue. The very process of obtaining an experimental drug requires a lot of medical oversight, which we appreciate and rely on. However, patients are intelligent adults whose only desire is to change the status quo of scientific research for the benefit of both the current and future generations of PALS.

The 1992 FDA Accelerated Approval Program (AAP) was designed to meet the needs of patient populations where there is an urgent and unmet need. In 2012, Congress passed and the President signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA), strengthening the agency’s ability to advance public health by equipping the FDA with tools intended to expedite the development and review of innovative new medicines that address certain unmet medical needs. Among the objectives, Title IX expanded the scope of products that qualify for accelerated approval. Specific language in this law states that the FDA is to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical. It is obvious that Congress and the President had in mind diseases just like ALS when passing and signing FDASIA into law, yet the FDA has done very little to incorporate these guidelines.

With Congress now discussing the 21st Century Cures Act, we at Hope Now for ALS believe that we are on the right side of history by insisting that PALS are given opportunities to access new investigational treatments through the FDA’s Accelerated Approval Program which, with its requirement for post-marketing Phase 4 data surveillance to confirm efficacy and safety, will continue to provide invaluable data on new treatments for ALS. As most patients are ineligible for standard clinical trials, this is our only option to contribute to research that will provide the same data at a faster rate among a larger population of patients – providing much needed data on subsets of the patient population. The Phase 4 requirements of Accelerated Approval also have the ability to save billions of dollars in research that is better spent developing more new and better investigational treatments for a myriad of neurological conditions.

I will grant 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 respected 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.

The Phase 2 was indeed also only a very small population, and in previous ALS trials of similar size it was impossible to collect reliable efficacy data in such a small cohort. However, 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). There was an erroneous though well-intentioned attempt to use the released FVC information as evidence of poor trial design. However, the comparison used a very inappropriate analogy population and was built on an assumption based on incorrect data.

I do have serious issues with a point used in arguments against GM6: The lithium debacle. The media reports which came out 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.

The Hope Now for ALS movement 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 NP001, Neurown, etc.). 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 a lot more courage.

In summary, the facts are:

  • Genervon asked FDA for Accelerated Approval at the post-Phase 2 meeting where they presented the complete trial data plus the case report for my Compassionate Use project. I know this to be true because I co-wrote the cover letter to the data package and it specifically asked for Accelerated Approval (and it was me who urged Genervon to pursue AAP).
  • The FDA should have responded with specific instructions on how to file. They did not and thus we were all left in a state of confusion. Then FDA took the unusual step of calling on Genervon to publicly release proprietary data. Genervon has no duty to do so and FDA has no authority to make such a request.
  • Genervon has perfectly complied with law and regulation. All they want is to help and they believe GM6 can do that. The data so far looks good (and I can say that, having actually seen it where all others commenting otherwise have not). It’s not a slam-dunk, but it’s positive and safe enough that I think all PALS should have access to it – not just those eligible for clinical trial.
  • The FDA Accelerated Approval Program, in place since 1992 to deal with fatal diseases for which no other treatments exist, is the best way to save lives. It opens access WHILE CLINICAL TRIALS STILL CONTINUE. It’s used for cancer and other diseases with less-severe prognosis. Why not ALS?
  • GM6 has a perfect safety record in over 50 patients across 3 separate neurological conditions plus a healthy initial safety cohort.
  • This is about patients deciding for themselves what risk to take in treatment. This is NOT about a company trying to avoid the clinical trial process or enrich itself on patients desperation. The AAP is an existing program which gives patients access to potentially life-saving treatment while collecting the valuable efficacy data.
  • Contrast Genervon’s completely legal and transparent actions to other companies marketing unproven products such as lunasin and aimspro directly to patients using email. Those companies use slick pitches with “proof” based purely on non-accepted metrics and anecdotes.
  • The movement behind GM6 is entirely grassroots.

The above are facts. All of the “expert opinion” going around is just biased speculation.

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Scuttle Rebuttal

I am a little peeved at a new attack on the push for FDA’s Accelerated Approval Program for the ALS treatment called GM6 (known as GM604 in clinical trials). This attack basically follows the same line as the one from the ALS Association (and in fact incorporated it by reference). Both are sloppy and disingenuous in style and content. They attempt false comparison to other previously-failed trials without including the reasons for those previous failures and they also try a very clumsy smear by comparison to an act of intentional clinical fraud. I am disappointed that such comparisons are presented to a public looking for facts as well as hope.

First let me discuss the false comparison to previous trial:

  1. The comparisons are false primarily because the old trials exclusively used the ALS Functional Rating Scale (ALSFRS) which is a horrible metric by even the most generous interpretation. This is the only way a call for large trials can be justified, because the numb insensitivity of the ALSFRS (even the Revised version) requires such to make any kind of meaningful conclusion in a heterogeneous disease like ALS. However, the GM6 trial used several biomarker candidates and other objective clinical measurements as surrogate end-points (keep that phrase in mind) which correlated which the subjective end-points such as the ALSFRS-R. The biomarkers used were suggested and evaluated by Dr. Robert Bowser, a 2015 winner of the Sheila Essey Award for significant research contributions to fighting ALS.
  2. Brain-Derived Neurotrophic Factor (BDNF), one of the neurotrophic factors listed in Dr. Dickie’s post, doesn’t cross the Blood Brain Barrier (BBB). It’s almost impossible to get a therapeutic dose into the patient without an intrathecal infusion (directly into spine) using a pump over time. This has numerous obvious drawbacks. It’s also very unclear whether a single neurotrophic factor is useful in ALS, which encompasses a host of deficiencies.
  3. Cilliary Neurotrophic Factor (CNTF) does cross the BBB and early animal model tests indicated efficacy. However, two human trials in 1996 using subcutaneous delivery and intrathecal delivery as well as a review in 2004 revealed no efficacy in lower doses and serious side-effects at high doses. It’s also important to note that the animal data came well before the excellent work ALSTDI did characterizing the extreme difficulties in using that model. Any ALS mouse data released prior to 2009 (and any subsequent found to not strictly follow those guidelines) should be considered suspect. I have personal knowledge of the difficulty in using this model and the false-positive data which can result from improper use.
  4. Next, Insulin-like Growth Factor 1 (IGF-1) also crosses the BBB but has a very very short biological half-life, meaning it is broken down and excreted in a matter of hours. That makes therapeutic levels almost impossible to maintain. A form was created with a buffering agent attached to IGF-1 which roughly doubled the half-life but even that was woefully inadequate. Anyone who remembers the IPLEX debacle of a few years ago knows the story.

The comparisons to such single-target neurotrophic factors as BDNF, CNTF, and IGF-1 are therefore flawed in logic and fact. It is very disingenuous for Dr. Dickie to compare GM6 to them as GM6 is a master regulator and acts in 12 relevant pathways simultaneously. This information is already in the public domain freely available for anyone to look up.

Next, Dr. Dickie compares the GM6 results with those of the initial results of NP001 (actually he links to his own blog post where he addresses the anecdotal reports which came before the official results were published). What he failed to mention was the updated post-hoc analysis which showed a halt of disease progression in 27% of patients in the trial. Further, the analysis showed statistically significant evidence of two biomarkers which identified responding sub-groups. This is a tremendous achievement in ALS clinical trial history. Unfortunately the biomarkers aren’t the same in the GM6 trial so the comparison of the two is incomplete at best. The only real similarity is that both trials used biomarkers as secondary end-points. However, the GM6 trial used them in a way that didn’t require post-hoc analysis.

The comparison with lithium is especially troubling. First, it was far from “recent”, with patient excitement starting in 2007. You can find the data collected in the first PALS-led and created clinical trial which coincidentally also involved lithium. What both ALSA and MNDA failed to report about the study which started the excitement (“Fornai, et al., 2008”) was that the study essentially “cooked the books” by assigning PALS with slow progression of disease to the treatment group while putting the more standard PALS in the placebo group. This was revealed only after the paper was published. In the GM6 trial, run by two leading and internationally well-respected ALS researchers and clinicians, all participants were randomly assigned to receive either drug or placebo. The only way the comparison to the lithium study would be accurate is if the researchers deliberately placed certain patients in each cohort. Genervon merely supplied GM6. The trial was run and data collected by the two principle investigators (fancy name for doctors who run clinical trials). The analysis was then also done by a contract research facility. So any implication that Genervon somehow fabricated the data is false and besmirches the reputations of two prominent ALS doctors.

It must be noted and repeated that the standard FDA clinical trial practice is indeed extremely important in terms of protecting the public from the unscrupulous. The collection of objective scientific data is the foundation of good medical care. Nobody calling for the Accelerated Approval of GM6 disputes this. However, because ALS is so rapidly and uniformly fatal, we are calling for FDA to utilize the discretion it was granted in the face of an earlier similar crisis (the AIDS epidemic). Further, we call on everyone to realize that the GM6 trial used much more than the ALSFRS as a metric and thus smaller trial populations are much more statistically significant than before. The other end-points used in the Phase 2 are objective and not subject to placebo effect. Therefore, the indication of efficacy observed in the trial should be considered stronger than in previous trials which relied almost solely on the ALSFRS.

The Accelerated Approval Program was created to bridge the gap between the need for data and the urgent unmet needs of patients with rapidly-fatal diseases. The GM6 trial was unique in the strength of the preliminary efficacy signal, largely due to the objective biomarker end-points used. Just like the early days AIDS crisis, PALS have no meaningful treatment options and thus no hope. We want to use the very FDA program created to deal with that situation. We admit the need for more scientific data. But we don’t want to die while it’s collected.

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Condition Green

As many of you might already know, I was the late-stage PALS mentioned in the recent Genervon press release. I got interested in this drug some time ago, did some research on it and wrote a blog post about it. I had contacted the company, Genervon, to get information for my post. Thereafter, a dialogue was maintained regarding clinical trial status and future development plans. Being that I am a late stage PALS and still extremely active in awareness, advocacy, and science, they agreed to my request for compassionate use. It was another 9 months going through the process of authorization (mostly because my local hospital had never done anything like this before and together we created a new protocol).

During that time the Phase 2A results came out and I was given access to some of the data. Those, combined with my own experience, gave me the satisfaction that this drug was safe and quite likely effective. I share the concerns about trial size, but like all PALS am concerned for the time required to go through the usual phases of clinical trials. The clinical trial program actually has four parts:

  • Phase 1 – single dose usually in healthy subjects for gauging safety
  • Phase 2 – use in actual patients looking at safety and initial efficacy
  • Phase 3 – larger patient population with different doses, efficacy and SAEs
  • Phase 4 – market surveillance for adverse events

Not only does it take time to fully enroll and execute a large clinical trial but it takes even more time to secure the funding necessary to begin each phase. This is especially true in this current era of venture capital avoiding biotech investment.

I have helped launch other initiatives to get PALS access to experimental treatments. It is critical that patients get more than one or perhaps two chances at early access to treatment while they are newly diagnosed. Drugs that are possibly effective must be made broadly available to patients who are facing otherwise-certain death. Based on the safety and the indication of efficacy in GM6 (mainly borne of my personal experience), I got behind the effort to seek what FDA calls Accelerated Approval so that many more PALS can try it and see where it takes us. Accelerated Approval requires full data surveillance for efficacy, not just serious adverse events (SAEs). The efficacy data determines whether final approval is made. Basically, Accelerated Approval is like a Phase 3 where patients/insurance pay for participation. I believe all PALS would gladly participate in such a program.

If the wider data don’t support the continued use of GM6 I will be the first to admit it. But right now I believe GM6 has the capability to effectively treat ALS in a way no previous drug ever has. And I want to get that opportunity as quickly as possible to as many PALS as possible.

After publishing the press release and posting it on social media and online forums, another PALS started a petition to the FDA to demonstrate the support in the ALS Community for this Accelerated Approval. I would like to urge all who are concerned about ALS – PALS/CALS/Friends – to sign this petition and share it among your social circles. At that link you can sign the petition and post comments to be included with your name. You can also find links to email Senators who oversee FDA and proposed text for those messages.

It is imperative that the comments left on the petition signatures be respectful. FDA isn’t the enemy. They really would like nothing better than to approve a treatment for ALS but need the data to support it. I think we have the data because even though the population was small, the slope of decline as measured by the ALSFRS-R was reduced significantly during the short treatment window. Also, certain biomarker candidates were tracked and correlated with progression. Nevertheless, FDA has to be very careful with the precedent it sets so we as patients must be partners with them in these decisions.

My own experience with GM6 has been positive. The worst part of the entire project was getting the PICC line and the lumbar punctures for CSF samples to make biomarker measurements. I experienced absolutely no adverse events related to the drug. Insofar as benefits, I must admit that the small gains in function noted in the press release are most likely due to surviving neurons branching out new axon terminals to cover the neuromuscular junctions (NMJs) abandoned by the dying motor neurons affected by ALS. GM6 will NOT regrow dead motor neurons. However, it does induce healing in injured ones. In my case, I probably don’t have many injured motor neurons – most of mine are gone. But people who are more recently diagnosed have a higher chance of regaining some lost function in addition to stopping progression.

Based on the information I have seen and my own positive experience, along with the considerable (at best) delay in commencing a larger Phase 2 or 3 trial, I think GM6 deserves Accelerated Approval. I also think this could set a beneficial precedent for future drugs which show similar safety and efficacy signals in early trials. Hence my hope for GM6 getting into the larger population of PALS.

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Pot Luck

An article appeared on social media about a group of parents using cannabidiol (CBD) for their children’s epilepsy. Unlike the usual reports of people using marijuana and subjectively reporting “improvements”, this group of patient advocates went and filed an Investigational New Drug (IND) with the FDA. Don’t get me wrong – I support the medical (and recreational) use of marijuana, but heretofore the real scientific data available has been extremely thin. Rather than going on Silk Road to get a bunch of medicine then post wonderful stories on social media, this group created a real clinical trial in cooperation with FDA and a company named GW Pharmaceuticals which supplied a pure oil formulation of CBD. This is a very important development in patient-driven access to investigational drugs. Far better than the usual DIY projects (even the handful started by yours truly), this type of project can deliver real, verifiable, and scientifically-accepted results.

The body contains cannabinoid receptors both in the CNS and periphery. The most well-known cannabinoid ligand is THC (a CB1 agonist) which is responsible for the euphoric psychoactive effect in marijuana. Both natural and synthetic cannabinoids long been of interest in treating disease. What’s of most interest in medicine are the anti-inflammatory effects of CB2 agonists such as cannabidiol or CBD. Endogenous CB2 receptors are upregulated in the spinal cords of SOD1 transgenic mice. CBD agonists show symptomatic improvement in several inflammatory diseases. There is evidence that CB2 receptors are upregulated in response to the inflammatory microglial activation in ALS. Several studies have shown that CB2 agonists have a beneficial effect in transgenic SOD1 mice. This data shows that more work, perhaps in in human patients, is warranted.

Alternative medicine is very popular in the ALS Community because, frankly, there is nothing currently available proven to extend the lives of PALS. Unfortunately most experiments are done without adequate objective observation and recording of data. Instead all that is reported are vague descriptions of improvement, skewing any rational perception of the particular alternative medicine. This causes more desperate patients to attempt the alternative with the same lack of adequate reporting.

This post, however, is not about calling for an IND for CBD (which would nevertheless be a good idea). The point here is to spotlight that a group of patients and/or advocates got together to do an experiment outside of an institutional clinical trial. They led the way and did it themselves while preserving the valuable objective data. They created their own hope in a seemingly hopeless situation. This is the ultimate expression of DIY Medicine, done properly and openly. Any other method is a waste of time, money, and health.

There is actually much more opportunity than just experiments with speculative alternative medicine. Hope exists for the approximately 60% of living PALS who don’t qualify for clinical trials. That hope is the FDA Expanded Access Program (EAP). PALS should request EAPs for those investigational treatments which have passed the Phase 2 endpoint requirements of safety and suggested efficacy. Furthermore, they should support efforts to bring EAPs to the ALS Community. Living, even for the healthy, requires hope. We, the ALS Community, like everything else we have accomplished, must create our own hope by being pioneers and responsible citizen scientists.