Tag Archives: treatment

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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.

Masitinib:

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-OLD-Scam

So apparently this is indeed not something new… While looking up the domain information for our friendly RCH4 website (which expired yesterday, July 5, 2016) to see if it would be updated, I stumbled across an older version (2011) of the site from the same person. This time he called himself “Michael Curram” of “Rixbiotech”. The address is exactly the same as “Michael Richards” who put up the RCH4 website, and the contact email given on this older website is the same – “alsnewdrug@aol.com”.

You can see the front page of the older website which was named “als-amyotrophic-lateral-sclerosis-a-new-drug.com” (history provided by Web Archive’s Internet Wayback Machine). Unfortunately none of the other pages were picked up from the site. But the substance described by this site is different from that of RCH4, apparently being some kind of way to correct a suspected autoimmune disorder that would be applicable to a variety of conditions.

The language sounds suspiciously like that of the substance “TDI-846” which was developed by the ALS Therapy Development Institute and successfully treated the SOD1G93A mice. It’s an antibody specifically for rodents and is available on the market for testing purposes only – NOT for human consumption. ALSTDI has more recently developed a human version which they are putting into human trials, but whatever this website was promoting isn’t it. The website promoting RCH4 made it sound to me like a knock-off of GM6, the peptide manufactured by Genervon. Michael Curram/Richards might well be trying to create a treatment for ALS, but he is clearly an amateur and is not going about it the right way. This makes me extremely wary and I urge all PALS to stay far away from anything this guy is promoting.

Domain information is:
Domain Name: ALS-AMYOTROPIC-LATERAL-SCLEROSIS-A-NEW-DRUG.COM
Updated Date: 2013-11-29 12:27:20
Creation Date: 2008-12-29 17:12:46
Registrar Registration Expiration Date: 2014-12-29 17:12:46
Registry Registrant ID:
Registrant Name: Michael Curram
Registrant Organization: Rixbiotech
Registrant Street: 56 Amanda Close
Registrant City: Chigwell
Registrant State/Province: Essex
Registrant Postal Code: IG7 5JG
Registrant Country: GB

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ALS-New-Drug-New-Scam? – Redux

So it looks like the entity behind “ALS New Drug” is back, this time with a new website host. The site has been changed so that every page begins with erroneous whining about how ALSUntangled supposedly ended some kind of “charitable funding”. First, that person, persons, or organization has no status as a charity in any country. Second, ALSUntangled has taken no stance on the subject whatsoever because the entity refuses to cooperate whatsoever by revealing any information about itself or the product it promotes.

Let me explain the facts of the situation:

Back in July of 2015 the “als-new-drug.com” domain was purchased by a man in Great Britain named Michael Richards. Apparently around September 2015, the website was put up. A [non-exhaustive] search of the Internet and PubMed reveals no Michael Richards from Essex, Great Britain, involved in neurology or ALS.

In April, 2016, the site was brought to my attention by another PALS. I read through the site and read a lot of claims backed up by absolutely no objective information in the form of links to studies involving the drug in question, no objective or clear information about what the drug actually is or how it works, and no identification of the inventor(s) or the entity promoting the drug. A deep Internet and PubMed search for RCH4 or the “scientific” name given revealed absolutely no hits (very unusual and highly improbable for a real drug that has supposedly been in development for many years). In fact, absolutely no objective information exists about this drug except for the claims made on the website.

After failing to find any corroborating information, my Internet domain information lookup results, and my decades of professional experience identifying Internet scams, I made the initial assessment published on my blog in the post titled “ALS New Drug New Scam?”. Because this had been brought to my attention by another PALS who was considering taking this “treatment” and because other patients were apparently already using it, I felt it was urgent to publish a warning that something was not right about this. I have been publishing this blog for exactly this reason since 2009 and I am known for my understanding of the neuroscience and pharmacology of ALS. That’s one of the reasons I was invited to join the ALSUntangled Review Group.

After I published my initial assessment – based on all the available objective information – I contacted Dr. Bedlack to ask if he knew anything about the subject. He informed me that it was on the list of Open Reviews (I don’t keep the list updated in my memory). Because it’s quite a long list and Dr. Bedlack is busy running a major ALS clinic, he asked if I would be interested in taking the lead in gathering information for this project and writing an initial draft report (something I have previously done multiple times for ALSUntangled). Of course, I agreed to assist. There is no title of “Lead Investigator” for ALSUntangled but I used that in email and forum postings to communicate with others because it’s a more succinct and convenient identification of my association with ALSUntangled. I then sent a request for information to the entity promoting RCH4 at the AOL email address given as contact on the website and began asking for patient experience and information on various forums dedicated to ALS.

The questions I sent to the contact email was the standard set sent to every promoter of an alternative treatment option, plus a few of my own customized to this case which were relevant to the investigation. The questions are:

  1. What exactly is this drug and how did you discover it?
  2. How does it work?
  3. What is published on the mechanism?
  4. What pre-clinical ALS data are there?
  5. Are these pre-clinical ALS data published?
  6. How many patients with ALS have taken this?
  7. What are you measuring in patients with ALS that take this?
  8. What happened to those measurements?
  9. Over what period of time and how often are measurements made?
  10. Has anyone had any side effects from this drug?
  11. What percentage of people who take it have any side effects?
  12. What are the most common side effects?
  13. What are the most serious side effects and how often did these happen?
  14. How much do you charge patients for this drug?

Additionally:

  1. If not why not and how are you capitalized?
  2. Will you identify the members of your group so that their qualifications can be examined?

These are standard questions that ALSUntangled asks of EVERY promoter of an alternative treatment option. They are intended to gather relevant data so that a scientific evaluation of the substance can be made, and I included the financial question so patients would have some information about the possibility of long-term access. The promoter is always free to not answer any particular question. The entity behind RCH4 reacted instead with hostility – as if the questions were attacks on their very character. Moreover, apparently they have patients sign nondisclosure agreements before any distribution of the drug begins so that automatically increases the difficulty of discovering the truth of the subject. These two facts, along with the lack of any objective information made available on their site or to prospective clients inquiring about it, only reinforces my personal initial assessment that something is very wrong with this entire program.

The entity says that ALSUntangled and/or I made an allegation of some criminality on their part. In fact, ALSUntangled has made no statement of any kind about RCH4 and I merely opined based on all the [still paucity of] currently-available information and my many years of professional training and experience. The entity says I have no medical credentials. This is true, but neither does it. I do have years of dedicated learning and am recognized as an expert on the subject of ALS and treatment options for it. The entity says I have no experience with drug development. This is untrue, as I have experience both in aiding others’ programs and in developing my own via my research organization, SciOpen Research Group. I also have quite a bit of knowledge of the development process from my experience with and founding of WideTrial, my experience with and founding of Hope NOW for ALS (both organizations deal with improving clinical trials and involve dealing with regulatory authorities and pharmaceutical companies). I also have nearly a decade of experience in advocacy and awareness in the ALS space. My record is impeccable and very publicly transparent. I invite the entity promoting RCH4 to exhibit the same public transparency.

The entity says that my blog post warning patients away from whatever RCH4 is somehow cost them their “charitable funding”. I was never contacted by anyone representing themselves as being affiliated with the RCH4 entity. While I realize that I have a reputation in the ALS Community of being knowledgeable, I highly doubt any funding organization would base its decisions on my personal opinion alone. But if for some reason it did, there was obviously very little faith in the RCH4 entity to begin with.

To recap:

  • In July 2015, a domain called “als-new-drug.com” was created and shortly thereafter the website promoting RCH4 was put up on the same URL;
  • In April of 2016, I was informed about it and did a personal search on RCH4 and the entity behind it;
  • After failing to find any objective information verifying any of the claims on the website or the identity of the entity and/or supporting scientific staff (a situation that persists to this moment), I posted my findings on my personal blog;
  • I then communicated with Dr. Bedlack about RCH4 where he asked me to gather information for an ALSUntangled review, including sending the standard questions to the entity promoting RCH4 and asking PALS claiming to be taking RCH4 about their experiences, an activity I began immediately;
  • I very quickly learned that PALS were required to execute nondisclosure agreements with the prior to being provided RCH4;
  • I received a response from the entity via comment to my blog post full of overly-dramatic wounded pride and a pledge to not cooperate with the ALSUntangled investigation;
  • Patients currently using RCH4 were warned by the entity to not cooperate with the ALSUntangled investigation;
  • In an effort to smooth any hurt feelings, I recused myself from the investigation – to no avail;
  • Shortly thereafter, the website disappeared and the entity apparently began informing patients that continued supply was in jeopardy;
  • I received hateful comments from a few patients – including death threats – demanding that I take down my post (as if that would suddenly change anything?);
  • The website returned, blaming ALSUntangled and/or me for ruining a “charitable treatment program”.

I made my initial personal assessment based on my many years of professional experience and more recent scientific knowledge, and upon previous public lectures by Dr. Bedlack on how to spot treatment scams. I was not acting on behalf of ALSUntangled but entirely on my own. Afterward, I was asked to gather information for their own review – information which would have been reviewed and discussed before a report is published by the entire group which includes many well-known MDs and PhDs involved in ALS research and treatment. The amount of available objective information has not increased one bit since my initial assessment. I would love to be proven wrong but that would require objective and verifiable information. The RCH4 entity is not only not helping, they are actively resisting all efforts at learning any facts about RCH4. Facts are not just unsubstantiated claims on a website. Facts are independently verifiable objective information. All scientists and doctors, retired or not, understand that they have a duty to first provide scientific rationale and preclinical data about their drug along with a clear description of its chemical makeup before providing it to patients. That is a basic fact about drug development which apparently I know and the RCH4 entity does not.

If the RCH4 entity wants my personal assessment and warning to PALS taken down, they can very easily provide me and/or ALSUntangled with the answers to the questions sent, and allow patients to communicate about their experiences. Until then, my personal blog post will stay up as a warning to PALS to not inject into their bodies an anonymous substance sent by an anonymous source. As stated earlier, I would love to be proven wrong, and indeed welcome it. However, everything so far has proven me right.

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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:
Domain Name: ALS-NEW-DRUG.COM
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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Icebreaker

My readers know that I have serious differences with the ALS Association (ALSA). However, my promise to deliver the truth (though bathed in hope in the delivery) cuts both ways. When something good happens, no matter who is behind it, I must give kudos to the deserving.

The 2014 social media phenomenon known as the Ice Bucket Challenge marked a seminal moment in the history of public awareness of ALS and in funding for research. Since then, PALS have been demanding that ALSA actually use that money rather than sitting on it. It now appears that ALSA is finally indeed mobilizing a little of that money (about $3M or 2.5%) on two wise and popular targets. This is good news, although there is a slight catch…

ALSA is helping fund a Phase 3 of the Cytokinetics drug tirasemtiv and a Phase 2B of Neuraltus’ drug NP001. Tirasemtiv is a muscular activator, meaning it causes the muscles to react more strongly than normal to a neural input. Tirasemtiv does nothing to halt the death of the motor neurons, but it can let PALS have more independence for longer than without it. NP001 is a highly purified and pH-balanced form of sodium chlorite that reverts the chronic inflammatory attack on the neurons back to a pro-growth state. Some of you might remember our dear departed friends Rob Tison and Ben Harris who experienced remarkable results during the Phase 2A. Now we know why: Based on inflammatory biomarkers discovered in post-hoc analysis, Neuraltus believes it has found a responder subgroup and is restricting the Phase 2B to those patients. I expect very good news from the 2B.

[UPDATE (07-13-2015) From my friend Jenica Lancy at ALSA GoldenWest: Today, The ALS Association announced its support of 58 new research grants totaling $11,621,638 to find treatments and a cure for ALS. The research awards announced today include investigator-initiated grants, drug development contracts, Milton Safenowitz Postdoctoral Fellowships and support of the NEALS/TREAT ALS™ Clinical Trials Network. You can see a full list of the grants here.]

Now for the catch: What ALSA is really doing is funding operations at one of the clinics which promote and direct funding toward ALSA. Both trials will be conducted by that clinic (the excellent Forbes-Norris ALS Clinic in San Francisco).

However, the fact remains that ALSA is supporting two very promising clinical trials. Some of us might wish they would do more, sooner, but they are moving in the right direction. I believe the proper response should be “Thanks! Keep it up!”. Let’s all applaud ALSA and encourage further progress along this path.

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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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Of Mice And Me

As many of my readers know, about two years ago I came across a study investigating a novel molecule for the treatment of Alzheimer’s. The molecule, J147, is a synthetic derivative of curcumin. Curcumin and other similar molecules have long been under study for neurodegenerative diseases. Unfortunately curcuminoids have rather poor bioavailability, meaning they are quickly excreted from the body and require high amounts to have a therapeutic value. Like curcumin, J147 is “orally available” (meaning it is introduced to the body by eating it) but is more than 100X as potent. This means a much smaller quantity is necessary for therapeutic effect. So far, we haven’t found a toxic dose of J147. Work on toxicity is ongoing.

In the Alzheimer’s study J147 had remarkable results in that model. The pathways acted upon were quite relevant to ALS. These include potent antioxidant effects, significant reduction of microglia activation and migration, and reduction of heat-shock protein expression which indicates a shift back toward cellular homeostasis. More recent data (unpublished) indicates an effect in reducing astrocyte activation, which is sufficient to rapidly kill even healthy motor neurons.

Unfortunately, because J147 is pleiotropic, pharmaceutical companies weren’t interested. The current research paradigm is to focus on single molecular targets. For diseases with a single mechanisms, that’s a fine method of attack. But ALS has quite a few things going on simultaneously. All prior single-target treatments have failed and the current growing opinion is that successful treatment would require a cocktail of drugs. Better to have a single pleiotropic substance than a mixture of chemicals with uncertain interactions.

In April, 2013, I created SciOpen Research Group in order to have an entity capable of negotiating research and licensing of novel molecules with the promise of treatment of ALS. J147 is our first project. In the early summer of 2013, SRG applied to Prize4Life for access to their colony of G93A transgenic research mice at Jackson Laboratories. Our research proposal for J147 was accepted and we were given granted sufficient animal numbers to properly conduct our study. We received the mice and started the experiment at the end of January.

We are very excited to have commenced our first research program and demonstrate that guerrilla biotechs can perform quality science. To that end, we created a crowdfunding campaign on Indiegogo to obtain funding for the next step of the experiment – microscopic tissue examination. This will tell us exactly what J147 did to help the motor neurons in the mice.

Please donate if you can. All donations are tax-deductible. If you cannot donate please spread word about SRG and our need for funding this new and exciting research.

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Carpe Fragments

In the developing embryo, motor neurons develop and nearly half preferentially die prior to birth (Henderson, et al., 1997, “Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons”). As shown in Forger, et al., 2001 (“Blockade of Endogenous Neurotrophic Factors Prevents the Androgenic Rescue of Rat Spinal Motoneurons”), loss of muscular targets also leads to post-natal motor neuron degeneration. Post-natal mice engineered to have degenerated muscle spindles exhibit ataxia and resting tremors, indicating a decrease in proprioception due to loss of sensory-motor synapses (Frank, et al., 2002, “Muscle Spindle-Derived Neurotrophin 3 Regulates Synaptic Connectivity between Muscle Sensory and Motor Neurons”).

One interesting factor seems to suggest a link with testosterone in preserving motor neurons, which could be a possible explanation for the statistically higher numbers of men affected in middle-age or above, and that of women in post-menopause, when hormone levels experience radical shift. Indeed, Cilliary Neurotrophic Factor, a potent motor neuron trophic factor, is regulated by gonadal hormones (Forger, et al., 1998, “Ciliary Neurotrophic Factor Receptor in Spinal Motoneurons is Regulated by Gonadal Hormones”).

Leaving aside the question of hormone levels, there is much evidence that muscle-derived neurotrophic factors are necessary for the health and survival of the motor neurons. One in particular, Motoneuronotrophic Factor 1 (MNTF1), appears essential to this critical process. Experiments in Wobbler mice show that motor neuron disease increases as MNTF1 levels decrease (http://www.ncbi.nlm.nih.gov/pubmed/10453487). MNTF1 was first described in the early 90s, and the human form was successfully cloned as an artificial protein. Various fragments were extracted and shown to have neurotrophic effect.

Two overlapping domains of a 33 amino acid fragment of MNTF1, dubbed the Fred and Wilma domains, are sufficient to stimulate motor neuroprotection in a manner similar to the whole 33 amino acid MNTF1 fragment. The Fred domain is sufficient to direct selective reinnervation of muscle targets by motor neurons in vivo in a manner similar to the 33 amino acid MNTF1 fragment. A recombinant protein containing the Fred domain maintained motoneuron viability, increased neurite outgrowth, reduced motoneuron cell death/apoptosis and supported the growth and spreading of motoneurons into giant, active neurons with extended growth cone-containing axons.

For those curious about the amino acids in each domain, please refer to the image below:

Genervon has patented these fragments and is using them in a Phase 2-A clinical trial in ALS.

From the above it is quite possible that at least some forms of ALS are caused by a sort of a muscular dystrophy (not to be confused with the distinct condition by that name). It therefore stands to reason that there is reason for hope that some will benefit. The standard caveat of basic and preclinical research often not translating to human trials obviously applies. However, we are entering an exciting time where extremely potent shots are being taken at more fundamental aspects of ALS. One or a combination seem likely to have the effect we have been waiting for.

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Precision Stem Cell

The following should not be taken as a recommendation (or warning) regarding Precision Stem Cell. However, that facility was recently rendered an injustice which requires correction.

On March 19, 2013, ALS Worldwide (ALSWW) published a report on the procedure carried out by Dr. Jason Williams at Precision Stem Cell in Gulf Shores, Alabama (PSC). The report was particularly scathing. However, it was replete with inaccuracies. I would like to contrast points from the ALSWW report with facts reported to me from a number of independent sources which include Dr. Williams, persons who have visited his clinic, and patients treated by Dr. Williams in the subject stem cell procedure. To begin with, I will briefly explain the theoretical underpinnings of the procedure Dr. Williams performed, as well as his motivation for doing something outside of his original medical training.

Dr. Williams explains his history, procedure, rationale, and plans for development in a recently-released video. He had been doing mesenchymal stem cell (MSC) extraction and delivery into joints for a time, a somewhat routine procedure done in many clinics as a sports rehabilitation therapy. A friend, Frank Orgel, approached him about trying the procedure to treat his own ALS. Dr. Williams was initially skeptical but after online literature research learned of studies done using this technique in laboratory settings. Note that the link here is not necessarily the one used by Dr. Williams. The reader can search PubMed using the terms “autologous stem cells amyotrophic mesenchymal” and be presented with results which are representative of the applicable published studies.

Selegiline (Anipryl, L-deprenyl, Eldepryl, Emsam, Zelapar) is a drug used for the treatment of early-stage Parkinson’s disease, depression and senile dementia. Dr. Williams found published studies suggesting that selegiline treatment of MSCs was sufficient to trans-differentiate them toward a neural lineage. Dr. Williams extracts the MSCs via machines made exactly for the purpose of extraction of adipose (fat) tissue and real-time separation of MSCs from the adipose tissue. The extraction and separation process is all done in a sterile closed system. The MSCs are then bathed in selegiline solution created by from powder mixed with sterile saline using a professional compounding protocol. After treatment, the cells are then injected into the spine via lumbar puncture The idea is that the treated cells are a mixture of MSCs and neural-lineage cells which then quell the inflammatory aspect of ALS and provide neurotrophic factors. The extent and duration of benefit is presumed based on severity of progression (ie patients with a slower, less aggressive, progression would experience more benefit and of a longer duration).

TCA Cellular of Louisiana had been previously conducting a clinical trial using intrathecal delivery of MSCs to treat ALS until they were shut down for improperly administering the procedure outside of trial (including allogenic products delivered to some patients). Currently, The Mayo Clinic is conducting a similar trial. Clearly there is scientific rationale for investigating this procedure as a treatment for ALS. While Dr. Williams started with the cart before the horse, if you will, he has matured his operation into a true investigative research program. He is partnering with accredited researchers and is forming a company specifically to handle the research program. Together they are working on a genetic modification of the MSCs to more abundantly deliver anti-inflammatory and neurotrophic factors as well as concurrent delivery of the treatment vehicle to the patient cells to help the host cells defend themselves from disease process. This can be likened to the Brainstorm product which nearly everyone is excited about.

1. Precision Stem Cell is conducting a trial
As discussed above, Dr. Williams never claimed that his procedure was a clinical trial. He expanded his current practice of treating joint damage to ALS by request of a friend seeking the possibility of relief via MSC injection. Labeling the procedure as a “trial” and then remarking that there is no rigorous data collection is disingenuous at best. Further, discussion of pricing in the report appears deliberately worded to taint Dr. Williams as a con artist of the sort endemic in the world of life-threatening diseases. Dr. Williams is indeed now planning a trial, in preparation for which he has ceased treating patients, but none of the previous treatments were ever represented as a trial. Dr. Williams had been planning to transition to a trial many months prior to the ALSWW visit.

2. Dr. Williams has no credentials as a neurologist/plastic surgeon
This is true. However, neither of these qualifications are necessary to perform the subject procedure. Mechanically it is almost no different from the joint therapy he has been performing for years. Injection into the spine does carry extra risk. However, nurses without neurology credentials routinely administer spinal taps and injection of spinal block anesthesia daily around the United States, and without benefit of the imaging equipment employed by Dr. Williams. Insofar as the liposuction, Dr. Williams is certified in the use of that equipment since 2010 and can produce a copy of such certificate upon demand.

3. Positive effects lasted only 1-4 days
While the positive effects noted by some patients could indeed merely be placebo effect (impossible to determine either way absent double-blind trial), how Mr. Byer makes this claim is a puzzle. He never contacted any of the patients referred to him by Dr. Williams. The “days” time estimate Mr. Byer repeated in the ALSWW report appears to have come from a public post from a person on the ALSTDI forum. That person denies having been contacted by Mr. Byer.

4. The clinic is a poorly-equipped “stem cell facility”
Leaving aside a discussion of exactly what a “stem cell facility” is, PSC is a radiological facility. No surgical procedures are performed. The equipment used to extract, manipulate, and reintroduce the MSCs are all routine equipment useful in many procedures involving filtering and extraction of select fluids/tissue. The protocol for harvesting MSCs has been well-documented for decades. The liposuction and extraction are done with machines built exactly for those tasks in a closed system which guarantees sterility. The mention of the equipment not being FDA-approved for extracting MSCs is a total red herring apparently intended to taint the reader’s opinion of PSC.

5. Sterile procedures are not followed – infection risk
Sterile procedures are indeed not followed. The reason for this is that they are unnecessary. The entire movement of cells is done via hypodermics, transferring from the patient from one sealed sterile container to another throughout the entire process and back to the patient. Alcohol swab wipe on external surfaces prior to injection is all that is necessary. There is no open surgery requiring a sterile environment. Despite the claim in the ALSWW report, surgical drapes are indeed used during liposuction. Talking about the radiology suite as an “OR” is another disingenuous attempt to discredit PSC. The table talked about is a standard flouroscopy table so Dr. Williams can use imaging guidance for his procedure. Photographs reveal the table to be very clean and in fine shape. Since patients are not under general anesthesia or sedation, the risk of “easily falling off” is a function of zero.

6. Patients have retracted statements of benefit
This claim is a mystery because the patients to whom Dr. Williams referred Mr. Byer deny having been contacted. The patient Mr. Byer apparently used in this example denies having been contacted by Mr. Byer. Further, he maintains his original statement.

7. Williams uses a 0.8 micron filter making MSC harvest impossible
Dr. Williams uses an 80 micron filter. It is possible that Mr. Byer was observing another filter type or misread the label. Dr. Williams admits the possibility of having handed Mr. Byer a 0.8 micron filter by accident. Nevertheless, this question could have been resolved by email or phone call prior to publication.

8. The selegiline mixture is unsanitary
The selegiline is not, as claimed in the ALSWW report, ground in a mortar and pestle at PSC. The selegiline solution used for bathing the MSCs is made with sterile saline (not distilled water) under the guidance and protocol of David Rothbardt, a registered compounding pharmacist. According to Dr. Williams, neither Mr. Byer nor his medical adviser Dr. Hematti ever observed compounding of selegiline at PSC. Further, the selegiline is removed via rinse after bathing period and prior to reintroduction to the patient.

9. The PSC facility has no vapor lock system
Perhaps Mr. Byer has confused PSC with a biohazard facility? This allegation makes no sense and appears another in a long string of comments included to confuse the uninformed and unwary.

As demonstrated above, the report by ALSWW is full of inaccuracies, misrepresentations, and diversions from truth. The motivations for Mr. Byer to publish that report are beyond the scope of this blog post. The facts are that PSC is a clinic offering a treatment used by many clinics for joint rehabilitation. The equipment and techniques are common and well-documented. The facility is clean and the procedure is carried out under appropriately-sterile conditions. The applicability of this treatment to ALS is unknown, although the study data available is compelling enough for The Mayo Clinic to run a clinical trial.

There are some questions regarding the treatment provided by Dr. Williams. The dosages administered are estimates based on instrument capacity rather than actual flow cytometry count. The data regarding selegiline needs further independent verification. Without evaluation, it’s impossible to know how complete is the presumed process of trans-differentiation of MSCs to neural lineage. The efficacy of either straight or selegiline-treated MSC intrathecal injection is still an open question.

However, one thing is clear: PSC did not deserve such a baseless derogatory review from ALSWW.