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.

IceBucket The Blue Sky

The #ALSIceBucketChallenge has been nothing short of a miracle for patients and researchers. Internet memes are rather capricious, having a nearly random hit/miss ratio. That this became so huge is a stroke of incredible luck. The awareness, and resulting increase in donations, has been a huge windfall. This surge couldn't have come at a better time as researchers now have exquisite investigational tools not available even 5 years ago.

There is then the begged question, "Why did it take a patient and a tractor trailer full of luck to bring awareness to the public?" For decades there have been organizations claiming to represent ALS patients. Yet never has there been a sustained national awareness project executed. Patients were left largely on their own to create awareness. This is a question to which we as patients should demand an answer.

Nevertheless, the windfall is upon us. I believe that this boost in funding should be used to create a critical mass of awareness and outreach. As stated, Internet memes are capricious and subject to fading from the public memory with all the speed and ferocity with which it entered. This is the perfect time to keep the message sustained in the public view. Certainly the money to do so is now available.

Another question the ALS patient community should be asking is how much of the massively increased donations are going to be actually used for research, and in what programs. Some donations are going directly to research facilities but the bulk of them are not. Is that bulk to be hoarded and doled out in tiny slices and without focus to a wide variety of basic research projects, never giving any sufficient amounts to fully complete the work? Or will a significant effort be launched which will fund focused work on high-value pathways, including helping fund clinical trials in humans (there are a few promising treatments languishing for lack of funding to pay clinics to conduct Phase 2-3 trials).

This is the time for organizations representing the ALS patient community to step up. The shelf-life of popular public awareness is notoriously short. We need to take this opportunity to create a program of sustained awareness and lobbying for research funding, along with a focused research effort encompassing basic research through to human trials. It is also the time for all research and advocacy organizations to come together as a united front in order to make ALS nothing more than an unpleasant memory.

Eye Caramba!

I would like to urge all of my readers to immediately visit this Kickstarter project. So much better than potato salad, this device is a revolutionary step forward in personal portable Speech Generating Device (SGD) technology. It's wearable and allows eye contact with your conversation partner while using eyegaze.

DIG THE BEAUTY OF THIS DESIGN:

The keyboard and other controls are displayed right before your eyes. The generated voice comes from the glasses so it appears to come from you, creating a more natural conversation experience. You're outside in bright sunlight? No problem! The glasses come with pop-on shades and because the eye-tracking camera is inside, it's shielded from solar infrared glare. And best of all, the control unit is basically an Android-powered smart phone. This means superior portability and an open-source platform for future app development!

The man behind this innovation, Ivo Vieira, has a history of successful optical technology in satellites (his original company, Luso-Space, has a very exciting mission nearing launch to measure gravity waves with orbiting lasers). His father has ALS and is very disappointed with current eyegaze technology. Furthermore, we have met personally and I am very impressed not only with his development, but with his future plans to increase quality while decreasing costs. I am proud to recommend this project to you all. Please support this Kickstarter and help get the Eyespeak into commercial production ASAP.

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.

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.

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:

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.

Jumping Joan!

Only Two Days Until The Jump!

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