Tag Archives: FDA

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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.

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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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The ALSETF

As my readers may know, my posts this year have been a little farther and further between. I have been working on some projects. Hopefully one or more can make a real difference for PALS. It’s time to talk about one of these projects: The ALS Emergency Treatment Fund.

The ALSETF is about bringing treatments in late development (post-Phase 2) to ALS patients. Right now there is no hope for the majority of living patients because over 50% do not qualify for clinical trials. For a newly diagnosed patient, the odds of living to see a drug approved which is starting trials at the same time is about 10% (actually much less considering the historical approval rate of ALS treatments). However, with recent advances into the nature of ALS, certain drugs have been developed which show real promise for treating at least a subset of PALS. More are planned to enter trials in the United States very soon. We at ALSETF mean to get that hope ASAP to PALS who are currently living.

ALSETF is a 501C3 non-profit organization with the mission to partner with government and industry agencies to enable Expanded Access Programs. Expanded Access Programs (EAPs) are FDA authorized programs that permit the use of yet-unapproved drugs under medical supervision, in specific cases where those drugs are in late stages of development and have shown preliminary evidence of safety and efficacy. EAPs are only for immediately life threatening conditions for which no effective approved therapies exist. We have open communication with the FDA’s Office of Neurology products for guidance on EAPs involving investigational drugs for ALS. We also maintain open discussion with clinical leaders on the best practices for EAPs, as well as with certain pharmaceutical companies with drugs in trial and in the pipeline.

Our focus right now is to raise up to $5M to help fund certain costs of an EAP such as upgrading manufacturing to clinical-grade, production quantity necessary for fulfilling EAP demand, etc. These are all issues which can currently prevent a pharmaceutical company (especially the small start-ups likely to take a chance on ALS) from accommodating a large EAP. We believe the financial issues can be solved and that the drugs being talked about with excitement in the ALS community can be brought to those who don’t qualify for trials now, while they are still living.

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Under Press-Sure

Over the past two weeks ALS has gotten some much-needed national coverage, first from the Wall Street Journal followed shortly by ABC News. I also just completed the first round of questions for an article due to appear in July in the-scientist.com. More opportunities seem to be materializing and I will do my best to keep the momentum going to keep the message of ALS in front of the public. I would like to call upon everyone to contact their local press, mention the WSJ and ABC News articles, and tell them YOUR stories. If you think it would help to mention a relationship to me, do so and I will back you.

There were a few points in the articles that I wanted to clarify:

  • I did not design the computer I use. It is a TabletKiosk Sahara Slate PC i440T with a Point Grey Flea-2 CCD camera with an infrared light and lense. The system uses the ERICA software made by Eye Response Technologies (since purchased by DynaVox). The only part of the computer I modified was my work environment and I installed certain programs and utilities which I use. I did help design the overhead mount which slides along the overhead track I use for my lift.
  • NP001 is indeed sodium chlorite, but when ingested orally the acid in the stomach breaks down most of it. The most optimistic data I have seen (based on rats exposed to it in drinking water) is a maximum 30% reaching the bloodstream. I would expect that to be less, and to be variable, in most people.
  • Because NP001 is already in clinical trial, I arranged the project more as an “early access” model with data-keeping as secondary.
  • I have three criteria for any such projects:
    • drug must be relatively safe
    • drug must be inexpensive
    • drug must be legal to obtain

It’s very important to me that I don’t recklessly put other PALS in physical, financial, or legal jeopardy with any project. My intention is to help not harm. We all already have enough problems to deal with.

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Guest: Persevering On NP001

A few days ago my friend, who goes by the handle Persevering on the TDI Forum, posted an evaluation of the PALS who have been self-reporting their experience with the Neuraltus Phase 2 trial of NP001 (which I have discussed here in the past). While the data looks exciting, I must caution that this isn’t official data and makes some assumptions which, if wrong, could totally invalidate the evaluation. However, I have enough faith in Persevering to bring this to your attention. For those who don’t have Patients Like Me accounts, I reproduce the graphs here.

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I have analyzed the NP001 phase 2 data from PLM to date.

I am aware of 37 PLM members who have participated in the trial and 34 who have entered sufficient data to track progress. This is roughly 1/3 of the listed full trial enrollment, and offers a great sample to predict actual trial results. The trial consists of 6 infusion cycles over 21 weeks (147 days), followed by 4 follow-up visits adding 16 more weeks. 13 have completed dosing. 11 will complete within 4 weeks, and all within 8 weeks.

In my thinking, since each infusion cycle is 4 weeks total, the first non-dosing follow up at week 25 (175 days) ends the dosing phase, and I have chosen to review data to day 175 in terms of FRS change. The variable of interest is FRS slope, and is very commonly used to evalauate efficacy for ALS clinical trials. For example, it was used in the recent report of Dexpramipexole phase 2 data, and was used for the official Lithium clinical trials in the US.

FRS for all 37 reporting

In my opinion it is possible to review reports of side effects for commonality to approximate those getting drug (either dose) versus placebo. I do not believe it is 100% accurate, and I also expect those getting a higher dose to have more or greater side effects, but it is not entirely possible to segregate the drug groups (high vs. low). Some may not be prone to side effects on drug and others could experience “nocebo” effects, so again this is not a true substitute for unblinding, which should occur later and allow a timely re-analysis of PLM data.

With that assumption/disclaimer, the summary statistics are:
(Green is improved FRS score, yellow is stable FRS down to -0.49/mo, and red is loss of FRS)

With side effects:

  • n = 20
  • Mean ALSFRS-r slope: 0.00
  • Standard Deviation ALSFRS-r slope: 1.24

FRS for those reporting side effects

Without side effects:

  • n = 14
  • Mean ALSFRS-r slope: -1.01
  • Standard Deviation ALSFRS-r slope: 0.68

FRS with no side effects

Comparison: 100.4% mean improvement

2-tailed t-test p-value for difference = 0.0093

The most exciting outcome to me is that the difference in progression rate is very statistically significant (p<0.05), even with only 34 data points! This would be unprecedented for a phase 2 ALS clinical trial. For example, the recent exciting report regarding Dexpramipexole, with a 31% mean improvement versus placebo in the first 12 weeks had a p-value ~ 0.20, a value 4 times higher than acceptable to conclude drug is better than placebo, by convention (based on a sample size of 53).

There is rumor of an official NP001 trial efficacy review soon, based on all data available on January 24, 2012. Let’s hope for statistical significance there as well, and potentially FDA accelerated approval, as occurs for cancer and HIV drugs.
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Thanks to Persevering for the work and for the guest-blog!

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Jury Duty

As many of you know, I have two previous posts about a drug in trial called NP001 (see “Salty Dog” and “All Roads”). In the past few days ALSA released a statement about this trial. I thank ALSA for doing this service for pals in spreading the word about this trial.

Recent research seems to finally hold real promise of effective treatment for ALS, the realization of over a century of work. However, until we have the hard data all we have is promise and hope (which while powerful are still ineffective treatments for real disease). It is the responsibility of eligible PALS to become “jurors” in these trials and help us all to find the facts which can free us from the death sentence which Fate has issued.

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Brainstorm Coming

Some more very good news for PALS in the USA: Brainstorm is bringing it’s stem cell clinical trial to the US! This technology, named NurOwn, uses a patient’s own mesenchymal stem cells to produce little factories for neurotrophic factors (proteins that nourish and strengthen neurons). This would provide a constant and lifetime production of support for the neighboring neurons, a much more effective approach than drugs which are only present for a short time or may be reduced or blocked by the Blood-Brain-Barrier.

Note that this is not a replacement therapy, but rather one to help feed and protect existing neurons.

You can read about the trial protocol here. For recently diagnosed patients they will inject into muscles to try to take advantage of axonal uptake in the hope that this will preserve the axon and its attachment to the muscle (neuromuscular junction). Patients in later stages of disease will have an injection into the spine to treat the neurons’ cell bodies directly.

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Apollo 13

“Houston, we have a problem.”

Apparently you can’t believe everything you read. Whether it is a problem of vanishing results, reliance on unrepeatable or outdated information, or the fact that not all publications are created equally, there seems to be a serious problem with relying on medical publications. While research papers provide valuable clues, only after those results are repeatedly verified can they reach the status of fact. And even that could change over time as the sample set grows beyond what is practical for a single study.

It seems that even rigorous science can fall prey to the human failing that people see what they want to see. This results in selective reporting as well as selective publication (rarely do negative results get submitted). And in the pharmaceutical industry there is the ever-present threat of monetary corruption. Note that this should not create a panic of Nihilism, but rather instill healthy skepticism and diminish false hope.

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More Baby Steps

In June I posted a discussion about a prospective regenerative therapy. On December 1, I received a press release that the company developing this therapy has filed an IND with the FDA. This is a huge step forward for people suffering from motor neuron disease (especially late-stage PALS like myself). However, it is but the first baby step in the clinical trial journey. Let’s hope that the FDA acts swiftly and positively on this IND.