Tag Archives: media

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MAGIC Mitochondria (and more)

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.

ENV AAN Cert

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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Cyborg With ALS (podcast)

New Blog Format!

Folks Logo

Audio Podcast Here (192kbps MP3 for download).

YouTube video version here.

Hello to my readers, and now listeners. Welcome to my new blog format where I will post the same text and web hyperlinks as always, but now there will be an audio podcast version on my Youtube channel in the new Podcast List. My electronic avatar, which I specifically created to look like me, will “read” the podcast and a link to it will precede the corresponding post. My channel also has various videos related to ALS and a few personal videos from my past. I will also have a lower-bitrate sound file available as a download link on each blog post. My hope is that this format will make my blog easier for people to enjoy. Everyone now can listen to my posts and then later check out the text version and follow the embedded links to learn more.

This post is to announce my latest interview with a new lifestyle magazine called “Folks”. It’s a publication by PillPack, a full-service pharmacy which separates medication into individual doses. This is pretty handy for people who regularly take medication and may have difficulty with prescription adherence, and institutions like nursing homes and hospitals. The publication was launched about 9 months ago and features people living with various medical conditions, refusing to be defined by that condition. I guess that would include me.

I had the good fortune to be contacted by Josh Andrew. He is one of the writers for Folks and he had heard my recent interview by Reply All, a podcast by Gimlet Media. Our interview was conducted over email. Unlike the podcast, I did not need to also send sound files. The link to the Folks article is in the text version of this blog post. Josh was kind enough to assist me with this podcast by answering a few questions about Folks and how they found me, and how the interview was done. The questions I asked were:

  1. Please describe what Folks Magazine is and what it’s all about.
  2. Please describe how you found me and why my story was interesting to Folks Magazine.
  3. What was the interview by email like?
  4. Have you ever done this before?

His answers are in the podcast.

Thanks for listening and/or viewing. Please leave a comment on this blog post and let me know what you think of the new format.

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Cyborg Is As Cyborg Does – Reply All Interview

World’s First Fully-Functional Cyborg

Reply All Cyborg

I am the world’s first fully-functional cyborg! Need proof? My part in this Reply All podcast starts at 16:35.

This interview took place over about 3 weeks including one live telephone call and approximately 40 questions over email to which I replied both with text and individual MP3 files of the audio of my computer speaking each answer. It was a rather interesting experience and one that would certainly come in handy for any future interviews. Sruthi Pinnamaneni and Rick Kwan did a great job of stitching all of the questions and answers together to make a single coherent interview.

My desire was to demonstrate that life goes on after diagnosis and that there is still PLENTY that someone can still do despite full paralysis and being dependent on a ventilator. Hopefully other more newly-diagnosed PALS listening to the podcast can take a little inspiration to keep living and contributing your individual wonderful gifts to the world. Together, our voices are amplified and we can create the change we want to happen in the world.

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Reply All – ALS Reversals

Reply All Podcast – The Reversal

ReplyAll-Podcast-Logo

As many of you may know, Dr. Richard Bedlack has been investigating a very rare phenomenon known as “ALS Reversal” where the normally inevitably fatal disease can stop progressing and even where the patient recovers slightly or nearly fully. Over the past few months Dr. Bedlack has been interviewed for a podcast called “Reply All” (I know the timing because I was also being interviewed for supporting material). The podcast is worth a listen, and you can get read the transcript at the Reply All website.

This is more good exposure for ALS awareness. Thanks to Dr. Bedlack and to Reply All for a great story.

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A Boost For Joost

“There are two things people take for granted every day: Time and health. When you lose those, then you wake up.”
— Joost van der Westhuizen

In 1994, Nelson Mandela became the first black President of South Africa. That same year, South Africa also hosted the Rugby World Cup. In that tournament, the home team, the Springboks, overcame considerably unfavorable odds and decades of international isolation (due to the government’s policy of apartheid) to win the Rugby World Cup. This is widely considered one of the greatest moments of South African sporting history and was the basis for the 2009 film Invictus. On that team was a young scrum-half named Joost van der Westhuizen.

In 2003 Joost retired from rugby. By then he was a superstar of South African rugby, having more caps than any other South African player. In 2011 the rugby world suffered a blow with the news that Joost had been diagnosed with ALS. Rather than retreat from the world, Joost decided to make a difference in the lives of people also coping with this dread diagnosis. He formed the J9 Foundation to educate the general public and medical practitioners about ALS, grow ALS research in South Africa, and to aid other South African PALS.

Joost’s story has been made into a documentary called “Glory Game“. In addition to the trailer, you can read about the movie here. The film has done well in South Africa and is now going to be shown first in Vancouver, British Columbia, on April 10, 2016 and in Los Angeles, California, on April 15, 2016. I urge all my friends in those areas to go see it. I have seen it and it’s simultaneously hilarious, upsetting, and uplifting. It shows the courage and determination which made Joost van der Westhuizen such a force on the rugby pitch. I am proud to call him and the Director of the film, Odette Schwegler, my friends.

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TransFatty Lives – a film review

Last Saturday evening I watched TransFatty Lives and was stunned by the unique method of simultaneously telling two stories. The first story is his slow but inevitable descent into total quadriplegia following a diagnosis of ALS and the second is writing a time capsule letter to his son to explain his absence and inability to participate deeply in his son’s life. The film was scattered with amazing images showing POB’s delightful deliberate eccentricity and with scenes both hilarious and disturbing. Some scenes were personally disturbing as I remembered my own experience with that phase of decline. Others were colorful and outrageous in a way only Patrick could make them.

TransFatty Lives is a perfect film for seeing the effects of a fatal diagnosis on a young hedonistic man. As he faces each step of decline he becomes a little more introspective and gains more awareness of the value of the little moments that give life its value. How POB takes the viewer along reveals his genius – you don’t know you have learned something until the next scene begins.

Even more than “The Theory of Everything” or “You’re Not You”, “Transfatty Lives” is the most important film involving ALS. The faithful and honest treatment of both the horror and triumph which is ALS, and the amazingly creative style of POB, makes this a must-see for all PALS and CALS and their families. It should also be widely promoted for all people worldwide. Even for those for whom ALS is just a disease named for some baseball player, this is a wonderful film about human trial, triumph, survival, and love.

This film is amazing to experience. It is much more than a simple documentary. I easily rate this 5 stars, two thumbs up, one poop, etc. Rent or buy this film immediately and have a viewing party.

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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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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.

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PSAwesome

On Monday of last week, this excellent PSA was released by Team Gleason. It was shown on the big screens inside the Superdome but needs to be shown repeatedly on major network television (ie ABC/CBS/NBC). Please watch, share with friends, and send to your local network television stations. This is the kind of message that needs to get in front of the eyeballs of America. This is the celebrity action we have been asking for. Now let’s do our part in getting it out there.

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Open Book – Pt. 2

(sorry for the long delay between parts but I was engaged in other projects, and I had to find the top of my head)

As I said in Part 1, Elsevier, a multibillion-dollar scientific publishing company, is trying to present itself as a friend of Open Access.

Is this a joke?

Elsevier was behind a recent lobbying effort to bottle taxpayer-funded scientific research behind their paywalls. The very lifeblood of this company is its ability to keep research papers behind its subscription system. This is like Microsoft touting an Open Source initiative. This is like a lion touting a vegan diet. 

The key behind Elsevier’s business model is in the traditional name for scientific publications: papers. Believe it or not, there was a world before The Internet, when companies would disseminate information on bound collections of flat pressed dead trees. This required large installations of printing presses and binderies, and a network of distribution to deliver these papers to your door. Now there is electronic distribution which significantly lowers costs. However, Elsevier continues to charge excruciating prices for access to the very many journals it controls. Not content with that, it actually tried to buy a law that taxpayer-funded research would also be hidden behind their subscription system, even though taxpayers funded the research and funded creation of the distribution system it now uses!

The scientific process was built on collaboration and free exchange of ideas. Science was originally done by citizens enraptured by the pure pursuit of knowledge (think Benjamin Franklin). It later became a creature held captive by institutions, and its dissemination captive to those with physical distribution channels. However, now with The Internet and the access to learning and communication it provides, citizens are again becoming more involved with science. The return from discovery was never in the information of how you got there, but from the end product itself (don’t get me started about the perversion of patent law and how much that stifles innovation…).

Distribution is now extremely cheap, and business models must adjust to this new reality or get out of the way. In fact, the reality is that distribution can be done by the authors themselves and more each day are turning to free and open publication. This is the new wave that Elsevier is trying to ape. Don’t be fooled. Elsevier is not Open Access – they are Open Wallet.