Tag Archives: success

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Spicy News

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

Welcome back to the Cripple Command Center or C-to-the-3 podcast on ericvalor.org. My name is Eric Valor and I will be your host and head nerd in charge. In this episode I will report on a recent webinar given by CIRM, the California Institute of Regenerative Medicine, and a particular clinical trial discussed therein. I will also report on a new potential treatment target for ALS found using CRISPR, a new proposed treatment for SOD1-linked ALS, a new open-label trial for a form of curcumin, and a new stem cell model to assess possible treatments for neurodegenerative diseases such as ALS.

The first item up for bids is the new CRISPR study. Researchers at Stanford University have used CRISPR/Cas9 gene editing technology to gain insight into the genetic basis of ALS. The team, led by Doctor Aaron Gitler, used the technology to sift through the entire human genome to find genes that help neurons defend against toxic protein aggregation. In ALS it is known that proteins inside the motor neurons clump together, depriving the cell of the beneficial function of these proteins as well as choking the machinery which normally breaks down malformed or deficient proteins for recycling by the cell. The Stanford team used CRISPR to sequentially alter genes which either help cells cope with protein aggregation or enhance the toxicity. They ceased the function of each gene one by one in what’s called a “genetic knock-out” and evaluated the effect. That way they can identity potential drug targets for future therapies. You can read more about this in the Stanford News Center website. You can read the paper in Nature Genetics.

Our next item is the CIRM webinar and the upcoming clinical trial described therein. The webinar was held on Facebook. It was an “Ask The Experts” format where information is presented and then questions are asked by people watching the webinar online. The presentation was made by Doctors Clive Svendsen, Bob Baloh, and Ralph Kern. First, a little information was shared first about the NurOwn therapy in trial by Brainstorm. The Phase 3 trial is enrolling 300 people with enrollment expected to finish by early 2019. The protocol is repeat injections of the person’s own mesenchymal stromal cells which reduce local inflammation and secrete trophic factors which help the motor neurons heal and grow.

The juiciest part of the webinar was the presentation of the new Phase 1 clinical trial being prepared by Cedars-Sinai in Los Angeles. This trial is similar to the old Neuralstem trial using human fetal brain-derived neural progenitors which are multi-potent stem cells which can only become cells of neural lineage (neurons, astrocytes, microglia, etc.). In contrast to the Neuralstem product where the cells mostly became interneurons these cells become astrocytes which would replace the native astrocytes which become toxic in ALS. The cells are transduced using GDNF (glial-derived neurotrophic factor).

Cedars also uses a new method called “chopping” (which when you read the paper on the method should really be called “slicing”) to expand the cell line into a pharmaceutically-relevant number. A clump of neural cells called a neurosphere is repeatedly sliced up and the parts allowed to expand. The usual method is to break apart the neurosphere by hand and individually plate the cells. Chopping is much faster and increases yield by allowing the cells to be cultured in 3D rather than in 2D. This means the cells have more contact with others which promotes health and growth. Instead of having cells just on the left and right and on top and bottom, they also have cells above and below. Like penguins grouping together tightly in a snowstorm the cells fare much better in a 3D arrangement as in the body. Like the Neuralstem trial the Cedars trial uses a laminectomy to inject the cells into the spine but uses a new rig which is significantly less invasive. The patients undergo a year of immunosuppression to ensure the body doesn’t reject the implants. After that the cells are expected to survive for life.

Next up is the new clinical trial for the spice curcumin being put together by my friend and ALS Untangled colleague Doctor Richard Bedlack. The trial is called ROAR for Replication Of ALS Reversals. ROAR is open-label with no placebo and is designed to have faster enrollment with much better retention, and wide inclusion criteria like no 2-year cutoff or many of the other exclusions found in usual trials. That’s not to say that the usual trial design is “bad” but ROAR is looking for a huge unmistakable signal: A reversal of ALS such as regaining use of limbs or getting out of a wheelchair (the latter being a more extreme example). The trial will also have few/no in-person visits. ROAR will use a particular product called Theracumin which is a highly concentrated form of curcumin which is readily absorbed, properly metabolized, and is well-tolerated even in high doses. Trial participation for each person is 6 months. The real-time results will be available on Patients Like Me and the full protocol will be made available on www.alsreversals.org should anyone not in the trial want to follow along.

Why curcumin? Because it’s generally regarded as safe and is inexpensive to obtain. There are some 12,000 published papers studying curcumin’s effects. Curcumin has powerful antioxidant effects, can reduce protein aggregation in cells, can induce beneficial gene activation, and can alter the gut microbiome, the vast population of bacteria in the stomach and intestines, in ways that are beneficial to health including the brain and nervous system (seriously!). In mouse neuroblastoma cells transfected with mutant TDP43, curcumin improved excitotoxicity, improvd mitochondrial function, and reduced oxidative stress and protein aggregation. Unfortunately these studies have not been independently replicated. You can learn more about curcumin and prior data as relates to ALS in the ALS Untangled report on the subject and by watching the video presentation Dr. Bedlack gave on the ROAR trial.

Alrighty, what do we have next? Ah, yes, the new stem cell model meant to assess potential treatments for neurodegenerative diseases like ALS. The model is specifically for Alexander disease (AxD) because of its relatively simple pathology. But it’s relevant to Alzheimer’s, Parkinson’s, and ALS because it focuses in on malfunctioning astrocytes. In AxD, astrocytes with a mutation in glial fibrillary acidic protein (GFAP) secrete a protein called CHI3L1, a marker of neuroinflammation that suppresses neural development-related processes, including myelination. The CHI3L1 suppresses cells that are precursors to oligodendrocytes, the cells that wrap the neural axons in a fatty substance called myelin. Myelin acts like the plastic insulation of electrical wires and performs much the same function. The idea is that by understanding more about astrocytes that would reveal clues about how to treat diseases like Alzheimer’s and ALS.

And that’s all for this episode of the C-to-the-Three Podcast on ericvalor.org. I am, and always will be, Eric Valor. Until next time, breathe easy.

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MAGIC Mitochondria (and more)

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

Hello and welcome back to my podcast.

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

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

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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Quora Top Writer Of 2017!

WOW! – Quora Top Writer Of 2017!

Quora-Logo

I just received an email today notifying me that I have been named a Quora Top Writer Of 2017! My contributions are tightly focused in the topic of Amyotrophic Lateral Sclerosis (which I created on Quora) with some attention in the broader topic of Neurodegenerative Diseases, along with a few answers in the topics Science, Physicists, and Stephen Hawking (to give a long-term patient’s perspective on some questions asked about the Professor, including one asking how he fathered children where my answer has 1.4 million views and over 20,000 up-votes – the Quora equivalent of a Like). I have to thank my friend Laura Copeland for introducing me to and getting me involved at Quora. Laura and I met in 2011 when she interviewed me for a story in my local newspaper. She and I remained friends ever since.

Quora is probably the best place to go for answers to questions about anything from science to global social issues and politics to personal hobby interest (maybe I should start a Surfing topic..?). It’s a highly erudite place, especially for a social media site and has astonishingly remained so for many years. Quora is a place where trolls are not tolerated and from which is almost totally free.

I am quite flattered to receive this distinction and am happy that my contributions have been deemed useful for the many people who have read my answers and those who have engaged in enlightening discussions after. It’s been a wonderful experience so far, where I have been able to definitely expand global public awareness of ALS/MND is a positive and engaging way. I am thankful for the opportunity and for the response. I look forward to many more years of engagement and enlightenment.

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Neuraltus News!

Phase 2B Enrollment Open Now!

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

What It Is

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

Sign Up Now!

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

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

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On Masitinib

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

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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WordPressure

Wow.. I spent two days working to get a favicon to appear in the browser and use the same image (the original source for the 16×16 .ico file) for the Facebook image override (it normally pulls a random image from the website). No WordPress plugin worked at all so I had to discover what Facebook wanted (Open Graph meta tags in the <head> section) using Facebook Debugger (https://developers.facebook.com/tools/debug/og/object/) and insert my own tags in the child-theme’s header.php file:

<meta property=”og:url” content=”http://www.ericvalor.org/” />
<meta property=”og:image” content=”http://www.ericvalor.org/…/blogpic300x300…” />
<meta property=”og:site_name” content=”EricValor.org” />
<meta property=”og:title” content=”EricValor.org” />
<meta property=”og:description” content=”The Web Home of Eric N. Valor” />
<link rel=”shortcut icon” href=”<?php echo get_stylesheet_directory_uri(); ?>/favicon.ico” />

That was a very frustrating experience but I did learn a lot more about manipulating WordPress than I wanted at the moment…

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Residentiality

Last night (at time of writing) I was treated to a personal guided tour of the Steve Saling ALS Residence in Chelsea, MA. My tour guide, via laptop webcam, was my friend Lisa Jones-Wyhlidko, the dynamo who does such excellent volunteer work for ALS Guardian Angels. She dialed me up using Google Hangout (up to 9 people in a group teleconference – a really wonderful free tool!) and said she was going to walk me around and show off the Residence.

I was amazed right off the line. The attention to detail giving the place the feel of a regular residential condominium was exquisite. Except for someone coming down the hall in a wheelchair you would never suspect this wasn’t a condo full of young professionals. The common area was the first hint of difference with tables built high enough to roll wheelchairs under. The professional kitchen made me drool. Tucked into the soft and comfortable construction were cleverly concealed safety features such as fire doors which seal off the kitchen in case of accident.

Next up was the first floor with the kosher New York style deli (complete with molded tin ceiling) and bakery. The bakery had a nice outdoor patio for use in the fair seasons. Around here I was introduced to some staff who were a little surprised to be talking to a head in a chat window at 3:30 in the morning. They were absolutely pleasant and friendly and further surprised I was on the West Coast. I love technology.

Next was the hair/nail salon and spa with jacuzzi style tub. You read that right – hair/nail salon with jacuzzi tub! PALS have a right to a hair-fluff and mani-pedi just like everybody else! The salon was pretty standard except perhaps for shampoo bowls being a little higher. The spa had vertical overhead track lifts and the tub tilted up to ease the PALS in, with contours for head and neck support.

This entire tour was done without break with a laptop using standard WiFi connection. The entire building is saturated with WiFi connection, even the outside patios and lawns (which have substructure below the sod to ensure a wheelchair doesn’t get stuck in a bog). Going up and down in elevators was seamless. This is so PALS in power chairs can call elevators and open doors for maximum independence. The PEAC system integrated into the network allows doors and other utilities to be operated by a PALS with an eyegaze system.

Simply put, this place is awesome! Readers who know me know that I despise the over-use of that word in contemporary vernacular, so you know I really mean it. Steve Saling had magnificent vision, and the Chelsea Jewish Foundation was bold and progressive in working with Steve to realize his vision in building the Steve Saling ALS Residence into the Leonard Florence Center for Living. I am proud to support the ALS Residence Initiative and hope to see at least one in every state in the country. Thank you Steve for having vision and the skill and determination to see it realized!

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Rescuebook

Technology is extraordinary. The level of communication made possible today by technology is unprecedented. This ability is also available for people with extreme disability (I wrote this purely with eye movement to distribute to the world…).

Part of the explosion of communication technology is the invention of social media. This especially has allowed people like myself who were previously called “shut-ins” to virtually travel around the world and socialize. The benefit has already helped PALS.

Tonight the social media giant Facebook helped save the life of another PALS. I was watching TV with my caretaker when a PALS messaged me on Facebook saying her caretaker wasn’t answering her alarm and asking me to call her house phone to alert the caretaker. I could have called using my web-based Google Phone but asked my caretaker to use my house phone to call. We were one of a few others calling, but in the end the caretaker was alerted and the PALS’ needs were met.

Technology rocks.

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The Fix-Up

To communicate (and do other things like write this blog) I use a computer set up with a special infrared camera and software which allows me to control the computer with my eye. The hardware platform this system runs on is a very nice little tablet PC from TabletKiosk. I chose the ERICA system from ERT specifically because it was based on this tablet which, even 4 years later, is way more powerful than all other competitors I know save one (and the new i500T easily matches that). Being an Information Technology professional I knew that I would be doing quite a bit more than just typing and talking, and would require the computing power and features of the Sahara Slate PC.

After years of heavy, daily, use, the system started having trouble with the sliding power switch. Sometimes the power light would come on but the system would make no noise and the screen would remain blank (it would fail to POST, for my fellow geeks). My assistant would have to hold the power switch for 5 seconds to turn the machine off and then try again. This frequently resulted in a total hang which required pulling the power cable and battery. Because the machine was mounted and had a docking cradle attached, this required some disassembly to get at the battery. Needless to say, as this problem became more frequent I became more worried that each procedure would result in a fried computer.

I looked up support on the TabletKiosk site and saw that they had a nice little online Forum for questions and user support. I posted a message and also emailed tech support in the hope they would answer (mind you this system is over 3 years old). After some anonymous queries back to me for more information I was contacted by the Director of CorpComm who helped me set up a process by which they shipped me a loaner identical to my system, I popped my hard disk in the loaner, shipped my system back to them for evaluation and repair, and then the reverse. This way I was able to keep my heavily-customized work environment during the couple of weeks required to complete the process.

The problem was with the motherboard, which was replaced. I have my system back and it’s as good as new. These TabletKiosk PCs are nice and solid with a great list of features. I would recommend these to all my friends who want a reliable and powerful tablet computer that is Linux-ready (hint hint). TabletKiosk was extremely courteous and supportive and got me through what could have been a total disaster in my life.

I would like to thank by name John Kwan for his patient support and Lisa Herbert for getting the ball rolling and overseeing the process. It’s not often that CorpComm meddles with TechSupport without tactical nukes being deployed… I would also like to thank the entire TabletKiosk team for making this able to happen. I very much appreciate their products and support

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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!