Science AMA Series: I’m Jef Akst, an editor at The Scientist. I recently wrote an e-book on a group of ALS patients who, unable to get their hands on an experimental drug, began dosing themselves with chemical substitutes purchased online. Eric Valor was one of those patients. Ask us anything!

Abstract

Hi reddit!

ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s Disease) is fatal. There is no effective treatment or cure. In 2011, the drug company Neuraltus conducted a Phase 2 trial for the experimental treatment NP001, which dramatically slowed and even reversed progression in several patients. But the company could not afford to offer continued treatment after the trial was complete, prompting one group of patients to take matters into their own hands. Dozens of ALS patients meticulously researched NP001 and dosed themselves with chemical substitutes purchased online, all the while tracking their results openly online. Unfortunately, the do-it-yourself experiment was less successful than the official trial, and many of those patients have since passed away. This September, after working for five years to secure funding, Neuraltus finally launched a follow-up study to move the drug toward FDA approval.

We will be back at 1 pm EDT to answer your questions, ask us anything!

I have a few questions.

Why was Neuralus not able to find funding for this drug?

Are there more stories like this, of very promising drugs never make it into trial or development?

Do side effects matter as much to patients that are terminally ill?

Littledipper310

Why was Neuralus not able to find funding for this drug? The ALS drug development space is notoriously risky. In fact, around the time that the NP001 Phase 2 trial was showing promise, another very promising drug (dexpramipexole) failed in Phase 3. As Neuraltus CEO Rich Casey told me last year, “ALS is viewed as kind of a black hole for investors.”

Are there more stories like this, of very promising drugs never make it into trial or development? I couldn’t say how common it is, but lack of funding is absolutely a road block for a lot of drug development, especially of generic drugs for which there is no possibility a company could get a return on their investment. There are several nonprofit companies that focus on funding and running such trials to get the medicines into the hands of patients who need them.

Do side effects matter as much to patients that are terminally ill? I’ll let Eric weigh in on this one as well, but based on my conversations with such patients, I would say there is a definite shift in the risk-payoff calculation depending on the severity of the disease, with side effects mattering less to the terminally ill. That said, for someone who is paralyzed and bed-ridden, certain side effects (such as diarrhea) could be a much bigger problem than for someone with a mild ailment.


I have a few questions.

Why was Neuralus not able to find funding for this drug?

Are there more stories like this, of very promising drugs never make it into trial or development?

Do side effects matter as much to patients that are terminally ill?

Littledipper310

Eric Valor (ENV2005): Neuraltus is a very small company with a single product which is a novel method of treatment for ALS, considered by the pharmaceutical industry to be a very small market (incorrect but I won't go into that now). So the effect of investment money drying up after the "Dot-Bomb" bubble was amplified here.

For patients, side-effects are real issues but one of comparative risk which varies with the individual. Some side-effects can be very serious and turn a very bad situation much worse. Some say "what's worse than death" and the answer is continued life with excruciating pain. ALS sucks enough already without unnecessarily compounding it...


My dad is a PALS and 2 years into his diagnosis. My eyes have been opened to the disconnect between clinical trial and those who are sick and progressing fast. What are your thoughts on Right to Try laws and FDA compassionate use? How long did it take for these patients to track down the substitutes? Do you think it's dangerous to have these substitutes available when we don't know what they do? Should researchers be tracking patients willingly taking these substitutes anyway, like an informal trial (I think Rick Bedlack is doing something like this with an OTC antioxidant or something)? Thanks for doing this AMA!

princessfartybutt

I think Jamie Heywood of PatientsLikeMe put it best: “I don’t believe that in America, where the Declaration of Independence has life, liberty, and the pursuit of happiness as a fundamental right, that the regulatory authorities or medical authorities should deny any consenting, understanding patients the ability to do anything that can help them.”

Patients of sound mind should absolutely be able to make their own medical decisions, including trying experimental treatments. There are risks, of course, but the patients should be able to do their own risk assessments based on their personal circumstances.

And yes, researchers should definitely be keeping tabs on patient outcomes when they self-experiment or try off-label drugs. It may not be a controlled trial, but their data can nonetheless inform future drug development. The PatientsLikeMe platform where patients can share their own information is a good start, but initiatives to mine electronic medical records could be incredibly valuable for this as well.


My dad is a PALS and 2 years into his diagnosis. My eyes have been opened to the disconnect between clinical trial and those who are sick and progressing fast. What are your thoughts on Right to Try laws and FDA compassionate use? How long did it take for these patients to track down the substitutes? Do you think it's dangerous to have these substitutes available when we don't know what they do? Should researchers be tracking patients willingly taking these substitutes anyway, like an informal trial (I think Rick Bedlack is doing something like this with an OTC antioxidant or something)? Thanks for doing this AMA!

princessfartybutt

Eric Valor (ENV2005): I am a member of the ALSUntangled review board with Rick Bedlack and you are talking about Lunasin, a soy product. I was initially skeptical, but the review we did was just positive enough that the substance warranted further investigation which the company behind it supported. It's ongoing right now.

There is a long and sordid history of quacks selling bogus medicine to the unwary, a practice which FDA was created to stop. Most patients are unable to sufficiently evaluate medical claims so let's not open the drug market back up to that danger. I am a little hesitant to throw my full support behind RTT and am actually working with FDA on a way to expand access while getting solid data on drug safety and efficacy.


Hi Jef and Eric,

What kind of protections can be introduced to protect against wishful-thinking run amok? Desperate patients will cling to anything that promises hope of cure, and confirmation bias can lead to neutral or negative effects being interpreted as positive. If patients are testing with themselves outside of the clinical trial apparatus, how can we help this process occur in a way that is still objective and not subject to bias?

superhelical

These are all excellent questions. If we, as a scientific society, could answer them, I think we’d greatly accelerate our drug development process. But it’s obviously a tricky situation. As I mentioned in one of my responses already, we do have regulations in place to prohibit companies from marketing their drugs before their achieve FDA approval. But we all know that there are plenty of snake oil salesmen out there who can and do take advantage of desperate patients. Resources such as ALS Untangled are invaluable, but these are very limited. I think at this point we have to trust patients to make their own informed decisions. And then researchers need to develop ways to capture patient data and make sense of it, despite the inherent bias. DIY efforts will never replace placebo-controlled Phase 3 trials, but I do think that patient data can inform the direction of drug development to accelerate the process and reduce wasted spending on dead-end options.


What, if any, are the ethical concerns within the self-dosing community? Is there discussion on this front?

I've spent about 5 minutes reading up on this, so forgive me if it's out there.

johnsix

In response to another question, I wrote: “Patients of sound mind should absolutely be able to make their own medical decisions, including trying experimental treatments. There are risks, of course, but the patients should be able to do their own risk assessments based on their personal circumstances.”

More to your question, I think ethical concerns would arise if a company were to encourage such behavior, but this is prohibited by the regulatory system we have in place (companies cannot market their drugs nor charge more than the cost of the drug itself until after FDA approval), and Neuraltus never advocated for patients to come up with NP001 substitutes to take outside the context of a clinical trial.


How can chemical substitutes be selected properly? Things like crystal structure and small changes in molecular structure can have a big effect. Were these guys actually using the real deal?

mandragara

This was the biggest concern among researchers about this DIY experiment, and in my opinion, likely explains why the DIY efforts ended up being much less successful than the official trial in which patients were given the real NP001 drug. The researcher who developed NP001 told me she spent a lot of time working on NP001’s formulation to ensure its stability and proper localization within the body, whereas the patients in the DIY trial were buying purified sodium chlorite online. Moreover, NP001 is delivered intravenously, whereas the patients in the DIY trial were ingesting diluted solutions of sodium chlorite. Because the stomach is acidic, the sodium chlorite will undergo a chemical reaction in the stomach, and it’s likely that very little, if any, sodium chlorite actually made it all the way to the blood, where it would have an effect on the inflammatory macrophages believed to be involved in ALS pathogenesis.


Without giving too much away about the drug, what's the specific part of ALS that it's supposed to affect in order to slow or reverse the progression?

4437855

NP001 (a formulation of sodium chlorite) targets the body’s macrophages, immune cells most commonly known for engulfing and digesting cellular debris and pathogens. One theory of ALS was that an overly zealous inflammatory reaction triggers the neurodegeneration that causes paralysis, and that macrophages are to blame—the cells appear stuck in an activated state that somehow damages motor neurons. Experiments have suggested that NP001 flips a switch in macrophages so that instead of causing inflammation they help reduce it by gobbling up pathogens, dead cells, and toxins.


Was the ALS do-it-yourself experiment inspired by any similar situations in the past? One that leaps to mind is two participants in the AZT double-blind trial, one who turned out to be receiving AZT and one who turned out to be in the placebo control group, splitting half of their pills with each other. When there were literally no other treatments for AIDS, taking half of two pills -- that the patients couldn't distinguish from one another, except that one set of pills was prescribed to one patient and another set of pills to the other patient -- ended up giving both patients a dose of AZT, albeit a dose reduced by half.

drsjsmith

The most relevant example I came across in my research was a previous DIY trial among ALS patients who tried lithium carbonate, an approved drug for bipolar disorder. Here’s an excerpt from my book on that experiment:

In November 2007, researchers in Italy reported the results of a small trial in which sixteen ALS patients took doses of lithium carbonate, an approved drug for bipolar disorder. Twenty-eight additional patients served as placebo controls. According to the scientists, the treatment significantly slowed disease progression, and none of the patients taking lithium died during the fifteen-month trial.

Unfortunately, no one seemed to be planning a follow-up study. Lithium is a natural compound and not itself patentable, so perhaps there wasn’t money in such a venture. Whatever the reason, ALS patients chatting online began to discuss the possibility of trying lithium outside the context of an FDA-sanctioned clinical trial. It was already on the market for bipolar disorder, so all they needed was a doctor who was willing to write them a prescription for its off-label use.

Several people contacted the Italian group to get the dose, while others dug up what they could on lithium’s safety. Humberto Macedo, an ALS patient in Brazil, started a Google Docs spreadsheet for recording data, and Karen Felzer, a geophysicist whose father had ALS, built a website to host the results and share information about the treatment. By May 2008, nearly two hundred ALS patients had signed up for the experiment, including Eric.

Unfortunately, lithium ultimately proved unsuccessful in curtailing ALS progression. After about four months, Eric and most of the others saw no effects; some patients even reported that their decline had quickened. Karen used her background in statistics—normally devoted to analyzing earthquake aftershocks—to evaluate the data and confirmed the disappointment: there was no evidence that lithium slowed FRS decline. An analysis by researchers at PatientsLikeMe of the data reported on their site and more than one official clinical trial eventually came to the same conclusion: lithium does not help ALS patients, and may even accelerate the disease.


What made the DIY method less successful?

Lunmon

My best guess is that it had to do with the differences between NP001 and the sodium chlorite these patients purchased online. Here is how I explained it in response to a similar question:

The researcher who developed NP001 told me she spent a lot of time working on NP001’s formulation to ensure its stability and proper localization within the body, whereas the patients in the DIY trial were buying purified sodium chlorite online. Moreover, NP001 is delivered intravenously, whereas the patients in the DIY trial were ingesting diluted solutions of sodium chlorite. Because the stomach is acidic, the sodium chlorite will undergo a chemical reaction in the stomach, and it’s likely that very little, if any, sodium chlorite actually made it all the way to the blood, where it would have an effect on the inflammatory macrophages believed to be involved in ALS pathogenesis.


What made the DIY method less successful?

Lunmon

Eric Valor (ENV2005): FDA papers show rats fed sodium chlorite in water showed a buildup of the chemical, NaClO2, in the blood. So my dosing protocol used that for a guideline. Variation in patient metabolism and adherence to protocol were likely factors in the variable results. Also, some patients don't fit the likely responder profile. Ultimately, because the chemical is a very effective anti-microbial, there was a health risk from diarrhea discovered during the project (which is why I abandoned it).

i should also add that this project was much more of an attempt at an "expanded access" program than a real clinical trial and as such was not designed to capture robust data.

NP001 is a treatment best used in the early stages to stop progression. It cannot reverse any organic damage done.


I wager this is addressed in your book, but could you briefly weigh in on the ethics and indeed the legitimacy of self-administered clinical trials? Additionally, NP001 seems to be an ineffective therapy, and while much of that work was conducted in follow-up to the initial trial, I wonder if this event (patients dosing themselves) is a portent of things to come, with respect to desperate patients taking matters into their own hands in the face of a lack of viable therapies.

Finally, I was wondering if you could share any anecdotes regarding those patients experiences? ALS is a horrible and terrifying disease.

Izawwlgood

In terms of whether the data collected by patients during a DIY trial such as the one described in my book, the answers I’ve gotten from researchers are quite mixed. This angle of the story was the focus of a feature I wrote for The Scientist back in 2013: http://www.the-scientist.com/?articles.view/articleNo/34433/title/Do-It-Yourself-Medicine/. Basically, the concern is that the data—which are self-reported by a self-selected population of patients—are biased. That said, I do think there are valuable clues in such information that could perhaps point to new directions for the treatment of a particular disease.

And just to clarify, so far NP001 has proven promising. Neuraltus has recently launched a follow-up Phase 2 trial to continue moving the drug toward clinical approval.

With regard to anecdotes about patient experiences, I chose to focus my book on the personal stories of Eric Valor (who is here in this AMA today), Ben Harris, and Rob Tison—three ALS patients who were involved in the DIY effort surrounding NP001. Ben and Rob both participated in the first Phase 2 trial, and both benefited from the drug, but were unable to continue taking it after the trial ended. Tragically, both Ben and Rob died more than three years ago. https://www.amazon.com/Personal-Trials-Terminally-Patients-Treatment-ebook/dp/B01D01AC6C


When was Eric diagnosed, he alive, and what's his outlook? What was his original diagnosis?

Also, how long do you think before this drug becomes available? Are there any foreseen challenges with getting all the appropriate approvals, such as from the FDA?

mattemer

Eric was diagnosed with ALS in 2005. He is paralyzed, unable to move any part of his body except for his eyes and some of the muscles of his face, and is on a ventilator and feeding tube. But he is very much alive and an active member of the ALS community. In 2012, he cofounded the ALS Emergency Treatment Fund (ALS-ETF), which aims to organize early access programs for ALS drugs in development. In 2013, Eric helped launch the SciOpen Research Group, a self-proclaimed “guerrilla biotech” that avoids overhead costs associated with brick-and-mortar aspects of a traditional biotech company. Most recently, he cofounded Hope Now for ALS, which advocates for relaxing the p < 0.05 requirement for clinical trials of drugs for fatal diseases, and for patients’ access to experimental treatments through the FDA’s Accelerated Approval Program.

As for NP001's future, the company has just launched a follow-up Phase 2 trial. Depending on the results, it could potentially appeal to the FDA for accelerated approval, but they will likely need a larger Phase 3 trial as well. It's anyone's guess, but even if everything goes smoothly, it will likely be years before the drug hits the market.


First, thanks for being part of The Scientist. As a non-bench science worker (lab tech who mostly does sourcing/ordering now) it definitely allows me to keep up with trends and rising discoveries in life sciences, for free! And with consistently great illustrative style, which pushes all my artistic buttons. Love it.

Second, what would you say are the responsibilities of science journalists in an age where science is increasingly under partisan attack from all political directions on various issues? Is the job of a publication like The Scientist strictly to look at what's happening in the lab, or should part of it be to advocate for evidence based policy and respect for the scientific process in public life? (Without, obviously, necessarily saying "Politician X is a cretin who would throw us back to the dark ages")

Painting_Agency

Thanks very much for the kind words about The Scientist! I’ve worked here for more than seven years now and absolutely love it. With regard to your second question, we do feel a responsibility to identify the evidence (or lack thereof) supporting various policy proposals (and many other things, such as brain training, stem cell therapies, probiotics, etc.). We do not advocate for any particular policy or practice, but rather present the science and researchers’ opinions, and let our readers decide for themselves.


Do you have links to peer reviewed research on NP001? The official trial link you give is to a secondary non peer reviewed source.

hazpat

Here is the publication of the results from the first Phase 2 trial: R.G. Miller et al., “Randomized Phase 2 trial of NP001, a novel immune regulator,” Neurology: Neuroimmunology & Neuroinflammation, 2: e100, 2015. https://www.ncbi.nlm.nih.gov/pubmed/25884010


Should biomarker trials be de-linked from safety and efficacy trials? The design of the NP001 trial where they watched the people who had responded crash without the drug in order to track a biomarker seemed cruel to me. I think that every trial volunteer should ask, "What happens to me if this stuff actually works?"

ALSadvocacy

This is an interesting point that I think needs to be taken on a case-by-case basis. Obviously tracking biomarkers is important not only for assessing a drug's efficacy, but also for identifying patients who are most likely to benefit from a particular treatment. But stopping treatment to see if a biomarker falls in response does pose an important ethical issue. (For the record, Neuraltus never told me directly that this was part of the trial design, though I did hear it from others.) I think your last point is the most important: trial participants need to be informed ahead of time what their options will be following a trial.


In a social mindset, do things like the ice bucket challenge seem encouraging? Does it seem to be having an awareness impact or is it just people making silly videos?

bowtoboot

I think the #IceBucketChallenge was a boon to ALS research. In addition to the influx of money, the awareness raised is invaluable. I've heard from both patients and their families how much it meant to them to see such awareness for ALS after decades of being overlooked. Plus, the donations are already leading to new research findings, e.g., see: http://www.the-scientist.com/?articles.view/articleNo/43799/title/-IceBucketChallenge-Payoff/ and http://www.the-scientist.com/?articles.view/articleNo/46669/title/Additional--IceBucketChallenge-Payoffs/


Neuarltus, you say could not afford to continue treatment, but since this looks like the most effective way by far of ridding the disease, did they not get any icebucket money? It was one of the largest awareness/research programs I have seen and doesn't seem logical they ran out of cash. My dad died of ALS 10 years ago.

GardensOctopi

I don’t know if Neuraltus got any of the funds raised through the #IceBucketChallenge; I would guess not. The vast majority of those donations went to the ALS Association, and there was some discontent among the patient community, fearing that more money would go to awareness and patient services than to research. I wrote a bit about this for The Scientist back in 2014: http://www.the-scientist.com/?articles.view/articleNo/40925/title/-IceBucketChallenge-Highlights-Difficult-Funding-Decisions/


What is your view on the spread of Right to Try laws across the US?

kerovon

Here is my answer to this question, as posted in response to a similar question:

I think Jamie Heywood of PatientsLikeMe put it best: “I don’t believe that in America, where the Declaration of Independence has life, liberty, and the pursuit of happiness as a fundamental right, that the regulatory authorities or medical authorities should deny any consenting, understanding patients the ability to do anything that can help them.”

Patients of sound mind should absolutely be able to make their own medical decisions, including trying experimental treatments. There are risks, of course, but the patients should be able to do their own risk assessments based on their personal circumstances.


Was it legal to purchase these chemical substitutes and ingest them?

MudButt2000

For the most part, yes. The patients were purchasing sodium chlorite sold online for water purification and were not breaking any laws by dosing themselves in their own homes. Some patients were able to obtain an older drug called WF10, which is approved in Thailand for treating the autoimmune consequences of cancer radiation. The sellers who shipped that drug to the US were likely breaking some laws and regulations. While I have information on some of the Thai researchers that the patients were in touch with, I do not know who actually sold and shipped the drug.


I'm sure this is addressed in your book, but could you talk about how to distinguish the placebo effect and the social and economic advantages of these patients from actual effective drugs? I would think we'd be unable to tell if anything helped anybody from this experience.

sbeath

You are correct that the placebo effect can give a "false positive" in a sense—suggesting that a drug is effective when in fact it is not. This is why the FDA requires placebo-controlled trials for drug approvals. For DIY efforts like these, however, it is possible to glean some information through the use of historical controls: data from the placebo groups of completed clinical trials can be used to bolster analyses of new treatments in development is already being implemented. Neurologist Robert Miller has been collecting such data from ALS trials for fifteen years and has used the database to generate matched controls for recent clinical trials, including the NP001 Phase 2 trial that he helped run at the California Pacific Medical Center.


I am aware of patients, including sometimes self-diagnosed patients, who purchase experimental drugs over the internet by claiming to be clinical research organisations. Do you have a view on this practice?

AllanfromWales

I have never heard of this. It certainly sounds concerning. But if the companies selling the experimental drugs can only sell to clinical research organizations (for regulatory reasons??), presumably they would have a vetting process to make sure that is indeed who they are selling to...? But again, I'm am not familiar with this practice, so cannot comment further, unfortunately.


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