Here is a somewhat strange and moving story about smart and desperate people.
A few days ago a company, Neuvivo, published an article about their drug for ALS. Neuvivo researchers studied combined data from failed phase 2a (NCT01281631) and phase 2b (NCT02794857) trials of NP001. They found that NP001 slowed disease progression in a group of patients between the ages of 40 and 65, with high levels of inflammation at the start of their study.
NP0001 has been a known name for a long time in the field of drugs to fight ALS. A quite similar drug is WF-10.
Neuvivo actually looks a lot like the defunct Neuraltus company. Neuraltus was created in 2009 by Ari Azhir, now CEO of Neuvivo, and Michael McGrath, now Chief Scientific Officer of Neuvivo. Neuraltus ceased operations in 2019, after disappointing data from the phase 2 trials cited above, of NP0001.
NP0001 is similar to sodium chlorite, a common disinfectant which is promoted as a cure-all by a number of quacks, but this story is about an attempt by ALS patients to replicate this drug, design and conduct their own clinical trial.
Beginning in September 2011, some of those diagnosed with this fatal disease began researching published literature on NP0001, they communicated on the ALS Therapy Development Institute forum.
First patient effort in 2008
On this forum, this was not the first patient effort to study a potential therapy for ALS. One remarkable effort took place in 2008 following a promising phase 1 trial in Italy for treating the disease with lithium carbonate. The study of 44 patients suggested that lithium significantly slowed disease progression and none of the 16 lithium-treated participants died during the 15 months of the study. ALS patient discussion forums then began to discuss this result, as they do with every clinical trial and also the possibility of taking lithium.
It could be years before lithium was approved as a treatment for ALS, but the drug was already marketed for bipolar disorder, so it was not difficult for these patients to obtain it.
Some 350 ALS patients have therefore started trying lithium to treat their symptoms. An ALS patient posted a Google Docs spreadsheet to track self-reported ALSFRS-R scores. And Karen Felzer, a research scientist with the US Geological Survey's earthquake hazard team whose father had ALS, set up a website to host the project.
Felzer, who had a background in statistics, looked at patient outcomes at 3 and 6 months. Unfortunately both times she found no evidence that lithium slowed progression. So in November 2008, when Felzer published its second report on the project's website, most of the patients participating in the forum stopped taking the lithium.
In 2001, patients want to replicate a clinical trial
In September 2011, based on published papers and patents, ALS patients, such as Olly or HappyPhysicist on als.net forum conclude that the active ingredient in NP001 is sodium chlorite, a chemical used primarily to bleach paper pulp or to disinfect the water.
Some then buy the precursor to NP001, WF10, which was known to contain just over 50% sodium chlorite and could be ordered in Thailand, where the drug had been approved for the treatment of autoimmune consequences of cancer radiation.
But for many, the $12,000 cost for a one-year supply was prohibitive. Sodium chlorite, on the other hand, could be purchased from online suppliers for only $50 per liter, or 15 years at the dosage indicated in the patients' documented protocol.
Patients contacted the inventors of the drugs and talked to their doctors and to each other about the risks and the proper dosage.
Tom P..., Silverfox on the forum, who does not have ALS, posted on the forum information on the purity of chlorite solutions available for purchase, dilution and mixing, and the behavior of the chemical. More than a year and 1,000 forum posts later, twenty ALS patients decide that ingesting sodium chlorite was worth it.
This was not welcomed by some scientists of the domain. Organizing ALS clinical trials is not easy, there are few patients with ALS and due to the rapid deterioration (sometimes within a few months) and the risk of being assigned to the placebo group, patients could be more likely to get this drug on their own, to make sure they get the active compound.
Official ALS clinical trials already suffer from this patient shortage. With a small group of patients, and especially in the case of a heterogeneous disease like ALS, there is an imprecise measure of the rate of decline, therefore of the effectiveness of the drug being tested.
Additionally, self-reported data can include countless biases. Desperate patients are indeed likely to perceive an improvement where there is none.
Furthermore, the patients who choose to participate in such DIY experiments do not necessarily represent the entire ALS population. For example, patients who resort to self-experimentation must be able to read scientific articles, understand the intricacies of dosage and benefit from medical supervision, which is not the case for all patients.
On August 15, 2011, after his sixth dose of sodium chlorite, Eric Valor recorded his first positive effect.
"Apparently clearer speech," he wrote in his blog. Others have noted similar improvements. Excitement was sparked on the group's forum when one of the most pessimistic patients, Ron Schaffer, reported slight improvements in his energy levels.
In September, Valor, using only his right eye, completed construction of the project's website where those taking sodium chlorite could post their results.
First doubts
However in January 2012 the first doubts appear. HappyPhysicist writes on PatientLikeme; “It has now been 8 weeks since my last infusion. Over the past 4 weeks I have noticed a significant decline in my condition. My speech is considerably worse and my left leg is showing signs of weakness to the point that my gait has changed and I feel a little off balance. My swallowing is also worse. I now have to sip water to avoid choking and find that I have difficulty swallowing food, even choking on food on occasion. I feel like my progress has now picked up where it left off just before starting the NP001. infusions.”
In mid-July 2012, active patients on the als.net forum received an email from Jennifer Askt, editor of The Scientist magazine, about an article she had written about the CSO DIY trial and saying that she intended to write a book. She mentions that she is in contact with Eric Valor (ENV), Happy Physicist and Persevering in relation to the book. The Economist also publishes an article.
The common goal and the extremely disabling and deadly disease did not prevent doubts, ego disputes and other quibbles. Only a third and then four patients initially seem to have obtained beneficial effects from ingesting sodium chlorite, but years later only one patient will make this claim.
There is also what has been called by Ron Schaffer the "chlorite rage" People with ALS often have little patience, are harsh with others, including their caregivers. Chlorite makes it ten times worse. Some patients thought it might have something to do with frontotemporal dementia (FTD).
A regular forum participant, Ollie, remarks: "This disease is not static - once you initially alter the immune response, say with OSC (Oral Sodium Chlorite), any treatment has less and less effect as the system immune changes. There will come a time when taking a substance that worked in the beginning no longer has any value or may even block other repair pathways. Then, as the disease does not stop but progresses more slowly, other biological pathways become more important - the type of cascade action has changed. Any pharmacological intervention, if it does anything, will alter the disease state, and in doing so, the dosage rate becomes less effective over time, which means that as your system changes, you should have need fewer OSC. If this does not cure the disease, then the intervention strategy should change depending on the state of the disease and this change in dosage levels of the substance should be based on the rate of disease over time. "
Commentators like Nemesis doubted the benefits of NP001. He believed that NP001 only worked for ALS patients whose neuro-inflammatory component was stronger than the neurodegenerative component. For him, the problem is that it is difficult in advance whether you are a category A or B patient.
Disturbingly, the inventors of NP001 say sodium chlorite taken orally shouldn't work at all because the chemical will quickly be converted to chlorine dioxide, which is not only ineffective at suppressing macrophages, but could even be toxic. Indeed, a report published by PatientsLikeMe investigators last October on figshare.com found that "sodium chlorite has a potentially negative effect; we are over 80% confident that it worsens the rate of patient progression ."
SilverFox had warned forum attendees: “You must first realize that chlorite is a free radical. It can cause oxidative stress to the body. The body runs on oxidation, so it is able to handle oxidative stress to some degree. However, when you pass this point, you can do damage."
Frank Provost, who had participated in one of the clinical trials, said: "I felt a significant burn from NP001 at the injection site. I can only imagine how much damage would be caused if taken by orally at the dose required to be effective against ALS."
Since the work on WF-10 in 2001, it has been known that the reaction of chlorite with hemoproteins is a central step in the process of drug activation. The mode of administration therefore seems to be imperatively intravenously, while the patients of the als.net forum ingest sodium chlorite orally.
Similarly, Silverfox believed that since the pH of sodium chlorite is between 8 and 12, when injected into the blood there is an adverse reaction. WF10 had this flaw. For him, Neuraltus lowered the pH to be much closer to normal blood pH and far fewer side effects.
The mechanism evoked for WF-10 and NP000 involves a conversion of chlorite mainly to chloramine taurine which is a long-lived molecule with immunomodulatory properties. For example, chloramine taurine inhibits the generation of macrophage inflammatory mediators such as nitric oxide, prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) .
Aftermath
In the end, it turns out that only Ron Schaffer seems to have benefited from this DIY trial of sodium chlorite because his disease did not seem to have progressed afterwards. The next years he remained the sympathetic but pessimistic patient described above and passed away on September 22, 2022. He said the drug benefited him because unlike the other testers, he wanted to take an undiluted dose. He also said that only the dose initially administered had been beneficial, subsequent doses had brought him nothing.
These years were not easy, Ron remained an ALS patient almost paralyzed. Impossible to turn over in bed, to swallow without choking, no modesty possible. Yet he had a fierce sense of humor.