Lou Gehrig's disease

We've heard this story before: Raising loads of cash for unproven treatments

oracknows — Thu, 29 May 2014 01:15:25 +0000

We've heard this story before: Raising loads of cash for unproven treatments

Being a cancer surgeon, I realize that my tendency is to view my blogging material through the prism of cancer, particularly breast cancer, my specialty. it's easy to forget that there are diseases every bit as horrible, some arguably even more so than the worst cancer. When I think of such diseases, it's not surprising that amyotropic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease after its most famous victim. It's a progressive degenerative neurologic disease that affects the motor neurons, resulting in progressive muscle weakness throughout the body. Eventually, victims of this disease lose the ability to walk, use their arms, talk, and, near the end, breathe on their own. Most people with ALS die from respiratory failure within three to five years of diagnosis, with a median survival of around 39 months. While it's true that Stephen Hawking, another famous victim of ALS, has lived with the disease more than 50 years, he is a very unusual case. only around 4% survive longer than ten years. If there's a disease besides certain kinds of deadly cancer, like pancreatic or esophageal cancer, that scares the crap out of me, ALS is it.

Given the dire prognosis of ALS and the horrible way the disease relentlessly progresses, it just as unsurprising that its victims are desperate for anything that might slow the relentless deterioration of their muscle function caused by the disease. Unfortunately, that all too often means quackery. As of now, there's only one drug (riluzole) that's known to slow the progress of the disease and to prolong survival. Unfortunately, the effect is modest; so the search for better treatments goes on. While it goes on, there are victims of the disease like Lynne Grainger, who do what patients with with brain tumors who have become attracted to Stanislaw Burzynski do: Raise money to pursue unproven treatments. Unfortunately, that's exactly what Lynne Grainger is doing. Diagnosed with ALS in 2012 and rapidly deteriorating, she is trying to take a "holistic" approach. Her website describes her undertaking craniosacral therapy. This article describes her quest for a cure:

In line with her desire to take a holistic approach, she consulted Dr. Ruan Jin Zhao of the Center for Traditional Chinese Medicine in Sarasota. Zhao began acupuncture treatments, but was frustrated by how little he could offer.
“As a doctor, a diagnosis like this is very painful,” says Zhao, who remembers the names of all seven patients with ALS he has treated, none still living. “And especially with her, because she is so sweet, so good, always so present, and has a great spirit for living. As soon as I met her I could feel that. For this kind of soul, I want to do everything I can.”

On the one hand, it's tempting to feel a bit of schadenfreude for Ruan Jin Zhao. You mean there's actually a disease that acupuncture can't treat? I thought that acupuncture was good for everything that ails you, be it infertility, pain, menopausal symptoms, cancer, the need to quit smoking, and whatever. You mean it can't treat ALS? Who knew? I mean, Zhao's Center for Traditional Chinese Medicine claims to be able to treat arthritis, diabetes, cancers, asthma, hepatitis B and C, herpes, HPV, the flu, lupus, fibromyalgia, and many other diseases. Sadly, all Zhao can ofter is a kind word, because acupuncture is quackery. If that theatrical placebo brings Grainger a feeling of relief, I have a hard time being too critical.

Unfortunately, the search for a cure lead her to quackery:

Grainger also began alternative treatments — injections that had to be ordered from Switzerland, expensive supplements, aimed at cleansing her body of toxins and restoring her immune system, even a $5,000 machine (purchased by an ex-boyfriend) designed to tap into and heal the body's “frequencies.”

I can't be sure what that machine she got a hold of was, but my guess is that it was a Rife generator, which is based on the pseudoscience of radionics, which claims that diseases can be diagnosed and treated by tuning in on radio wave-like frequencies allegedly emitted by diseased organs and disease-causing agents. The ideas are, like most quack ideas, simple, persuasively compelling, and wrong. The claim is that all parts of the body emit electrical impulses with frequencies that vary with health and disease. Based on this, or so it was claimed, illnesses could be diagnosed by "tuning in" on a patient's blood or handwriting and treated by feeding back the correct vibrations into the body with a similar device.

Vibrations. It had to be...vibrations.

As critical as I am of this sort of quackery, make no mistake, Grainger's situation was even worse than just having ALS. She developed breast cancer. Although it was early stage and she didn't require chemotherapy, she did opt for a double mastectomy with reconstruction. After her last reconstruction her speech and walking became more compromised and her fatigue worsened, which is not uncommon after major surgery in patients with ALS. Also, although the article doesn't say this is the case for certain, it does state that Grainger believes that the reason she hasn't been eligible for any clinical trials for ALS is because of her history of cancer.

It was at this point that, well, I'll let the article tell it:

That left just one option: stem cell treatments available only outside the country.

But after spending than $30,000, she had used up all of her savings; she'd even moved in with Daudrumez for their first time in their relationship so she could rent out her own home for additional income.

So four months ago, she started a www.gofundme.com campaign aimed at raising the $45,000 she would need for a series of three treatments in Mexico, using stem cells grown from her own fat.

“People ask me, 'Why are you doing this?' ” she says. with halting, indistinct words. “But you have to navigate your own way. I know the body can heal, but sometimes, if it's very far gone, it can take a lot of work.”

Here's a good rule of thumb. If a clinic in Mexico, Central or South America, or Eastern Europe (among other places) is offering something that it calls "stem cell therapy" and is charging tens of thousands of dollars for it, chances are that what is being delivered contains neither stem cells nor effective therapy. Still, curious at what this therapy might be, I sought out Grainger's GoFundMe page, where there's a heartbreaking video of her asking for money with slurred speech juxtaposed with and older video of her bicycling. The procedure is described this way:

She is seeking stem cell treatment from a U.S. based lab, which does the actual procedure in Mexico. The whole thing costs $60,000. We did a fundraiser in March and April and now we are planning a cycling event. At this point, because of the constraints of time and organization, we can only do a "friendly ride" or "ride with friends" to benefit Lynne with donations. The thing is, we don't have much time before summer and also the beginning of her treatment.

Here's another hint. If the lab is in the US but the procedure is done in Mexico, you can be pretty sure it's not scientifically supported. It turns out that the company is a company called CellTex in Houston, where the procedure was described by Grainger thusly:

Let the healing begin! I had my fat extracted from a local plastic surgeon (Dr. Scott Engel). It was shipped on ice (seriously) to CellTex in Houston. There the lab begins the process of growing/banking stem cells, which will be for my treatment. It’s a process, but I should get my first treatment in May. Still fundraising as each treatment is $13,500 plus travel, etc. Regenerative medicine comes with a price. So, watch for a music fundraising event April 30th or go online to donate.

I hadn't heard of CellTex; so I checked out its web page. Basically, it's a stem cell banking company that is very careful to state that it does not treat patients or provide any health care services. However, apparently, if you can find a willing surgeon to remove some fat from your abdomen, CellTex will isolate "stem cells" from that fat and then grow them up if you need them. To me this is basically semantics; in essence CellTex is providing a biological treatment, whether it is administering it or not. Thus, to me CellTex is a medical company. As for Dr. Engel, apparently he is a believer that stem cells from abdominal fat can be useful and that these stem cells "rejuvenate the skin" when fat grafting is used as a filler. Maybe they can be, but if they are no treatment has been validated for them yet. Certainly no treatment for ALS based on stem cells has as yet been validated in a clinical trial.

In any case, although CellTex is very careful to inoculate itself against charges of practicing medicine or using an unapproved biological to treat disease through its disclaimer on its website. It also basically admits that stem cell treatment is unproven for most claimed indications by emphasizing that their stem cells are safe, touting a study from 2011 performed in South Korea. Basically, it was an animal study in which these stem cells were injected into immunodeficient mice and then into eight patients with spinal cord injury. No specific toxicity was observed. CellTex also touts "dozens of other clinical trials" that have demonstrated safety and "hundreds" of pre-clinical animal studies. In other words, there are no studies suggesting efficacy—for anything. But, hey, CellTex is sponsoring clinical trials. It is very vague about what these trials will be testing, but, damn if it's not sponsoring clinical trials. They've even been reviewed by an IRB! Too bad there isn't any evidence of a clinical trial demonstrating that these mesenchymal stem cells can impact the course of ALS.

I don't know for sure what quack clinic in Mexico has enticed this desperate woman to spend tens of thousands of dollars, but I rather suspect I know what clinic it is. Because I can't be sure, however, I won't name the company. I will, however, point out just how incredibly dubious CellTex is. The reason that CellTex is sending its patients to Mexico to receive stem cells is simple: It got busted by the FDA for administering stem cells to patients on US soil at its facility in Houston when a patient named Debbie Bertrand blogged about her experiences during a five-injection treatment with cells prepared at CellTex. The FDA was not amused. It also found significant deviations from current good manufacturing practice during an inspection in 2012. Nor were legitimate stem cell researchers amused:

Stem-cell scientists contacted by Nature are concerned by Celltex's activity. “Because we know so little about mesenchymal stem cells and whether they are indeed effective for treating any condition, I'd be very wary of how they are being infused into patients, and certainly concerned if practitioners are charging patients for medical procedures that haven't been proven to work and could in fact be harmful,” says George Daley, director of the Stem Cell Transplantation Program at Harvard Medical School in Boston, Massachusetts, who helped the ISSCR to draft its guidelines. In the opinion of Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco, “the very nature of Celltex's business plan, which involves charging patients considerable fees for so-called treatments for diseases and disorders for which there is no good clinical evidence of efficacy, crosses an ethical line”.

So, I would argue, is charging a dying woman desperate to live longer tens of thousands of dollars for a procedure that has not been demonstrated to have any efficacy against her disease. It gets even worse, though. CellTex hired bioethicist Glenn McGee to try to show the world that it was abiding by ethical standards in human research. He resigned after only three months on the job. Of course, one of the company's founders trots out the same old excuse used by unscientific practitioners the world over for why he can't do clinical trials:

Lotfi says that most of his patients claim to get better after the treatment, but he admits that there is no scientific evidence that the cells are effective. “The scientific mind is not convinced by anecdotal evidence,” he acknowledges. “You need a controlled, double-blind study. But for many treatments, that's not possible. It would take years, and some patients don't have years.”

“The worst-case scenario is that it won't work,” he adds. “But it could be a panacea, from cosmetics to cancer.” He says that Celltex is conducting a trial in which patients “will be their own control”. “If you can compare before and after and show improvement, there's no need for a placebo,” he explains. “How can you charge people, and then give them a placebo?”

I am still flabbergasted that anyone could have said something revealing such ignorance of placebo effects, the clinical trial process, and why doing placebo-controlled trials is important for many outcomes with a subjective component. While it is possible to do trials in which patients serve as their own control, it's not really an appropriate trial design, however, to demonstrate conclusively the efficacy of a treatment intervention like stem cell therapy. Moreover, what Lotfi said about there not being time for a trial is utter nonsense, given the near-miraculous improvements claimed. If the improvement is that dramatic, it wouldn't take long to do a clinical trial at all.

So how is CellTex getting away with it? Come on? Do you have to ask? It's Texas, home of some of the laxest (read: close to nonexistent) regulation of medicine in the country, home to Stanislaw Burzynski. Moreover, CellTex appears to be connected, counting Governor Rick Perry as one of its enthusiastic clients.

Which brings us back to Lynne Grainger. To me, she's no different than any patient of Stanislaw Burzynski I've discussed or any Burzynski patient whose story has been documented at The Other Burzynski Patient Group, and the promises made, either by CellTex or whatever quack clinic in Tijuana is using the stem cells that CellTex banks, are no different than Burzynski's claims. No, I take that back. Burzynski has actually done some clinical trials. True, he's never published a completed trial and what he has published is unimpressive, but he's one up on CellTex in that department.

My heart goes out to Lynne Grainger every bit as much as it has gone out to every Burzynski patient I've ever blogged about. She is a woman in the prime of her life facing a fatal illness and a horrible death. It's just depressing how there always seems to be someone willing to take advantage of the desperation of people like her who only want to live.

oracknows Wed, 05/28/2014 - 21:15

Last Week on ResearchBlogging.org

milhayser — Sun, 23 Mar 2014 18:14:42 +0000

Last Week on ResearchBlogging.org

For the first time, researchers have transformed induced pluripotent stem cells (iPSCs) into specialized bladder cells. Meanwhile the development of iPSCs from normal cells has been shown to depend on two proteins necessary for the induction of a glycolytic state. In order to make iPSCs, researchers have previously needed to collect significant amounts of skin, bone marrow, or blood from a donor, but researchers have demonstrated a new method that requires only a single drop of blood. In the future, you may be able to prick your finger, send a drop of blood to the lab, and have them grow a new bladder for you.

Paleontologists digging in the Dakotas have discovered "a giant crested bird-like dinosaur that the experts liken variously to an outsized cassowary, or a 'chicken from hell.'" The new genus of oviraptorosaur was named Anzu after a Mesopotamian bird-demon.

By coating gallium nitride semiconductors with "a layer of phosphonic acid derivatives," researchers increased the brightness and longevity of LEDs without having to increase energy input.

Human appetite for conch snails has reduced the size of mature specimens by 2/3 in the last seven millennia.

A study of dioxin exposure via breast milk in Vietnam showed a correlation between levels of the chemical and development of autism in children.

Regardless of how long you spend playing, video games (especially those played with others) may help you relax after a long day at work.

Mexico now beats the U.S. as the most obese country in the world; they also drink the most Coca-Cola. With Coke expanding aggressively in developing nations, chronically undernourished people are faced with too much of a good thing.

Getting less sleep is associated with having less 'gray matter' in the brain, but researchers can't determine the direction of causality. In another study, autistic children demonstrated shorter sleep duration than control groups.

Among sex-changing fish, the largest females are known to replace dominant males in a pinch, but male-to-female transitions are much more rare. By studying a bunch of widowed male wrasses, researchers observed that the males would pair up with the next individual they encountered--whether male, female, or juvenile--and when two widowed males paired up, the smaller would become a female.

Baseline risk of ACL and other ligament injury may be genetically determined.

To accelerate word learning in young children, read them a story and then put them down for a nap.

Lithium-air batteries use the atmosphere as a cathode and could boost the range of electric vehicles to 300 miles or more.

Computational research has postulated the structure of electromagnetic knots that satisfy Maxwell's equations.

And finally, a study of stem cell therapy for Lou Gehrig's disease (or ALS) showed that the cells can be safely transplanted into the spinal cord and do not accelerate progression of the disease, providing a green light for further research.

milhayser Sun, 03/23/2014 - 14:14

Patient-led “clinical trials” versus clinical research (2012 edition)

oracknows — Thu, 02 Aug 2012 01:10:58 +0000

Patient-led “clinical trials” versus clinical research (2012 edition)

Dying of cancer can be a horrible way to go, but as a cancer specialist I sometimes forget that there are diseases that are equally, if not more, horrible. One that always comes to mind is amyotropic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease. It is a motor neuron disease whose clinical course is characterized by progressive weakness, muscle atrophy and spasticity, with ultimate progression to respiratory muscles leading to difficulty breathing and speaking (dysarthria) and to the muscles controlling swallowing. The rate of clinical course is variable, often beginning with muscle twitching in an arm or a leg or slurring of speech. Ultimately, however, ALS progresses to the loss of ability to move, speak, eat, or breathe. The most common cause of death is from respiratory failure, usually within three to five years after diagnosis, although there is the occasional outlier with a less malignant form of the disease with a slower course of progression who can live a long time, such as Steven Hawking.

In other words, ALS is a lot like cancer in some ways. For instance, it is a progressive, fatal disease that usually kills within a few years at most. On the other hand, it is different from cancer in that, at least for many cancers we actually do have effective treatments that prolong life, in some cases indefinitely. In contrast the most effective treatment we currently have for ALS is a drug (riluzole) that is not particularly effective—it prolongs life by months—and can be best described as better than nothing, but not by a whole lot. So it is not surprising that ALS patients, like cancer patients, become desperate and willing to try anything. This is completely understandable, but sometimes, as with cancer, this desperation leads to activities that are far more likely to do harm than good. I was reminded of this when I came across a post in the antivaccine propaganda blog, Age of Autism, referring to an article in The Scientist entitled Medical Mavericks. (No, not "brave maverick doctors" but misguided "mavericks" nonetheless.) The fortuitous posting of this story, which was apparently designed to try to show that it's not as crazy as critics have said to be treating autistic children with "Miracle Mineral Solution" (MMS) (which is a bleach) given that the introduction explicitly mentioned Kerri Rivera and the patient described in the article used sodium chlorite to treat his ALS, provided me the opening to discuss a group whose existence and advocacy brings up a complex tangle of issues that boil down to questions of how far patient autonomy should be allowed to go. I'm referring to a company, PatientsLikeMe, which describes itself thusly:

PatientsLikeMe was co-founded in 2004 by three MIT engineers: brothers Benjamin and James Heywood and longtime friend Jeff Cole. Five years earlier, their brother and friend Stephen Heywood was diagnosed with ALS (Lou Gehrig’s disease) at the age of 29. The Heywood family soon began searching the world over for ideas that would extend and improve Stephen’s life. Inspired by Stephen’s experiences, the co-founders and team conceptualized and built a health data-sharing platform that we believe can transform the way patients manage their own conditions, change the way industry conducts research and improve patient care.

What I see PatientsLikeMe as doing is trying to mine a very unreliable source, namely thousands of testimonials. However, one other thing that needs to be kept in mind is that PatientsLikeMe is a for-profit company. Consequently, it's selling a product, and that product is its analyses of the information patients who sign up with the service reveal about their experiences with various medicine and products. It is true that the company has an admirable list of core values, such as putting patients first, promoting transparency, fostering openness, and creating "wow" (i.e., information that "wows" you), but the company is still selling a platform to its partners and using that platform to attract investors. It is described as a platform "where patients can share and learn from real-world, outcome-based health data." In essence, PatientsLikeMe (PLM) is a social media company for patients that mines the reported experience of its patients as, if you believe the hype, thousands of "N of 1" clinical trials. Unbeknownst to PLM, the autism "biomed" blogger who wrote the AoA post has a better analogy for what PLM is.

I first learned about PatientsLikeMe four or five years ago, when I wrote a series of posts about self-experimentation by cancer patients with an unproven, unapproved drug, dichloroacetate (DCA). As regular readers might recall, DCA is a small molecule drug that was used to treat congenital lactic acidosis in children through its inhibition of the enzyme pyruvate dehydrogenase kinase. This inhibition shifts the metabolism of glucose towards oxidative metabolism in the mitochondria and away from glycolysis, the product of which is lactic acid. In January 2007, Dr. Evangelos Michelakis of the University of Alberta had the clever idea of using DCA to target the Warburg effect in tumors and published an article in Cancer Cell describing preclinical experiments in rats in which DCA resulted in marked shrinkage of multiple tumor types. The Warburg effect was first described in 1928 by Otto Warburg and refers to the tendency of many tumors to rely on glycolysis for their energy supply rather than oxidative phosphorylation, even in the presence of oxygen, which in the case of normal cells favors oxidative metabolism. It turns out that DCA showed some promise against glioblastoma in a phase I clinical trial, but it is a long way from being approved.

Because DCA is a small molecule and relatively easy to synthesize, a man named Jim Tassano decided that he would sell "pet DCA" to treat cancer in pets. Tassano fooled no one, of course; people were not buying DCA to treat their dogs. His real purpose was to take advantage of desperate cancer patients, some of whom flocked to his BuyDCA.com website to purchase what he claimed to be pharmaceutical grade DCA. It also led to what I saw as a most disturbing phenomenon, namely self-experimentation by cancer patients with DCA and discussion among patients on online forums, which was even likened to "clinical trials," complete with reports of success based on magical thinking more than anything else. You will see echoes of this same story and the issue it raises in the article referenced by AoA.

This brings us to the link between MMS and PatientsLikeMe. MMS, as you recall, is being touted as a "miracle cure" for conditions as disparate as cancer and autism. It is nothing more than a 28% solution of sodium chlorite, a chemical widely used for water purification. A couple of months ago at that yearly quackfest of the "autism biomed" movement, Autism One, Terri Rivera gave a talk in which she advocated using MMS to treat autism. Her method of delivery included oral, bathing in it, and per rectum, as in MMS enemas. Yes, we're talking bleach enemas to treat autism. Administered orally according to Rivera's protocol, the amount of chlorine dioxide (the active chemical liberated when sodium chlorite is mixed into aqueous solution) is more than 120 times the amount that a child could expect to consume drinking tap water.

It turns out that the story being touted by AoA is about a man named Eric Valor who is taking sodium chlorite to treat his ALS:

In June 2010, he learned of an experimental ALS drug called NP001, being developed by Palo Alto–based Neuraltus Pharmaceuticals. Then just beginning Phase I trials, the drug targets ALS patients’ overactive immune cells, attempting to reduce the chronic neuroinflammation associated with the disease. It seemed promising to Valor, but unfortunately, his disease was too advanced for him to qualify for the trial. “I made various attempts to get [enrolled], but failed,” says Valor, who responded to The Scientist via e-mail because his ventilator limits his speech.

If he couldn’t participate in the trial, maybe he could get the drug another way, Valor reasoned. After an exhaustive literature search on PubMed, he identified the drug’s “cruder” precursor as WF10, which is available for purchase abroad. But he quickly learned that importing it from Thailand would cost more than $12,000 for a year’s supply. He then set out to see if he could get his hands on what he suspected—based on a literature search and a 2006 patent tracked down by fellow ALS patient and friend Rob Tison—was the active ingredient of NP001: sodium chlorite, which is used in water-purification kits for campers and in municipal water treatment.

This is an interesting story on many levels, not the least of which is the apparent finding that sodium chlorite might have an actual therapeutic use. But what is NP001? Due to its proprietary nature, it is not straightforward to figure out just what NP001 is from online sources. For instance, I found what was purported to be the structure of NP001 at the ALS Therapy Development Institute. Notice that there's no chlorine atom anywhere in chemical structure, making it incredibly unlikely that this molecule would generate chlorite as its active compound. However, more searching around the web made me question whether this is the actual structure of NP001, starting with this press release from the company describing promising results for the drug in a phase I study. Unfortunately, the trial appears not to have been published yet (PubMed searches using the usual suspects, such as "NP001," "Neuraltus Pharmaceuticals," and the study's principal investigator Robert G. Miller, among other strategies, failed to turn up anything); so I went to patent searches and found that Neuraltus Pharmaceuticals has patents for various buffered release systems for sodium chlorite, for example, this one, although searching using the term "NP001" didn't turn up anything related to ALS. Elsewhere, it is stated that NP001 is a modified form of WF10, which is basically sodium chlorite and has been tested with varying results as an immune modulator for various conditions. In brief, WF10 is a stabilized chlorite matrix that appears to have immunosuppressive effects, although it also appears to stimulate natural killer cell cytotoxicity and decrease macrophage activity. This patent describes the claims for WF10.

To sum it all up, NP001 appears to be some form of sodium chlorite in a matrix designed to control its release, perhaps with another compound. Certainly, this FDA application for orphan drug status by Neuraltus Pharmaceuticals, Inc. for sodium chlorite pretty much cemented in my mind that that's what NP001 is, as did the information on this discussion forum, which described how WF10 and NP001 relate to the drug from Thailand referenced in The Scientist article. Moreover, NP001 was granted not only orphan drug status but fast track status as well.

Now here's the problem with the sort of "do it yourself"-style "N of 1" clinical trials advocated by PatientsLikeMe:

Last June, Valor began taking oral doses of the chemical, which is not approved for the treatment of any disease. And he thinks it’s working. “I have improved breathing, which makes transfers [off his ventilator] much more comfortable,” Valor says. “My voice is louder and speech somewhat clearer. I am able to flex muscles that were previously still (though not enough for useful movement).”

So, basically Valor is taking MMS for his ALS. We don't know the concentration or the dose that he's taking. The key phrase above is that Valor thinks it's working; we have no idea whether there is any objectively measured improvement in his motor function. There are well-established rating scales for severity of ALS symptoms, and it would be much more useful to know whether these patients have any measurable improvement in concrete, objective measures of motor neuron and muscle function. I've looked, and I haven't been able to find any. Valor's impression could be the result of expectation bias, confusing correlation with causation (i.e., waxing and waning of symptoms correlating with drug administration by random chance alone), or other cognitive quirks to which humans are prone that lead to a mistaken impression of causation.

In addition, in The Scientist article, there is the story of Ben Harris, an ALS patient who was enrolled in the phase II clinical trial of NP001 last year:

At first, Valor didn’t tell other ALS patients about his experimentation, hoping to first establish that it was safe, “but by September, it had leaked,” he says. Medical physicist and ALS patient Ben Harris, who was enrolled in the NP001 trial, was the one to get the ball rolling. NP001 had improved his strength, speech, breathing, and ability to swallow, and he wanted to keep taking the drug after his participation in the trial ended. “The more I learned about [sodium chlorite], the more excited I got, and I felt it was too important to keep a secret,” says Harris, who also responded to questions via e-mail due to limitations associated with his disease. So he started a discussion thread on the website of Cambridge, Massachusetts-based biotech ALS Therapy Development Institute (ALS TDI), sparking widespread interest that helped launch the do-it-yourself (DIY) trial. Now more than two dozen other ALS patients are taking oral sodium chlorite, and recording their results on the social networking site PatientsLikeMe.

Here is Harris' phase II trial report, as posted on PatientsLikeMe, along with others. Note that most of the patient evaluations for NP001 or sodium chlorite can only be viewed if you have a PatientsLikeMe account. However, the two reports that are publicly available list the drug as having "major effectiveness," and have a lot of subjective accounts of symptomatic improvement with precious few objective measures (one, actually). At one point, Harris reports a large increase in the grip strength of his hands (the only objective measurement), but by the end of his participation in the trial in November 2011 his impression was this:

I just received my very last infusion of NP001. I think overall if I have declined during this study period it has been at a small fraction of the rate before starting the study. The only thing I can say that is worse is that I am more frequently wiping my lips. I think my lip muscles have atrophied but my tongue has not, neither have my left arm or leg. My left arm was getting weaker just before I started the study but it has held strong since. Along with the decrease in strength on my lips has been a very slight decline in my speech. I have been recording my speech weekly since August and it is very difficult to detect a change so the difference is very small. I believe overall NP001 has drastically slowed my progression if it hasn't stopped it. Overall, I am better than I was when I started the study.

However, elsewhere, he wrote:

The one way I think I may have declined is in drooling. I seem to have to wipe my lips more often than before and I noticed night time drooling for the first time about one month after starting the study. But the difference is very very small compared to what it was like about 9 months ago. I think perhaps my tongue is stronger but my lips are a little weaker. It is difficult to decide whether I am improving or declining, which in itself is a good thing. Before starting the study I would notice differences in my state every month and they were obvious to me. Right now I am struggling to decide whether there are changes in my state from 4 months ago.

Another thing that you should note: There is a 50-50 chance that Mr. Harris received the placebo. He even acknowledges this elsewhere by telling a reporter that he always tells patients to whom he speaks of this possibility. Yet he wrote his PatientsLikeMe diary as though he knew he was receiving the experimental drug. He seemed to assume that he was in the experimental group and, when the NP001 trial was over, decided to do what Eric Valor has been doing and start taking sodium hypochlorite on his own, as described in this Wall Street Journal story back in April:

Although no patient knows whether or not he received the drug or a placebo, Mr. Harris says he experienced dramatic improvement in his ability to swallow after his first infusion of NP001. After he finished with the infusions on the Neuraltus trial, he wanted to continue. He worried that swallowing sodium chlorite wouldn't be effective because it would be neutralized in the stomach, so in January, he started injecting it every three weeks. He says he feels no side effects. Mr. Harris says he didn't inform Neuraltus about what he is doing, but feels that it shouldn't have bearing on the formal trial since he didn't start infusing himself until after the NP001 infusions were completed.

Mr. Harris isn't sure he is benefiting but said last week that he gave himself an infusion and by evening, his swallowing had improved. The real proof, he says, will come when the participants do an analysis of the data collected online. Mr. Harris says he knows that the results will never compare to what Neuraltus is doing.

Eventually, the blinding will be lifted, and Mr. Harris will know. However, he could well be mistaken when he says that his use of sodium chlorite after his treatment as part of the trial was done has no bearing on the trial. If there are late measurements of motor neuron function and survival (and I assume there are), his use of what he believes to be NP001 could skew the trial data.

Unfortunately, this PatientsLikeMe "trial" is not a proper clinical trial at all, and it is highly unlikely that the "analysis" of the patient reports and data collected online will show any sort of conclusive evidence of benefit or lack thereof. The reason, of course, is that this is no more than a collection of anecdotes without a control group, without a standardized protocol covering dosage and administration of the drug, and without even a standardized source of the drug. That's not to say that analyzing the data might not be useful for examining patients' perceived side effects and for comparing perceived benefit to actual benefit measured objectively, but in reality what PatientsLikeMe is doing is more likely than not pretty close to useless for determining actual efficacy.

The Scientist article mentions a previous PatientsLikeMe trial looking at lithium as a treatment for ALS. It was this trial, as it turns out, that brought PatientsLikeMe to my attention in the first place, leading me to discuss the trial in depth using story from 2008 about ALS patients trying lithium to treat their ALS based on one promising study. Just as Tassano sparked "wild experimentation" of patients using DCA to treat cancer with little or no medical supervision based on a single study using rat tumor models, patient experimentation with lithium to treat ALS appears to have been sparked by an Italian study that reported a significant slowing of the progression of ALS. This study looked at both a mouse model and reported the results of a small randomized trial of lithium plus riluzole versus riluzole alone. As a result of this study, ALS patients started taking lithium off-label. Meanwhile, PatientsLikeMe proclaimed:

Together, with all the patients involved, we will run the first real-time, real-world, open and non-blinded, patient-driven trial. We believe we will have the power, within months, to begin answering the question of how much lithium modifies the progression of ALS. Unlike a blind placebo control trial, we are watching the use of this drug in the real world, and because of the number of patients and our system's sophisticated data modeling, we can determine the significance of each reported change in each patient as he/she deviates from his/her predicted course. There are many risks to our approach, patient optimism, the placebo effect, uncertain quality, and many other variables will compromise our data. Despite these, and many other challenges, we remain committed to solving this problem.

As I pointed out before, this "problem," as it was described, probably cannot be solved because it was inherent in the very design of this study, which was neither randomized nor blinded. There were no valid controls, only in essence historical controls (i.e., the "predicted course"). What's even more puzzling is that the organizers of this trial even seemed to recognize these problems, acknowledging that the placebo effect, patient optimism, and many other variables may compromise the data. Yet they nonetheless expressed optimism that their "sophisticated data modeling" could overcome these problems.

As it turns out, lithium doesn't improve survival or neurologic function in patients with ALS. Ironically, PatientsLikeMe published its observations several months before the official phase IIb clinical trial in a Nature Biotechnology paper and trumpeted on its blog that it had "refuted a published clinical trial," specifically, the original clinical trial in PNAS that suggested that lithium might be useful in ALS, stating:

PatientsLikeMe developed a novel algorithm designed to match patients who reported taking lithium with a number of other ALS patients that had similar disease courses. By using a matched control group, PatientsLikeMe was able to reduce biases associated with evaluating the effects of treatments in open label, real world situations and improve the statistical power of the study making each patients contribution more meaningful.

Maybe. More likely, it was nothing more than wishful thinking to believe that this novel algorithm, whatever it is, does an adequate job of controlling for the enormous number and quantity of biases that exist in anecdotal reports from patients. Indeed, I can't help but think that it is a rather apt comparison when AoA equates PatientsLikeMe "to many of the autism biomed boards." The main difference is that in the case of PatientsLikeMe there is a company asking members of its website to take polls about the effectiveness of whatever they are trying at the moment and then trying to analyze the anecdotes in order to sell the results to its business partners. In fact, when you come right down to it, PatientsLikeMe is a lot like another social networking site, namely Facebook. Like Facebook PatientsLikeMe has members communicating online. Also like Facebook, its business model is to sell the results of its analyses of the data these members provide. Facebook sells to advertisers; PatientsLikeMe sells to its business partners. In all fairness, to be sure, PatientsLikeMe appears to be a lot more transparent than Facebook. It also doesn't sell its members' personal information to advertisers and marketers. Even so, its business model is not that different from that of Facebook. Certainly, there is a lot of marketing going on.

ALS is a horrible disease. I know I've already said that, but it is something that bears repeating. Consequently, I can't blame a single patient for wanting to get his hands on NP001, even to the point of being willing to mix up some home-brewed sodium chlorite or buy non-pharmaceutical grade chemical from whatever supplier he can find. I get it. They don't have the time to wait for drugs to wend their painfully slow way through the FDA approval process any more than patients with advanced cancer do. Like Derek Lowe, I can't even say that I wouldn't be sorely tempted to do the same thing myself, particularly with chemicals that are small molecules that can be purchased elsewhere or synthesized in my laboratory. I can even somewhat understand the motivation behind PatientsLikeMe. No doubt the founders of the company think they are somehow accelerating drug discovery while doing good. Unfortunately, they have yet to show that they are accelerating anything. If you look at their publications, none of them demonstrate positive efficacy, and most of them (for instance, the latest three) are about patient attitudes and validation of ratings scales. Nowhere is there any example of a study that has shown anything about the efficacy of a new treatment that adds anything to what conventional clinical trials show. For example, in the case of the lithium trial, no one's going to believe the results of and Internet survey (which is what, in essence, the lithium trial was); they're going to wait for the results of a real clinical trial.

PatientsLikeMe has always promoted a rather radical idea, namely that it is possible to tell whether a drug works by analyzing, in essence, a bunch of testimonials from a group of self-selected patients self-medicating with therapies in an unblinded fashion with no proper control group. I suppose it's worth seeing if it is possible to glean any useful information out of the morass of stories that constitute the database utilized by PatientsLikeMe, but I've never had much confidence that the company would be successful at it, and I've seen no publications yet that suggest to me that my original assessment was wrong. From what I've seen thus far, from a scientific and drug development standpoint PatientsLikeMe appears to have failed, even as it has been wildly successful as a social network for patients. Unfortunately, with this most recent foray into reporting on home-brewed NP001-lookalike drugs (a.k.a. sodium chlorite), PatientsLikeMe is entering dangerous territory that it has eschewed in the past. Remember DCA? PatientsLikeMe could have done then for DCA what it's doing now for sodium chlorite, but at the time it did not—and rightly so, I might add. Indeed, from a strictly analytic standpoint, DCA would have been a better test case because the DCA patients were using was chemically identical to DCA that showed promising results in the original rodent studies. In contrast, we have no idea whether the sodium chlorite patients reporting to PatientsLikeMe are using is chemically identical to NP001. Very likely it is not.

There's a reason why AoA loves PatientsLikeMe, and that's because it cannily sees it as a more sophisticated version of what "autism biomed" proponents have been doing in discussion groups for a long time: Setting up an online place where people trying anything under the sun up to and including the rankest form of quackery can get together and swap anecdotes and testimonials. One wonders how long it will be before members of the "autism biomed" movement starts infiltrating PatientsLikeMe in order to see if the company will examine their assessments of the various interventions to which they subject their autistic children, such as MMS enemas, hyperbaric oxygen chambers, untold varieties of supplements, chelation therapy, and other dubious and sometimes dangerous interventions. Indeed, given that PatientsLikeMe has recently published on its assessment of the efficacy of drugs given for off-label indications, one wonders whether its founders would be willing to examine whether Lupron works for autism. The precedent has been set with sodium chlorite, after all.

I hope that in the future PLM sticks with off-label drug uses and exploring the experiences of patients on existing clinical trials as an adjunct to the actual trial. There, it might actually be able to do some good. It's highly unlikely that anything good can come of "studies" like the one being undertaken to ask patients taking sodium hypochlorite if they think it's working and very likely that bad things will happen.

oracknows Wed, 08/01/2012 - 21:10

Patent Dispute Prevents Patients From Getting Promising Drug for Lou Gehrig's Disease

rskloot — Sun, 17 May 2009 08:29:56 +0000

Patent Dispute Prevents Patients From Getting Promising Drug for Lou Gehrig's Disease

Speaking of the debate over patents interfering with medical care, there's a story in today's New York Times that mentions the drug Iplex, which has shown promise for treating Lou Gehrig's disease -- a deadly and thus far untreatable degenerative disease (also known as amyotrophic lateral sclerosis).

From the article:

Iplex ... is believed to protect the motor neurons whose
death leads to paralysis in A.L.S. Some patients had persuaded their
doctors to prescribe the drug when the F.D.A. approved it in late 2006
for children with growth deficiencies. "I started on Tuesday," Debbie Gattoni, an A.L.S. patient in New Jersey, had written on a Web discussion forum, "and on Sunday, I noticed that my right index finger, which was bent, was straightening and moving on its own."
But
almost immediately, the drug's maker, Insmed, lost a patent
infringement lawsuit to a biotechnology firm that was already selling a
drug for short stature that had similar properties. Iplex , however, was thought to be more potent for treating A.L.S. Insmed agreed to pull its drug off the market. Only the Italian Health Ministry, which had begun to distribute the drug to A.L.S. patients under a compassionate use program, could continue to buy it ... [but] only Italian citizens could receive Iplex through the program.

This situation is quite different from the breast cancer gene patent situation I wrote about in my recent Slate Double X column -- the Iplex dispute is over drugs, which are clearly inventions, and no one is questioning the legality of drug patents. But it does raises some relevant questions about the intersection of patents and medical care.

rskloot Sun, 05/17/2009 - 04:29