ALS Untangled®

ALSUntangled® reviews alternative and off label treatments (AOTs), with the goal of helping people with ALS make more informed decisions about them.

Patient trials

Curcumin

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Oral curcumin is safe, inexpensive, and has at least four potential mechanisms by which it might theoretically be useful in treating PALS. Flawed preclinical studies showed benefits of a curcumin chemical analog in a cell model of ALS, three PALS experienced validated motor improvements on regimens including curcumin (although there are several alternative explanations for these improvements) and there is one small pilot trial showing some benefit of curcumin in PALS. Based on the evidence presented in this review, some of us are planning a trial of Theracurmin at 90 mg twice daily in PALS.‌‌‌

Click here to download the complete review.

Hyperbaric Oxygen

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Although there are plausible mechanisms by which HBOT could work in ALS and a flawed pre-clinical study showing benefit in a mouse model, the best available human trial of HBOT showed no benefit. Given this negative human trial and the fact that HBOT has potentially serious complications, we do not recommend HBOT for patients with ALS at this time.

Kim Cherry’s ALS reversal, which occurred on HBOT and several other alternative treatments, appears very interesting. We do not think this is due to HBOT alone. There are other rare examples of ALS reversals on different (or sometimes no) treatments (28). Other explanations for these reversals include undetected ALS mimics syndromes or endogenous mechanisms that confer resistance to the disease (28). We look forward to further study of cases like this (29).‌‌

Declaration of interest: ALSUntangled is sponsored by the ALS Association and the Motor Neurone Disease Association.‌

Click here to download the complete review.

Inosine

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Inosine is a low-cost supplement that increases the levels of urate, a naturally occurring antioxidant. With appropriate blood and urine monitoring, it appears reasonably safe. Epidemiologic data suggest that high urate levels may be associated with improved survival in ALS, which prompted preclinical studies and clinical trials of inosine. These are still ongoing and will help determine whether inosine could be a useful treatment for ALS.‌

Declaration of interest: ALSUntangled is sponsored by the ALS Association and the Motor Neurone Disease Association.

Click here to download the complete review.

GM604

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At this time ALSUntangled finds no independently verifiable data supporting the efficacy or even the safety of GM604 in patients with ALS. We believe that independent peer review and replication are fundamentals of good science (36,37). Accordingly, we share the FDA’s April 2015 opinion that the data on GM604 in ALS should be released now for

independent peer review (38). If these preliminary data are confirmed to be positive, statistics on the false-positive rate of small trials (29,30) and consensus ALS trial guidelines (35) dictate that they be replicated in a larger, longer duration study before GM604 is deemed effective or even safe for patients with ALS.‌‌

ALSUntangled generally supports the use of expanded access programs during ALS drug development. We believe that these should be reserved for treatments that have at least some independently verifiable safety data. In our opinion, that is not the case with GM604, so we feel that expanded access is premature at this time. When we can independently verify safety data, we hope to see a GM604 group expanded access program that has transparent entry criteria, systematic objective outcome measures, full disclosure of results, and, as suggested by the FDA, allows for a sponsor’s cost recovery but not for profit (39).‌‌‌

Click here to download the complete review.

Lunasin

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Lunasin has interesting mechanisms of action that might be useful in treating ALS, and it appears reasonably safe although some forms of it are expensive. While some PALS have reported improvements on lunasin, we have thus far found only one in which we were able to independently validate these improvements. This patient had atypical features for ALS including a history of myasthenia gravis, which can produce weakness that improves spontaneously. At this time there is not enough evidence to recommend that PALS take lunasin. A reasonable next step would be a small pilot trial of lunasin with validated ALS diagnoses and outcome measures.

Click here to download the complete review.

TUDCA

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Ursodiol has interesting mechanisms of action, appears reasonably safe and well-tolerated, has anecdotal reports of benefit in 6/21 of patients who report taking it, and a form of it (Yoo’s solution) was associated with slightly slower ALS progression in one out of three outcome measures within a poorly designed study that did not account for large numbers of drop-outs. However, analyses of ursodiol data from the well-conducted randomized, double-blind ceftriaxone trial show that ursodiol 300 mg twice a day is no better than placebo at prolonging survival or slowing ALS progression. Based upon this review, ALSUntangled does not recommend off-label use of ursodiol as a treatment for ALS, at least at doses of 300 mg twice a day. Determining whether higher doses or different formulations are effective will require further well-designed studies.

Vitamin D

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At this time, there is evidence that PALS, like those with other chronic illnesses, are at increased risk for vitamin D deficiency. It is, therefore, reasonable to screen PALS for this. If vitamin D deficiency is found, it seems reasonable to supplement vitamin D according to established guidelines (31) in order to avoid medical complications of vitamin D deficiency. It is not yet clear, however, that vitamin D supplementation can slow disease progression, improve muscle strength, or reduce falls in PALS. We support further studies to answer these questions.

Fecal Transplants

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There is rapidly expanding evidence implicating alterations in the fecal microbiome in wide-ranging human diseases, including potential contributions via a gut-brain signaling axis in neurodegenerative and neuroimmunologic disorders. Proposed mechanisms such as immune modulation and the production of neurotoxins by clostridia or other microbiota could bypass an intact blood-brain barrier. To date, there are no data directly implicating the fecal microbiome in ALS, nor published case reports of FMT being tried in PALS. Data in other neurodegenerative and neuroimmunologic disorders are largely circumstantial, comprising a handful of published case reports. Therefore, ALSUntangled does not recommend FMT as a treatment for ALS at this time. However, it is plausible that the fecal microbiome plays a role in some neurologic disorders, including ALS. Given the lack of effective therapies and the relatively low cost and low risk of FMT – if performed by experienced clinical centers we support further investigations in this developing field. A reasonable next step would be a detailed molecular analysis of gut bacteria in ALS patients; certainly, these are the types of studies being advocated by the NIH Human Microbiome Project. If alterations are detected in the gut microbiome of ALS patients, a following step would be properly controlled studies in animal models, such as ALS mice. These studies could employ the same germ-free, and/or probiotic treatment regimens published in mouse models of EAE, Alzheimer’s disease, and obesity.