In Small Trial, EH301 Appears to Halt Progression of ALS

Could a dietary supplement marketed directly to consumers moonlight as an effective treatment for ALS? It is within the realm of possibility, according to the results of a small Phase 1 pilot study testing EH301 in people with the disease. Essentially the same product as EH301 is sold under the name Basis by New York-based Elysium Health as a supplement to support cellular health.

  • In four-month trial, EH301 apparently slowed ALS.
  • In open-label extension, the treatment reportedly held off decline at one year.
  • EH301 is for sale on the internet as Basis, an unregulated dietary supplement.

In the January issue of the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, researchers led by José Estrela at the University of Valencia, Spain, reported that ALS patients taking EH301 for four months not only stopped getting worse, but even improved, on several clinical endpoints. What’s more, the treatment appeared to stave off decline for up to one year in participants enrolled in an open-label extension. The authors, as well as outside commentators, called for a larger study to evaluate EH301 in ALS.

“It is remarkable and encouraging to see that the investigators report a clinical improvement in the ALS patients, and not just a slowing of progression of this devastating disease,” commented Patrick Weydt of University Clinic Bonn, Germany. “Findings like these urgently require independent confirmation,” Weydt wrote, (full comment below).

Elysium Health co-founder and chief scientist Leonard Guarente, Massachusetts Institute of Technology, is a co-author on the paper. Guarente forwarded Alzforum’s request for an interview to the company’s public relations office, which declined it. Estrela originally scheduled an interview, but backed out several days later upon company direction.

Weydt and other commenters pointed out several caveats with the trial, including its small size, short duration, and 38 percent dropout rate. Merit Cudkowicz of Massachusetts General Hospital in Boston noted that the data were encouraging, but not definitive. “Because ALS is such a heterogenous disorder, results from small studies can sometimes not bear out when a larger confirmatory study is done,” Cudkowicz wrote, “It would be important to move forward expeditiously, though, for a confirmatory trial in larger groups of participants and for longer duration.” (Full comment below).

EH301 is a combination of pterostilbene (PT)—an analog of resveratrol found in blueberries—and nicotinamide riboside (NR), a precursor to the coenzyme nicotinamide adenine dinucleotide (NAD+). In addition to its pivotal role in the mitochondrial oxidative metabolism that fuels cells, NAD+ drives the activity of sirtuins. The human genome encodes seven sirtuins. They carry out multiple functions, including deacetylation of transcription factors, histones, and other targets, and are involved in processes known to go awry during aging and in neurodegenerative disease, including energy metabolism, inflammation, and DNA repair.

NAD+ reportedly wanes with age in the human brain, and animal studies suggest boosting it could extend lifespan (Zhu et al., 2015; Zhang et al., 2016; Fang et al., 2016). Differentially altered sirtuin levels have been reported in postmortem brain and spinal cord samples of people with ALS (Körner et al., 2013). 

Some years after Elysium Health started selling Basis to consumers, it published a Phase 1 trial of 120 healthy seniors, reporting that daily doses of up to 500 mg per day of NR and 100 mg per day of PT, taken for eight weeks, elevated serum NAD+ levels by 90 percent (Dellinger et al., 2017). The regimen was safe, though a slight increase in LDL levels was noted.

To explore EH301 as a potential treatment for ALS, first author José de la Rubia, of the Catholic University San Vicente Mártir in Valencia, and colleagues conducted a placebo-controlled, randomized trial between February and June 2017. Upon recruitment, Estrela or de la Rubia assigned 15 participants to receive 1,200 mg of EH301 daily, and 17 to receive placebo. In other words, the trial was blinded with the exception of its two directors.

The trial continued for four months, with clinical evaluations at baseline, two, and four months. The modified ALS functional rating scale (ALSFRS-R) served as the primary endpoint. Secondary outcomes included measures of pulmonary function, muscle strength, and skeletal muscle weight and activity.

Twelve of the 32 randomized participants dropped out of the trial. Five withdrew before starting treatment, and the other seven—four in the placebo and three in the treatment group—discontinued between their two- and four-month appointments. Of the four dropouts from the placebo group, two were related to trauma, one to gastroenteritis, and one to bronchitis. In the treatment group, one dropout was related to trauma, one to hepatitis, and one to depression. The researchers presented findings only from the 20 participants who finished the trial.

The groups were not exactly matched at baseline. Compared with completers on placebo, those on treatment had lower ALSFRS-R scores, weaker muscles, lower activity in some muscles, and had had symptoms for a shorter duration of time. These baseline differences raised the possibility that the treatment group might have had, on average, a slightly more aggressive form of the disease.

Seven of the 10 completers on EH301 improved significantly on the ALSFRS-R. The group posted an average improvement of 3.4 points by two months, and 2.5 points by four months. Conversely, nine of the 10 completers in the placebo group declined, by an average of 3.0 and 5.5 points at two and four months, respectively.

The EH301 group also improved on secondary measures, according to the paper. Nine participants gained muscle strength, as measured by the Medical Research Council grading scale index, while six gained pulmonary function, as gauged by forced vital capacity. Using surface electromyograms, the researchers found that participants on EH301 had a boost in activity in several muscle groups. They also gained an average of 0.5 kg of skeletal muscle weight, while the placebo group lost an average of 1.3 kg.

As expected, everyone in the placebo group declined on every clinical endpoint throughout the trial, with the exception of one participant who improved by one point on the ALSFRS-R. Conversely, the entire EH301 group showed improvement on at least one endpoint, with only one participant improving on less than two endpoints.

Adverse events were reported by four participants in the placebo group and five in the treatment group. They included mild diarrhea, moderate stomachache, and mild headache. They were short-lived and deemed unrelated to treatment.

Following the blinded portion of the trial, participants were offered an open-label extension to continue EH301. All 20 participants joined, but the researchers only reported one-year data from the 10 participants who had initially been randomized to the treatment group. By one year, they still had not declined relative to baseline on the ALSFRS-R, nor in muscle strength or activity in six out of eight muscle groups tested. The authors note that people with ALS typically decline by one point per month on the ALSFRS-R. That said, forced vital capacity did weaken by 11.5 percent relative to baseline, a dip that was still less than what the placebo group lost during the first four months of the trial.

These are seemingly positive results. Still, commentators expressed caution about their interpretation. Besides the small size, uneven randomization, and large dropout, Richard Bedlack of Duke University in Durham, North Carolina, particularly noted that the authors only analyzed data from people who stayed to the end, instead of running an intent-to-treat analysis that would include everybody who enrolled. “By analyzing only those patients remaining in the study at each time point, biases may have been created,” Bedlack wrote. “Finally, three of the authors received salary support and stock options from Elysium Health, the company that owns EH301. This creates a potential for bias and conflict of interest,” he noted, (full comment below.)

Jonathan Glass of Emory University School of Medicine, Atlanta, raised similar concerns. “The data shown here seem extraordinary in that the active group seemed to actually improve over the four-month trial period,” he wrote. “If true, fantastic! But it reminds me a bit of the Italian trial of lithium—amazing results in a small cohort and completely negative results in a true placebo-controlled trial.” (Full comment below.) Glass, Bedlack, and other commenters said they would like to see larger, multicenter trials on EH301.

Elysium Health is embroiled in an intellectual property battle with ChromaDex, its former supplier of NR and holder of multiple patents covering NR production. Elysium Health twice attempted, in vain, to challenge ChromaDex’s patents, and ChromaDex recently announced plans to sue Elysium Health for patent infringement (see news report; news report). According to Elysium Health’s website, the company now manufactures its own supply of NR, in a formulation it claims does not infringe on ChromaDex’s patents (see statement). ChromaDex also claims Elysium Health still owes it $3 million for a final shipment of NR in 2016, and has accused the company of stealing trade secrets (see news report). 

Both companies have stacked their scientific advisory boards with prestigious scientists. Still, critics have pointed out that no human studies exist to support claims that the compounds promote healthy aging or extend lifespan (see news report). 

A number of studies have drawn connections between NAD+, sirtuins, and cancer, with some studies suggesting these anti-aging factors give cancer cells an edge, and others concluding the opposite (Gujar et al., 2016; Yaku et al., 2018; Islam et al., 2019). 

According to a study published February 18 in Nature Cell Biology, NAD+ drives a pro-inflammatory phenotype in senescent cells, which has a tumorigenic effect. The researchers, led by Rugang Zhang at the Wistar Institute in Philadelphia, reported that supplementation with NAD+ precursors promoted cancer growth in animal models. “A dietary NAD+-augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects,” they write in the paper. While scientists agree that broad aging indications urgently require human research on long-term safety, cancer risk is less of a concern in ALS, where a majority of patients succumb to the disease within four years of onset (Chiò et al., 2009). 

Against this backdrop, both Elysium Health and ChromaDex are testing whether their supplements might work as treatments for neurodegenerative disease. In March 2018, Elysium Health announced that the U.S. Food and Drug Administration had granted EH301 orphan drug status to treat ALS, based on preliminary data from the current trial. Their press release also announced that a larger Phase 2 trial—in collaboration with the Mayo Clinic in Rochester, Minnesota—would begin at the end of 2018. Efforts to reach Eric Sorenson, the Mayo neurologist quoted in the release, for comment were unsuccessful. Last August, the Mayo Clinic entered into an exclusive license agreement with Elysium Health. That press release states that the “Mayo Clinic has a financial interest in Elysium Health.”

ChromaDex is currently testing its NR product, Tru Niagen, for effects on mood, sleep, and cognition in 40 older adults in an ongoing trial in Boca Raton, Florida (see clinicaltrials.gov). A trial testing Tru Niagen in people with Alzheimer’s disease is slated to begin later this year at Massachusetts General Hospital in Boston. Clinicaltrials.gov currently lists 33 studies for nicotinamide riboside, for conditions ranging from metabolic and mitochondrial diseases to Parkinson’s, muscle injury, and sarcopenia.—Jessica Shugart

Comments

  1. The data shown here seems extraordinary in that the active group seemed to actually “improve” over the four-month trial period. If true, fantastic! But it reminds me a bit of the Italian trial of lithium—amazing results in a small cohort and completely negative results in a true placebo-controlled trial.

    Also, this is not a new target, and it is surprising that this company has come up with a magic bullet. Elysium Health is a bit of a controversial company, selling anti-aging pills, which I believe are at least related to EH301, over the internet. Maybe it’s all true, and I really hope it is, but I would like to see a larger multicenter trial done by another, independent group.

    View all comments by Jonathan D. Glass

  2. It is very remarkable and encouraging to see that the investigators report a clinical improvement in the ALS patients and not just a slowing of progression of this devastating disease. Findings like these urgently require independent confirmation.

    One has to keep in mind that this is a very small cohort at a single center, and such a trial design is very vulnerable to statistical outliers and other biases. Therefore an independent confirmation with a more robust study design that includes more patients, multiple centers, and ideally objective biomarkers such as neurofilaments and possibly a dose response is required before firm conclusions on the efficacy of this promising approach can be drawn.

    View all comments by Patrick Weydt

  3. I do think the data support proceeding to another study. I also encourage the company and investigators to develop biomarkers to measure the biological effects of treatment.

    It is, of course, exciting to see positive results in an ALS trial. The caveats—which are important—include that the study was very small, duration of follow-up short in the double-blind period, and that about one-third of people stopped treatment early. I couldn’t tell from paper how drop-outs were handled in the analysis.

    Because ALS is such a heterogenous disorder, results from small studies can sometimes not bear out when a larger confirmatory study is done (e.g., lithium and dexpramipexole studies). The data here is encouraging but not definitive. It would be important to move forward expeditiously, though, for a confirmatory trial in larger group of participants and for longer duration.

    View all comments by Merit Cudkowicz

  4. This was a randomized, placebo-controlled, double-blinded trial of EH301 (which elevates NAD+ and activates sirtuins) in patients with ALS. The authors concluded that that the drug was safe and associated with significant improvements, not just slowing of decline, in several important outcome measures including ALSFRS-R, MRC manual muscle testing, and forced vital capacity. Placebo-treated patients declined on all these measures at a rate consistent with that seen in other published trials. The authors call for a larger Phase 2 trial of EH301.

    There are several problems with interpreting the results of this study. First, the sample size was quite small (only 15 patients assigned to drug and 17 assigned to placebo). Following randomization, the two groups were unfortunately not well-balanced in disease duration and starting ALSFRS-R or starting MRC, meaning it is not clear how comparable they were even before they received any treatment. The duration of follow-up in the randomized trial was short (four months). In spite of this short duration, there were a surprising number of patients who did not complete the study in each group (5/15 in the drug-treated and 7/17 in the placebo-treated group).  We are told that none of the dropouts (or adverse events) were related to treatment, but no explanations were given for the “hepatitis” or “profound mental depression” that caused two drop-outs in the EH301 group. It does not appear that the data in this study were analyzed via “intention to treat.” By analyzing only those patients remaining in the study at each time point, biases may have been created. Finally, three of the authors of this study received salary support and stock options from Elysium Health, the company that owns EH301. This creates a potential for bias and conflict of interest.In spite of these problems I agree that these results warrant a follow-up trial. I hope that this new trial will have a larger sample size, longer duration, be clearer about the causes of adverse events, and utilize intention to treat analyses. It would also be nice if the follow-up study measured NAD+ or sirtuin activation and utilized different dosages of EH301 so we could see whether there is any dose-response curve on any of the clinical outcomes or biomarkers.

    One final question many patients will have is how EH301 compares to the over-the-counter supplement called Basis currently being sold by Elysium Health, which ALSUntangled reviewed in 2017. Hopefully Elysium Health will shed some light on this in the near future so patients can make an informed decision on whether they now want to try Basis for their ALS. 

    View all comments by Richard Bedlack

  5. This pilot study, although small, is very exciting. The fact that many of the patients taking the drug did not show decline in several clinical endpoints measured in the study is promising. The preclinical data available in cell culture models suggest that the two components of EH301 have the potential to engage multiple mechanisms that could be neuroprotective in the context of ALS pathology. Overall, this seems to be a promising, and reasonably safe, therapeutic approach for ALS treatment. Further confirmation in a bigger cohort will be necessary in order to establish its effectiveness to slow disease progression in patients with ALS.

    View all comments by Marcelo Vargas

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References

Paper Citations

  1. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2876-81. Epub 2015 Feb 17 PubMed.
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  4. Körner S, Böselt S, Thau N, Rath KJ, Dengler R, Petri S. Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS?. Neurodegener Dis. 2013;11(3):141-52. Epub 2012 Jul 10 PubMed.
  5. Dellinger RW, Santos SR, Morris M, Evans M, Alminana D, Guarente L, Marcotulli E. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis. 2017;3:17. Epub 2017 Nov 24 PubMed.
  6. Gujar AD, Le S, Mao DD, Dadey DY, Turski A, Sasaki Y, Aum D, Luo J, Dahiya S, Yuan L, Rich KM, Milbrandt J, Hallahan DE, Yano H, Tran DD, Kim AH. An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):E8247-E8256. Epub 2016 Dec 7 PubMed.
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  8. Islam S, Abiko Y, Uehara O, Chiba I. Sirtuin 1 and oral cancer. Oncol Lett. 2019 Jan;17(1):729-738. Epub 2018 Nov 16 PubMed.
  9. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG, Eurals Consortium. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):310-23. PubMed.

External Citations

  1. Phase 1 trial
  2. news report
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  4. website
  5. statement
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  8. press release
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  10. clinicaltrials.gov
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Further Reading

Papers

  1. Bedlack R, ALSUntangled Group. ALSUntangled 42: Elysium health's "basis". Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):317-319. Epub 2017 Sep 18 PubMed.

Primary Papers

  1. de la Rubia JE, Drehmer E, Platero JL, Benlloch M, Caplliure-Llopis J, Villaron-Casales C, de Bernardo N, AlarcÓn J, Fuente C, Carrera S, Sancho D, GarcÍa-Pardo P, Pascual R, JuÁrez M, Cuerda-Ballester M, Forner A, Sancho-Castillo S, Barrios C, Obrador E, Marchio P, Salvador R, Holmes HE, Dellinger RW, Guarente L, Estrela JM. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Feb;20(1-2):115-122. Epub 2019 Jan 22 PubMed.

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