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Researchers, therapists, patients, and caretakers came together 5-7 December 2012 for the 23rd Annual Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Disease in Chicago, Illinois. They shared a common goal of finding a cure. “We look forward to hearing the word ‘survivor,’” said Wendy Abrams, executive director of the Les Turner ALS Foundation in Skokie, Illinois, which hosted the conference. Toward that end, early results from Phase 1 and 2 trials for several treatments offered a glimmer of hope, but more immediately, two large studies disappointed (see below).

Researchers also puzzled over one bit of good news for patients, namely that placebo controls are performing better than expected in trials. In the unsuccessful Phase 2/3 study for olesoxime (see ARF related news story), presented by Timothée Lenglet of Pitié-Salpêtrière Hospital in Paris, France, placebo survival over 18 months approached 70 percent—compared to 50 percent over a median of 18 months in a 1996 study (Lacomblez et al., 1996). In another trial, one-tenth of untreated controls showed no change on the ALS Functional Rating Scale (ALSFRS), a common trial outcome measure, over six months. Lenglet suggested this might be because their symptoms are being better managed nowadays. In addition, simple alterations to diet or activities might have a noticeable impact over time, suggested Angela Genge of the Montréal Neurological Institute and Hospital, Canada, in an interview with Alzforum. The findings echo a current trend in Alzheimer's trials, where placebo groups decline more gradually than has been seen in the past (see ARF related news story).

The slower decline in patients is not just academic. Modern clinical care and increased survival may underlie the recent failures of trials for ceftriaxone and olesoxime, suggested Benjamin Brooks of the University of North Carolina School of Medicine, Charlotte, in an e-mail to Alzforum. Careful analysis may show that the disease trajectory researchers predict at the start of a trial is too steep, he suggested. “If that is true, then we are at a point where longer trial times are necessary, similar to the early days of breast cancer treatment in the past,” Brooks wrote.

In addition, changing placebo numbers could affect the use of historical controls in trials. That practice was approved for the first time by the Food and Drug Administration in 2011 to amplify the power of an ALS trial for sodium chlorite, a mineral formulation also known as NP001. Robert Miller of the Forbes Norris MDA/ALS Research Center in San Francisco, California, who presented the trial results at the meeting (see below), hoped the use of historical controls would make recruitment easier. Since amyotrophic lateral sclerosis progresses quickly, some patients are reluctant to join a trial when they risk being assigned a placebo. Coupled with the rarity of ALS, this can make it difficult to fill a trial. By tapping old records for control data, researchers performing Phase 1 or 2 studies should be able to reduce the control populations they need, the theory goes, boosting participants' chances of receiving active drug and improving recruitment (see ARF related news story).

Given the lengthening survival of control subjects, Genge considers use of historical controls a mistake. Historical data may not reflect the current state of ALS progression, Genge said. Miller agreed in an e-mail to Alzforum that people with ALS are living longer, but countered that rates of decline in the ALSFRS have remained steady (Miller et al., 2011). He noted the historical approach has received support from the FDA as well as other scientists (Donofrio and Bedlack, 2011).

Large Phase 3 Studies Fall Flat
Long-term hopeful signs notwithstanding, ALS researchers in Chicago had to deal with two major setbacks immediately before them. They discussed disappointing results from two recent Phase 3 studies. In addition to the olesoxime report, Merit Cudkowicz described final results of a Phase 3 study of ceftriaxone. This drug upregulates the astrocyte excitatory amino acid transporter 2, which recycles synaptic glutamate to counteract excitotoxicity in ALS (Rao and Weiss, 2004). This trial used an adaptive design, meant to move seamlessly from Phase 1 through 3 as long as the data indicated it should continue (see ARF related news story). The study had reached Phase 3, with 513 subjects enrolled, when the organizers at the Northeast ALS Consortium in Charlestown, Massachusetts, decided to call it quits because it did not look as if the drug was working. There was no improvement in survival, ALSFRS score, or lung capacity, Cudkowicz reported.

Since the ALS/MND meeting, Biogen Idec of Weston, Massachusetts, announced on 3 January 2013 that dexpramipexole, a mitochondrial modulator similar to olesoxime, also failed to meet its endpoints in a Phase 3 study. The company released top-line results showing that none of the outcome measures—primary and secondary endpoints and subgroup analyses—of the 943-patient trial in 11 countries showed efficacy (see press release). The news was particularly disappointing because the trial was well designed and Phase 2 results seemed promising, said Steven Perrin of the ALS Therapy Development Institute in Cambridge, Massachusetts, who was not involved in the study. Phase 2 results indicated that dexpramipexole slowed decline on the ALSFRS by 31 percent (see ARF related news story and Cudkowicz et al., 2011). Perrin noted that the ceftriaxone trial also had encouraging Phase 2 data. The lesson here, he said, is that Phase 2 studies should enroll more than 100 patients in order to give clear results that can support a go or no-go decision on a Phase 3 trial.

Phase 2 Trials Offer Hope for Treating Disease, Symptoms
NP001, as Miller described, presented encouraging Phase 2 results that reached statistical significance once he added the historical data. The rationale for using this drug is based on the link between ALS and neuroinflammation (see ARF related news story; ARF news story; ARF news story), which suggests that dampening the immune response could slow disease. NP001 has been reported to reorient toxic inflammatory macrophages that invade the central nervous system into normal, protective ones (Zhang et al., 2005). The 12-month, multisite study of 136 participants with early-stage ALS, sponsored by Neuraltus Pharmaceuticals, Inc., of Palo Alto, California, wound down two months ago. In Chicago, Miller shared data from the first six months.

In a double-blind trial, patients were randomly assigned to groups that received placebo, or 1 or 2 milligrams of NP001 per kilogram of body weight. They received intravenous infusions in short series: five days in a row for initial treatment, followed by three days in a row once a month for five months thereafter. This treatment was safe and well tolerated, said Miller, though the drug caused pain at the infusion site. This was a concern, as it may have unblinded some participants.

The researchers tracked rate of decline on the ALSFRS compared to a person’s rate of decline before starting treatment. Those on the higher dose of NP001 deteriorated 13 percent more slowly than did controls. This was not statistically significant, Miller said. Looking at the data a different way, and adding in historical controls, Miller found that the drug crossed the significance threshold for some patients. While 27 and 19 percent of those on the high- and low-dose treatment, respectively, remained stable during the trial, 11 percent of those in the placebo group retained baseline function.

Neuraltus plans to start a Phase 3 study this year. Despite the experimental nature of NP001, some people with ALS have started taking sodium chlorite outside the trial (see Wall Street Journal article). Physicians do not recommend this. Miller noted that swallowing the medication would not work; it must be injected to be absorbed properly.

Scientists are considering other immunomodulators besides NP001. In Chicago, Perrin discussed his hopes for Gilenya®, the trade name for fingolimod. Made by Novartis, this fungal derivative locks up T cells in the lymph nodes and prevents them from circulating. Already approved for multiple sclerosis, Gilenya increases survival in ALS mice by a week—a meaningful amount given the severity of the model, Perrin said. ALS-TDI has been planning a Phase 2a safety trial since early 2012 (see ARF related news story). Filing paperwork with the FDA took longer than planned, Perrin told Alzforum, but he expects to hear back from the FDA later in January and to enroll patients before April. Neil Cashman of the University of British Columbia in Vancouver, who attended the Chicago meeting, told Alzforum he was excited about the Gilenya studies because the role of the immune system in ALS has spent a long time on the back burner. “Finally, this orphan hypothesis is getting some play,” he said.

Although the immune-system drugs aim to extend survival, that is not the only outcome people with ALS are seeking, noted Genge in a satellite session on clinical trial design. They also want to maintain muscle strength and function. Jeremy Shefner of the State University of New York Upstate Medical University in Syracuse reported on a drug aiming to amp up muscle power. Tirasemtiv has been through three Phase 2a studies so far, each asking a specific question as researchers fine-tuned the dosage. Developed by Cytokinetics, Inc., of South San Francisco, tirasemtiv, aka CK-2017357, was designed to counter the effects of muscle atrophy that occurs as input from damaged motor neurons wanes. It works by tightening the interaction between troponin and its inhibitor, calcium; the ion keeps the contraction-blocking troponin away from actin and myosin fibers (Russell et al., 2012).

Three Phase 2a studies, examining a single dose, daily doses, or escalating doses, indicated that tirasemtiv enhanced muscle strength and endurance. Although it caused dizziness when people started taking the medication, that went away with time and the medicine was generally well tolerated (see ARF related news story and Shefner et al., 2012). At the conference, Shefner focused on the second trial. In addition to testing three doses of tirasemtiv, that trial examined interactions between the muscle enhancer and riluzole, the only FDA-approved drug for ALS. Riluzole is metabolized by cytochrome P450 1A2, but tirasemtiv inhibits that breakdown pathway, leaving researchers concerned that the new treatment would raise concentrations of riluzole.

Shefner described that, of the 49 people with ALS who participated in the Phase 2a study, 24 did not use riluzole while the others took 50 milligrams daily—half the normal dose. The goal was to achieve the appropriate plasma level of riluzole despite blocking its metabolism. Each subject group was then split into those who received tirasemtiv or a placebo for two weeks. Patients on the drug received escalating doses, starting at 250 mg daily and going up to 500 mg a day. All doubled riluzole levels in plasma. Shefner concluded that their approach, halving the riluzole, worked to maintain the desired concentration for people taking tirasemtiv.

Shefner told Alzforum in an e-mail that tirasemtiv development progresses apace. A multicenter Phase 2b trial now underway will enroll approximately 400 people, half to receive placebo and half to receive tirasemtiv for three months. People who are on riluzole at the start of the trial will take the reduced dose during the study.

Phase 1 Candidates Prove Safe
On separate drugs, two Phase 1 studies offered safety results. Tim Miller of Washington University in St. Louis, Missouri, reported work from Isis Pharmaceuticals, Inc., of Carlsbad, California. Isis is developing an antisense oligonucleotide therapy to dampen expression of the mutant superoxide dismutase 1, which is responsible for 13 percent of familial ALS cases, Miller said.

A multisite trial of ISIS 333611 took place in four stages. Each included two people on placebo, plus six receiving the oligonucleotide via intrathecal infusion. The researchers started with a dose of 0.15 milligrams and raised it with each stage, to 0.5, 1.5, and 3 mg. The infusion was safe and tolerable; in fact, some subjects returned to complete two or even three stages of the study. Most adverse events were related to the intrathecal delivery; the worst were headaches from leaking cerebrospinal fluid, suffered by one-third of participants. Researchers are now redesigning the oligonucleotide to make it more potent and safer, Miller said.

Jonathan Glass of Emory University in Atlanta described the latest findings from a stem cell trial. Glass reported on three new patients who have been treated, adding to the 12 previously described (Riley et al., 2012; see also ARF related news story). Surgeons injected spinal cords of the recipients with half a million or more neural stem cells, derived from fetal spinal cord by Neuralstem Inc., in Rockville, Maryland. Previously, the team injected cells into the lumbar region; in Chicago, Glass reported on some of the most recent patients who received cervical injections.

In this Phase 1 trial, the treatment appeared safe. Since the surgeries began in 2010, six patients have died—five from ALS and one from heart problems. The deaths were unrelated to the treatment, Glass said. Autopsies revealed that the stem cell injection sites had healed, and donor DNA was found in the autopsied spinal cords, Glass reported.

Most patients in Neuralstem's trial continued their downward trajectory, but there was one exception. Glass reported on a patient "who needed a walker and a cane before surgery, and was dancing with his wife at a wedding after it” (see article in Crain’s Detroit Business). The researchers do not understand why this man improved so much, and his result is a topic of intense discussion, Glass said. The team is awaiting FDA approval to double the number of stem cells implanted. Genge expressed doubt about stem cell therapies, suggesting that any benefit might have resulted from the immunosuppressant drugs the participants received, that is, their ability to quell neuroinflammatory pathology.

For its part, preclinical research offers reason to hope neural stem cell transplants could eventually work (see Teng et al., 2012). Researchers led by joint first authors Yang Teng of Brigham and Women’s Hospital, and Susanna Benn of Massachusetts General Hospital, both in Boston, meta-analyzed data from 11 independent, double-blinded experiments. In each, researchers implanted neural stem cells from the same cell bank into mice expressing mutant human superoxide dismutase 1. The transplanted cells slowed disease onset and progression, and prolonged survival, concluded the researchers. The work was supervised by senior authors Robert Brown of the University of Massachusetts Medical School in Worcester; Evan Snyder of the Sanford-Burnham Medical Research Institute in La Jolla, California; and Yang Teng. More stem cells yielded longer survival. Some animals passed the one-year mark—a significant effect in an animal model that lives but a few months. The implants did not replace degenerating neurons, but supported endogenous ones by making trophic factors and stifling inflammation, suggested the authors. Stem cells were particularly effective when they settled across a broad area, or in regions that control survival functions such as breathing.

Overall, scientists in Chicago were optimistic about future ALS trials. “Some may look at recent failures and be discouraged,” wrote Richard Bedlack of the Duke ALS Clinic in Durham, North Carolina, in an e-mail to Alzforum. Thanks to advances in genetics and biomarkers, and a list of potential target pathways, “I think this is a time of unprecedented hope and excitement in ALS research” (see full comment, below).

“People’s expectations have to be reasonable,” added Genge. If any of the current crop of experimental drugs manages to extend life by even a year, then that would indicate which pathways are worthy targets for further drug development, she noted. And if more than one adds even months to survival, then researchers can start building cocktails to look for additive effects.—Amber Dance


  1. The question remains whether the true information from the recently failed clinical trials of ceftriaxone and olesoxime lies in the fact that the overall clinical care of patients with ALS has significantly altered, at this point in time, disease trajectory for patients. I believe a careful analysis of these "failed" trials might suggest that the disease trajectory over the time in the clinical trial may be different from that projected at the original design of the clinical trial. If this is true, then the good news might be that we are at a point where longer trial times are necessary, similar to the early days of breast cancer treatment in the past.

  2. Some may look at recent failures and be discouraged. In contrast, I think this is a time of unprecedented hope and excitement in ALS research. Thanks in large part to advances in genetics, we understand the disease better than ever. We can now identify a genetic cause for ALS in 15-20 percent of our patients. We are starting to identify subtypes of ALS, which I personally believe is necessary for us to find disease-modifying therapy that makes a large difference. For example, we have genetic subtypes which may respond to antisense oligomers. We have overactivation in the co-stimulatory pathway in a subset of patients with sporadic ALS, which should soon allow us to target this subset with specific immunomodulators. We have surrogate biomarkers, such as this co-stimulatory pathway, that can at least tell us whether we are hitting our targeted mechanism with the drug and dosing regimens we choose, and we have evaluative biomarkers such as electrical impedence myography that allow us to follow patients more efficiently (meaning we should be able to do smaller, shorter duration studies). We have more potential ALS targets than ever before (transcription, translation, protein aggregation, mitochondria, neuroinflammation, axonal sprouting, muscle contraction), and creative ways to manipulate these. We have novel and unique partnerships with patients to identify promising drugs and supplements that warrant further and more traditional study (such as ALSUntangled and patient-led trials on PatientsLikeMe), and to tackle barriers to enrollment in our studies (such as the ALS Clinical Research Learning Institute). We have never been closer to finding meaningful ALS drug therapies than we are today.

  3. The multimodality of transplanted neural stem cells may also be a feature of endogenous neural stem cells; thus, factors that promote endogenous neural stem cell generation may have comparable benefit.

    View all comments by Roberta Diaz Brinton

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News Citations

  1. News Brief: ALS Drug Olesoxime Fails in Phase 3 Trial
  2. Chicago: Studies Probe Diminishing Placebo Decline, Part 1
  3. NEALS: In ALS Trials, One Design Does Not Fit All
  4. Research Brief: Dexpramipexole Results Look Promising for ALS
  5. Peripheral Innate Immunity—Not So Peripheral to ALS?
  6. ALS: T Cells Step Up
  7. Microglia in ALS: Helpful, Harmful, or Neutral?
  8. ALS: Speeding Ahead With Trial of Immunomodulator
  9. More Power! Mechanisms of a Muscle-Maxing Medicine
  10. Honolulu: So Far, So Good in Stem Cell Safety Study for ALS

Paper Citations

  1. . Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25;347(9013):1425-31. PubMed.
  2. . Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology. 2011 Sep 6;77(10):973-9. PubMed.
  3. . Historical controls in ALS trials: a high seas rescue?. Neurology. 2011 Sep 6;77(10):936-7. PubMed.
  4. . Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004 Jan;27(1):17-23. PubMed.
  5. . The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Dec;17(12):1652-6. PubMed.
  6. . Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2005 Feb;159(1-2):215-24. PubMed.
  7. . Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med. 2012 Mar;18(3):452-5. PubMed.
  8. . Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012 Sep;13(5):430-8. PubMed.
  9. . Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes. Neurosurgery. 2012 Aug;71(2):405-16; discussion 416. PubMed.
  10. . Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med. 2012 Dec 19;4(165):165ra164. PubMed.

Other Citations

  1. Read a PDF of the entire series.

External Citations

  1. Phase 2/3 study
  2. trial
  3. Phase 3 study
  4. press release
  5. 12-month, multisite study
  6. Wall Street Journal article
  7. Phase 2a study
  8. Phase 2b trial
  9. multisite trial
  10. stem cell trial
  11. article

Further Reading


  1. . New considerations in the design of clinical trials for amyotrophic lateral sclerosis. Clin Investig (Lond). 2011 Oct;1(10):1375-1389. PubMed.
  2. . Enhancing clinical trials in neurodegenerative disorders: lessons from amyotrophic lateral sclerosis. Curr Opin Neurol. 2012 Dec;25(6):735-42. PubMed.
  3. . Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2012 Mar;21(3):297-320. PubMed.
  4. . Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole. Ther Clin Risk Manag. 2012;8:359-66. PubMed.
  5. . Future therapeutical strategies dictated by pre-clinical evidence in ALS. Arch Ital Biol. 2011 Mar;149(1):169-74. PubMed.

Primary Papers

  1. . Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med. 2012 Dec 19;4(165):165ra164. PubMed.