Researchers announced on 14 February 2012 that they are planning to start a clinical trial this year to treat amyotrophic lateral sclerosis with Gilenya, an immunomodulator already approved to treat multiple sclerosis. The Amyotrophic Lateral Sclerosis Therapy Development Institute (ALS-TDI) in Cambridge, Massachusetts, started pursuing this idea in mice in late 2010, after discovering that immune pathways are key to the disease. With only 18 months between the idea’s inception and the start of a clinical study, “this is the definition of bench to bedside,” said Steven Perrin of the ALS-TDI.

Gilenya is the trade name for fingolimod. The drug removes lymphocytes from circulation. The hope is that regulating the immune system in this way will slow the progression of ALS, said James Berry of Massachusetts General Hospital (MGH), who is co-principal investigator on the study with Merit Cudkowicz, also at MGH. However, the primary goal for the upcoming Phase 2a and 2b trials will be to determine the drug’s safety profile and appropriate dose for people with ALS. Perrin suspects that a lower dose than is used for multiple sclerosis (MS) could be effective. The Northeast ALS Consortium, of which Cudkowicz is co-chair, will manage the study (see ARF related news story). The ALS-TDI is cooperating with Novartis, maker of Gilenya, to plan the trial, although Novartis is not an official partner in the study.

The immune system has been repeatedly linked to ALS, although its precise role in the disease remains muddled (see ARF news story; ARF related news story on Chiu et al., 2009). “Immune activation in ALS is multifaceted, with both beneficial and harmful aspects,” noted Isaac Chiu of Harvard Medical School, who is not involved in the trial, in an e-mail to ARF (see full comment below). Gilenya interacts with the sphingosine-1-phosphate (S1P) receptor on lymphocytes; on binding to the receptor, it prevents the lymphocytes from exiting lymph nodes and circulating throughout the body (Rosen et al., 2003; Baumruker et al., 2007).

Multiple sclerosis is an autoimmune disease in which the body attacks nerves’ myelin sheaths. The concept behind fingolimod is to sequester the lymphocytes and prevent that immune response. Gilenya treatment minimizes the relapse rate in people with MS (Kappos et al., 2010). It was approved by the Food and Drug Administration in the fall of 2010 as the first oral medicine for MS. Berry suspects that knocking out circulating lymphocytes could help in ALS, but said it remains to be seen whether one or another subtype of immune cell is most relevant to the drug’s effects in ALS.

“This will be the first trial specifically targeting peripheral immune cells, so I eagerly await their results,” Chiu wrote. However, he cautioned, “if Gilenya is purely blocking T cells from entering the central nervous system, we would be careful as Stan Appel’s and our work has shown that, at least in ALS mice, T cells are mainly neuroprotective” (see Beers et al., 2008; Chiu et al., 2008). Monitoring trial participants for adverse effects will be crucial, Berry and Perrin acknowledged. Gilenya’s known side effects include a slowed heart rate, shortness of breath, and increased risk of infection. One person died after starting the drug, the FDA reported in December. Perrin thinks the possible benefits outweigh the potential hazards: “There is no effective treatment for ALS out there and patients are willing to take more risk, so the safety profile of this drug does not frighten me at all from a patient perspective, as long as we do it right,” he said. For example, researchers will have to monitor participants for several hours after they receive the first dose, as is done with Gilenya for MS.

Gilenya is one of two treatments with which the ALS-TDI hopes to start trials this year. The Institute initially got into the immune system field when they discovered that blocking the interaction between CD40 on T cells and its ligand CD40L on antigen-presenting cells extended lifetime in ALS model mice (see ARF related news story on Lincecum et al., 2010). The ALS-TDI partnered with Bioden Idec of Cambridge, Massachusetts, to develop an antibody that interferes with CD40L. However, the team expects this project to take a while, needing time to make a human version of the antibody and run a Phase 1 trial, Perrin said, so the researchers in parallel tested a handful of medicines they hoped would have similar immunomodulatory effects but a shorter development time.

Like the CD40 antibody, Gilenya reduced the number of circulating lymphocytes and diminished macrophage attacks on peripheral nerves in ALS model mice overexpressing mutant human superoxide dismutase 1, which causes familial ALS. The single Gilenya dose that the ALS-TDI tested in those mice extended lifespan by a week. The ALS-TDI has not yet published these preclinical data. Given that Gilenya is already FDA approved, Institute scientists decided to go straight to a human study, Perrin said.

The researchers have not finalized their study design, but it will likely include two phases. The first, Perrin said, will be a Phase 2a trial with perhaps 30-50 volunteers to make sure the drug is safe for people with ALS. Following that, he envisions a larger, Phase 2b of approximately 250 people.

Since Gilenya is already available, it is possible that people with ALS would prefer to get it themselves, rather than risk ending up on the placebo arm of an experiment (see ARF related news story). This has happened before with minocycline and lithium, which some patients rushed to obtain before studies showed they were ineffective, even potentially harmful (Gordon et al., 2007; see ARF related news story on Aggarwal et al., 2010). Certainly some people will obtain Gilenya outside the trial, Perrin said, but he and Berry hope that off-label use will not slow recruitment. “I think physicians will be appropriately cautious about prescribing this drug off-label because it does have some side effects that need to be monitored,” Berry said. In addition, he noted, Gilenya is pricey. It costs approximately $50,000 a year, according to an article in the Wall Street Journal about the ALS-TDI trial, and since insurance companies are reluctant to fund off-label prescriptions, it could be difficult for interested patients to obtain the drug. Ultimately, “we do not know about [Gilenya’s] effectiveness in ALS; the only way to learn this is through a trial,” Berry said. His hopes are high: “The preclinical science is compelling…we really are very excited about this trial,” he told ARF.—Amber Dance.


  1. Immune activation in ALS is multifaceted, with both beneficial and harmful aspects. Therefore, we think specific pathways should be targeted instead of the whole response. One cautionary tale is the clinical trial of minocycline, which blocks microglia activation. It resulted in surprising acceleration of disease progression in patients.

    In the spinal cord, the motor neuron cell body is affected by microglia, the resident immune cell of the central nervous system (CNS). A large part of the microglia response may be beneficial to motor neurons. We found that microglia secrete protective factors, including insulin-like growth factor 1 and progranulin. At the same time, we have found that there is also an important peripheral immune component involving adaptive immune cells such as T cells and NK cells, humoral immunity (complement and antibodies), and innate immunity including circulating monocytes, which enter the peripheral nerves to become inflammatory macrophages. We believe these nerve-infiltrating macrophages may be inhibitory to motor axon growth that would in turn be harmful to motor neurons.

    Gilenya blocks S1P receptors, which are involved in lymphocyte migration from lymph nodes into the CNS. The drug has a beneficial effect in multiple sclerosis. What is interesting is that Gilenya also has an effect on monocyte-endothelial cell adhesion. It would be interesting to know if blocking S1P receptors prevents monocyte/macrophage entry into peripheral nerve tissues during ALS neurodegeneration. We hypothesize this action may be protective. If Gilenya is purely blocking T cells from entering the CNS, we would be careful as Dr. Stan Appel's and our work has shown that, at least in ALS mice, T cells are mainly neuroprotective. It would be interesting to see their preclinical data to determine which cell types are most affected in Gilenya treatment. Of course, the other very important point to keep in mind is that mutant SOD1 mice are not ALS patients, and therefore the type of immune response in patients may also differ from what we see in inbred mice.

    Overall, I am excited that ALSTDI and others are bringing neuroimmune interactions to the forefront of possible mechanisms involved in ALS, especially in the arena of therapeutic development. This will be the first trial specifically targeting peripheral immune cells, so I eagerly await their results to see the effects. I believe this will be an important element affecting motor neuron survival, especially in the symptomatic phase of disease.

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News Citations

  1. NEALS: Collaboration for a Cure to ALS
  2. ALS: T Cells Step Up
  3. Peripheral Innate Immunity—Not So Peripheral to ALS?
  4. ALS-TDI Scours Transcriptome, Targets CD40L
  5. NEALS: In ALS Trials, One Design Does Not Fit All
  6. Paper Alert: Lithium for ALS Deemed Futile, Study Stops Early

Paper Citations

  1. . Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20960-5. PubMed.
  2. . Egress: a receptor-regulated step in lymphocyte trafficking. Immunol Rev. 2003 Oct;195:160-77. PubMed.
  3. . FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Expert Opin Investig Drugs. 2007 Mar;16(3):283-9. PubMed.
  4. . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):387-401. PubMed.
  5. . CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63. Epub 2008 Sep 22 PubMed.
  6. . T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17913-8. Epub 2008 Nov 7 PubMed.
  7. . From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nat Genet. 2010 May;42(5):392-9. PubMed.
  8. . Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007 Dec;6(12):1045-53. PubMed.
  9. . Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. PubMed.

External Citations

  1. FDA reported
  2. superoxide dismutase 1
  3. Wall Street Journal

Further Reading


  1. . Autoimmunity in amyotrophic lateral sclerosis: past and present. Neurol Res Int. 2011;2011:497080. PubMed.
  2. . Neuroinflamm-aging and neurodegenerative diseases: an overview. CNS Neurol Disord Drug Targets. 2011 Aug 1;10(5):621-34. PubMed.
  3. . The Role of immune and inflammatory mechanisms in ALS. Curr Mol Med. 2011 Apr;11(3):246-54. PubMed.
  4. . Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16021-6. PubMed.
  5. . Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2005 Feb;159(1-2):215-24. PubMed.
  6. . Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):459-70. PubMed.