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.