Background

Riluzole is the first FDA-approved medication for amyotrophic lateral sclerosis. It has been marketed in dozens of countries around the world since the late 1990s, and generic versions became available in the U.S. in 2013. Adverse events include blurred vision, difficulty breathing, weakness, dizziness, gastrointestinal discomfort, and others (see Mayo Clinic Drug Information).

Riluzole's mechanism of action is not fully understood, but it has been shown repeatedly to modulate glutamate neurotransmission by inhibiting both glutamate release and postsynatpic glutamate receptor signaling. It also has been reported to inhibit voltage-gated sodium channels and to be neuroprotective by suppressing astrocytosis (Martin et al., 1993, Hubert et al., 1994, Carbone et al. 2012).

Findings

Riluzole was approved for ALS because in several clinical trials it modestly extended survival or time to insertion of a breathing tube. Initial clinical trial reports of a slowing of muscle deterioration or symptomatic benefits were not corroborated in subsequent studies (see Bensimon et al., 1994; Lacomblez et al 1996). Pharmacoeconomics research has challenged the cost-effectiveness of riluzole treatment of ALS (Messori et al., 1999).

Riluzole completed Phase 3 clinical trials for the treatment of both Parkinson's and Huntington's diseases. Both programs had negative results and were discontinued (Bensimon et al., 2009; Landwehrmeyer et al., 2007).

Because glutamate-mediated excitotoxicity has been implicated in Alzheimer's disease, a rationale is seen to evaluate whether riluzole can slow neuronal loss and cognitive dysfunction in this disease. Starting in April 2013, a Phase 2, six-month, investigator-initated trial at Rockefeller Univeristy started testing riluzole in 48 patients with mild Alzheimer's who were already taking the cholinesterase inhibitor donepezil. Expected to run until 2017, this study will assess changes in cognitive function, changes in brain concentration of the neuronal viability marker N-acetylaspartate (NAA) as measured by magnetic resonance spectroscopy (MRS), and changes in brain glucose metabolism as measured by FDG-PET. Twenty-four patients will receive riluzole, and 24 will receive placebo tablets made at the Rockefeller University pharmacy.

In addition, riluzole has been, or is being, investigated for a variety of neurologic and neuropsychiatric conditions in various investigator-initiated academic trials. These include autism, ataxia, Fragile X, multiple sclerosis, spinal cord injury, depression and bipolar disease, obsessive-compulsive disorder, spinal muscular atrophy, and others. Riluzole is also being tested against melanoma and other forms of cancer.

Clinical Trial Timeline