Because riluzole has low aqueous solubility, Brain Trust Bio developed and patented a novel IT formulation of riluzole to test its effectiveness. When introduced intrathecally in animals, a well-characterized and safe route of administration not previously attempted with this drug. Riluzole is the only FDA-approved treatment known to improve survival in patients with amyotrophic lateral sclerosis (ALS), but the effect is modest. Oral dosing creates fluctuating tissue-levels of the drug, providing inconsistent neuroprotection. Moreover, as the disease progresses, the expression of drug efflux transporters at the blood-brain barrier increases and drives a progressive resistance to CNS riluzole entry, reducing the drug net tissue concentration over time. Finally, riluzole dosage is limited by the drug’s impact on hepatic functions, and some patients poorly tolerate the asthenia that can be induced by the drug’s effects on the brain and may discontinue treatment. Additionally, oral riluzole can impair cognitive function. Our team postulated that intrathecal (IT) infusion of low doses of riluzole could elevate drug spinal cord (SC) concentrations without a significant increase in systemic or brain exposure relative to that achieved with oral dosing.

Dogs were implanted with Medtronic Synchromed II pumps and Ascenda catheters. One group received continuous intrathecal (IT) infusion. A second group received only oral doses of riluzole. A third group received a combination of IT and oral riluzole. IT administration began with five days of continuous infusion at escalating doses (n=6).

Blood was collected on the fifth day after infusion initiation for each dose tested. Necropsy was performed after the fifth day of infusion at the highest dose. In the oral group, a riluzole dose equivalent to the approved 50 mg BID dose in humans was administered for two weeks (n=4) and blood was collected one hour after the last oral dose.

Intrathecal (IT) infusion of riluzole provided minimal concentration in the blood when administered alone and did not increase the blood levels provided by oral riluzole when given as a combination treatment. Bioanalysis of riluzole in the nervous system showed IT infusion alone or in combination with oral administration was able to increase SC concentrations as much as ten-fold above those provided by oral administration only.

In contrast, brain concentrations of riluzole were much lower in animals receiving IT riluzole than observed in dogs receiving the drug orally and did not increase when IT infusion and oral dosing were combined. Combinations of oral and IT Riluzole administration were well tolerated over a five-day infusion period and did not induce any adverse events or significant clinical pathology at any dose tested.

Continuous IT administration of riluzole when combined with oral administration can increase SC concentrations of riluzole above those achievable with oral therapy, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects on the brain. Therefore, IT riluzole infusion, when used in conjunction with oral therapy, may safely enhance lower motor neuron neuroprotection and improve the survival benefit of the drug through enhanced SC delivery, and, with careful selection of IT doses, could be implemented in patients with ALS.

Development of Intrathecal Riluzole: A New Route of Administration for the Treatment of Amyotrophic Lateral Sclerosis Patients – Juanmarco Gutierrez, MD, MS; Thais Federici, PhD; Bethany Peterson, PhD; Ray Bartus; Alexandre Bétourné, PhD; Nicholas M. Boulis, MD

Neurosurgery, Volume 63, Issue CN_suppl_1, 1 August 2016, Pages 193