Earlier Start With Riluzole Could Help to Prolong Survival With ALS

'Strong argument' seen in study for prompt ALS diagnosis, treatment initiation

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Starting treatment with riluzole earlier in the disease course could prolong overall survival for people with amyotrophic lateral sclerosis (ALS), a database study suggests.

A one-year delay in beginning with riluzole may lower median survival by 1.9 months and a two-year delay by a median of 4.9 months, its researchers estimated.

The study, “Early initiation of riluzole may improve absolute survival in amyotrophic lateral sclerosis,” was published in Muscle & Nerve.

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Riluzole is the first therapy approved to treat ALS in the U.S., available as a tablet formulation called Rilutek. Currently, it is also the main ingredient of two other approved formulations: Exservan (riluzole oral film) and Tiglutik (riluzole oral suspension).

The exact mechanism by which riluzole treats ALS is unknown, but the medication is thought to help slow the deterioration of nerve cells by blocking the release of the chemical messenger glutamate.

Relatively large ‘incremental gains’ seen with earlier use of riluzole

Studies have consistently shown that riluzole can slow progression of ALS symptoms and improve survival, but some uncertainty remains as to the optimal timing of treatment.

“A re-analysis of original trial data implied that riluzole improved survival through prolonging advanced stages of disease … the trial cohort, however, did not include early … [stage] patients, precluding estimation of early benefits,” the researchers wrote, adding that later analyses “suggested early-stage as well as late-stage benefits of treatment, and greater benefit with shorter time from onset.”

To gain more insight, a U.S. research team analyzed data in PRO-ACT, a large database of ALS patients who participated in clinical studies.

Of the 4,778 patients in these analyses, 3,446 (72.1%) had been treated with riluzole. The overall median survival time was significantly higher among riluzole-treated patients (22.6 vs. 20.2 months). Statistical analyses suggested that treatment with riluzole reduced the risk of death by more than 20%.

“Our survival benefit estimate is almost identical to that obtained from original riluzole randomized controlled trials,” the researchers noted.

In a battery of further statistical tests, the researchers compared riluzole’s effect on survival among patients who had started on the therapy at different points after disease onset. Results generally did not show any significant differences — the effects of riluzole in extending survival were consistent regardless of when the therapy was started or how long it was used.

“Importantly, we did not find evidence of significant variation in riluzole effect for different [times from onset to starting riluzole], nor did [risk] reduction from riluzole change with duration of treatment,” the researchers wrote.

They stressed, however, that this finding “does not imply that timing and duration of treatment do not matter.”

On the contrary, the risk of death in these models is cumulative. In other words, the longer a person spends on the treatment, the more time they are spending with a significantly reduced risk of death — so the overall risk of death ends up being lower with a greater amount of time spent on treatment.

As an illustration, the researchers calculated that the total median survival time would be 1.9 months shorter (40.1 vs. 38.2 months) if riluzole was started at 18 months after disease onset rather than at six months after onset. If the treatment’s use began 30 months after disease onset, survival would be even shorter, at a median of 35 months.

“Calculations assuming a uniform riluzole protective benefit indicate an improved median survival from onset by almost 2 months, with about 4% more patients surviving at 2 [years] from onset, if treatment is started at 6 months from onset rather than at 18 months from onset,” the scientists wrote. “Although these incremental gains from early treatment are rather small in absolute terms, they are relatively large compared to the modest overall benefit seen with any ALS treatment to date.”

These findings provide “a strong argument for early treatment, and therefore, for urgent diagnosis of ALS,” the researchers concluded, adding that “this argument applies to riluzole, and potentially also to other treatments.”

They noted this study is limited by its reliance on clinical trial data from the PRO-ACT database, noting that they had to make some assumptions about the timing of treatment initiation and whether patients were taking treatments as directed, as well as the potential of variation among different trials.