Levacetylleucine efficacy and safety
1 evidence topic · 9 sources
Summary
- Design: IB1001-303 (NCT06673056, Trial 2 in the prescribing information) was a phase 3, randomized, double-blind, placebo-controlled, two-period crossover trial at ten research hospitals in Germany, Slovakia, Spain, Switzerland, the United Kingdom, and the United States. It randomized 73 participants aged 4 to 50 years (47 pediatric and 26 adult) with genetically confirmed A-T and a SARA score of 7 to 34 to levacetylleucine followed by placebo (36 participants) or placebo followed by levacetylleucine (37 participants), with 12 weeks of each treatment at 2 g, 3 g, or 4 g per day by body weight. Seventy participants (96%) completed the study. The crossover was immediate, with no washout between the periods; the protocol states that its analysis method does not require a washout, and the publication describes the placebo period that followed levacetylleucine as having served as a washout.
- Efficacy in the U.S. prescribing information: the primary efficacy outcome was the functional SARA (fSARA), which rescores the gait, sitting, stance, and speech disturbance domains of the SARA to a total of 0 to 16, with higher scores indicating worse neurological status. The least squares mean fSARA total score was 7.2 on levacetylleucine and 7.8 on placebo, a treatment effect of -0.6 (95% CI -0.9 to -0.2; two-sided p = 0.0013).
- Efficacy in the publication: the protocol primary endpoint was the SARA total score, on which the maximum is 40. The mean change was -1.92 (SD 2.81) on levacetylleucine and -0.14 (SD 2.38) on placebo, a linear mixed model treatment effect of -1.88 (95% CI -2.70 to -1.06; p<0.0001). Treatment effects on secondary endpoints were -2.84 (95% CI -4.87 to -0.81) on the ICARS and 0.01 (95% CI -0.06 to 0.07) on the SCAFI; no adjustment for multiple comparisons was prespecified, and the publication states that no definite conclusions can be drawn from the secondary endpoints. Participants assigned to levacetylleucine first had a mean SARA increase of 1.81 (SD 3.12) during the placebo period that followed.
- Safety: in the prescribing information, the adverse reactions in Treatment Period I with an incidence of at least 5% and greater than placebo were fall (2 of 36 participants, 6%, on levacetylleucine and 1 of 37, 3%, on placebo), skin laceration (2 of 36, 6%, and 0 of 37), and urinary tract infection (2 of 36, 6%, and 1 of 37, 3%). The publication reports 54 adverse events in 29 participants on levacetylleucine and 75 adverse events in 25 participants on placebo, no treatment-related serious adverse events or deaths, and three withdrawals after serious adverse events assessed as unrelated to treatment (acute T-cell leukemia, diffuse large B-cell lymphoma, and a lower respiratory tract infection). The label lists no contraindications and one warning, embryo-fetal toxicity: in pregnant rats and rabbits, levacetylleucine during organogenesis increased embryo-fetal death and skeletal malformations at approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose of 4 g per day. The label directs verification that a female of reproductive potential is not pregnant before initiation and advises effective contraception during treatment and for 7 days after the last dose.
- Earlier trials of N-acetyl-L-leucine in A-T: a randomized, double-blind, placebo-controlled crossover trial at Ghaem Hospital in Mashhad randomized 16 participants (mean age 9.8 years) to 1 to 4 g per day or placebo for 6 weeks each, separated by a 4-week washout, and found no significant effect on the SARA or on the SCAFI components (p > 0.05). The sponsor's open-label, rater-blinded phase 2 trial IB1001-203 planned approximately 39 participants and was terminated after 17 were enrolled. Its primary endpoint, the Clinical Impression of Change in Severity during treatment minus that during washout, had a mean of 0.16 (SD 1.65) in 16 participants, and the registry posts no statistical test.