Clobazam, Cannabidiol, Rufinamide Among Most Efficacious ASMs for Lennox-Gastaut, Meta-Analysis Suggests

Safety outcomes of the study demonstrated a lower risk of treatment-emergent adverse events and serious adverse events, along with a high risk of drug withdrawal because of adverse events for high-dose clobazam.

Data from a recently published systematic literature search of 6 antiseizure medications (ASMs) for Lennox-Gastaut syndrome (LGS) suggest that clobazam (CLB; Sympazan; Aquestive Therapeutics), cannabidiol (CBD; Epidiolex; GW Pharmaceuticals) and rufinamide (RFM; Banzel; Eisai) are the safest and most efficacious, with high-dose clobazam leading the hierarchy.

The analysis, which included 15 studies comprising of 1263 patients with LGS, showed that treatment with high-dose CLB (1.0 mg/kg/day; CLB-H) was significantly associated with at least a 50% reduction in drop seizure frequency (odds ratio [OR], 4.9; 95% CI, 2.3-10.8) as compared with placebo, and achieved the highest-ranking probability (0.89) based on surface under the cumulative ranking curve (SUCRA) values. High-dose CBD (20 mg/kg/day; CBD-H) had significantly higher odds for occurrence of any treatment-emergent adverse events (TEAEs) and had the highest-ranking probability (SUCRA, 0.85).

"These results need to be interpreted carefully considering the limitations of indirect comparison, overlapping confidence intervals of effect size of these drugs, drug interactions with various comedications, and heterogeneity in reporting outcomes in different studies," senior investigator Dipika Bansal, MD, assistant professor, National Institute of Pharmaceutical Education and Research, and colleagues concluded. "Hence, head-to-head trials between these drugs are much needed to draw some definite conclusions."

The meta-analysis included only randomized controlled trials (RCTs) evaluating the short-term (≤16 weeks of therapy) and long-term (beyond 1 year) efficacy and safety of ASMs and dietary therapy for the management of LGS. In addition to CLB, CBD, and RFM, the analysis included felbamate (FLB; Felbatol; MEDA Pharmaceuticals), lamotrigine (LTG; Lamictal; GlaxoSmithKline), and topiramate (TPM; Topamax; Janssen). Additionally, open-label extension (OLE) studies of the RCTs were also included to evaluate long-term outcomes.

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In long-term studies, CLB had the highest proportion of patients with at least 50% reduction in drop seizures (78%; 95% CI, 70-85) whereas CBD had the highest proportion with a reduction in total seizures (63%; 95% CI, 56-70). In one specific OLE, 156 participants had achieved at least 50% seizure reduction with CLB after 3 months of treatment with CLB; of these, 74 sustained response for 3 years.

CBD-H continued to have the highest probability on SUCRA values for achieving at least 25% reduction (0.69) and 75% reduction (0.92) in drop-seizure frequency in the short-term among the included ASMs. Four OLE studies had reported on at least 75% reduction for CBD, CLB, RFM, and TPM. Among them, CLB-treated participants had the highest proportion of at least 75% reduction in drop-seizure (65%; 95% CI, 57-74) and total seizure (53%; 95% CI, 44-62) frequency.

During the treatment period, 47% (292 of 620) participants had shown improvement in CGIC in 5 RCTs. In comparison with placebo, those on CBD-H (OR, 2.10; 95% CI, 1.3-3.28), CBD low dose (10 mg/kg/day, CBD-L: OR, 2.78; 95% CI, 1.5-5.2) and TPM (OR, 2.8; 95% CI, 1.2-6.5) had shown statistically significant improvement in CGIC score, with the CBD-L group demonstrating the highest probability of improvement (SUCRA, 0.77).

In total, 94% of participants (788 of 836) had experienced TEAEs on long-term treatment with CBD, CLB, and RFM, of which CBD had the highest proportion with the occurrence of TEAEs (96%; 95% CI, 95-98). On treatment-related AEs (TRAEs), there was no statistically significant relation on direct or indirect comparison between ASMs and placebo; however, RFM (SUCRA, 0.72) had the highest-ranking probability for the occurrence of TRAEs.

Both the low- and high-dose CBD groups had the highest odds of serious AEs (SAEs) and also had the highest-ranking probability for the occurrence of SAEs in the short-term. Using 4 studies, investigators identified the highest proportion of reported SAEs with CLB-treated patients (43%; 95% CI, 37-49) as compared with CBD and RFM.

"This lower risk of TEAE and SAEs needs to be interpreted with caution in day-to-day practice since CLB-M was associated with a higher risk of TEAEs and SAEs," Bansal et al wrote. "These conflicting results might be due to the fact that patients on CLB-M experiencing TEAEs and SAEs would not have undergone further dose escalation to CLB-H."

The analysis did have a few limitations, including the fact that it did not include the studies on the use of steroids or hormonal therapy due to the observational nature of these studies. Additionally, the pooled estimates for total seizure and nonseizure outcomes could not be calculated due to the unavailability of raw data and heterogeneity in reporting in different studies.

REFERENCE
1. Devi N, Madaan P, Ameen R, Sahu JK, Bansal D. Short-term and long-term efficacy and safety of antiseizure medications in Lennox-Gastaut syndrome: a network meta-analysis. Seizure. Published online April 8, 2022. doi:10.1016/j.seizure.2022.04.004