Abstracts

Rationale: Once-daily USL255, Qudexy® XR (topiramate) extended-release capsules, is approved in patients ≥2 years of age as monotherapy and adjunctive therapy for the treatment of certain seizure types. USL255 demonstrated efficacy without a high rate of adverse events (AEs) in a phase 3 study (PREVAIL [NCT01142193]; N=249) and its open-label extension study (PREVAIL OLE [NCT01191086]; N=210). In 2014, USL255 was approved by the FDA and now exists among a crowded field of >20 antiepileptic drugs (AEDs), including immediate-release topiramate (TPM-IR; approved in 1996). These numerous AEDs and increasing placebo rates over the past several decades present challenges to comparing study results and identifying the most appropriate agent for an individual patient. Presented here are the results from USL255 studies compared with other second-generation AEDs. Methods: In PREVAIL, patients with partial-onset seizures (POS) taking 1-3 concomitant AEDs were randomized to PBO (n=125) or USL255 (n=124), titrated over 3 weeks (50 mg/wk), and maintained at 200 mg/d for 8 weeks. In this review, efficacy results from PREVAIL were compared with a study of similar design evaluating add-on TPM-IR (Guberman et al, 2002). Safety comparisons evaluated AEs reported in the prescribing information for USL255 (200 mg/d [the dose investigated in PREVAIL]), lacosamide (LCM; 200–400 mg/d), lamotrigine (LTG; ≤500 mg/d), levetiracetam (LEV; ≤3000 mg/d), oxcarbazepine (OXC; 600–1200 mg/d) and TPM-IR (200 mg/d). AE risk ratios (RR) were calculated using methods described in the Cochrane Handbook for Systematic Reviews of Interventions [2005]). Results: During PREVAIL, 200 mg USL255 resulted in significantly greater reduction in POS frequency vs PBO (39.5% vs 21.7%, P < .001) and higher 50% responder rate (37.9% vs 23.2%, P=.013); this was similar to results for TPM-IR vs PBO from the Guberman et al publication (52% vs 20%, P < .001 and 51% vs 24%, P < .001, respectively). Of the six 2nd-generation AEDs listed above, the commonly shared AEs for which incidences were reported for all were somnolence, dizziness, and diplopia. Further, all AEDs compared to PBO had: a) a greater risk for somnolence (USL255, RR=6.0; LTG and OXC, RR=2.0; LEV, RR=1.9; TPM-IR, RR=1.7; LCM, RR=1.4) and dizziness (LCM, RR=3.1; LTG, RR=2.9; LEV, RR=2.3; OXC, RR=2.2; TPM-IR, RR=1.8; USL255, RR=1.2); and b) an increased risk for diplopia—except for USL255—(LCM, RR=4.5; OXC, RR=4.4; TPM-IR, RR=4.3; LTG, RR=4.0; LEV, RR=2.0 vs RR=0 for USL255). Conclusions: Once daily USL255 demonstrated similar efficacy to a TPM-IR study conducted ~15 years earlier, when limited AEDs were available and PBO response rates were generally lower. USL255 has a low rate of AEs that, other than somnolence, are often similar to or lower than TPM-IR and other AEDs. Together, this review demonstrates that despite the introduction of multiple AEDs, USL255—a unique formulation of topiramate—may provide benefit for patients with epilepsy as adjunctive therapy with a favorable safety profile. Funding: Support: Upsher-Smith Laboratories, Inc.