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Efficacy with ONTOZRY®▼ (cenobamate)

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▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Adverse events and product complaint should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard for the UK or www.hpra.ie for Ireland. Adverse events and product complaint should also be reported to Angelini Pharma on (UK) +44 2034889643, (IRE) +353 1 584 4671 or UKIReporting@angelinipharma.com

GB: This medicinal product is indicated for the adjunctive treatment of focal-onset seizures with or without secondary generalisation in adult patients with epilepsy who have not been adequately controlled despite treatment with at least 2 anti-epileptic medicinal products.1 Please refer to the NI and ROI indication in the prescribing information.

ONTOZRY® was evaluated in two multicentre, randomised, double-blind, placebo-controlled efficacy and safety studies and one open-label safety study:

Click on each study to reveal more information

  • C017 was a Phase IIb, multicentre, randomised, double-blind, placebo-controlled efficacy and safety study with an optional open-label extension2

    Patient inclusion characteristics included:2

    • Aged 18–70 years
    • Focal epilepsy, uncontrolled despite treatment with at least one ASM within the last 2 years as defined by the ILAE
    • Taking 1–3 concomitant ASMs at stable doses for at least 4 weeks before screening
    • NOT having taken diazepam, phenytoin, or phenobarbital within 1 month of screening because of the potential for drug–drug interactions with ONTOZRY®

    Patients were randomised 1:1:1:1 to each study group, receiving either placebo or 100 mg/day, 200 mg/day or 400 mg/day of ONTOZRY® and were titrated up over 6 weeks as shown in the diagram below. If a patient did not tolerate the next highest dose, the dose could be reduced to the previous dose.

    Primary endpoints:2†

    • % of patients achieving ≥50% reduction from baseline in focal seizure frequency during the 12–week maintenance phase (required by the European Medicines Agency)
    • % change from baseline in focal seizure frequency averaged over 28 days in the 18–week double blind treatment period (required for the US Food and Drug Administration regulations)

    Key secondary endpoints:2†

    • ≥75%, ≥90% and 100% reductions in seizure frequency
    • Change in seizure frequency by seizure type

    Baseline demographic and epilepsy related characteristics were generally similar across groups:

    Open label extension (OLE)

    At completion of the double blind period, patients who continued to meet study eligibility, with the exception of the seizure frequency requirement, could enrol in an OLE. Participants underwent a blinded 2–week conversion to a target dose of ONTOZRY® 300 mg/day.

    Footnotes:

    *Initial starting dose of ONTOZRY® in the original, faster titration schedule was 100 mg/day, with weekly increments of 100 mg/day until the target dose was reached. The amended titration schedule reduced the initial starting dose to 50 mg/day and slowed the titration rate to improve tolerability.2

    †Please note, only the results of the EMA mandated endpoint are presented.

    ‡During the 2-week conversion, the investigator could increase or decrease the open label dosage, if clinically indicated, to a minimum of 50 mg/day and a maximum of 400 mg/day.

  • C013 was a Phase II, multicentre, randomised, double-blind, placebo-controlled parallel group efficacy and safety study3

    Patient inclusion characteristics included:3

    • Aged 18–65 years
    • Focal epilepsy, drug resistant as defined by the ILAE6*
    • Taking 1–3 concomitant ASMs at stable doses for at least 12 weeks before randomisation
    • NOT having taken phenytoin or phenobarbital within 1 month of screening because of the potential for drug–drug interaction with ONTOZRY®

    Patients were randomised 1:1 to receive placebo or 200 mg/day ONTOZRY® and were titrated up over 6 weeks as shown in the diagram below.

    Primary endpoint:

    • % change from baseline in focal seizure frequency per 28 days during the double blind treatment period (both titration and maintenance phases)

    Key secondary endpoints:

    • Responder rate (≥50% reduction in seizure frequency)
    • Assessment of seizure frequency by seizure type

    Safety outcomes were also assessed:

    Baseline demographic and epilepsy-related characteristics were generally similar in each treatment group:3

    Footnotes:

    *Defined as the failure of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.6

    †OLE target dose was initially 200 mg/day but was increased to 400 mg/day ~2 years after OLE initiation.3

  • C021 was a Phase III, open-label, long-term safety study (interim analysis)4

    This ongoing, open-label safety study was designed to assess the long-term safety of adjunctive ONTOZRY® and to test the hypothesis that the rate of DRESS would be lower with a lower initial starting dose of ONTOZRY® and a slower titration schedule compared with study C017.

    Patient inclusion characteristics included:4

    • Aged 18–70 years old
    • Focal epilepsy, uncontrolled despite treatment with at least 1 ASM within the past 2 years, as defined by the ILAE
    • Taking 1–3 concomitant ASMs at stable doses for at least 3 weeks before initiation of ONTOZRY®
    • No history of any drug-induced rash or hypersensitivity reaction

    The initial dose of ONTOZRY® was lower (12.5 mg/day) and the titration rate was slower (every 2 weeks for 12 weeks) than in previous clinical studies. Except for patients taking concomitant phenytoin or phenobarbital, patients' concomitant ASMs could be removed, added, or adjusted, and ONTOZRY® doses could be adjusted during the titration phase, as clinically needed, including downward dose adjustments for tolerability during the maintenance phase for all patients once the target dose of 200 mg/day was reached.

    Primary endpoint:

    • Long-term safety and tolerability of ONTOZRY®

    At data cut-off, 1339 patients had received ≥1 treatment dose (safety population):

    Footnotes:

    *The recommended titration period for ONTOZRY® is 10 weeks as per the SmPC.1,4

ONTOZRY® Reduces frequency of focal onset seizures by ≥50% in over half of patients2

In patents who had uncontrolled focal-onset seizures despite a history of treatment with 2–4 ASMs and taking standard of care (SOC; 1–3 concomitant ASMs at stable doses for at least 4 weeks prior to screening).2*†

Primary endpoint:

Percentage of patients with ≥50% reduction in seizure frequency (measured over a 12-week maintenance phase) when adding placebo or ONTOZRY® to SOC.2

Footnotes:

*Inclusion criteria: Patients' epilepsy had to be uncontrolled despite treatment with at least one ASM within the past 2 years. Patients must have been taking 1-3 concomitant ASMs at stable doses for at least 4 weeks before screening (standard of care). In the randomly assigned population at baseline, median number of previous ASMs taken at any time before the start of the study was 3 (range 2-4); these might or might not have been ongoing during the study. 74% (n=322/437) of patients were taking 2-3 concomitant ASMs during the study.2

†During the 12-week maintenance phase, mITT-M population (all randomly assigned adult patients who completed the 6-week titration phase, took at least one dose of study drug in the maintenance phase, and had maintenance phase seizure data). All p values vs placebo.2

ONTOZRY® is associated with dose-dependent improvements in ≥75%, ≥90% and 100% responder rates2*†

Secondary endpoint:

Percentage of patients with ≥75%, ≥90% and 100% reduction in seizure frequency (measured over a 12-week maintenance phase) when adding placebo or ONTOZRY® to SOC.2

Seizure freedom is possible with ONTOZRY® for some drug-resistant patients*2

In patients who had uncontrolled focal onset seizures, seizure-freedom (measured over a 12-week maintenance phase) was achieved by:2†

Footnotes:

*When added to standard of care (an ongoing regime of 1-3 ASMs).2

†In patients who had focal onset seizures, uncontrolled despite a history of treatment with 2-4 ASMs and taking 1-3 concomitant ASMs at stable doses for at least 4 weeks prior to screening. Inclusion criteria: patients' epilepsy had to be uncontrolled despite treatment with at least one ASM within the past 2 years. Patients must have been taking 1-3 concomitant ASMs at stable doses for at least 4 weeks before screening (SOC). In the randomly assigned population at baseline, median number of previous ASMs taken at any time before the start of the study was 3 (range 2-4); these might or might not have been ongoing during the study. 74% (n=322/437) of patients were taking 2-3 concomitant ASMs during the study.2

High rates of sustained 100% seizure freedom (≥12 months) were achieved7

In a post hoc analysis of 240 patients in the safety study C021, 36.3% (n=87) were seizure-free at any consecutive ≥12 month duration of the study.7

The mean duration of 100% seizure reduction was 23.5 months.7

The median duration of exposure for the 240 patients in the post hoc open-label study was 30.2 months.7

Retention at 12 and 24 months of treatment was 80% and 73% respectively.7

Reductions in seizure freedom were maintained with ONTOZRY® at >3 and up to 4 years when added to an ongoing regimen of 1–3 ASMs5

Results from the long-term open-label extension study (C017)

Footnotes:

*82.5% (n=293/355) of patients in the OLE were taking 2–3 concomitant ASMs at the baseline of the double-blind study. During the OLE treatment phase, concomitant ASMs could be added, removed, or adjusted (no ONTOZRY® monotherapy allowed) and ONTOZRY® dose could be adjusted. 
Percentages of patients with ≥50%, ≥75% and ≥90% seizure reductions were analysed using the OLE mITT population (all patients who had taken at least 1 dose of cenobamate and had any seizure data recorded in the OLE) at consecutive 1-year intervals using the observed or active patient population (i.e. patients continuing ONTOZRY® treatment) at each 12-month interval as the denominator. Data cut-off: 1st July 2019.5

Abbreviations:

AE = adverse event(s), ASM = anti-seizure medication; CI = confidence interval; DRESS = drug reaction with eosinophillia and systemic symptoms; ECG = electrocardiogram; ILAE = International League Against Epilepsy; MedDRA = Medical Dictionary for Regulatory Activities; mITT-M = modified intention-to-treat maintenance phase; OLE = open-label extension; OR = odds ratio; SOC = standard of care; TEAE = treatment-emergent adverse event. 

1. ONTOZRY® Summary of Product Characteristics.

2. Krauss GL, et al. Lancet Neurol. 2020;19(1):38–48.

3. Chung SS, et al. Neurology. 2020;94(22):e2311–22.

4. Sperling ME, et al. Epilepsia. 2020;61(6):1099–1108.

5. Klein p, et al. Neurology. 2022 Jun 15;99(10):e989–98.

6. Kwan P, et al. Epilepsia. 2010;51(6):1069–77.

7. Sperling MR, et al. Epliepsia. 2021 Dec;62(12):3005–3015.

UK16589P | March 2023