Epilepsy digest
American Academy of Neurology - 2021

Epilepsy digest
American Academy of Neurology - 2021

Eisai presentations @ AAN: Fycompa

Fycompa (Perampanel) – Eisai

Post hoc analysis of Phase 3 FREEDOM study of perampanel monotherapy in untreated patients with partial-onset seizures

Abstract title

Trial details

Efficacy

Safety

Perampanel monotherapy beyond initial titration to achieve seizure freedom in patients with partial-onset seizures (POS), with/without secondarily generalized seizures (SGS): Post Hoc Analysis of Phase 3 Study 342 (FREEDOM)

NCT03201900; Phase 3 in epilepsy; N=91; Perampanel Titration Period (6 weeks): 2mg /4mg OD; Maintenance Period (26 weeks) 4mg/8mg OD

N=73 patients in the mITT population over the 26-week maintenance period

  • 46 patients achieved seizure freedom

4 mg/day (4-mgresponders):

·         37/46 (80.4%) early-responders

·         9/46 (19.6%) non early-responders

·         27 patients did not achieve seizure freedom

(4-mg non-responders)

·         18/27 (66.7%) had seizures during titration; 9/27 (33.3%) early responders

NA

A) Long-term (1-year) seizure freedom with adjunctive Perampanel in pediatric patients (aged 4–<12 years) with partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTCS): Post hoc analysis of study 311

B) Long-term (1-Year) evaluation of adjunctive Perampanel on mental health in pediatric patients (aged 4−<12 years) with partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTCS) in study 311

NCT02849626; Phase 3 in epilepsy; N=208; Perampanel 0.5mg/ml oral suspension

For POS

  • 13/17 (76.5%) seizure-free patients during the core Study remained seizure free for 6 months (with EIASMs, n=3/5 [60.0%]; without EIASMs, n=10/12 [83.3%]; 4–<7 years, n=1/3 [33.3%]; 7–<12 years, n=12/14 [85.7%])
  • 6/11 (54.5%) remained seizure free for 12 months (with EIASMs, n=2/5 [40.0%]; without EIASMs, n=4/6 [66.7%]; 4–<7 years, n=0/1; 7–<12 years, n=6/10 [60.0%])

For SGS

  • 3/8 (37.5%) seizure-free patients remained seizure free for 6 months (with EIASMs, n=0/1; without EIASMs, n=3/7 [42.9%]; 4–<7 years, n=0/3; 7–<12 years, n=3/5 [60.0%])
  • 1/5 (20.0%) patients remained seizure free for 12 months (with EIASMs, n=0/1; without EIASMs, n=1/4 [25.0%];

For PGTCS

  • 6/10 (60.0%) seizure-free patients remained seizure free for 6 months (no PGTCS seizure-free patients received EIASMs; 4–<7 years, n=1/2 [50.0%]; 7–<12 years, n=5/8 [62.5%])
  • 3/7 (42.9%) patients remained seizure free for 12 months (4–<7 years, n=0/1; 7–<12 years, n=3/6 [50.0%])
  • 71/180 (39.4%) patients reported psychiatric TEAEs (Core Study, n=66; Extension A, n=5)
  • Common psychiatric TEAEs were irritability (n=24 [13.3%]) and aggression (n=18 [10.0%])
  • 3 (1.7%) patients reported serious psychiatric TEAEs
  • 11 (6.1%) patients discontinued due to psychiatric TEAEs
  • 4 (2.7%) patients with no reported lifetime history of suicidality
  • No additional TEAEs of suicidality were recorded during Extension A
  • 3 patients had a lifetime history of suicidality

Conclusion:

  • Majority of patients with an early response during titration continued to be seizure free during maintenance, some patients without an early response during titration could still achieve seizure freedom upon continued maintenance treatment with perampanel 4 mg/day
  • Despite small patient numbers, seizure-freedom rates are maintained during long-term perampanel treatment in pediatric patients, consistent with analyses in adolescents/adults
  • These data suggest long-term perampanel treatment is safe and well tolerated in terms of mental health in pediatric patients with POS or PGTCS, however psychiatric TEAEs should be monitored 

Lorcaserin – Eisai

Design/Methods of MOMENTUM, a Phase 3, randomized study to explore if adjunctive Lorcaserin can reduce convulsive seizure frequency in DS

Abstract title

Trial details

Trial Design

MOMENTUM (Study 304; NCT04572243): A multicenter, Phase 3, double-blind, randomized, placebo-controlled, parallel-group study of adjunctive Lorcaserin in patients with dravet syndrome (DS)

NCT04572243; Phase 3 in epilepsy with Dravet syndrome; N=58; Lorcaserin (PO) 5, 10, and 20 mg/day +/-Placebo

  • MOMENTUM comprises a core study (Pre-randomization screening/baseline [4-weeks]; randomization [stratified by history of fenfluramine use and weight; 14-week Treatment; 4-week Follow-up]) and Open-Label Extension (OLEx) Phases [12-week Treatment; 4-week Follow-up])
  • Eligibility criteria: DS diagnosis; aged ≥2 years; ≥4 convulsive seizures during Pre-randomization; receiving ≥1 anti-seizure medication
  • Exclusion criteria: presence of another progressive neurological disease; received lorcaserin (4-weeks) and/or fenfluramine (2-months) before Screening; previous lack of efficacy with lorcaserin/fenfluramine; recent or concomitant use of serotonergic drugs or monoamine oxidase inhibitors; enrolled in another clinical study
  • Patients completing the Core Study can enter the OLEx and long-term Expanded Access Program (Study 405; NCT04457687)
  • Core Study primary endpoint: change in convulsive seizure frequency/28 days
  • Secondary endpoints: convulsive seizures 50% responder/seizure-freedom rates; PK; TEAE
  • Exploratory endpoints: Clinical Global Impression of Change; quality of life; change in frequency of total seizures/non-convulsive seizures/per seizure type. History of epilepsy-related genetic mutations will be collected. Safety assessments: vital signs; weight; ECG; clinical laboratory tests; echocardiography
  • Study completion is expected in 2021. The restricted randomization method will randomize ~58 patients 1:1 to adjunctive lorcaserin/placebo at ~20 US sites

Preampanel long term treatment was safe and well tolerated in pediatric patients; The new Phase 3 (MOMENTUM) trial will explore Lorcaserin as a potential therapy for Dravet syndrome

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CI Scientists Remarks:

About Fycompa:

  • A highly selective, non-competitive AMPA receptor antagonist that is postulated to reduce neuronal hyper-excitation associated with seizures by targeting glutamate activity at AMPA receptors on postsynaptic membranes
  • Fycompa is currently approved for monotherapy and adjunctive use in the treatment of POS (with or without secondarily generalized seizures) in patients with epilepsy 4 years of age and older, as well as adjunctive treatment for PGTCS in patients (≥12 years) with epilepsy in Japan, US and EU
  • At AAN the real-world experiences of Fycompa including early adjunctive use or monotherapy were presented

Future strategy:

  • Eisai is conducting a global Phase 3 clinical study (Study 338) to assess the effect of perampanel as an adjunctive anti-epileptic treatment in reducing the number of drop seizures in patients with inadequately controlled seizures associated with Lennox-Gastaut Syndrome (LGS)
  • They are also developing an injectable formulation 

About Lorcaserin:

  • It is a selective serotonin agonist of 5-HT2C, a protein receptor for the neurotransmitter serotonin. In the US, lorcaserin was previously available, under the brand name Belviq, as a medication to aid weight loss
    • However, it was voluntarily withdrawn after a safety trial showed a possible increase in the occurrence of cancer
    • Despite these concerns, the agency noted that the cause of the cancer was uncertain, and officials could not conclude that lorcaserin contributes to cancer risk
  • Lorcaserin is believed to reduce seizure frequency in people with Dravet. Preclinical data have supported the efficacy of lorcaserin in animal models of this syndrome
  • Lorcaserin was granted ODD by the FDA for Dravet syndrome
  • This trial will evaluate the safety, pharmacokinetics and tolerability of lorcaserin in people with Dravet syndrome 

– Monalisa Baral, CI Scientists

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