Date: 2014-11-21
Type of information: Product launch
Product name: Fycompa®
Compound: perampanel
Therapeutic area: CNS diseases - Neurological diseases
Action mechanism: Perampanel has a different mechanism of action to current antiepileptic drugs (AEDs). As an AMPA receptor antagonist, perampanel is the first of a new class of AED. The neurotransmitter glutamate plays a major role in the mediating seizures and perampanel is the only agent that selectively targets the transmission of seizures by blocking post synaptic glutamate AMPA receptors. AMPA receptors are currently not selectively targeted by any other available AED.
Company: Eisai (Japan)
Disease: adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older
Latest news: * On November 21, 2014, Eisai announced that its Hong Kong subsidiary Eisai (Hong Kong) Co., Ltd. has launched Fycompa® (perampanel) in the region as an adjunctive treatment for partial-onset seizures with or without secondary generalized seizures in patients with epilepsy aged 12 years and older. This marks the first launch of Fycompa® in the Asia region. * On November 3, 2014, Eisai announced that Fycompa® (perampanel) has received reimbursement in Australia. It is indicated for the adjunctive treatment of partial onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older. Discovered and developed by Eisai in Europe and Japan, perampanel is manufactured in the UK and was approved by the European Commission on 23 July 2012. * On August 19, 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) announced that there is still no proof of added benefit of perampanel for epilepsy. In a new early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG), IQWiG examined whether perampanel offers an added benefit over the appropriate comparator therapy. However, such an added benefit cannot be derived from the new dossier either, as the drug manufacturer did not submit any relevant data for this comparison. Already in the first dossier assessment in December 2012, there was no proof of an added benefit of perampanel because the manufacturer dossier provided no suitable data. The new assessment was conducted upon application of the manufacturer to the Federal Joint Committee (G-BA), which specifies the appropriate comparator therapy. The G-BA approved the manufacturer's application for reassessment of the drug according to AMNOG because the appropriate comparator therapy had to be expanded following the change in the AMNOG Regulation for Early Benefit Assessment of New Pharmaceuticals (in §6 (1), Sentence 2, AM-NutzenV): Originally the more economical comparator therapy had to be chosen if several options were available, preferably a treatment with a fixed price. This regulation was dispensed with in 2013. If the G-BA specifies several options as appropriate comparator therapies, the manufacturer is now free to choose a therapy irrespective of the costs. The G-BA therefore specified 10 different drugs for the appropriate comparator therapy in form of an individual antiepileptic add-on therapy: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproic acid or zonisamide for all age groups, eslicarbazepine or pregabalin only for adults, or lacosamide only for patients aged 16 years or older. It depends on the basic and prior therapy as well as the reason for treatment switching which of these drugs is used. If a patient is known to have pharmacoresistance, intolerance or another contraindication to the chosen drug, this drug cannot be used. In its second dossier, the manufacturer wanted to prove the added benefit of perampanel as add-on therapy only for a certain part of the approval population: for patients with pharmacoresistant and continuing active epilepsy. In its dossier, the manufacturer defined these as patients diagnosed with epilepsy for more than 5 years who, as add-on therapy in basic therapy, already receive at least one antiepileptic drug specified by the G-BA as appropriate comparator therapy. The manufacturer justified this by claiming that, at first, new antiepileptics are mainly prescribed for resistant patients and in epilepsy centres or specialized practices. From the company's point of view, the manufacturer's proof of added benefit should preferably cover the population that is most likely to benefit from perampanel in the foreseeable future. In the three relevant randomized controlled trials (RCTs) used by the manufacturer, each of three different dosages of perampanel is compared with a dummy drug (placebo): The patients either received perampanel as add-on therapy or placebo in addition to their ongoing basic therapy, which consisted of one to no more than three antiepileptics. At least one of the 10 drugs specified by the G-BA was part of the basic treatment. The dose of antiepileptics of the basic therapy was not allowed to be changed during the treatment phase of 19 weeks. Hence there was no possibility to adapt or change the treatment of patients who continued to have epileptic seizures. The manufacturer regarded the treatment in the subpopulation described to already be highly individual so that it could not be further improved by add-on therapy. Hence, from the company's point of view, the added benefit of perampanel as add-on therapy derives from the comparison with placebo. However, it was not presented in the dossier in a comprehensible way why none of the 10 drugs of the ACT should not be suitable as add-on therapy. The G-BA explicitly allowed the choice for the individual patient. There were also no indications that the study participants were no longer eligible for individual add-on therapy. In contrast, the study data suggest that not all options of drug treatment have been exhausted for these patients. The appropriate comparator therapy was therefore not implemented in any of the studies presented. Hence the company again presented no relevant data for the assessment of the added benefit of perampanel. An added benefit of the drug is therefore still not proven. * On August 15, 2014, Eisai announced that the company is disappointed that the report issued by the Institute for Quality and Efficiency in Health Care (IQWiG) has determined no additional benefit for new generation epilepsy treatment Fycompa® (perampanel), when compared to conventional antiepileptic drugs (AEDs) as defined by the Federal Joint Committee (G-BA). It is expected that the G-BA will publish their decision after due and balanced consideration of all relevant aspects of the IQWiG report, written statements and oral hearing, in November 2014. Eisai is confident that the G-BA will take a more flexible, patient-oriented approach to their decision making process which considers both the evidence of perampanel's clinical benefit and the needs of people with poorly controlled epilepsy. Perampanel was approved by the European Commission in 2012 and is indicated for the adjunctive treatment of partial onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older. The IQWiG assessment concludes that Eisai deviated from the appropriate comparative therapy as defined by the G-BA. The assessment does not include a statement with regard to perampanel's proven clinical efficacy and safety, as demonstrated by the studies submitted to the G-BA and used for the EU approval of perampanel in September 2012. The efficacy and safety of adjunctive perampanel in the treatment of partial onset seizures in real world clinical practice is investigated in a multi-centre, six-month observational study from nine epilepsy centres in Germany and Austria. Half of the 281 people with highly refractory epilepsy who took part in the study experienced at least a 50% reduction in seizure frequency and up to 15% became seizure free with adjunctive perampanel. Seizure freedom was achieved in 15% of patients. Adverse events were reported by 52% of patients, with somnolence (24.6%) and dizziness (19.6%) being most frequently reported. The retention rate after six months was 60%. The mean perampanel dosage was 7.7 mg. In some patients, a marked response could be observed at relatively low dosages. * On August 4, 2014, Fycompa® (perampanel) launches in Belgium. In Belgium, approximately 60,000 people live with epilepsy and 150,000 people will experience an epileptic episode at some point in their life. The successful treatment of partial onset seizures remains a significant challenge in some patients and the incidence of uncontrolled partial epilepsy remains high despite many AEDs. Currently, between 20-40% of patients with newly diagnosed epilepsy will become refractory to treatment. Perampanel's reimbursement approval in Belgium is based on three randomised, double-blind, placebo-controlled and dose-escalated global pivotal Phase III studies (304, 305, 306) and an open-label extension study (307). The three global pivotal studies show consistent results in the efficacy and tolerability of perampanel as an adjunctive therapy in people with partial onset seizures, with or without secondary generalisation. The most commonly reported adverse events were dizziness, somnolence, fatigue, headache, falls, irritability and ataxia.[6],[7],[8] Results from the open-label extension study also demonstrate perampanel's efficacy and favorable tolerability profile over the longer term. Discovered and developed by Eisai in Europe and Japan, perampanel is manufactured in the UK and was approved by the European Commission on 23 July 2012. * On June 9, 2014, Fycompa® (perampanel) has been launched in Russia. The therapy is indicated for the adjunctive treatment of partial onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older. * On May 13, 2014, Fycompa® (perampanel), launches in the Netherlands. The new therapy is indicated for the adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older.Perampanel's reimbursement approval in the Netherlands is based on three randomised, double-blind, placebo-controlled and dose-escalated global pivotal Phase III studies (304, 305, 306) and an open-label extension study (307). * On October 22, 2013, Fycompa® (perampanel) has been approved in Israel. The new therapy is indicated as an adjunctive treatment for partial-onset seizures, with or without secondary generalised seizures, in people with epilepsy aged 12 years and older. In Israel, perampanel will be launched and marketed by Megapharm, Eisai's local CNS partner. Perampanel was approved by the European Commission on 23 July 2012, and in Europe the drug is currently available in the United Kingdom, Denmark, Germany, Republic of Ireland, Sweden, Norway, Austria and Switzerland. The FDA approved perampanel for use in the US on 22 October 2012. Discovered and developed by Eisai in Europe and Japan, perampanel is manufactured in the UK. * On March 19, 2013, Eisai has announced that Fycompa® (perampanel), the first in an entirely new class of treatment for uncontrolled partial-onset seizures (the most common form of epilepsy), has been launched in Switzerland. The new therapy is indicated as an adjunctive treatment for partial-onset seizures, with or without secondary generalised seizures, in people with epilepsy aged 12 years and older. Perampanel's approval by the Swiss agency for the authorisation and supervision of therapeutic products, Swissmedic, was based on three global pivotal Phase III studies with 1,480 subjects. These randomised, double-blind, placebo-controlled and dose-escalated studies showed consistent results in the efficacyand tolerability of perampanel as an adjunctive therapy in people with partial-onset seizures (with or without secondary generalisations). The most commonly reported adverse events were dizziness, somnolence, fatigue, headache, falls, irritability and ataxia. Perampanel was approved by the European Commission on 23 July 2012, and in Europe the drug is currently available in the UK, Denmark, Germany, Sweden, Norway and Austria. Swissmedic approved perampanel for use in December 2012 and the FDA approved perampanel for use in the US on 22 October 2012. Discovered and developed by Eisai in Europe and Japan, perampanel is going to be manufactured in the UK. * On January 8, 2013, Eisai has announced that Fycompa® has been approved by Swissmedic, the Swiss agency for the authorisation and supervision of therapeutic products. The new therapy is indicated as an adjunctive treatment for partial-onset seizures, with or without secondary generalised seizures, in people with epilepsy aged 12 years and older. * On January 7, 2013, Eisai has announced that the company has launched Fycompa® (perampanel) in Norway as a treatment for partial-onset seizures, with or without secondarily generalised seizures, in people with epilepsy aged 12 years and older. The Norwegian price for perampanel was received from the Norwegian Board of Health Supervision on 15 November 2012. Perampanel received CHMP positive opinion in May 2012, was approved by the EC on 23 July 2012 and first launched in the UK on 13 September 2012. * On October 22, 2012, the FDA approved Fycompa® (perampanel) tablets to treat partial onset seizures in patients with epilepsy ages 12 years and older. Results from three clinical trials showed improvement in seizure control in patients taking Fycompa® compared with those taking an inactive pill (placebo). Fycompa®’s label has a boxed warning to alert prescribers and patients about the risk of serious neuropsychiatric events, including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and mental status changes. Some of these events were reported as serious and life-threatening. Violent thoughts or threatening behavior was also observed in a few patients. Patients and caregivers should alert a health care professional immediately if changes in mood or behavior that are not typical for the patient are observed. Health care professionals should closely monitor patients during the titration period when higher doses are used. * On September 18, 2012, Eisai has announced that Fycompa®(perampanel) has been launched in Denmark. Following the UK and Germany, Denmark is one of the first countries in Europe to launch Fycompa®. The Danish price for Fycompa® was received from the Danish Health and Medicines Authority on 5 September 2012. Perampanel received CHMP positive opinion in May 2012, was approved by the EC on 23 July 2012 and first launched in the UK on 13 September 2012. The FDA accepted the resubmission of New Drug Application for perampanel in March 2012 and has assigned a Prescription Drug User Free Act (PDUFA) target date of 22 October 2012. * On September 13, 2012, Eisai Co has announced that it will launch the AMPA receptor antagonist Fycompa® (perampanel), a first-in-class antiepileptic agent discovered and developed in-house, in Europe ahead of other regions in the world for use as an adjunctive treatment for partial onset seizures, with or without secondarily generalized seizures, in patients aged 12 years and older. Following the launch of the agent in the United Kingdom today, Fycompa® will also be launched successively in European Union member states such as Germany, Austria and Denmark. A New Drug Application for Fycompa was submitted in the United States in December 2011, while a Phase III clinical study is currently underway in Japan for the same indication. Eisai is also conducting a global Phase III study to evaluate the agent as a potential treatment for generalized epilepsy. * On May 28, 2012, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for the use of Fycompa® (perampanel) as an adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older.The CHMP based its decision on clinical data from three pivotal Phase III, global, randomised, double-blind, placebo-controlled, dose-escalation studies in 1,480 epilepsy patients. Each of the studies showed consistent results in the efficacyand tolerability of perampanel as an adjunctive therapy in patients with partial-onset seizures (with or without secondary generalisations).Perampanel delivers the benefit of once-daily dosing, thereby helping to reduce the potential pill-burden a person with epilepsy may experience. The most commonly reported adverse events were dizziness, headache, somnolence, irritability, fatigue, falls, and ataxia. The clinical development plan for perampanel consisted of three global Phase III studies: Studies 306, 305 and 304 in which a total of 1,480 patients participated. The key goal of Study 306 was to identify the minimal effective dose and included four treatment arms (placebo, 2mg, 4mg, and 8mg). Studies 304 and 305 included three arms (placebo, 8mg, and 12mg) and were to evaluate a more extended dose range. The studies were similar in design: global, randomised, double-blind, placebo-controlled, dose-escalation, parallel-group studies. The primary and secondary endpoints were the same in all the studies: percentage change in seizure frequency, 50% responder rate, percentage reduction of complex partial plus secondarily generalized seizures, and evaluation for dose response. The primary endpoint for the EMA is 50% responder rate and the FDA is median percent change in seizure frequency. Study 306- Germany, Bulgaria, Portugal, Lithuania, India, and China (Krauss GM. Serratosa JM, Villanueva V et al. Randomized Phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012). Study 306 showed that perampanel was well-tolerated and effective in reducing median seizure frequency and increasing responder rates. Specifically the results showed: - The 50% responder rates compared to placebo for the ITT (intention-to-treat) population were: 2mg = 20.6% (p=ns), 4mg = 28.5% (p=0.0132), and 8mg = 34.9% (p=0.0003) versus 17.9% with placebo. - The median percent change in seizure frequency for the ITT population shown: 2 mg = -13.6% (p=0.420), 4 mg = -23.3% (p=0.0026), 8 mg = -30.8% (p<0.0001) versus -10.7% with placebo - The most frequent treatment-emergent adverse events were dizziness, headache and somnolence.Study 305[10]- Europe, USA, South Africa, Israel, Russia, India, Australia. There was a significant difference in median percent change in seizure frequency with perampanel 8mg and 12mg. Specifically the preliminary results for Study 305 showed: - The 50% responder rates compared to placebo for the ITT population were: 8mg = 33.3% (p=0.0008), 12mg = 33.9% (p=0.0006) versus 14.7% with placebo - The median percent change in seizure frequency for the ITT population were: 8mg = -30.5% (p=0.0008), 12mg = -17.6% (p=0.0105)) versus -9.7% with placebo - The most reported adverse events were dizziness, fatigue, headache and somnolence. Study 304- USA, Canada and South America (Perampanel Reduces Treatment-Resistant, Partial-Onset Seizures. Neurology Reviews 2011;19(6):1,26-29.) Study 304 showed consistent results in the efficacy and tolerability of perampanel given as a treatment for patients with partial-onset seizures. Specifically: - The 50% responder rates compared to placebo for the ITT population were: 8mg = 37.6% (p=0.0760), 12mg = 36.1% (0.0914) versus 26.4% with placebo. - The median percent change in seizure frequency for the ITT population were: 8mg = -26.3% (0.0261), 12mg = -34.5% (p=0.0158) versus -21.0% with placebo - The most common side effects were dizziness, somnolence, irritability, headache, falls, and ataxia. * On July 23, 2012, the European Commission has issued Marketing Authorisation Approval for the use of Fycompa® (perampanel) as an adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in people with epilepsy aged 12 years and older. With the EC's approval, the European Union is the first region in the world to approve Eisai's perampanel.
Patents:
Submission of marketing authorization application USA : 2011-12-00
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2012-10-22
UE authorization: 2012-07-23
Favourable opinion UE: 2012-05-24
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news: * On September 9, 2013, Eisai EMEA has announced the establishment of a named patient access programme to ensure that patients continue to receive an uninterrupted supply of the anti-epilepsy drug Fycompa (perampanel), following the temporary suspension of commercial distribution in Germany. This access programme will be managed by Clinigen Global Access Programs (Clinigen GAP), part of Clinigen Group plc. The access programme is not expected to be utilised until the beginning of 2014 as there are sufficient stocks of Fycompa in Germany to meet demand until the end of December. Under the access programme, all patients will receive an uninterrupted supply at no cost to the German healthcare system. The access programme will remain in place until commercial distribution resumes. The company intends to submit Fycompa for reassessment at the earliest opportunity.
