•
`
`PLOS ONE
`
`RESEARCH ARTICLE
`
`Thirty Years of Orphan Drug Legislation and
`the Development of Drugs to Treat Rare
`Seizure Conditions: A Cross Sectional Analysis
`
`Jan Henje Doring1'2°, Anette Lampert3'4C, Georg F. Hoffmann1.2, Markus Ries1'2*
`
`1 Pediatric Neurology and Metabolic Medicine, Center for Pediatrics and Adolescent Medicine, Heidelberg
`University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany, 2 Center for Rare Diseases,
`Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany, 3 Department of
`Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld
`410, 69120 Heidelberg, Germany, 4 Cooperation Unit Clinical Pharmacy, Heidelberg University Hospital, Im
`Neuenheimer Feld 410, 69120 Heidelberg, Germany
`
`CrossMark
`
`click for updates
`
`These authors contributed equally to this work.
`* markus.ries@uni-heidelberg.de
`
`G OPEN ACCESS
`Citation: Daring JH, Lampert A, Hoffmann GF, Ries
`M (2016) Thirty Years of Orphan Drug Legislation and
`the Development of Drugs to Treat Rare Seizure
`Conditions: A Cross Sectional Analysis. PLoS ONE
`11(8): e0161660. doi:10.1371/joumal.pone.0161660
`
`Editor: Emilio Russo, University of Catanzaro, ITALY
`
`Received: June 6, 2016
`
`Accepted: August 9, 2016
`
`Published: August 24, 2016
`
`Copyright: © 2016 Daring et al. This is an open
`access article distributed under the terms of the
`Creative Commons Attribution License, which permits
`unrestricted use, distribution, and reproduction in any
`medium, provided the original author and source are
`credited.
`
`Data Availability Statement: All relevant data are
`within the paper.
`
`Funding: We acknowledge the financial support of
`the Deutsche Forschungsgemeinschaft and
`Ruprecht-Karts-Universitat Heidelberg within the
`funding programme Open Access Publishing.
`
`Competing Interests: AL received a personal
`scholarship from "Dr. August and Dr. Anni Lesmuller
`foundation." MR received consultancy fees or
`research grants from Alexion, GSK, Oxyrane and
`Shire. JHD and GFH report no conflict of interest.
`There are no patents, products in development or
`marketed products to declare. This does not alter our
`
`Abstract
`
`Background
`Epilepsy is a serious chronic health condition with a high morbidity impairing the life of
`patients and afflicted families. Many epileptic conditions, especially those affecting children,
`are rare disorders generating an urgent medical need for more efficacious therapy options.
`Therefore, we assessed the output of the US and European orphan drug legislations.
`
`Methods
`Quantitative analysis of the FDA and EMA databases for orphan drug designations according
`to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria.
`
`Results
`Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e.
`clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin,
`lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the
`EMA granted six orphan drug designations whereof two compounds were approved, i.e.
`rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan
`drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms,
`Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which
`was approved in the US and the EU to treat rare seizure conditions, the process seems
`faster in the EU (2.2 years) than in the US (4.3 years).
`
`Conclusion
`Orphan drug development in the US and in the EU delivered only few molecular entities to
`treat rare seizure disorders. The development programs focused on already approved
`
`PLOS ONE I D01:10.1371/journal.pone.0161660 August 24, 2016
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`.PLOS ONE
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`data and materials, as detailed online in the guide for
`authors.
`
`Abbreviations: FDA, Food and Drug Administration;
`EMA, European Medicines Agency.
`
`Orphan Drugs for Rare Seizures
`
`4
`
`antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved
`in the US are not approved in the EU to treat rare seizures although some were introduced
`after 2000 when the EU adopted the Orphan Drug Regulation.
`
`Introduction
`Epilepsy is a serious chronic health condition with a high morbidity impairing the life of
`patients and affected families through seizures, hospitalizations, emergency department visits,
`and medication burden [1, 2]. Particularly, seizure onset in childhood can compromise the
`child's development and frequently causes lifelong disability and dependency [2]. Epilepsy
`comprises a large group of syndromes whereof some meet the criteria for a rare disease accord-
`ing to the World Health Organization (WHO), i.e. a condition affecting less than 65-100 in
`100,000 inhabitants [3]. For example, Lennox-Gastaut syndrome with an estimated prevalence
`of 15/100,000, West syndrome (infantile spasms) with an estimated prevalence of 8/100,000,
`Dravet syndrome (severe myoclonic epilepsy in infancy) with an estimated birth-prevalence of
`2.5/100,000, or Pyridoxine-dependent epilepsy with 0,2/100,000 fulfill the WHO definition of a
`rare disease [4]. Today clinically available anti-epileptic drugs can control seizures in approxi-
`mately two-third of patients [5-7], particularly in rare seizure conditions such as Lennox-Gas-
`taut or Dravet syndrome long term prognosis is guarded and most patients are refractory to
`medical treatment [8, 9]. Psychomotor delay and neuropsychiatric symptoms occur regularly.
`In addition, most often anti-epileptic pharmacotherapy is limited by drug-drug interactions,
`adverse drug events, and complex dose regimens impairing adherence [10-13].
`Since 1983, the US Orphan Drug Act has stimulated the development of orphan drugs by
`granting various incentives, such as seven years marketing exclusivity, tax credit for 50% of
`clinical trial costs, protocol assistance, Food and Drug Administration (FDA) fee waiver, and
`orphan products grant programs [14]. A compound qualifies for the incentives described in
`the US Orphan Drug Act when a disease affects less than 200,000 patients in the US or when
`economic viability is lacking although prevalence exceeds 200,000 [3]. In 1999, the European
`Medicines Agency (EMA) adopted the legislation for orphan drugs (Regulation (EC) No 141/
`2000), which came into force in 2000, to stimulate orphan drug development in the European
`Union (EU) by granting, for example, up to ten years marketing exclusivity after approval
`(plus two years for orphan drugs with a pediatric investigation plan), fee reduction, and proto-
`col assistance [15]. In the EU, a compound qualifies for orphan drug designation when it is
`indicated for a life-threatening or chronically debilitating condition affecting less than five in
`10,000 persons or when it is improbable to sufficiently generate return of investment although
`a life-threatening, seriously debilitating or serious and chronic condition affects more than five
`in 10,000 patients [16]. A furtherprerequisite is absence of a satisfactory method of diagnosis,
`prevention, or treatment, or if it exists, the new medicinal product must be of significant benefit
`to the patients [16].
`During the last decades scientists, policy makers, and pharmaceutical companies have advo-
`cated to respond to challenges in orphan drug development. In addition, political and legisla-
`tive developments, such as the US Orphan Drug Act and the Orphan Drug Regulation in the
`EU, have changed the environment in orphan drug development. Considering the unmet med-
`ical need for anti-epileptic treatments, drug development in orphan epilepsy—as in any rare
`disease—is challenged by small sample sizes, heterogeneous pathomechanisms, and involve-
`ment of children. Therefore, we systematically analyzed the impact of the US Orphan Drug Act
`
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`Orphan Drugs for Rare Seizures
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`and the Orphan Drug Regulation in the EU on orphan drug development in rare seizure condi-
`tions by investigating orphan drug designations and approvals, time to approval, compounds
`and indications. In addition, we examined pivotal trial designs to illustrate quality indicators,
`such as randomization or control, in clinical research of approved orphan drugs to treat rare
`seizure conditions.
`
`Methods
`This cross-sectional analysis was conducted according to STrengthening the Reporting of
`OBservational studies in Epidemiology (STROBE) criteria.
`
`Data acquisition
`In December 2015, we searched the FDA database "Search Orphan Drug Designations and
`Approvals" [17], the EMA databases "Rare disease (orphan) designations" [18], "European
`public assessment reports/orphan medicines" [19], and "Register of designated Orphan Medic-
`inal Products" [20] for designated and approved orphan drugs to treat rare seizure conditions.
`First a semantic search was performed using search terms, such as seizure, epilepsy, status epi-
`lepticus, and spasm followed by a specific search for epilepsy syndromes based on the ILAE
`definition of electroclinical syndromes and other epilepsies [21]: West syndrome, Dravet syn-
`drome, myoclonic encephalopathy, Panayiotopoulos syndrome, Lennox-Gastaut syndrome,
`Landau-Kleffner syndrome, Otahara syndrome, and early myoclonic encephalopathy. Addi-
`tionally, an inverse search for known and new substances for epilepsy and seizure treatment
`based on recent EILAT reports [22] and ATC code (NO3A Antiepileptics) was added: brivara-
`cetam, bumetanide, cannabidiol, cannabidivarin, carbamazepine, carisbamate, clobazam, do-
`nazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine or retigabine,
`felbamate, fosphenytoin, gabapentin, ganaxolone, lacosamide, lamotrigine, levetiracetam, lor-
`azepam, metharbital, oxcarbazepine, paramethadione, perampanel, phenacemide, phenobarbi-
`tal, phenytoin, phensuximide, pregabalin, primidone, rufinamide, stiripentol, tiagabine,
`topiramate, trimethadione, valproic acid or valproate, vigabatrin, and zonisamide. The Orpha-
`net Report series was consulted for epidemiological data on rare seizure conditions [4]. Infor-
`mation on design and endpoints of clinical trials was extracted from the drug label which was
`accessed by entering the respective drug name as search term at https://www.accessdata.fda.
`gov/scripts/cder/drugsatfda/ or from the European Public Assessment Reports (EPAR). JHD
`and AL independently performed the database search and extracted the information from the
`databases.
`
`Definitions
`Time to FDA approval or marketing authorization by the EMA and European Commission
`was defined as the time period from orphan drug designation until approval by the FDA or
`EMA and European Commission.
`
`Statistical analysis
`Data were summarized using techniques of descriptive statistics. As such, continuous variables
`were summarized with means and standard deviations, and categorical variables were summa-
`rized with frequencies and percentages. Statistical analyses were performed using SAS Enter-
`prise Guide version 9.1 (SAS, Cary, NC, USA). Data from the FDA and EMA were analyzed
`both separately and comparatively. Missing data were not imputed and sensitivity analysis was
`not performed.
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`Results
`Designations and approvals
`The FDA granted 40 orphan drug designations for treatment of rare seizure conditions result-
`ing in nine approvals representing an acceptance rate of 23% (Fig 1). Two designations, i.e. Pr-
`122 (redox-phenytoin) and Pr-320 (molecusol-carbamazepine), were withdrawn. Reasons for
`non-approval were not publicly available. In the EU, six compounds received a positive opinion
`by the EMA's Committee on Orphan Medicines (COMP) and were designated as orphan
`drugs (Fig 1). Midazolam hydrochloride for oromucosal use for the treatment of seizures
`which continue for at least five minutes received a negative opinion. The European Commis-
`sion granted a central marketing authorization for two compounds to treat rare seizure condi-
`tions, i.e. rufinamide and stiripentol, representing an acceptance rate of 33%. Only rufinamide
`was designated and approved to treat Lennox-Gastaut syndrome in the US and in the EU.
`Eight compounds that were approved in the US for treatment of rare seizure conditions and
`epilepsy syndromes were not submitted for orphan drug designation in the EU, i.e. clobazam,
`diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine,
`repository corticotropin or adrenocorticotropic hormone, topiramate, and vigabatrin. Three of
`these compounds (i.e. clobazam, repository corticotropin or adrenocorticotropic hormone,
`and vigabatrin) were designated and approved in the US after the year 2000 when the Orphan
`Drug Regulation was already introduced in the EU. In total, 20 designations were obtained in
`the US after the Orphan Drug Regulation was introduced in 2000 in the EU, while these desig-
`nations were not obtained in the EU. Two compounds, i.e. fosphenytoin and repository corti-
`cotropin or adrenocorticotropic hormone, were first approved within the US Orphan Drug Act
`(Fig 1).
`Until December 2015, the US Orphan Drug Act has delivered 500 approved orphan drugs
`in total, while in the EU 103 orphan drugs have received marketing authorization since 2000.
`
`Time to approval
`Mean time to approval for orphan drugs for treating rare seizure conditions was 5.7 years
`(standard deviation ± 2.0 years, range 3 to 8.8 years) in the US and in the EU 2.2 years for rufi-
`namide and 5.1 years for stiripentol (Fig 2). For rufinamide, a compound that was approved in
`the US and the EU for the same indication, time to approval was 4.3 years in the US and 2.2
`years in the EU.
`
`Compounds and indications
`Cannabidiol obtained most designations (FDA N = 6 and EMA N = 1) (Table 1). Cannabidiol
`obtained two orphan drug designations by the FDA for treatment of Dravet syndrome (time
`difference between designations was 2 months) and two orphan drug designations for treat-
`ment of Lennox-Gastaut syndrome (time difference between designations was 4 months)
`(Table 1). Designations within the same conditions were granted by different companies. Des-
`ignations were most frequently granted for treatment of Lennox-Gastaut syndrome (FDA
`N = 8 and EMA N = 1), infantile spasms (West syndrome) (FDA N = 7 and EMA N = 1),
`and Dravet syndrome (severe myoclonic epilepsy in infancy) (FDA N = 4 and EMA N = 3)
`(Table 1). Orphan drugs were approved for conditions including Lennox-Gastaut syndrome,
`infantile spasms, Dravet syndrome, and status epilepticus. Most compounds were approved for
`treatment of Lennox-Gastaut (FDA N = 5 and EMA N = 1) (Table 1). Compounds designated
`in the US and the EU obtained orphan drug designation for the same indication. Rufinamide
`was approved in the US and in the EU for treatment of Lennox-Gastaut syndrome. Seven FDA
`
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`Orphan Drugs for Rare Seizures
`
`Eslicarbazepine acetate •
`Lacosamide*
`Rufinamide•
`Stiripentol•
`Pregabalin •
`Levetiracetam
`Tiagabine •
`Topiramate •
`Gabapentin•
`Felbamate•
`Oxcarbazepine •
`Lamotrigine • (cid:9)
`Zonisamide • (cid:9)
`Vigabatrin • (cid:9)
`Progabide• (cid:9)
`
`Diazepam intranasal 0
`Perampanel • (cid:9)
`OCannabidiol
`Cannabidiol 0
`Ganaxolone 0
`Cannabidiol 0
`Allopreganolone 0
`Cannabidiol 0
`Cannabidiol 0
`Fenfluramine hydrochloride 0
`Cannabidiol 0
`Sulthiame 0
`Topiramate injection 0
`Carbamazepine intravenous 0
`Diazepam auto-injector 0
`Tetracosactide hexaacetate (beta 1-24-corticotropin)O
`Diazepam intranasal 0
`MidazolamO
`Perampanel0
`Carisbamate0
`Pyridoxine°
`(15,35)-3-amino-4-(dufluormethylene)cyclopentanecarboxylic acid hydrochloride 0
`Levetiracetam 0
`Midazolam 0
`Stiripentol 0
`Clonazepam intranasal spray()
`
`ClobazamO
`Midazolam 0
`Bdvaracetam 0
`Rufinamide 0
`Repository corticotropin or adrenocorticotropic hormone°
`VigabatrinO
`
`Clobazam•
`
`DCannabidiol
`0 F..1 .ni..
`hydrochlonde
`
`II Rufinamide
`•Stiripentol
`
`Clobazam•
`LamotrigineO (cid:9)
`• Reposilory cortiookoein
`Ganaxolone 0
`Vigabatrin•
`Topiramate 0
`Rufinamide• (cid:9)
`Diazepam viscous solution for rectal administration 0 (cid:9)
`Topiramate.
`Fosphenytoin 0 (cid:9)
`(15.3.5).3.anvno.4-(dufluormelhylene3 (cid:9)
`.. (cid:9)
`Lamotrigine
`cyclopentanecarboxylb SCA hydrochionde 0 (cid:9)
`PR-320 (M olecusol-Ca rbamazepine) 0 D.z.,,,,wous ,,,,,,,,,,, • (cid:9)
`PR-122(Redox-Phenytoin) 0 br rectal edreinIsration• (cid:9)
`Brivaracetam0
`Antiepilepsirine 0 (cid:9)
`Fosphenytoin • (cid:9)
`Rufinamide0 (cid:9)
`Felbamat 0 FelbamatO (cid:9)
`Stiripentol 0 (cid:9)
`
`40
`
`35
`
`30
`
`25
`
`20 (cid:9)
`
`15 (cid:9)
`
`10 (cid:9)
`
`5 (cid:9)
`
`0
`1850 (cid:9)
`
`Clonazepam•
`Valproate •
`Carbamazepin•
`Diazepam*
`Sulthiame •
`Chlordiazepoxide•
`Ethosuximide •
`Ethotoin •
`Methsuximide •
`Primidone*
`Phensuximide•
`Phenacemide•
`Corticosteroids/ACTH•
`Paramethadione •
`Mephenytoin •
`Trimethadione •
`Acetazolamide •
`Phenytoin •
`Mephobarbital•
`Phenobarbital*
`Borax*
`*Bromide
`
`1900 (cid:9)
`
`1950 (cid:9)
`
`1960 (cid:9)
`
`1970 (cid:9)
`
`1985 (cid:9)
`1980 (cid:9)
`Year of introduction
`
`1990
`
`1995
`
`2000
`
`2005
`
`2010
`
`2015
`
`Fig 1. Cumulative number of approved non-orphan antiepileptic drugs (•) illustrating the year of first licensing or the first mention of
`clinical use in a country of Europe, the United States, or Japan (adapted from [31]). Cumulative number of US orphan drug designations (0) and
`approvals (0). Cumulative number of orphan drug designations (1=1) and approvals (•) in the EU.
`
`doi:10.1371/journal.pone.0161660.g001
`
`10-
`
`8-
`
`6-
`
`4-
`
`2-
`
`• •
`•
`
`• •
`• •
`•
`•
`
`•
`
`•
`
`time to approva
`
`0
`
`FDA (cid:9)
`EMA
`Fig 2. Time to approval of compounds intended to treat orphan epileptic conditions. Lines indicate
`means.
`
`doi:10.1371/journal.pone.0161660.g002
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`Orphan Drugs for Rare Seizures
`
`Table 1. Compounds for rare seizure conditions designated or approved by the FDA and EMA.
`
`Compound (cid:9)
`
`Regulatory
`authority
`
`Condition
`
`(15,35)-3-amino-4-(difluoromethylene) FDA
`cyclopentanecarboxylic acid
`EMA
`hydrochloride
`
`Treatment of infantile spasms
`
`Treatment of infantile spasms
`
`Date of designation (cid:9)
`(FDA) or positive
`opinion (EMA)
`15 September 2010
`09 February 2012
`
`Date of approval (FDA) or
`marketing authorization
`(EMA)
`n/a
`n/a
`
`Allopregnanolone (cid:9)
`Antiepilepsirine
`
`Brivaracetam
`
`Cannabidiol
`
`Carbamazepine intravenous
`
`Carisbamate (cid:9)
`Clobazam (cid:9)
`Clonazepam intranasal (cid:9)
`Diazepam intranasal (cid:9)
`
`Diazepam auto-injector
`
`FDA
`
`I FDA
`
`FDA
`EMA
`FDA
`
`EMA
`FDA
`
`FDA
`FDA
`FDA
`FDA
`
`FDA
`
`Diazepam viscous solution for rectal
`administration
`
`FDA
`
`Felbamate
`Fenfluramine hydrochloride
`
`Fosphenytoin (cid:9)
`
`Ganaxolone
`
`Lamotrigine
`Levetiracetam
`Midazolam
`
`FDA
`FDA
`
`EMA
`FDA
`
`FDA
`
`FDA
`FDA (cid:9)
`FDA
`
`Perampanel
`PR-122 (Redox-Phenytoin)
`
`FDA
`FDA
`
`PR-320 (Molecusol-Carbamazepine)
`
`FDA
`
`Pyridoxine (Vitamin B6)
`Repository corticotropin or
`adrenocorticotropic hormone
`
`FDA
`FDA (cid:9)
`
`Treatment of status epilepticus (cid:9)
`Treatment of drug resistant generalized tonic-clonic (cid:9)
`epilepsy in children and adults
`Treatment of symptomatic myoclonus
`Treatment of progressive myoclonic epilepsies
`Treatment of infantile spasms
`Treatment of neonatal hypoxic ischemic encephalopathy
`Treatment of Lennox-Gastaut syndrome (cid:9)
`Treatment of Lennox-Gastaut syndrome (cid:9)
`Treatment of Dravet syndrome
`Treatment of Dravet syndrome
`Treatment of Dravet syndrome
`Treatment of epilepsy patients who cannot take anything by
`mouth
`
`Treatment of infantile spasms (cid:9)
`Treatment of Lennox-Gastaut Syndrome (cid:9)
`Treatment of recurrent acute repetitive seizures (cid:9)
`Management of acute repetitive seizures (cid:9)
`Management of acute repetitive seizures (cid:9)
`Management of selected, refractory patients with epilepsy
`on stable regimens of antiepileptic drugs, who require
`intermittent use of diazepam to control bouts of increased
`seizure activity
`Management of selected, refractory, patients with epilepsy
`on stable regimens of antiepileptic drugs, who require
`intermittent use of diazepam to control bouts of increased
`seizure activity
`Treatment of Lennox-Gastaut syndrome. (cid:9)
`Treatment of Dravet Syndrome
`Treatment of Dravet syndrome
`For the acute treatment of patients with status epilepticus of
`the grand mal type
`Treatment of Protocadherin 19 (PCDH19) female epilepsy
`Treatment of infantile spasms
`Treatment of Lennox-Gastaut syndrome
`Treatment of neonatal seizures
`Treatment of nerve agent-induced seizures
`Rescue treatment of seizures in patients who require control
`of intermittent bouts of increased seizure activity (e.g. acute
`repetitive seizures, seizure clusters)
`Treatment of bouts of increased seizure activity in selected
`refractory patients with epilepsy who are on stable regimens
`of anti-epileptic drugs and who require intermittent use of
`midazolam
`Treatment of Lennox-Gastaut Syndrome
`For the emergency rescue treatment of status epilepticus,
`grand mal type.
`For the emergency rescue treatment of status epilepticus,
`grand mal type.
`Treatment of pyridoxine dependent seizures.
`Treatment of infantile spasms
`
`20 April 2014
`
`23 March 1989
`
`10 May 2005
`26 August 2005
`23 July 2015
`22 April 2015
`23 June 2014
`27 February 2014
`7 January 2014
`
`14 November 2013
`15 October 2014 (cid:9)
`27 June 2013 (cid:9)
`
`16 March 2012 (cid:9)
`
`18 December 2007
`19 December 2007
`16 November 2015
`
`31 July 2012
`
`30 May 2013
`
`n/a
`
`n/a
`
`n/a
`n/a
`n/a
`n/a
`
`n/a
`n/a
`n/a
`n/a
`n/a
`n/a
`
`n/a
`21 October 2011
`n/a
`n/a
`n/a
`n/a
`
`25 February 1992
`
`27 July 1997
`
`24 January 1989
`20 December 2013
`16 January 2014
`06 April 1991
`
`29 July 1993
`n/a
`n/a
`08 May 1996
`
`24 March 2015
`25 May 1994
`23 August 1995
`30 April 2010
`24 July 2012
`20 October.2009
`
`05 August 2006
`
`12 July 2012
`07 May 1990
`
`20 July 1990
`
`3 March 2011
`21 May 2003
`
`n/a
`n/a
`24 August 1998
`n/a
`n/a
`n/a
`
`n/a
`n/a
`
`n/a
`
`n/a
`15 October 2010
`
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`Table 1. (Continued)
`
`Compound
`
`Regulatory Condition
`authority
`
`Rufinamide
`
`Stiripentol
`
`Sulthiame
`
`FDA
`EMA
`FDA
`EMA
`FDA
`
`Tetracosactide hexaacetate (beta FDA
`1-24-corticotropin)
`Topiramate (cid:9)
`Topiramate injection (cid:9)
`
`FDA
`FDA
`
`Vigabatrin
`
`FDA
`
`Treatment of Lennox-Gastaut Syndrome.
`Treatment of Lennox-Gastaut syndrome
`Treatment of Dravet syndrome
`Treatment of Dravet syndrome
`Treatment of patients with benign epilepsy of (cid:9)
`childhood with centrotemporal spikes (BECTS) also
`known as rolandic epilepsy
`I Treatment of infantile spasms
`
`Treatment of Lennox-Gastaut syndrome
`Treatment of partial onset or primary generalized
`tonic-clonic seizures for hospitalized epilepsy
`patients or epilepsy patients being treated in an
`emergency care setting who are unable to take oral
`topiramate
`Treatment of infantile spasms
`
`n/a = not applicable because compound is not approved.
`
`doi:10.1371/journal.pone.0161660.t001
`
`Orphan Drugs for Rare Seizures
`
`Date of designation
`(FDA) or positive
`opinion (EMA)
`10 August 2004
`20 October 2004
`30 October 2008
`5 December 2001
`25 July 2013
`
`Date of approval (FDA)
`or marketing
`authorization (EMA)
`14 November 2008
`16 January 2007
`n/a
`4 January 2007
`n/a
`
`31 October 2012
`
`n/a
`
`25 November 1992
`24 July 2013
`
`28 August 2001
`n/a
`
`6 December 2000
`
`21 August 2009
`
`orphan drug designations focused on a route of administration other than the oral route for
`acute clinical conditions or when patients are unable to take anything by mouth, i.e. intrave-
`nous carbamazepine (N = 1), intranasal clonazepam (N = 1), intranasal diazepam (N = 2),
`diazepam in an auto-injector (N = 1), viscous solution for rectal administration of diazepam
`(N = 1), and injectable topiramate (N = 1).
`
`Pivotal clinical trial designs, primary outcomes, and sponsors
`Except for fosphenytoin, where a bioequivalence study in comparison to phenytoin was per-
`formed, all other pivotal clinical trials were randomized controlled trials (Table 2). The main
`outcome measure in most studies was seizure frequency (N = 10 studies). All drug develop-
`ment programs investigating compounds for treatment of West syndrome (N = 2) focused on
`proportion of seizure-free patients as an outcome measure. Pivotal clinical trials were small
`(population size between N = 29 and N = 298) and short (12 hours to 19 weeks). For orphan
`drug designations granted by the FDA, 39 sponsors were pharmaceutical companies and one
`sponsor was a university (levetiracetam for the treatment of neonatal seizures). For FDA
`orphan drug designations, 36 sponsors were located in the US, three in the UK, and one in
`France. For orphan drug designations in the EU, four sponsors were located in the UK, one
`sponsor in France, and one sponsor in Belgium.
`
`Discussion
`Productivity output
`Our analysis revealed that in the US nine compounds and in the EU two compounds were
`approved to treat rare seizure conditions. The ratio between orphan drug designation and
`approval was higher in the EU which is contradictory to general acceptance rates, i.e. 15.4% in
`the US and 7% in the EU [3]. However, in relation to the low number of designated orphan
`drugs to treat rare seizure conditions in the EU, the approval of one compound less would
`
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`Page 00007
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Table 2. Pivotal clinical trial design of FDA and EMA approved compounds for rare seizure conditions.
`
`Study duration
`
`Main outcome measures and top line
`results*
`
`Generic Name (cid:9)
`
`Approved Indication (cid:9)
`
`Clobazam (cid:9)
`
`Adjunctive treatment of seizures (cid:9)
`associated with Lennox-Gastaut (cid:9)
`Syndrome inpatients 2 years of age or
`older
`
`N ' Age (years) (cid:9)
`
`Study (cid:9)
`design
`Description of pivotal clinical trial
`RCT (cid:9)
`238 2-54 (cid:9)
`
`4 wk baseline, 3 wk titration,
`12 wk maintenance period
`
`add-on therapy with clobazam vs. placebo
`RCT
`68 2-25 (cid:9)
`4 wk baseline, 3 wk titration,
`4 wk maintenance period
`
`Diazepam viscous
`solution for rectal
`administration
`
`Management of selected, refractory,
`patients with epilepsy on stable regimens
`of antiepileptic drugs, who require
`intermittent use of diazepam to control
`bouts of increased seizure activity
`
`high dose vs. low dose
`91 (cid:9)
`n/a (47 children, (cid:9)
`44 adults) (cid:9)
`
`observation period 12-24
`hours after fist application
`
`sequential doses of diazepam rectal gel vs. placebo
`RCT (cid:9)
`114 n/a (53 children, (cid:9)
`observation period 12 hours
`61 adults) (cid:9)
`after application
`
`Felbamate
`
`single doses of diazepam rectal gel vs. placebo
`n/a (cid:9) n/a (cid:9)
`As adjunctive therapy in the treatment of RCT
`baseline period, 70 days
`observation period
`partial and generalized seizures
`associated with the Lennox-Gastaut
`syndrome in children
`
`0
`
`Orphan Drugs for Rare Seizures
`
`• percent reduction in weekly frequency of drop
`attacks from 4 wk baseline to 12 wk
`maintenance period
`• placebo: -12.1%
`• low dose:-41.2%
`• medium dose -49.4%
`• high dose: -68.3%
`
`• percent reduction in weekly frequency of drop
`attacks from 4 wk baseline to 4 wk
`maintenance period
`• high dose: -93%
`• low dose: -29%
`
`• seizure frequency during the period of
`observation and a global assessment of
`severity and nature of seizures
`• diazepam: 0 seizures/hour
`• placebo: 0.3 seizures/hour
`
`• seizure frequency during the period of
`observation
`• diazepam: 0 seizures/12 hours
`• placebo: 2.0 seizures/12 hours
`
`• seizure frequency during the period of
`observation, parent/guardian global
`evaluations
`• felbamate: -26% (total seizures)
`• placebo: +5% (total seizures)
`
`Fosphenytoin
`
`For the acute treatment of patients with
`status epilepticus of the grand mal type
`
`add-on therapy with felbamate to 1-2 antiepileptic drugs vs. placebo
`112 n/a (cid:9)
`n/a
`n/a (cid:9)
`• infusion tolerance fosphenytoin vs. iv
`phenytoin
`• local intolerance (9% vs. 90%)
`• infusion disrupted (21% vs. 67%)
`• infusion time (13 min vs. 44 min)
`
`ADME and infusion tolerance fosphenytoin vs. phenytoin
`
`(Continued)
`
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`co
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`

`
`Table 2. (Continued)
`
`Generic Name
`
`Lamotrigine
`
`Repository
`corticotropin or
`adreno-corticotropic
`hormone
`
`PLOS ONE I D01:10.1371/journal.pone.0161660 August 24, 2016
`
`Co
`
`Orphan Drugs for Rare Seizures
`
`• percent change in total seizure frequency per
`28 days; The percent change in tonic-atonic
`(drop attacks) seizure frequency per 28 days;
`Seizure severity from the Parent/Guardian
`Global Evaluation of the patient's condition
`• rufinamide -35.8% (total seizures)
`• placebo -1.6% (total seizures)
`
`• more than 50% reduction in the seizure
`frequency
`• stiripentol: 72% responders
`• placebo: 5% responders
`
`• effectiveness were the percent reduction in
`drop attacks and a parental global rating of
`seizure severity
`• topiramate: 14.8% (reduction in
`drop attacks)
`• placebo: -5.1% (reduction in drop
`attacks)
`
`(Continued)
`
`Rufinamide
`
`Adjunctive therapy of seizures
`associated with Lennox-Gastaut
`syndrome. (cid:9)
`
`high-dose corticotropin vs. prednisone
`4 wk stable baseline
`RCT (cid:9)
`139 4-30 (cid:9)
`followed by 12 wk double-
`blind phase (2 wk titration,
`10 wk maintenance)
`
`Stiripentol
`
`Topiramate
`
`As adjunctive therapy of refractory
`generalized tonic-clonic seizures in
`patients with severe myoclonic epilepsy
`in infancy (Dravet syndrome) whose
`seizures are not adequately controlled
`with clobazam and valproate.
`
`As adjunctive therapy in patients two (cid:9)
`years and older with seizures associated (cid:9)
`with Lennox-Gastaut syndrome
`
`add-on therapy with rufinamide vs. placebo
`RCT (cid:9)
`41 >3 (cid:9)
`4 wk baseline, 8 wk
`observation
`
`add-on therapy to clobazam and valproate
`RCT (cid:9)
`4 wk baseline, 3 wk titration,
`95 > 2 (cid:9)
`8 wk stabilization
`
`add-on therapy with topiramate vs. placebo
`
`Study duration
`
`Main outcome measures and top line
`results*
`
`Approved Indication
`
`Monotherapy to treat infantile spasms (cid:9)
`
`Study IN Age (years) (cid:9)
`design (cid:9)
`Description of pivotal clinical trial
`Adjunctive treatment of Lennox-Gastaut RCT (cid:9)
`169 lamotrigine mean 4 wk baseline, 6 wk titration, • change in percent from baseline in the
`syndrome in pediatric and adult patients. (cid:9)
`frequency of drop attacks and tonic-clonic
`9,6 years, placebo 10 wk observation period (2 (cid:9)
`mean 10.9 years wk fixed dose, 8 wk dose (cid:9)
`seizures
`could be increased)
`• lamotrigine:-34% (drop attacks)
`• placebo: -9% (drop attacks)
`add-on therapy with Lamotrigine to 1-2 antiepileptic drugs vs. placebo
`14 days (cid:9)
`RCT (cid:9)
`29 <2 (cid:9)
`• number of patients having complete
`suppression of both clinical spasms and
`hypsarrhythmia
`• corticotropin: 86.7%
`• prednisone: 28.6%
`
`Page 00009
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Table 2. (Continued)
`
`Generic Name (cid:9)
`
`Approved Indication
`
`Vigabatrin
`
`For infantile spasms (IS)-1 month to 2
`years of age
`
`Study N Age (years) (cid:9)
`design
`Description of pivotal clinical trial
`RCT (cid:9)
`221 < 2
`
`Study duration
`
`Main outcome measures and top line
`results*
`
`Titration over 7 days,
`followed by a constant dose
`for 7-14 days.
`
`• proportion of patients who were spasm-free
`for 7 consecutive days beginning within the
`first 14 days of vigabatrin therapy
`• low-dose: 7%
`• high-dose: 15.9%
`
`• post-hoc alternative efficacy analysis
`(average percent change in daily spasm
`frequency), using a 24-hour clinical
`evaluation window:
`• vigabatrin: -68.9%
`• placebo: -17.0%
`
`high dose vs. low dose
`RCT 40 n/a
`
`Baseline 2-3 days, followed
`by a 5-day treatment phase
`with vigabatrin