Ganaxolone as adjuvant therapy for epilepsy with cyclin-dependent kinase-like 5 deficiency disorder
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HEALTH TECHNOLOGY BRIEFING
MAY 2021
Ganaxolone as adjuvant therapy for
epilepsy with cyclin-dependent kinase-like
5 deficiency disorder
NIHRIO ID 20377 NICE ID 10560
Developer/Company Marinus UKPS ID N/A
Pharmaceuticals
Inc
Licensing and Recently completed phase III clinical trials.
market availability
plans
SUMMARY
Ganaxolone is in development, as a novel treatment option for children and young adults
with Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD). CDD is a debilitating
disease that mainly manifests in children within a few months of birth. It affects the brain by
impairing development, including the ability to learn speech and coordinate movement, and
causes frequent epileptic seizures. Children with CDD are unable to communicate verbally
and often require the use of tube feeding due to the physical difficulties associated with the
disorder.
Ganaxolone is administered as an oral suspension to be taken three times a day. It is an
agonist (initiator) for a receptor in the brain called GABAA, this means it “switches on” the
receptor resulting in a mechanism that suppresses neurone activity. By doing so it reduces
the chance of seizures occurring. If licenced, ganaxolone may offer a treatment option
where none is currently available for this specific condition.
This briefing reflects the evidence available at the time of writing and a limited literature search.
It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health
technology covered and should not be used for commercial purposes or commissioning without
additional information. A version of the briefing was sent to the company for a factual accuracy
check. The company was available to comment.
Page 1 of 7PROPOSED INDICATION
Adjuvant therapy for the treatment of seizures in paediatrics and young adults 2 years of
age and older with genetically confirmed CDKL5 gene mutation.a
TECHNOLOGY
DESCRIPTION
Ganaxolone (CCD-1042) is a new molecular entity1 that is a synthetic analogue (a molecule
that is similar in structure and function) of the natural neurosteroid allopregnanolone.2,3 It is
a GABAA receptor agonist1,2 meaning it can initiate the GABAergic mechanism in order to
inhibit neuronal excitation. It does so through by allowing chloride ions to enter post-
synaptic neurons and inhibit neuronal transmission.2 This is expected to calm excess
electrical activity in the brain from seizures and improve symptoms.4
Ganaxolone is in phase III clinical development for the treatment of paediatric patients and
young adults with epileptic seizures due to CDD.5 It is administered in doses of
63mg/kg/day (up to 1,800mg/day), three times daily as an oral suspension for 17 weeks.a
INNOVATION AND/OR ADVANTAGES
There are no curative or specific treatments for patients with CDD.4,6
Allopregnanolone binds to a distinctive binding site on GABAA that is different to GABA,
benzodiazepines, and barbiturates, which could be important for the treatment of patients
who have developed tolerance to benzodiazepines and barbiturates. However, there is an
issue with back-conversion of allopregnanolone to its metabolic precursor progesterone.
Ganaxolone shows similar potency and efficacy to allopregnanolone but has an added
methyl group to prevent back-conversion to progesterone.2
DEVELOPMENT STATUS AND/OR REGULATORY DESIGNATIONS
Ganaxolone does not currently have Marketing Authorisation in the EU/UK for any
indication.
Ganaxolone is in phase II and III clinical trials for:a
• Tuberous sclerosis (oral ganaxolone)
• Status epilepticus (IV ganaxolone)
Ganaxolone has an Orphan Drug designation in the EU in November 2019 for the treatment
of CDD.4
a Information provided by Marinus Pharmaceuticals Inc.
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
Page 2 of 7PATIENT GROUP
DISEASE BACKGROUND
Gamma (ƴ) aminobutyric acid (GABA) is an amino acid made by the body that inhibits
neurotransmission in the brain to counteract neuronal excitation.7,8 GABA is formed within
GABAergic axon terminals and is released into the synapse, where it binds to GABA
receptors to induce this response.7 There are two types of receptors: GABAA which controls
chloride entry into the cell, and GABAB which increases potassium conduction, decreases
calcium entry and inhibits presynaptic release of other transmitters. The GABAergic
inhibition is primarily mediated by synaptic GABAA receptors.7 Research indicates GABA has
an important role in the mechanism and treatment of epilepsy, particularly if there are
abnormalities in GABAergic function (including the GABA receptors and GABA
production).7,8
CDD is a rare X-linked genetic disorder, which results in a distinct developmental epileptic
encephalopathy (DEE).6,9,10 DEEs are characterised by early-onset refractory epilepsy, severe
neurodevelopmental impairment and major motor delay.11 Seizures associated with CDD are
highly refractory to treatment with existing antiseizure medications and improvements may
be short lived.12 CDKL5 instructs protein synthesis that is essential for normal brain and
neuron development, including regulating neuronal proliferation, maturation and synaptic
plasticity.9,13 Whilst CDD is genetic it appears that most mutations are “de novo”, meaning
they spontaneously occur, as opposed to being hereditary (passed down through families).9
Most people with CDD begin having epileptic seizures within the first few months of life and
typically have difficulty moving, talking, and eating and drinking. Other symptoms include
cortical visual impairment, constipation, sleep difficulties, hand stereotypies, teeth-grinding
(bruxism), poor muscle tone (hypotonia), intellectual disability, hypersensitivity to touch,
gastroesophageal reflux, gastrointestinal problems, breathing irregularities, curved spine
(scoliosis), difficulty making purposeful movements (apraxia), and limited motor skills.9,10,14
There is no known cause of spontaneous CDLK5 gene mutations, however these have been
found in children diagnosed with Infantile Spasms, West Syndrome, Lennox-Gastaut, Rett
Syndrome, cerebral palsy, autism and intractable epilepsy of unknown origin.9,15
Children with CDD typically have 1-5 seizures a day, and 1 in 5 children use a feeding tube
due to eating difficulties.16
From a study on quality of life (QOL) in individuals with CDD, participants’ physical health
was primarily affected by seizures, with most experiencing daily seizures that took longer
recovery times. It was found that comorbidities, such as gastrointestinal problems and sleep
difficulties, affected participants’ daily routines including education, attending therapies and
social inclusion. Most children in the study were nonverbal (21/25) meaning they relied on
their caregivers to recognise changes in their behaviour and vocalisations to make their
needs known.17
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
Page 3 of 7CLINICAL NEED AND BURDEN OF DISEASE
In the UK there are 750 new CDD cases registered every year, with over 13,000 families
affected.18
In England in 2019-20 there were 1,820 finished consultant episodes (ICD-10 code G40.4
“Other generalized epilepsy and epileptic syndromes”, which includes CDD ICD-10 code
G40.42),19 which resulted in 387 day cases and 5,342 FCE bed days.20
Due to CDD being X-linked it affects more females than males (5 times more).9,10,18 However,
males with the disorder are affected more severely than females.10
Occurrence of CDD is believed to be 1 in 40,000-60,000 live births, making it one of the
most common forms of genetic epilepsy.9,13 At least two children are diagnosed with CDD
each week. Most newly diagnosed are paediatric patients, with some adults being reportedly
diagnosed in their 40s and 50s. As CDD discovery is still relatively new, as the causative gene
was discovered in 2004, it is unclear what the life expectancy is for patients.9
PATIENT TREATMENT PATHWAY
TREATMENT PATHWAY
Seizures associated with CDD are difficult to treat and families report periods of time where
their children are seizure-free after starting a new medication, however the seizures often
return as antiseizure medicines lose their efficacy.9,12 There are no specific treatments for
CDD, but the condition is managed with epilepsy medications and a low-carbohydrate diet
(ketogenic diet).4 Additional options include vagal nerve stimulation, neurosurgery such as
corpus callosotomy (surgical severance of corpus callosum to limit seizure activity spreading
between the two halves of the brain) and other dietary changes.9 Early interventional
therapies, such as physical/physiotherapy, occupational, speech and augmentative
communication are recommended.6
CURRENT TREATMENT OPTIONS
The common pharmacological treatment for CDD are anti-epileptic drugs (AEDs).4,9
PLACE OF TECHNOLOGY
Ganaxolone could offer an option for patients with CDD who have no current specific
treatment and an unmet need.4
CLINICAL TRIAL INFORMATION
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
Page 4 of 7Trial Marigold; NCT03572933; 2018-001180-23; A Double-
blind, Randomized, Placebo-controlled Trial of Adjunctive
Ganaxolone Treatment in Children and Young Adults With
Cyclin-dependent Kinase-like 5 (CDKL5) Deficiency Disorder
(CDD) Followed by Long-term Open-label Treatment
Phase III – Completedb
Location(s): EU (including UK), USA, Australia, Russia and
Israel
Primary completion date: July 2020
Trial design Randomised, quadruple-masked, parallel assignment.
Population N=101 b (actual); aged 2 to 21 years old; genetically
confirmed CDKL5 gene mutation; seizure onset by 1 year of
age; lack of independent ambulation by 2 years of age;
failure to control seizures despite 2 or more anti-seizure
medications.
Intervention(s) Ganaxolone oral suspension (50mg/ml) 63mg/kg/day (up to
1,800mg/day) three times a day for 17 weeks.b
Comparator(s) Matched placebo.
Outcome(s) Percent change in 28-day major motor seizure frequency [
Time Frame: End of the double-blind 17 week treatment
period ].b
See trial record for full list of other outcomes.
Results (efficacy) Median 28-day major motor seizure frequency reduction of
32.2 percent compared to 4.0 percent for placebo
(p=0.002).21
Results (safety) Ganaxolone was generally well tolerated and the
discontinuation rate in the active treatment arm was less
than 5 percent.21
ESTIMATED COST
The cost of ganaxolone is not yet known.
RELEVANT GUIDANCE
NICE GUIDANCE
No relevant guidance found.
NHS ENGLAND (POLICY/COMMISSIONING) GUIDANCE
b Information provided by Marinus Pharmaceuticals Inc.
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
Page 5 of 7No relevant guidance found.
OTHER GUIDANCE
• International Foundation for CDKL5 Research. CDKL5 Disorder: An Introductory
Guide. 201722
ADDITIONAL INFORMATION
Marinus Pharmaceuticals Inc did not enter information about this technology onto the UK
PharmaScan database; the primary source of information for UK horizon scanning
organisations on new medicines in development. As a result, the NIHR Innovation
Observatory has had to obtain data from other sources. UK PharmaScan is an essential tool
to support effective NHS forward planning; allowing more effective decision making and
faster uptake of innovative new medicines for patients who could benefit. We urge
pharmaceutical companies to use UK PharmaScan so that we can be assured of up-to-date,
accurate and comprehensive information on new medicines.
REFERENCES
1 Specialist Pharmacy Service. Ganaxolone. 2020. Available from:
https://www.sps.nhs.uk/medicines/ganaxolone/ [Accessed 16 Mar 2021].
2 Marinus Pharmaceuticals Inc. Ganaxolone Mechanism of Action. 2016. Available from:
https://vimeo.com/150832614 [Accessed 16 Mar 2021].
3 Reddy DS. Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials.
Progress in Brain Research. 2010;186:113-37. Available from:
https://dx.doi.org/10.1016%2FB978-0-444-53630-3.00008-7.
4 European Medicines Agency (EMA). EU/3/19/2224 - Orphan designation for ganaxolone for the
treatment of CDKL5 deficiency disorder. 2019. Available from:
https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3192224 [Accessed
17 Mar 2021].
5 Clinicaltrials.gov. Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With
CDKL5 Deficiency Disorder (Marigold). Trial ID: NCT03572933. 2018. Status: Active, not
recruiting. Available from: https://clinicaltrials.gov/ct2/show/NCT03572933 [Accessed 16 Mar
2021].
6 National Organization for Rare Disorders (NORD). CDKL5 Deficiency Disorder 2020. Available
from: https://rarediseases.org/rare-diseases/cdkl5/ [Accessed 17 Mar 2021].
7 Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(suppl. 3):8-12. Available
from: https://doi.org/10.1046/j.1528-1157.2001.042suppl.3008.x.
8 Epilepsy Foundation. GABA Receptors in Status Epilepticus. 2018. Available from:
https://www.epilepsy.com/article/2018/2/gaba-receptors-status-epilepticus [Accessed 16 Mar
2021].
9 International Foundation for CDKL5 Research (IFCR). About CDKL5. 2021. Available from:
https://www.cdkl5.com/about-cdkl5/ [Accessed 18 Mar 2021].
10 Epilepsy Foundation. CDKL5 Disorder. 2015. Available from:
https://www.epilepsy.com/learn/epilepsy-due-specific-causes/genetic-causes-epilepsy/specific-
genetic-epilepsies/cdkl5 [Accessed 18 Mar 2021].
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
Page 6 of 711 Olson HE, Demarest ST, Pestana-Knight EM, Swanson LC, Iqbal S, Lal D, et al. Cyclin-Dependent
Kinase-Like 5 Deficiency Disorder: Clinical Review. Pediatr Neurol. 2019 Aug;97:18-25. Available
from: https://doi.org/10.1016/j.pediatrneurol.2019.02.015.
12 Müller A, Helbig I, Jansen C, Bast T, Guerrini R, Jähn J, et al. Retrospective evaluation of low
long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related
epilepsy. Eur J Paediatr Neurol. 2016 Jan;20(1):147-51. Available from:
https://doi.org/10.1016/j.ejpn.2015.09.001.
13 Jakimiec M, Paprocka J, Śmigiel R. CDKL5 Deficiency Disorder-A Complex Epileptic
Encephalopathy. Brain sciences. 2020;10(2):107. Available from:
https://doi.org/10.3390/brainsci10020107.
14 CDKL5 UK. What is CDKL5 Disorder. 2021. Available from: https://curecdkl5.org.uk/what-is-
cdkl5/cdkl5-description/ [Accessed 18 Mar 2021].
15 CDKL5 UK. History of CDKL5. 2021. Available from: https://curecdkl5.org.uk/history-of-cdkl5/
[Accessed 18 Mar 2021].
16 Genetic and Rare Diseases Information Center (GARD). CDKL5 deficiency disorder. 2018.
Available from: https://rarediseases.info.nih.gov/diseases/12173/cdkl5-deficiency-disorder
[Accessed 18 Mar 2021].
17 Tangarorang J, Leonard H, Epstein A, Downs J. A framework for understanding quality of life
domains in individuals with the CDKL5 deficiency disorder. American Journal of Medical Genetics.
2019 Feb;179(2):249-56. Available from: https://doi.org/10.1002/ajmg.a.61012.
18 CDKL5 UK. About Us. 2021. Available from: https://curecdkl5.org.uk/cdkl5-uk/ [Accessed 18 Mar
2021].
19 International Foundation for CDKL5 Research (IFCR). CDKL5 Deficiency Receives ICD-10-CM
code: G40.42. Available from: https://www.cdkl5.com/news-list/cdkl5-deficiency-receives-icd-10-
cm-code/ [Accessed 25 Mar 2021].
20 NHS Digital. Hospital Episode Statistics for England. Admitted Patient Care statistics, 2019-20.
Available from: https://digital.nhs.uk/data-and-information/publications/statistical/hospital-
admitted-patient-care-activity/2019-20 [Accessed 25 Mar 2021].
21 Marinus Pharmaceuticals Inc. Ganaxolone Achieves Primary Endpoint in Phase 3 Trial for CDKL5
Deficiency Disorder (CDD), a Rare Form of Genetic Epilepsy. 2020. Available from:
https://ir.marinuspharma.com/news/news-details/2020/Ganaxolone-Achieves-Primary-
Endpoint-in-Phase-3-Trial-for-CDKL5-Deficiency-Disorder-CDD-a-Rare-Form-of-Genetic-
Epilepsy/default.aspx [Accessed 18 Mar 2021].
22 International Foundation for CDKL5 Research (IFCR). CDKL5 Disorder: An Introductory Guide.
2017. Available from: https://www.cdkl5.com/wp-
content/uploads/2017/01/CDKL5_Introductory-Guide.pdf [Accessed 13 Mar 2021].
NB: This briefing presents independent research funded by the National Institute for Health
Research (NIHR). The views expressed are those of the author and not necessarily those of the
NHS, the NIHR or the Department of Health.
Copyright © National Institute for Health Research Innovation Observatory (NIHRIO), The University of Newcastle upon Tyne
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