Delving into the Latest Updates on Ganaxolone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Ganaxalone-IV, Ganaxolone (USAN/INN), gnx

+ [4]

Target

GABAA receptor

Mechanism

GABAA receptor positive allosteric modulators(Gamma-aminobutyric acid A receptor positive allosteric modulators)

Therapeutic Areas

Nervous System DiseasesNeoplasmsCongenital Disorders+ [2]

Active Indication

SeizuresCDKL5 Deficiency DisorderEpilepsy+ [5]

Inactive Indication

Arthropathy, Progressive Pseudorheumatoid, of ChildhoodBehavioural disordersDepression, Postpartum+ [8]

Originator Organization

Purdue Pharma LP

Active Organization

Tenacia Biotechnology (Shanghai) Co. Ltd.

Marinus Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

US (18 Mar 2022),

CDKL5 Deficiency Disorder

RegulationOrphan Drug (US), Rare Pediatric Disease (US), Priority Review (US), Priority Review (CN), Orphan Drug (EU)

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Structure

Molecular FormulaC22H36O2

InChIKeyPGTVWKLGGCQMBR-FLBATMFCSA-N

CAS Registry38398-32-2

This study will assess the efficacy, safety, and tolerability of ganaxolone (GNX) compared with placebo (PBO) as adjunctive therapy to the participant's standard anti-epileptic medication for the treatment of seizures in pediatric patients from 6 months to less than 2 years old with genetically confirmed CDD during a 12-week, DB phase. Pharmacokinetic (PK) assessments and population PK analyses will also be performed during this time. The DB phase will be followed by an optional long-term OL phase at which time all participants will receive GNX as an adjunct to their standard anti-seizure medication. Efficacy, safety and tolerability, and PK assessments will continue to be performed.

Start Date01 Dec 2024

Sponsor / Collaborator

Marinus Pharmaceuticals, Inc.

NCT05814523 / WithdrawnPhase 3

A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Intravenous Ganaxolone Added to Standard of Care in Refractory Status Epilepticus

This is a multicenter, double-blind, randomized, placebo-controlled study that will evaluate the efficacy, safety, and tolerability of intravenous (IV) ganaxolone versus placebo co-administered with IV antiepileptic drug (AED) according to standard of care for the treatment of RSE. Approximately 70 participants will be randomized in a 1:1 ratio to receive ganaxolone IV solution or placebo IV solution along with standard of care (SOC) IV AED.

Start Date01 Mar 2024

Sponsor / Collaborator

Marinus Pharmaceuticals, Inc.

CTR20233334 / RecruitingPhase 3

一项在结节性硬化症（TSC）相关癫痫儿童和成人患者中评价Ganaxolone（GNX）添加治疗的开放标签III期研究（TrustTSC OLE）

[Translation] An Open-Label Phase III Study Evaluating Ganaxolone (GNX) as Add-On Therapy in Children and Adults with Tuberous Sclerosis Complex (TSC)-Related Epilepsy (TrustTSC OLE)

主要目的：评估GNX作为儿童和成人TSC相关癫痫发作的添加治疗的长期安全性和耐受性。

[Translation]

Primary objective: To evaluate the long-term safety and tolerability of GNX as an add-on treatment for TSC-related seizures in children and adults.

Start Date05 Dec 2023

Sponsor / Collaborator

Altasciences Co., Inc.

[+2]

100 Clinical Results associated with Ganaxolone

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100 Translational Medicine associated with Ganaxolone

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100 Patents (Medical) associated with Ganaxolone

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189

Literatures (Medical) associated with Ganaxolone

01 Nov 2024·NEUROSCIENCE LETTERS

Neurosteroids foster sedation by engaging tonic GABAA-Rs within the mesopontine tegmental anesthesia area (MPTA)

Article

Author: Baron, Mark ; Devor, Marshall

Neurosteroids are endogenous molecules with anxiolytic, anticonvulsant, sleep-promoting and sedative effects. They are biosynthesized de novo within the brain, among other tissues, and are thought to act primarily as positive allosteric modulators of high-affinity extrasynaptic GABA_Aδ-receptors. The location of action of neurosteroids in the brain, however, remains unknown. We have demonstrated that GABAergic anesthetics act within the brainstem mesopontine tegmental anesthesia area (MPTA) to induce and maintain anesthetic loss-of-consciousness. Here we asked whether endogenous and synthetic neurosteroids might also act in the MPTA to induce their suppressive effects. Direct exposure of the MPTA to the endogenous neurosteroids pregnenolone and progesterone, their metabolites testosterone, allopregnanolone and 3α5α-THDOC, and the synthetic neurosteroids ganaxolone and alphaxalone, was found to be pro-anesthetic. Although we cannot rule out additional sites of action, results of this study suggest that the suppressive effects of neurosteroids are due, at least in part, to actions within the MPTA, presumably by recruitment of dedicated neuronal circuitry. This undermines the usual presumption that neurosteroids, like other sedatives, endogenous somnogens and anesthetics, act by nonspecific global distribution.

01 Nov 2024·DEVELOPMENTAL PSYCHOBIOLOGY

Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs

Article

Author: Dyson, Rebecca M. ; Moloney, Roisin A. ; Shaw, Julia C. ; Palliser, Hannah K. ; Berry, Mary J. ; Sixtus, Ryan P. ; Pavy, Carlton L. ; Hirst, Jonathan J.

ABSTRACT:

The postnatal environment is challenging for the preterm neonate with exposure to hypoxic and excitotoxic events, amplified by premature loss of placentally derived neurosteroids. Between preterm birth and term equivalent age (TEA), cerebellar development continues despite these challenges. We hypothesize that neurosteroid replacement therapy during this time will support optimal cerebellar development. Guinea pig sows delivered at term (∼69 days gestation) or were induced to deliver preterm (∼62 days), with preterm pups receiving ganaxolone or vehicle until TEA. Postnatal assessments comprised salivary cortisol (corrected postnatal age [CPA] 0, 7, 38), behavioral analysis (CPA7, 38), and tissue collection (CPA0 and CPA40). Neurodevelopmental markers (MBP, Olig2, and NeuN) were assessed in the cerebellum by immunohistochemistry, whereas RT‐PCR was utilized to investigate key inhibitory/excitatory pathways and oligodendrocyte lineage markers. Following preterm birth, there was evidence of a hyperactive phenotype, increased salivary cortisol concentrations, and impaired myelination and oligodendrocyte maturation at the protein level. mRNA expressions of key inhibitory/excitatory pathways and myelin stability were also altered following preterm birth. Importantly, we showed that neurosteroid replacement therapy returns cerebellar development and behavior toward a term‐like phenotype. Therefore, ganaxolone may reduce the vulnerability of the cerebellum to postnatal challenges arising from preterm birth.

01 Sep 2024·CNS DRUGS

Caregiver Perspective of Benefits and Side Effects of Anti-Seizure Medications in CDKL5 Deficiency Disorder from an International Database

Article

Author: Olson, Heather E ; Rajaraman, Rajsekar R ; Leonard, Helen ; Pestana-Knight, Elia M ; Wong, Kingsley ; Junaid, Mohammed ; Downs, Jenny ; Alexander, Solomon

BACKGROUND AND OBJECTIVE:

CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database.

METHODS:

Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population.

RESULTS:

The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits.

CONCLUSIONS:

The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management.

115

News (Medical) associated with Ganaxolone

14 Nov 2024

·firstwordpharma.com

Marinus trims 45% of staff in fresh round of layoffs

In the wake of multiple clinical setbacks, including two late-stage failures of its lead asset ganaxolone, Marinus Pharmaceuticals has initiated another round of layoffs. Following a 20% workforce reduction earlier this year and a subsequent round of job cuts last month, this time the company is trimming approximately 45% of staff to further preserve cash.Although the oral ganaxolone programme saw the end of its road after tanking a Phase III study for tuberous sclerosis complex (TSC)-associated seizures in October, a glimmer of hope persists for the drug’s intravenous (IV) version despite falling short on the early stopping criteria of the Phase III RAISE study for refractory status epilepticus (RSE). Marinus noted it has secured a Type C meeting with the FDA later this year to explore potential next steps for IV ganaxolone in RSE. On a positive note, oral ganaxolone — approved by the FDA in 2022 for CDKL5 deficiency disorder (CDD) under the name Ztalmy — generated $8.5 million in third-quarter sales, marking a 56% growth over the same quarter last year. Moreover, Marinus continues to pursue the commercial growth of Ztalmy, with ongoing FDA and European Medicines Agency commitments related to the CDD indication. The company has revised its full-year revenue forecast to $33 to $34 million, down from $33 to $35 million, and will explore strategic alternatives with Barclays as an advisor.With net quarterly losses amounting to $24.2 million, Marinus held $42.2 million in cash and equivalents, adequate to fund operations through mid-2025.

Drug ApprovalPhase 3Financial Statement

25 Oct 2024

·www.biopharmadive.com

GSK invests $800M in manufacturing; Amgen sets small discount for Eylea biosimilar

Today, a brief rundown of news from GSK and Amgen, as well as updates from Roche, AbbVie, and Marinus Pharmaceuticals that you may have missed.Amgen set a list price of $1,665 per shot for its biosimilar version of Regenerons Eylea, a 10% discount from the eye drugs current wholesale cost, RBC analyst Brian Abrahams wrote in an Oct. 25 note to clients. On Tuesday, Amgen said it would launch its biosimilar, branded Pavblu, without a legal settlement with Regeneron following a court decision that lifted a temporary injunction on its launch. Such at risk launches are uncommon, and could result in steep penalties for Amgen if subsequent legal judgments side with Regeneron. The small discount means the market impact of Pavblu may be more muted than Amgen investors feared, Abrahams wrote. Further price erosion could occur when additional biosimilars launch. The FDA has approved four others. Jonathan GardnerGSK is making its largest investment in U.S. manufacturing, committing $800 million to expand a site in Marietta, Pennsylvania with new drugmaking facilities. One will handle production of sterile liquid vaccines and medicines, and should be ready by the end of 2028. Another will include a drug substance facility set to start operations by the end of 2027 as well as a pilot plant for making clinical trial medicines. Ned PagliaruloRoche has inked a second research collaboration with gene therapy specialist Dyno Therapeutics. The companies originally linked up in 2020 and, similar to that deal, the one announced Thursday revolves around neurological diseases. Roche and Dyno think the latter's technology can be used to create better “viral vectors“ the microscopic tools that shuttle genetic medicines to a desired target. The new deal tasks Dyno with designing these improved vectors, which will then be applied to potential gene therapies for nervous system disorders. Roche will be responsible for testing the therapies and, if they make it to the market, selling them. Dyno is getting $50 million upfront, plus research payments. It's also eligible for royalties on resulting products, and could nab north of $1 billion more by hitting certain milestones. Jacob BellLongtime partners AbbVie and Gideon Richter are working together on another brain-focused project. Through a sparsely detailed agreement announced Thursday, the companies hope to discover new targets that could be used to treat neuropsychiatric conditions. They plan to share the costs of the necessary research and development. Richter will receive $25 million upfront, and could take home more through milestone and royalty payments. AbbVie, meanwhile, will get worldwide rights to programs that advance to commercialization, except in traditional markets of Richter, such as Europe and Russia. Jacob BellMarinus Pharmaceuticals will lay off staff, cut costs and consider strategic alternatives, after results from a Phase 3 study showed the companys seizure drug ganaxolone did not meet the trials goal. On Thursday, Marinus said the data, while finding nominal reductions in seizure frequency that favored ganaxolone, were likely not enough to support an approval application. The study tested ganaxolone in people with epilepsy related to tuberous sclerosis complex; the drug is already cleared for use treating seizures in people with a condition called CDKL5 deficiency disorder. Ned Pagliarulo '

Phase 3

24 Oct 2024

·endpts.com

Marinus plans another round of layoffs, cost cuts following Phase 3 fail

Marinus Pharmaceuticals is reducing its workforce again and taking other measures to reduce costs after its epilepsy treatment failed a late-stage trial. The TrustTSC trial investigating oral ganaxolone for the treatment of seizures associated with tuberous sclerosis complex (TSC) missed the primary endpoint of percent change in TSC-associated frequency of seizures at 28 days. While there was a reduction in seizures in the treatment arm, the results weren’t statistically significant. The median reduction in seizure frequency was 19.7% for patients on ganaxolone compared with 10.2% for placebo, earning a p-value of 0.09. The company’s stock $MRNS tumbled on Thursday morning, dropping about 80%. “We are disappointed that the results of the TrustTSC trial are not likely to be sufficient for an sNDA filing,” Marinus CEO Scott Braunstein said in a statement . Marinus now plans to discontinue all clinical development of ganaxolone, and it started a “strategic alternatives” process that includes layoffs. The company didn’t specify how many employees it would let go. As of Dec. 31, Marinus had 165 full-time employees, though it cut about 20% of its workforce in May when it also implemented other cost-reducing measures. Since 2022, ganaxolone has been approved as Ztalmy for the treatment of seizures associated with CDKL5 deficiency disorder.

Phase 3Drug ApprovalClinical Result

100 Deals associated with Ganaxolone

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External Link

KEGG	Wiki	ATC	Drug Bank
D04300	Ganaxolone	-	DB05087

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Seizures	EU	Marinus Pharmaceuticals, Inc.	26 Jul 2023
Seizures	IS	Marinus Pharmaceuticals, Inc.	26 Jul 2023
Seizures	LI	Marinus Pharmaceuticals, Inc.	26 Jul 2023
Seizures	NO	Marinus Pharmaceuticals, Inc.	26 Jul 2023
CDKL5 Deficiency Disorder	US	Marinus Pharmaceuticals, Inc.	18 Mar 2022

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Phase 3	US	Marinus Pharmaceuticals, Inc.	17 May 2022
Epilepsy	Phase 3	US	Tenacia Biotechnology (Shanghai) Co. Ltd.	17 May 2022
Epilepsy	Phase 3	AU	Marinus Pharmaceuticals, Inc.	17 May 2022
Epilepsy	Phase 3	AU	Tenacia Biotechnology (Shanghai) Co. Ltd.	17 May 2022
Epilepsy	Phase 3	BE	Tenacia Biotechnology (Shanghai) Co. Ltd.	17 May 2022
Epilepsy	Phase 3	BE	Marinus Pharmaceuticals, Inc.	17 May 2022
Epilepsy	Phase 3	CA	Marinus Pharmaceuticals, Inc.	17 May 2022
Epilepsy	Phase 3	CA	Tenacia Biotechnology (Shanghai) Co. Ltd.	17 May 2022
Epilepsy	Phase 3	FR	Tenacia Biotechnology (Shanghai) Co. Ltd.	17 May 2022
Epilepsy	Phase 3	FR	Marinus Pharmaceuticals, Inc.	17 May 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04391569 (RAISE, Biospace) Manual	Phase 3	Epilepsy	96	Ganaxolone	urltxswgic(jvdqwavuuz) = hmkmhsnrsz qmoljqvbwz (msywsebpmh ) Met View more	Positive	17 Jun 2024
				Placebo	urltxswgic(jvdqwavuuz) = qiacoyrpur qmoljqvbwz (msywsebpmh ) Met View more
NCT03572933 (MARIGOLD Study, AAN2024)	Phase 3	CDKL5 Deficiency Disorder	101	Valproate	vfpicorguq(fcxohvmypa) = TEAEs and SAEs were similar in ganaxolone-treated patients across all concomitant ASM subgroups. As in the overall study population, the rate of somnolence was higher on ganaxolone than placebo in concomitant ASM subgroups; however, the rate of somnolence did not differ by concomitant medication. lpmyzacdwf (izzhvwdlug ) View more	Positive	09 Apr 2024
				Levetiracetam
CNS2023	Not Applicable	CDKL5 Deficiency Disorder	101	Ganaxolone	ejbemqcqah(pwqbihyyzx) = There was one death reported, which was deemed unrelated to study treatment fofdrrvseq (vdranunzdd ) View more	Positive	01 Oct 2023
IEC2023	Not Applicable	CDKL5 Deficiency Disorder	101	Ganaxolone	sqlsjjtecw(uqoeasoazv) = 1 xqavoetciv (wggbrarlrm ) View more	Positive	04 Sep 2023
				Placebo
IEC2023	Phase 1	-	36	IV ganaxolone 10mg	jnebgdmrvq(twtjcqpnba) = No deaths were reported riiyaqipdf (hgdxcyzjcy ) View more	-	04 Sep 2023
				IV ganaxolone 30mg
NCT00442104 (CTgov)	Phase 2	Spasms, Infantile	54	Ganaxolone	ynpzxrlcbw(yqjaxuanaf) = qzwhcdfcea nzhovcskwn (fevrlnuyjf, zdpvtfnush - qegkofnijf) View more	-	02 Jun 2023
NCT01725152 (CTgov)	Phase 2	Fragile X Syndrome	59	Ganaxolone (Ganaxolone)	hcgtaiigxf(npucfwjfyi) = kyjgquogch bouoqdcose (yphgpwwllg, xaprwrxaxu - qjtxtazbhj) View more	-	10 Apr 2023
				placebo+Ganaxolone (Placebo)	hcgtaiigxf(npucfwjfyi) = thcnkyuqne bouoqdcose (yphgpwwllg, hkwwctpdip - fkgyfiluss) View more
NCT04285346 (TSC, CTgov)	Phase 2	Tuberous Sclerosis	23	Ganaxolone (Treatment Period: Ganaxolone)	ypgpxzijnd(nihiptaoif) = kbxixoczzh mindgxnxep (hsotwblxqr, gkupptzaci - lhsirouiib) View more	-	04 Apr 2023
				Ganaxolone (Open Label: Ganaxolone)	gegsqnkmdl(yezfvtainv) = jawrxhngey neqgfegirh (ydysploeiv, nteoovisxn - nwnshxbtly) View more
NCT00465517 (CTgov)	Phase 2	Seizures \| Epilepsies, Partial	147	Ganaxolone	stimhqfike(jwjiumivqc) = tzoqohqwqk attefscepd (eulxioysms, gsuyjdskke - spgospvaqo) View more	-	15 Mar 2023