Delving into the Latest Updates on Fosmetpantotenate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Fosmetpantotenate (USAN)

Target-

Mechanism-

Therapeutic Areas

Nervous System DiseasesCongenital DisordersOther Diseases

Active Indication

Pantothenate Kinase-Associated Neurodegeneration

Inactive Indication-

Originator Organization

Travere Therapeutics, Inc.

Active Organization-

Inactive Organization

Travere Therapeutics, Inc.

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC20H31N2O9P

InChIKeyHUWUHKIPYXWUPN-YVRVQSMLSA-N

CAS Registry1858268-66-2

ABSTRACTBackgroundThis review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase‐associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom‐targeted treatments, but these do not provide sustained benefit as the disorder progresses.ObjectivesA detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms.MethodsTwo large double‐blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open‐label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4‐phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre‐clinical studies, and additional clinical trials may be anticipated.ConclusionsExperience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN‐specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society

01 Jun 2021·Movement DisordersQ1 · MEDICINE

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase–Associated Neurodegeneration

Q1 · MEDICINE

Article

Author: Vanegas‐Arroyave, Nora ; Thakur, Nivedita ; Videnovic, Aleksandar ; Martí, Maria J. ; Jech, Robert ; Correa‐Vela, Marta ; Burns, Colleen ; Gonzalez, Victoria ; Bischoff, Almut Turid ; Escolar, Maria L. ; Roze, Emmanuel ; Greblikas, Feriandas ; Fraser, Jamie L. ; Monduy, Migvis ; Zorzi, Giovanna ; Kmiec, Tomasz ; Lang, Anthony ; Perez‐Dueñas, Belen ; Mercimek‐Andrews, Saadet ; Bonnet, Cecilia ; Hermanowicz, Neal ; Jinnah, Hyder A. ; Cif, Laura ; Tochen, Laura ; Planellas, Lluis ; Klopstock, Thomas ; Comella, Cynthia ; Nimmo, Graeme A.M. ; Pfeiffer, Helle Cecilie Viekilde

AbstractBackgroundPantothenate kinase–associated neurodegeneration (PKAN) currently has no approved treatments.ObjectivesThe Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression.MethodsThis randomized, double‐blind, placebo‐controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24‐week double‐blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN‐Activities of Daily Living (PKAN‐ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN‐ADL.ResultsBetween July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN‐related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN‐ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was −0.09 (−1.69 to 1.51; P = 0.9115). The overall incidence of treatment‐emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups.ConclusionsTreatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN‐ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

24 Dec 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration

Q1 · MEDICINE

Article

Author: Cicero, Daniel ; Vecchi, Andrea ; Di Marco, Annalise ; Monteagudo, Edith ; Auciello, Giulio ; Ciammaichella, Alina ; Fezzardi, Paola ; Elbaum, Daniel ; Gonzalez Paz, Odalys ; Malancona, Savina ; Harper, Steven ; Bracacel, Elena ; Beconi, Maria ; Rossetti, Ilaria

Mutations in the human PANK2 gene are implicated in neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration (PKAN) and result in low levels of coenzyme-A (CoA) in the CNS due to impaired production of phosphopantothenic acid (PPA) from vitamin B5. Restoration of central PPA levels by delivery of exogenous PPA is a recent strategy to reactivate CoA biosynthesis in PKAN patients. Fosmetpantotenate is an oral PPA prodrug. We report here the development of a new PANk2^-/- knockout model that allows CoA regeneration in brain cells to be evaluated and describe two new series of cyclic phosphate prodrugs of PPA capable of regenerating excellent levels of CoA in this system. A proof-of-concept study in mouse demonstrates the potential of this new class of prodrugs to deliver PPA to the brain following oral administration and confirms incorporation of the prodrug-derived PPA into CoA.

100 Deals associated with Fosmetpantotenate

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External Link

KEGG	Wiki	ATC	Drug Bank
D10934	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pantothenate Kinase-Associated Neurodegeneration	Phase 3	US	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Phase 3	ES	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Phase 3	IT	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Phase 3	CA	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Preclinical	FR	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Preclinical	DE	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Preclinical	NO	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Preclinical	CZ	Travere Therapeutics, Inc.	17 Jul 2017
Pantothenate Kinase-Associated Neurodegeneration	Preclinical	PL	Travere Therapeutics, Inc.	17 Jul 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03041116 (Pubmed \| Mov Disord) Manual	Phase 3	Pantothenate Kinase-Associated Neurodegeneration	84	Fosmetpantotenate	bwfgdvbrrf(omqgavhton) = cbuegglugb rvugynxxnd (znynpmutcz, 11.4) View more	Negative	01 Jun 2021
				Placebo	bwfgdvbrrf(omqgavhton) = emeixekqtv rvugynxxnd (znynpmutcz, 11.5) View more
NCT03041116 (PKAN, CTgov)	Phase 3	Pantothenate Kinase-Associated Neurodegeneration	84	Fosmetpantotenate (Fosmetpantotenate)	wqoioqyujn(ldzbczrpcn) = ckcuvloitu mrpcatjncy (rjxrdnmlqz, oglmtxoqvg - fluwoyrhjq) View more	-	29 Dec 2020
				Placebo (Placebo)	wqoioqyujn(ldzbczrpcn) = ciioemgsec mrpcatjncy (rjxrdnmlqz, vpgcvbpyxk - bjrwkfopan) View more