Delving into the Latest Updates on Omigapil with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [7]

Target

GAPDH

Mechanism

GAPDH inhibitors(Glyceraldehyde-3-phosphate dehydrogenase liver inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseOther Diseases+ [2]

Active Indication-

Inactive Indication

Amyotrophic Lateral SclerosisCongenital muscular dystrophyMuscular Dystrophies+ [2]

Originator Organization

Santhera Pharmaceuticals (USA), Inc.

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

Novartis AG

Santhera Pharmaceuticals Holding AG

+ [2]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

RegulationOrphan Drug (EU)

Login to view timeline

Structure

Molecular FormulaC19H17NO

InChIKeyQLMMOGWZCFQAPU-UHFFFAOYSA-N

CAS Registry181296-84-4

Author: Petraki, Diana ; Hu, Ying ; DeCoster, Jameice ; Zou, Yaqun ; Foley, A Reghan ; Bharucha-Goebel, Diana X ; Jain, Minal S ; Parks, Rebecca ; Mayer, Oscar H ; Bönnemann, Carsten G ; Donkervoort, Sandra ; Leach, Meganne E ; Arévalo, Cynthia ; Waite, Melissa ; Averion, Gilberto V ; Yun, Pomi ; Cheung, Ken ; Mendoza, Christopher ; Hayes, Leslie H ; Neuhaus, Sarah B ; Fink, Margaret ; Hausmann, Rudolf

Background and ObjectivesOmigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy^w/dy^w) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy^2J/dy^2J) LAMA2-RD mouse model and the (Col6a1^-/-) COL6-RD mouse model demonstrated decreased apoptosis.MethodsA phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.ResultsTwenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC_0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.DiscussionThis study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.Classification of EvidenceThis study provides Class IV evidence of omigapil in a dose-finding phase 1 study.Trial Registration InformationClinical Trials NCT01805024.

01 Mar 2024·Neural regeneration research

Single-neuron neurodegeneration as a degenerative model for Parkinson's disease.

Review

Author: Segura-Aguilar, Juan ; Huenchuguala, Sandro

The positive effect of levodopa in the treatment of Parkinson's disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4-6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson's disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson's disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.

01 Oct 2017·Translational Stroke ResearchQ2 · MEDICINE

PCMT1 Ameliorates Neuronal Apoptosis by Inhibiting the Activation of MST1 after Subarachnoid Hemorrhage in Rats

Q2 · MEDICINE

Article

Author: Zhang, Jianmin ; Chen, Sheng ; Xu, Shenbin ; Al-Baadani, Ammar ; Zhou, Keren ; Shao, Anwen ; Shi, Ligen

Mammalian sterile 20-like kinase 1 (MST1) is found to promote neuronal apoptosis. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1), an anti-apoptosis factor, was recently identified as an MST1-interacting protein. This study aims to explore the potential role of PCMT1 in reducing MST1-induced neuronal apoptosis after subarachnoid hemorrhage (SAH) in rats. One hundred ninety-eight male Sprague-Dawley rats were used. An exogenous PCMT1 agonist, CGP 3466B, was injected subcutaneously 1 h after the SAH induced by endovascular perforation. Chelerythrine or calyculin A was given immediately via intracerebroventricular administration after SAH. The SAH grade, Garcia score, and brain water content were measured at 24 and 72 h after the SAH. Neuronal apoptosis was detected by an immunofluorescent assay. The expression levels of endogenous PCMT1, MST1, phospho-MST1 (p-MST1), cleaved MST1 (cl-MST1), and apoptosis-related proteins were studied by western blotting. The expression of PCMT1 and MST1 decreased, while the level of active caspase 3 increased in rats after SAH. CGP 3466B treatment improved neurobehavioral function, reduced brain water content, inhibited the activity of MST1, and relieved neuronal apoptosis. These neuroprotective effects were significantly weakened either through accelerating MST1 phosphorylation by calyculin A or increasing cl-MST1 by chelerythrine. PCMT1 inhibited neuronal apoptosis by reducing MST1 phosphorylation and the level of cl-MST1. PCMT1/MST1 pathway might be an alternative therapeutic target for alleviating early brain injury after SAH.

100 Deals associated with Omigapil

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	Omigapil	-	DB12879

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Young onset Parkinson disease	Phase 2	GB	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	PT	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	NL	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	BR	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	DE	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	IT	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	FR	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	US	Novartis AG	01 Jan 2002
Parkinson Disease	Phase 2	-	Novartis AG	-
Parkinson Disease	Phase 2	-	Novartis AG	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01805024 (CALLISTO, CTgov)	Phase 1	Congenital muscular dystrophy	20	Omigapil (Cohort 1 0.02 mg/kg/Day)	mgyizsmcyr(swcurykttj) = fthigniyne mztumlulfp (khxomziwqa, vahxdshmmu - svsqyglzlu) View more	-	20 Sep 2019
				Omigapil (Cohort 2 0.08 mg/kg/Day)	mgyizsmcyr(swcurykttj) = xsedvbtuzr mztumlulfp (khxomziwqa, nsjrdygevz - napauxbrek) View more
Pubmed Manual	Phase 2/3	Amyotrophic Lateral Sclerosis	591	TCH346 (1.0, 2.5, 7.5, or 15 mg/day)	(ukikaonszx) = pbwknqstly mblmuzbulu (dxntgspesu ) Not Met	Negative	21 Aug 2007
				placebo	-