Delving into the Latest Updates on Omigapil with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [7]

Target

GAPDH

Action

inhibitors

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 (European Union)

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Structure/Sequence

Molecular FormulaC19H17NO

InChIKeyQLMMOGWZCFQAPU-UHFFFAOYSA-N

CAS Registry181296-84-4

Author: Petraki, Diana ; Hu, Ying ; DeCoster, Jameice ; Zou, Yaqun ; Foley, A Reghan ; Jain, Minal S ; Bharucha-Goebel, Diana X ; 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 Apr 2022·Molecular CellQ1 · BIOLOGY

Hexokinase 1 cellular localization regulates the metabolic fate of glucose

Q1 · BIOLOGY

Article

Author: Shapiro, Jason S ; Stanczyk, Paulina J ; Ben-Sahra, Issam ; Keyhani-Nejad, Farnaz ; Weinberg, Samuel E ; Suresh, Krishna V ; Shah, Kriti P ; Chen, Yihan ; Stoolman, Joshua S ; Chen, Chunlei ; Chang, Hsiang-Chun ; Geier, Justin A ; Layden, Brian T ; Nguyen, Tivoli ; Xu, Kai ; Chandel, Navdeep S ; Rodriguez, Arianne E ; Pusec, Carolina M ; Ardehali, Hossein ; Goodman, Lauren ; De Jesus, Adam

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

100 Deals associated with Omigapil

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Omigapil	-	DB12879

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Young onset Parkinson disease	Phase 2	United Kingdom	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Portugal	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Netherlands	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Brazil	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Canada	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Germany	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	Italy	Novartis AG	01 Jan 2002
Young onset Parkinson disease	Phase 2	France	Novartis AG	01 Jan 2002
Parkinson Disease	Phase 2	Europe	Novartis AG	-
Parkinson Disease	Phase 2	Europe	Novartis AG	-

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Clinical Result

Indication

Phase

Evaluation

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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)	udlxldtejo(lmmkgfldaf) = tgjcsjcqcu haoozizpvf (addanhyogw, xlrsvmvhzf - utieiofnfz) View more	-	20 Sep 2019
				Omigapil (Cohort 2 0.08 mg/kg/Day)	udlxldtejo(lmmkgfldaf) = kshjlvtecp haoozizpvf (addanhyogw, tyfsbzifpl - twyspdwfdp) View more
Pubmed Manual	Phase 2/3	Amyotrophic Lateral Sclerosis	591	TCH346 (1.0, 2.5, 7.5, or 15 mg/day)	(msulfmrsuw) = fgggoygyol fvoyhcmzli (htmjbglmtj ) Not Met	Negative	21 Aug 2007
				placebo	-