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Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.
Foley, A Reghan; Yun, Pomi; Leach, Meganne E; Neuhaus, Sarah B; Averion, Gilberto V; Hu, Ying; Hayes, Leslie H; Donkervoort, Sandra; Jain, Minal S; Waite, Melissa; Parks, Rebecca; Bharucha-Goebel, Diana X; Mayer, Oscar H; Zou, Yaqun; Fink, Margaret; DeCoster, Jameice; Mendoza, Christopher; Arévalo, Cynthia; Hausmann, Rudolf; Petraki, Diana; Cheung, Ken; Bönnemann, Carsten G.
Afiliação
  • Foley AR; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Yun P; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Leach ME; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Neuhaus SB; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Averion GV; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Hu Y; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Hayes LH; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Donkervoort S; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Jain MS; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Waite M; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Parks R; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Bharucha-Goebel DX; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Mayer OH; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Zou Y; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Fink M; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • DeCoster J; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Mendoza C; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Arévalo C; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Hausmann R; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Petraki D; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Cheung K; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
  • Bönnemann CG; From the Neuromuscular and Neurogenetics Disorders of Childhood Section (A.R.F., P.Y., M.E.L., S.B.N., G.V.A., Y.H., L.H.H., S.D., D.X.B.-G., Y.Z., M.F., J.D., C.M., C.A., C.G.B.), Neurogenetics Branch, NINDS, NIH, Bethesda, MD; Division of Neurology (M.E.L.), Oregon Health and Science University, P
Neurol Genet ; 10(3): e200148, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38915423
ABSTRACT
Background and

Objectives:

Omigapil 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 (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis.

Methods:

A 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.

Results:

Twenty 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 (AUC0-24h) 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.

Discussion:

This 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 Evidence This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Trial Registration Information Clinical Trials NCT01805024.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article