Phase II/III randomized trial of TCH346 in patients with ALS

Miller, Robert G.; Bradley, Walter G.; Cudkowicz, Merit; Hubble, Jean; Meininger, Vincent; Mitsumoto, Hiroshi; Moore, Dan H.; Pohlmann, Harald; Sauer, Dirk; Silani, Vincenzo; Strong, Michael J.; Swash, Michael; Vernotica, E.; Cashman, Neil R.; Eisen, Andrew; Krieger, Charles; Genge, Angela; Kalra, Sanjay; Turnbull, John; Lacomblez, Lucette; Camu, William; Destée, Alain; Ludolph, Albert C.; Dengler, Reinhard; Meyer, Thomas; Chiò, Adriano; Berg, Leonard H van den; Visser, Marjolein; Vingerhoets, François; Hardiman, Orla; Leigh, Nigel; Shefner, Jeremy M.; David, William S.; Graves, Michael C.; Heiman‐Patterson, Terry; Neville, Hans E.; Rosenfeld, Jeffrey; Bromberg, Mark B.; Corse, Andrea M.; Waclawik, Andrew J.; Pioro, Erik P.; Sufit, Robert; Appel, Stanley H.; Pascuzzi, Robert M.; Kissel, John T.; Jackson, Carlayne E.; Barohn, Richard J.

doi:10.1212/01.wnl.0000269676.07319.09

Cited by 111 publications

(57 citation statements)

References 26 publications

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“…Based on these positive preclinical results, omigapil was tested in clinical trials for Parkinson's disease and amyotro- jpet.aspetjournals.org phic lateral sclerosis. Although omigapil was shown to be safe, no significant difference in key outcome measures could be demonstrated between placebo-and omigapil-treated patients (Olanow et al, 2006;Miller et al, 2007), and the possible reasons for this failure were explored and discussed (Waldmeier et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Erb

Meinen²,

Barzaghi³

et al. 2009

J Pharmacol Exp Ther

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Laminin ␣2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

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Section: Discussionmentioning

confidence: 99%

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Erb

Meinen²,

Barzaghi³

et al. 2009

J Pharmacol Exp Ther

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“…In a phase III study of minocycline in ALS, a statistically significant trend toward faster progression in the ALS Functional Rating Scale-revised (ALSFRS-R) in patients treated with minocycline versus placebo; there was a trend in the same direction for MMT, but this was not significant [6]. A large, phase II trial of TCH346 in ALS showed a trend toward detriment on most outcome measures assessed but no effect on MMT [7]. Other studies have employed MMT testing in ALS, spinobulbar muscular atrophy, and spinal muscular atrophy (SMA) [8][9][10][11][12].…”

Section: Methods Of Strength Assessment Manual Muscle Testingmentioning

confidence: 99%

Strength Testing in Motor Neuron Diseases

Shefner

2017

Neurotherapeutics

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Loss of muscle strength is a cardinal feature of all motor neuron diseases. Functional loss over time, including respiratory dysfunction, inability to ambulate, loss of ability to perform activities of daily living, and others are due, in large part, to decline in strength. Thus, the accurate measurement of limb muscle strength is essential in therapeutic trials to best understand the impact of therapy on vital function. While qualitative strength measurements show declines over time, the lack of reproducibility and linearity of measurement make qualitative techniques inadequate. A variety of quantitative measures have been developed; all have both positive attributes and limitations. However, with careful training and reliability testing, quantitative measures have proven to be reliable and sensitive indicators of both disease progression and the impact of experimental therapy. Quantitative strength measurements have demonstrated potentially important therapeutic effects in both amyotrophic lateral sclerosis and spinobulbar muscular atrophy, and have been shown feasible in children with spinal muscular atrophy. The spectrum of both qualitative and quantitative strength measurements are reviewed and their utility examined in this review.

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“…However, a neuroprotective effect in clinical trials involving PD and amyotrophic lateral sclerosis patients failed to show any beneficial effect during therapy (Olanow et al, 2006;Miller et al, 2007). Currently, Omigapil is under investigation in a study involving patients with congential muscular dystrophy.…”

Section: Fine-control and Specificity Of Gapdh As A Thiol Switch Gapdmentioning

confidence: 99%

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

Hildebrandt¹,

Knuesting²,

Berndt³

et al. 2015

Biological Chemistry

143

131

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Cytosolic glyceraldehyde 3-phosphate dehydrogenase (GAPDH, E.C. 1.2.1.12) is present in all organisms and catalyzes the oxidation of triose phosphate during glycolysis. GAPDH is one of the most prominent cellular targets of oxidative modifications when reactive oxygen and nitrogen species are formed during metabolism and under stress conditions. GAPDH harbors a strictly conserved catalytic cysteine, which is susceptible to a variety of thiol modifications, including S-sulfenylation, S-glutathionylation, S-nitrosylation, and S-sulfhydration. Upon reversible oxidative thiol modification of GAPDH, glycolysis is inhibited leading to a diversion of metabolic flux through the pentose-phosphate cycle to increase NADPH production. Furthermore, oxidized GAPDH may adopt new functions in different cellular compartments including the nucleus, as well as in new microcompartments associated with the cytoskeleton, mitochondria and plasma membrane. This review focuses on the recently discovered mechanism underlying the eminent reactivity between GAPDH and hydrogen peroxide and the subsequent redox-dependent moonlighting functions discriminating between the induction either of adaptive responses and adjustment of metabolism or of cell death in yeast, plants, and mammals. In light of the summarized results, cytosolic GAPDH might function as a sensor for redox signals and an information hub to transduce these signals for appropriate responses.

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Phase II/III randomized trial of TCH346 in patients with ALS

Abstract: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Cited by 111 publications

References 26 publications

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Strength Testing in Motor Neuron Diseases

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

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