oxepins and Amyotrophic-Lateral-Sclerosis

In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed.

Topics: Amyotrophic Lateral Sclerosis; Animals; Clinical Trials as Topic; Consensus Development Conferences as Topic; Humans; Oxepins; Riluzole

TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS.. Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT).. Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT).. The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Apoptosis; Central Nervous System; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Male; Middle Aged; Nerve Degeneration; Neuroprotective Agents; Oxepins; Placebo Effect; Treatment Failure

There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice.. As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 microg kg(-1), 3.9 microg kg(-1), 39 microg kg(-1), and 390 microg kg(-1)). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number.. We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B.. We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Motor Neurons; Oxepins; Superoxide Dismutase