Background: GSK3b is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3b activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy. Methods: Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n ¼ 8) or 1000 mg (n ¼ 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained. Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments. Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.

SUMMARY1. Fluctuations in the rate of secretion and metabolism of thyroxine in the pig were observed whilst the ambient temperature was reduced from 32 to 80 C. The quantity of food supplied was either maintained constant or doubled when the animals were exposed to the lower temperature.2. It was found that the rate of disappearance of [1251]thvroxine did not change when the animal was exposed to the cold, unless the animal's food intake was altered.3. The secretion of thyroxine increased temporarily after exposure to the cold. This was shown by a rise in the concentration of thyroxine in the plasma and a simultaneously increased loss of 1311 from the thyroid gland. The increase in secretion of thyroxine was not maintained throughout the exposure to cold when the food intake of the animal was kept constant.

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I . The rate of utilization (k) of labelled thyroxine increased when energy intake, given as standard pig meal, was doubled from 20 to 40 g/kg body-weight per d. When the bulk of food was increased, but not its energy content, the value of k did not change. Ambient temperature was constant throughout the experiment.2 . Groups of pigs were given pig meal at 20 g/kg body-weight, 40 g/kg body-weight or 20 g/kg body-weight plus a supplement. The supplement was of equivalent energy content to 20 g pig meal/kg body-weight and consisted of coconut (high-fat), fish meal (high-protein) or glucose. The values of k were similar on diets (g/kg body-weight) of 40 pig meal, 20 pig meal plus coconut, and 2 0 pig meal plus fish meal. When the supplement was glucose however the values of k were similar to that for 20 g pig meal/kg body-weight.3. The plasma concentrations of T4, and triiodothyronine were not affected by eating a meal, or by changing the energy intake presented as pig meal. A comparison between pigs given zo g pig meal/kg body-weight plus supplements of bran, coconut, fish meal or glucose revealed differences in the concentration of both hormones. When food was withdrawn for 5 d the concentrations of both hormones declined.A major factor influencing the rate of secretion and utilization of thyroid hormones in animals is a change in ambient temperature (Freinkel & Lewis, 1957;Reichlin, 1966). It has been demonstrated that an increase in heat loss from an animal is followed by the release of thyroid-stimulating hormone and a subsequent increase in the secretion of thyroxine found that although exposure to cold initiated an increase in the secretion of T,, the rate of utilization of T, remained unchanged unless food intake was increased. SubsequentlyIngram &t Kaciuba-Uscilko (1977) reported that, in growing pigs, changes as great as those associated with the combination of a fall in ambient temperature and an increase in energy intake, could be elicited by a similar increase in energy intake alone.The next steps were to determine: (I) whether the stimulus to an increased rate of use of T4 was a simple increase in energy intake, or if the quantity of specific nutrients needed to be increased; (2) whether the change in the rate of use of T, associated with an increase in energy intake was accompanied by a change in the plasma levels of T4 and triiodothyronine (T3). In the present study these points have been investigated in young, immature pigs. MATERIALS A N D METHODSAnimals Sixty-eight pigs of the Large White breed aged between 2 and 3 months were used. HousingEach pig was housed separately in a cage at a controlled environmental temperature of 25" with continuous lighting.

SUMMARY Serum thyroxine (T4), thyroxine‐binding globulin (TBG) and T3 Uptake have been measured in 122 hospital inpatients, 116 healthy volunteers, 101 patients with thyrotoxicosis, thirty‐six patients with myxoedema, eighty‐five euthyroid subjects with high or low TBG concentration and ten patients on treatment with diphenylhdantoin (DPH). T4:TBG ratio and free thyroxine index (FTI = T4/T3Ux 100) were calculated for each individual. In euthyroid controls, TBG concentration was normally distributed, and was significantly greater in females (12.1 ± 1.6 mg/l, mean ± SD) than in males (10. 8 ± 2.9 mg/l). TBG was raised in myxoedema (14.7 ± 2.4 mg/l), and reduced in thyrotoxicosis (10.8 ± 2.4 mg/l) when compared with euthyroid females. There was a 24%, rise in TBG concentration during drug treatment of thyrotoxicosis (pre‐treat‐ment= 11.1 ± 2.5 mg/l, post treatment (3/12) = 13.8 ± 3.4 mg/l). In euthyroid persons, T4 was linearly correlated with TBG concentration (r = 0. 92), but there was a tendency towards a curvilinear relationship which may have been due to reduction in the concentration of thyroxine‐binding prealbumin (TBPA) at high concentrations of TBG. T4:TBG ratio and FTI were similar in their ability to distinguish between thyrotoxic, euthyroid and myxoedematous persons when TBG concentration was normal. T4:TBG ratio was found to have the considerable advantage of correcting for increases in TBG concentration over a five‐fold range, whereas FTI was misleading when TBG concentration was raised. Both FTI and T4:TBG gave unreliable results when TBG was low, and in such cases measurement of TBG should alert the clinician to the need for alternative tests. During DPH treatment, both indices tended to give‘myxoedematous’results. Retrospective analysis of T4:TBG ratio and FTI in 104 hospital in‐patients with T4< 110nmol/l and 40 in‐patients with T4<40nmol/l suggested that the T4:TBG ratio gave better diagnostic precision than FTI.