AGAMREE 40MG/ML Oral suspension

Pharmacotherapeutic group: glucocorticoids, ATC code: H02AB18 Mechanism of action Vamorolone is a dissociative corticosteroid that selectively binds to the glucocorticoid receptor, resulting in anti-inflammatory effects through inhibition of NF-κB-mediated gene transcription, while leading to reduced activation of other gene transcriptions.‍‍‍‍‍‍​​​‍​​​​​​ In addition, vamorolone inhibits activation of the mineralocorticoid receptor by aldosterone. Due to its specific structure, vamorolone is unlikely to be a substrate of 11β-hydroxysteroid dehydrogenase and therefore does not undergo local tissue amplification. The exact mechanism of therapeutic action of vamorolone in patients with Duchenne muscular dystrophy is not known. Pharmacodynamic effects In clinical studies, treatment with vamorolone resulted in a dose-dependent decrease in morning cortisol levels. In clinical studies with vamorolone, dose-dependent increases in haemoglobin, haematocrit, and red blood cell, white blood cell, and lymphocyte counts were observed. No significant changes in mean neutrophil or immature granulocyte counts were observed. HDL cholesterol (high-density lipoprotein) and triglyceride values increased in a dose-dependent manner. Over up to 30 months of treatment, there was no significant effect on glucose metabolism. Administration of vamorolone for 48 weeks did not result in decreased bone metabolism in clinical studies, as assessed by bone turnover markers, nor in significant decreases in lumbar spine mineralisation parameters, as assessed by dual-energy X-ray absorptiometry (DXA), unlike corticosteroids. The risk of bone fractures in patients with Duchenne muscular dystrophy treated with vamorolone has not been established. Clinical efficacy and safety The efficacy of AGAMREE in the treatment of Duchenne muscular dystrophy was evaluated in Study 1, which was a multicentre, randomised, double-blind, placebo- and active-controlled, parallel-group study lasting 24 weeks, followed by a double-blind extension phase. The study population consisted of 121 male paediatric patients with a confirmed diagnosis of Duchenne muscular dystrophy who were aged 4 to 7 years at the time of enrolment, were corticosteroid-naïve, and were ambulatory. In Study 1, 121 patients were randomised to one of the following treatments: vamorolone 6 mg/kg/day (n = 30), vamorolone 2 mg/kg/day (n = 30), active comparator prednisone 0.75 mg/kg/day (n = 31), or placebo (n = 30). After 24 weeks (Period 1, primary efficacy analysis), patients receiving prednisone or placebo were re-randomised according to the original randomisation schedule for an additional 20 weeks of treatment (Period 2) to either the vamorolone 6 mg/kg/day group or the vamorolone 2 mg/kg/day group. In Study 1, efficacy was assessed based on change in velocity in the Time to Stand Test (TTSTAND) at 24 weeks of treatment compared to baseline, comparing the vamorolone 6 mg/kg/day group with the placebo group. A pre-specified hierarchical analysis of relevant secondary endpoints examined change in TTSTAND velocity in the vamorolone 2 mg/kg/day group compared to the placebo group, and change from baseline in distance walked in the 6 Minute Walk Test (6MWT) in the vamorolone 6 mg/kg/day group and then the 2 mg/kg/day group compared to the placebo group. Treatment with vamorolone at 6 mg/kg/day and then at 2 mg/kg/day resulted in statistically significant improvement compared to placebo in change in TTSTAND velocity and change in 6MWT distance walked, comparing baseline with 24 weeks of treatment (see Table 2). Study 1 was not designed to maintain the overall type I error rate when comparing the vamorolone dose groups with the prednisone group, and therefore the overall assessment of treatment differences (expressed as percentage change from baseline with 95% confidence intervals) is displayed for these endpoints in Figure 1. Table 3: Analysis of change at Week 24 from baseline with vamorolone 6 mg/kg/day or 2 mg/kg/day compared to placebo (Study 1) TTSTAND velocity (stands/s) / TTSTAND in seconds (s/stand) Placebo Vamorolone 2 mg/kg/day Vamorolone 6 mg/kg/day Prednisone 0.75 mg/kg/day Baseline mean value stands/sBaseline mean value s/stand 0.205.555 0.186.07 0.195.97 0.224.92 Mean change at Week 24Stands/sImprovement in s/stand -0.012-0.62 0.0310.31 0.0461.05 0.0661.24 Differences versus placebo* Stands/ss/stand - 0.043(0.007; 0.079)0.927 (0.042;1.895) 0.059(0.022; 0.095)1.67 (0.684;2.658) not assessed not assessed p-value - 0.020 0.002 not assessed 6MWT distance walked (in metres) Placebo Vamorolone 2 mg/kg/day Vamorolone 6 mg/kg/day Prednisone 0.75 mg/kg/day Baseline mean value (m) 354.5 316.1 312.5 343.3 Mean change at Week 24 -11.4 +25.0 +24.6 +44.1 Differences versus placebo* - 36.3(8.3; 64.4) 35.9(8.0; 63.9) not assessed p-value - 0.011 0.012 not assessed Mean changes and differences are model-based least-squares mean (LSM) values and mean differences. Positive values indicate improvement from baseline. * LSM differences presented with 95% confidence interval (CI). Figure 1 Comparison of vamorolone with prednisone in timed motor function tests based on analysis as percentage change from baseline (mITT-1 population) TTSTAND velocity (VAM 6 mg/kg/day vs PDN) Endpoint (comparison) 6MWT (VAM 6 mg/kg/day vs PDN) TTSTAND velocity (VAM 2 mg/kg/day vs PDN) 6MWT (VAM 2 mg/kg/day vs PDN) Difference in % (95% CI) Test data are standardised using percentage change from baseline as the endpoint. Percentile changes are calculated according to the formula: (value at assessment – baseline value) / baseline value × 100%. VAM: vamorolone; PDN: prednisone. All percentage change values for these two endpoints are entered into a single statistical model (MMRM). For vamorolone 6 mg/kg/day, improvements in all tested parameters of lower limb function observed at Week 24 were largely maintained at Week 48. In contrast, the efficacy results for vamorolone 2 mg/kg/day were rather inconsistent, with deterioration of the relevant motor function parameters at Week 48, i.e. TTSTAND velocity and 6MWT results. These were clinically meaningful differences compared with vamorolone 6 mg/kg/day, but only minimal decreases in NSAA score. In patients who were switched from prednisone 0.75 mg/kg/day (Period 1) to vamorolone 6 mg/kg/day (Period 2) during Study 1, the benefit in these motor function endpoints appeared to be maintained, whereas deterioration was observed in patients who were switched to vamorolone 2 mg/kg/day. At study entry, children in the vamorolone groups were shorter in height (median -0.74 SD in height Z-score for the 2 mg/kg/day dose and -1.04 SD in height Z-score for the 6 mg/kg/day dose) than children receiving placebo (-0.54 SD) or prednisone 0.75 mg/kg/day (-0.56 SD). After 24 weeks, the change in height percentile and Z-score in children treated with vamorolone was similar to that in children receiving placebo, while these parameters decreased in children treated with prednisone. In Study 1, height percentiles and Z-scores did not decrease during vamorolone treatment over 48 weeks. When switching from prednisone after 24 weeks (Period 1) to vamorolone in Period 2, patients showed increases in mean and median height Z-scores up to Week 48.