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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - VISION DMD (VISION-DMD - Phase 2 Clinical Trials of VBP15: An Innovative Steroid-like Intervention on Duchenne Muscular Dystrophy)

Teaser

Summary

The overall objective of VISION-DMD is to advance and accelerate the clinical development of the orphan drug vamorolone (VBP15) for the treatment of Duchenne Muscular Dystrophy (DMD) through Phase 2a and 2b clinical trials. The studies will be conducted in Europe, the US, Canada, Israel, and Australia.

DMD is a progressive and severe, rare genetic disease affecting approximately 1 in 3,500 to 5,000 male births and very rarely girls. The disease is devastating: untreated, boys become progressively weaker during childhood, losing independent ambulation at an average age of 9 years, and death often occurs by early adulthood due to cardio-respiratory failure. The disease remains incurable, although long term use of corticosteroids (CS), are widely, but not universally accepted as standard of care. In February 2017, Emflaza (Deflazacort) became the first steroid treatment for DMD, approved by the FDA in the US. In other countries CS are used off label. Concerns about the severe side effects of all CS restrict their prescription across different countries and centres

Vamorolone is an innovative first-generation dissociative steroid-like drug designed to retain or improve the benefits of CS treatment in DMD whilst aiming to reduce side effects that currently restrict their use.

The VISION-DMD project is managed as a public/private partnership under venture philanthropy models, with strong involvement of patient groups, academic medical centres, and government programs (both European Commission, and USA National Institutes of Health). This model encourages innovations, including novel designs of clinical trials, research in clinical outcome measures, and use of biomarkers in multiple contexts of use.

Work performed

Two clinical trials of vamorolone in Duchenne muscular dystrophy patients have been completed; Phase 2a (VBP15-002; NCT02760264) and Phase 2a extension (VBP15-003; NCT02760277). These Phase 2a studies were conducted at eleven CINRG study sites, in the USA, Canada, Israel, Sweden, the UK and Australia. The Phase 2a (VBP15-002) clinical trial was an open label, multiple ascending dose study of Vamorolone on 48 steroid naÃ¯ve boys aged from 4 years old to less than 7 years old, with a 2-week treatment period (daily oral dosing), and 2-week washout period (no drug dosing). The results of this first study have been published (Conklin et al. 2018). Subjects were enrolled in four dose cohorts sequentially from 0.25 mg/kg up to 6.0 mg/kg of vamorolone. The primary outcome was the acute safety, tolerability and pharmacokinetics of vamorolone in DMD boys. All patients were then enrolled into the Phase2a 24-week extension study (VBP15-003) at the same dose level they were assigned in VBP15-002, and this extension study has also been completed. The primary outcomes of the Phase 2a extension trial were long term, safety, tolerability, efficacy as measured by the Time to Stand test, and safety as measured by body mass index. Results have not yet been published, but preliminary analyses indicated vamorolone has an acceptable safety and tolerability profile, with no clinically significant safety concerns identified. The PK of vamorolone is similar to that of glucocorticoids, and there is no evidence of drug accumulation between daily doses. Pharmacodynamic safety biomarkers bridged to clinical outcomes suggested improved safety compared to published studies of glucocorticoids. Vamorolone showed decreased insulin resistance, adrenal suppression, and bone turnover in both DMD boys and healthy adult male volunteers compared to published studies of prednisone (dose/dose) (Hoffman et al. 2018; Conklin et al. 2018). Exploratory efficacy biomarkers provide strong support for the anti-inflammatory mechanism of action of vamorolone (Conklin et al 2018). Exploratory pharmacodynamic biomarker data of serum creatine kinase suggests vamorolone has a membrane stabilising effect, or the anti-inflammatory effects may decrease myofiber degeneration or leakage, or both (Conklin et a. 2018).

The findings from the Phase 2a studies were supportive of further investigation of vamorolone in DMD. A double-blind, placebo-controlled, and prednisone-controlled Phase 2b clinical study (VBP15-003; NCT03439670) opened in August 2018 and is recruiting patients at about 30 sites in about 10 countries including the US, Canada, Sweden, UK, Netherlands, Czech Republic, Israel, Australia and Belgium. The Phase 2b study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to <7 years with DMD.

The VISION-DMD project has carried out a series of biomarker discovery and validation studies This has included research into biomarkers (serum protein and miRNA; DNA genetic modifiers) that influence disease severity and response to steroidal drug treatment (corticosteroids and vamorolone).

Final results

The VISION-DMD program is developing vamorolone as a first-in-class steroidal anti-inflammatory drug for Duchenne muscular dystrophy and other chronic inflammatory states. Innovations in clinical trial design, including integration of biomarkers as objective measures of safety and efficacy, are key to the VISION-DMD program.

A panel of biomarkers of different cellular functions will be developed within the EC VISION DMD project. The aim is to better predict and monitor clinical outcomes. This approach will be transferable to future drug development studies to monitor disease progression and response to therapies in Neuromuscular Diseases at early time points. The VISION-DMD project aims to validate corticosteroid- and vamorolone-responsive biomarkers (proteins, miRNAs), and predictive models in the Phase 2b study. This will set the stage for utilization of biomarkers in specific contexts-of-use in future clinical trials.

The VISION DMD project will use the vamorolone development programme as a case study that promotes how an innovative venture philanthropy business model can be used to support rare disease research and orphan drug development.
Advancing knowledge on the safety and efficacy of vamorolone in DMD will facilitate possible development of vamorolone in additional indications. The ReveraGen team is working with key opinion leaders in juvenile dermatomyositis, vasculitis, Becker muscular dystrophy, and paediatric ulcerative colitis to investigate these disorders as possible indications for vamorolone development.