Periodic Reporting for period 3 - VISION DMD (VISION-DMD - Phase 2 Clinical Trials of VBP15: An Innovative Steroid-like Intervention on Duchenne Muscular Dystrophy)
Reporting period: 2019-01-01 to 2020-06-30
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 (prednisone/prednisolone, deflazacort) 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.
At the end of the Phase 2a study, all patients were enrolled into the Phase2a 24-week extension study (VBP15-003) at the same vamorolone dose level they were assigned in VBP15-002. 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. The results of the 24 week extension study have been published (Hoffman et al. 2019). The study showed that 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- and prednisone-controlled Phase 2b clinical study (VBP15-003; NCT03439670) opened in August 2018 and is recruiting patients at about 30 sites in 11 countries including the US, Canada, Belgium, Czech Republic, Greece, Israel, Netherlands, Spain, Sweden, UK, Australia. 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).
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. A review of the status of biomarkers for DMD has been completed.
The VISION DMD project is using the vamorolone development programme as a case study that promotes how an innovative venture philanthropy (VP) business model can be used to support rare disease research and orphan drug development. Work is ongoing to engage rare disease and VP communities to identify good practice and promote the model.
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.