Periodic Reporting for period 4 - VISION DMD (VISION-DMD - Phase 2 Clinical Trials of VBP15: An Innovative Steroid-like Intervention on Duchenne Muscular Dystrophy) Reporting period: 2020-07-01 to 2021-12-31 Summary of the context and overall objectives of the project The objective of the VISION-DMD project was 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. 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 Food and Drug Administration (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. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Four clinical trials of vamorolone in DMD patients have been completed in the project lifetime; A Phase 2a open-label, multiple ascending dose study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and exploratory efficacy was completed in May 2018. (VBP15-002; NCT02760264). This was followed by a Phase 2a extension study to assess long term safety and efficacy (VBP15-003; NCT02760277) and a further long term extension study. (VBP15-LTE NCT03038399). These Phase 2a studies were conducted at eleven Cooperative International Neuromuscular Research Group (CINRG) study sites, in the USA, Canada, Israel, Sweden, the UK and Australia. 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. The results of the first study have been published (Conklin et al. 2018). 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 fourth vamorolone clinical trial (Phase 2b -VBP15-004; NCT03439670) was completed in August 2021 across 33 sites in 11 countries including the US, Canada, Belgium, Czech Republic, Greece, Israel, Netherlands, Spain, Sweden, UK, and Australia. The Phase 2b study was 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. Topline results indicate vamorolone given throughout the study showed sustained efficacy, across multiple endpoints over 48 weeks. The good safety and tolerability profile was confirmed. The FDA considered the safety and efficacy data of vamorolone at 24 weeks (period 1) was sufficient for a New Drug Application (NDA) filing. 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). Work successfully defined six exploratory efficacy biomarkers for drug anti-inflammatory effects and validated these biomarkers in 4 steroid-responsive disease states (three paediatric). This work was published in a peer-reviewed manuscript (Conklin et al. 2018a). Serum samples have been collected and banked in all 4 vamorolone clinical trials. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) VISION-DMD has significantly advanced the development of vamorolone as a first-in-class steroidal anti-inflammatory drug for Duchenne muscular dystrophy and other chronic inflammatory states. The drug has treated DMD boys in the VISION-DMD studies. There are now 143 DMD patients who are continuing treatment in ongoing trials, expanded access programmes (EAP) and compassionate use. A new patient led EAP in Canada is recruiting 44 boys with DM (in 2 age groups) from March 2022. An NDA submission to the FDA is planned for Q1/2, 2022. Discussions have taken place with the European Medicines Agency (EMA) on Marketing Authorisation Applications (MAA), and additional data requested has been collated. The development of vamorolone has significantly progressed for DMD with the strong possibility of licencing from EMA and FDA. Having a non-mutation specific drug on the market that replaces steroids, and reduces the associated side effects, will have huge impact for the Duchenne community. For other indications, funding has been granted to trial vamorolone in Becker Muscular Dystrophy, and pilot trial in Pediatric Ulcerative Colitis has been considered. Innovations in clinical trial design, include the return of individual patient data, and remote clinical monitoring and assessments instigated due to the global pandemic have been developed. The integration of biomarkers as objective measures of safety and efficacy will be transferable to future drug development studies to monitor disease progression and response to therapies in Neuromuscular Diseases at early time points. The Return of Patient Data provides a case study to encourage and accelerate the adoption of this good practice to help future research and support care team decision making. The VISION DMD project is using the vamorolone development programme as a case study to promote how an innovative venture philanthropy model can be used to both support rare disease research and orphan drug development, and develop more sustainable funding models for patient organisations and other philanthropists funding the research and innovation. Work has been ongoing to engage rare disease and VP communities to identify good practice and promote the model. Results have been disseminated and communicated during the project and will continue.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. Santhera exercised it's option in September 21 and obtained worldwide rights to vamorolone in DMD and all other indications, and are now contributing to further development of vamorolone. Project logo
