This is a summary of the webinar ‘Update on Vamolorone’. Click here to view the full webinar.
Presented by: Suzie-Ann Bakker (World Duchenne Organization), Dr Michela Guglieri (Newcastle University) and Dr Eric Hoffman (ReveraGen)
On 27th September a webinar[1] was given by VISION-DMD[2] to provide an update on the clinical trials for vamorolone (VBP-15). Vamorolone is a potential alternative for corticosteroids, retaining the beneficial anti-inflammatory action but limiting the side effects. The phase 2a study (VBP15-002) and 24-week extension study (VBP15-003) have been completed and patients have progressed into a long term (2 year) phase 2a extension study (VBP15-LTE). The phase 2b study started in August 2018 and is ongoing.
Preliminary results of the phase 2a open label, dose escalation trial, concerning the safety and inflammatory action, have been published.[3] Patients received doses ranging from 0.25 to 6 mg/kg/day. In the LTE most patients have escalated to the highest dose (6 mg/kg/day) which is equivalent to 8 times the dose usually used for prednisone (0.75 mg/kg). Studies have established vamorolone is safe, some weight gain has been observed comparable to prednisone resulting in some patients moving to a lower dose. Pharmacodynamic biomarkers for bone formation, insulin resistance and adrenal suppression showed some changes but only in the highest dose. The primary efficacy outcome (Time To Stand) showed significant improvement in the two highest doses compared to the two lowest doses and the CINRG natural history study. Furthermore, functional improvement was seen in secondary functional outcomes for the 6 and 2 mg/kg dose groups. Creatine kinase (CK) levels and nearly all of the exploratory efficacy biomarkers (6 out of 7) showed a dose-response effect.
The phase 2b study (NCT03439670) is a double blind, placebo-controlled study in 120 4 to <7-year-old steroid naïve DMD boys, comparing two doses of vamorolone to placebo and prednisone for 24 weeks. Thereafter boys will be treated with vamorolone (two doses) for an additional 24 weeks. The study will be conducted at over 30 sites in North America, Europe, Australia and Israel. Recruitment has been started in the USA and full recruitment is estimated to take 12-18 months. After the phase 2b study a safety study in a broader age range (2‑4 and 7‑18 years old) is planned to be initiated in 2019.
Questions & answers
- Why is there such a large difference between the two doses?
The main reason for the three-fold increase between the two doses (2 and 6 mg/kg/day) is the goal to find the therapeutic window of the lowest efficacious and highest safe dose. In the phase 2a LTE study an intermediate dose is now considered (4 mg/kg/day).
- When can patients currently being treated with corticosteroids switch to vamorolone?
First a full investigation to ensure the safety and efficacy profile has to be completed.
- Glasgow is still waiting for R&D approval. Is there a way to get this approved?
In the United Kingdom the approval systems take quite a long time. It has, however, recently be approved and sites will receive information in the next week, so site initiation can start in November.
- Is there a reason the trial is not conducted in Germany?
It was originally planned to also include Germany; however, in Germany there are strict regulations concerning radiation exposure (DEXA, x-rays), which would make it very challenging to obtain approval. Since the project is funded by patient foundations and US and EU grants, the project has tried to reduce the costs (cost-benefit ratio of the number of sites). In the phase 2a study, travel and accommodation costs were paid for families. If German patients would like to participate in another country, ReveraGen will finance this.
- When will protocols be sent to make up site files?
After regulatory approval, sites are contracted and visited to ensure all resources needed for the study are available. It is expected that all sites will be open for recruitment by the end of the year. Sites will be contacted soon with all information.
[1] https://youtu.be/Ty1QMp5N5c8
[3] Conklin, L. S. et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharmacological research, doi:10.1016/j.phrs.2018.09.007 (2018).
