Santhera and ReveraGen announce positive topline results with vamorolone after completion of the VISION-DMD study.

As previously reported, the FDA considered the safety and efficacy data of vamorolone at 24 weeks (period 1) sufficient for an NDA filing. Efficacy assessments at the now reported completion at week 48 (period 2) included Time to Stand (TTSTAND) velocity, 6-Minute Walk Test (6MWT), Time to Run/Walk 10 meters (TTRW) velocity, and North Star Ambulatory Assessment (NSAA). Vamorolone 6 mg/kg/day showed maintenance of efficacy across all parameters until end of study at week 48, and was statistically superior to 2 mg/kg/day for TTSTAND velocity and 6MWT but not for TTRW velocity or NSAA.

For subjects who continued on the same dose of vamorolone throughout the study, the safety profile was consistent between periods with no increase in frequency or severity of adverse events being observed over time. Subjects switching from 24-week treatment with prednisone to vamorolone 6 mg/kg/day showed no loss of efficacy through to the end of the study. In addition, vamorolone treatment at both doses reversed the growth impairment seen during prednisone treatment and was associated with fewer adverse events, including those associated with corticosteroid use.

VISION-DMD was a pivotal double-blind Phase IIb study designed to demonstrate efficacy and safety of vamorolone compared to placebo and prednisone (active control) in the treatment of DMD . In the first 24-weeks (period 1), 121 ambulant boys aged 4 to less than 7 years were randomized to receive vamorolone (2 or 6 mg/kg/day) or prednisone (0.75 mg/kg/day) or placebo. 114 subjects continued for another 24 weeks (period 2), where those on vamorolone 2 and 6 mg/kg/day continued to end of study on these doses, and those on prednisone and placebo had been previously randomized to receive vamorolone 2 or 6 mg/kg/day after a 4-week tapering period. 112 subjects completed the study.

Efficacy of vamorolone established at 24 weeks was maintained over 48-week treatment period: Efficacy at week 48 was assessed for measures including TTSTAND velocity, 6MWT, TTRW velocity and NSAA. The size of effect (change from baseline) observed at the primary endpoint at week 24 for vamorolone 6 mg/kg/day was maintained at week 48 for TTSTAND velocity (0.052 vs 0.045 rises/s), NSAA (3.4 vs 3.5 points), TTRW velocity (0.29 vs 0.23 m/s) and improved for 6MWT (37 vs 48 meters).Vamorolone 2 mg/kg/day showed clinically relevant and robust efficacy at week 24 for the pre-defined hierarchical endpoints of TTSTAND velocity and 6MWT, as well as NSAA which was an exploratory endpoint. At week 48, vamorolone 6mg/kg/day was statistically superior to vamorolone 2 mg/kg/day in TTSTAND velocity (p=0.010) and 6MWT (p=0.047) but not for TTRW velocity (p=0.37) and NSAA (p=0.60). The efficacy benefit seen with prednisone in period 1 was maintained when subjects were switched to vamorolone 6 mg/kg/day during period 2: TTSTAND velocity (0.28 vs 0.27 rises/s), 6MWT distance (407 vs 408 meters), TTRW velocity (2.20 vs 2.20 m/s) and NSAA (25.6 vs 26.2 points), all absolute values.

Safety:vamorolone at both doses was generally safe and well tolerated. Of the 114 subjects who entered into period 2, two subjects discontinued treatment (one adverse event, one withdrawn consent). Three serious adverse events thought to be unrelated to study drug were reported during vamorolone treatment. For subjects who continued on the same dose of vamorolone throughout the study, the safety profile was consistent at week 48 compared to the results previously reported at week 24 .Growth velocity was preserved at both vamorolone doses. Body mass index (BMI) was stable for subjects continuing on vamorolone 2 and 6 mg/kg/day between assessments at week 24 and week 48 (mean z-score 1.15 vs 1.25 for 6 mg/kg/day; 0.76 vs 0.91 for 2 mg/kg/day where a z-score of 0 would represent the median value of an age-matched general population).

Safety and tolerability of switching from prednisone to vamorolone : Comparison of the safety outcome parameters of prednisone at week 24, following cross-over to vamorolone 2 or 6 mg/kg/day, showed an improved safety profile. In subjects, who were switched from prednisone to vamorolone 6 mg/kg/day, the number of total adverse events was reduced by 37% (70 vs 44) and the number of adverse events typically associated with corticosteroids was reduced by 60% (40 vs 16). Of particular interest, the number of adverse events reported as behavioral changes decreased by 60% (15 vs 6). Stunting of growth observed with prednisone was reversed during treatment with vamorolone 6 mg/kg/day in period 2 (mean z-score -0.38 vs -0.12 where a z-score of 0 would represent a normal growth trajectory). An increase of BMI was observed with prednisone in period 1 (mean z-score from 0.94 to 1.40) but stabilized in period 2 with vamorolone 6 mg/kg/day (mean z-score 1.32).Similar effects for safety and tolerability were observed with the switch from prednisone to vamorolone 2 mg/kg/day.

“Back in June, we announced the pivotal 24-week data from the VISION-DMD study which the FDA recently considered sufficient for our planned NDA filing. Now, we are very pleased to announce the completion of the VISION-DMD study, providing longer term data which both confirm earlier findings but importantly also support the potential benefits of vamorolone in overcoming some of the challenges these young children and families face in tolerating long term use of corticosteroids,” said Dario Eklund, Chief Executive Officer of Santhera. “We look forward to commencing the NDA submission with our partner ReveraGen and working with regulators to making vamorolone available as soon as possible.”

“Short stature, behavioral changes and weight gain are some of the important concerns families and patients experience with corticosteroids, often limiting their use or even leading to treatment discontinuation. Based on data from the VISION-DMD study, promising data on restoration of normal growth, fewer side effects impacting behavior and encouraging data on body mass index (BMI) seen with vamorolone, this novel, first-in-class steroid has the potential to emerge as a valuable alternative to the current standard of care for DMD,” said Paula Clemens, MD, study Co-Chair, and Vice Chair of VA Affairs and Professor of Neurology, University of Pittsburgh School of Medicine.

Regulatory submissions in the US and Europe in preparation : On November 17, Santhera and ReveraGen announced the successful completion of a first pre-NDA meeting with the FDA for vamorolone for the treatment of DMD. Based on the data presented to date, the FDA considered both the proposed clinical efficacy and safety data sufficient for an NDA filing. Acceptance of the NDA will be subject to FDA`s review of the complete filing. Based on the Fast Track Designation for vamorolone, the FDA deemed the plan to pursue a rolling NDA review acceptable. The NDA submission is to commence in Q1-2022. In the EU, the submission of the full Marketing Authorization Application is planned by the end of Q2 2022.

Upon approval, Santhera intends to commercialize vamorolone for the treatment of DMD through its own organization in the United States and main markets in Europe, and is seeking collaborations outside those regions for DMD and for additional indications worldwide. Santhera estimates the peak sales potential for vamorolone in the indication DMD alone to be in excess of $ 500 million in the US and the largest five European countries combined.

Vamorolone was discovered by US-based ReveraGen BioPharma, Inc. and is being developed in collaboration with Santhera who owns worldwide rights to the drug candidate for all indications.