FDA Accepts New Drug Application for Duchenne Therapy Vamorolone

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With a PDUFA date of October 26, 2023, the FDA will review data from the phase 2b VISION-DMD study, in which vamorolone met its primary end point in change in TTSTAND velocity.

Dario Eklund, chief executive officer, Santhera

Dario Eklund

According to a recent announcement, the FDA has accepted Santhera Pharmaceuticals and ReveraGen BioPharma’s new drug application (NDA) for its investigational agent vamorolone, a first-in-class dissociative steroid, for the treatment of patients with Duchenne muscular dystrophy (DMD).1

The FDA has scheduled a PDUFA target action date of October 26, 2023, and do not plan to hold an advisory meeting to discuss the application. If approved, the therapeutic would be launched in Q4 of later this year. The submission was based on phase 2b data from the VISION-DMD study (NCT03439670), in which the agent met its primary end point of superiority of change in Time to Stand Test (TTSTAND) velocity relative to placebo.

"We are delighted that the FDA has accepted Santhera’s vamorolone NDA for filing. We believe this product addresses a clear unmet medical need and for Santhera, this represents the achievement of an important milestone with key significance for our future success," Dario Eklund, chief executive officer, Santhera, said in a statement.1 "We look forward to working closely with U.S. regulators to advance vamorolone towards approval."

VISION-DMD was a 2-part study that assessed the efficacy, safety, and pharmacokinectics of vamorolone administered orally at daily doses of 2.0 mg/kg/day and 6.0 mg/kg/day vs prednisone 0.75 mg/kg/day and placebo over a 24-week treatment period. The study featured ambulatory boys aged 4 to 7 years old with DMD across 33 trial sites.

In the original analysis published in June 2021, both dosed groups showed strong efficacy in the study’s primary and secondary end points. The primary end point, superiority in change of TTSTAND velocity, was represented by a difference of 0.06 (95% CI, 0.02-0.10) rises per second from baseline in the treated group (P = .002). Specifically, investigators observed improvements from 6.0 to 4.6 seconds in the treated group and a corresponding deterioration in the placebo group from 5.4 to 5.5 seconds.2

Secondary end points were also met, including TTSTAND velocity in the low-dose group (P = .02), 6-minute walk test in the high-dose (P = .003) and low-dose group (P = .009), and time to run/walk 10 m test in the high-dose group (P = .002). No statistically significant differences were observed between vamorolone high dose and prednisone on the secondary end points. Vamorolone showed a favorable safety and tolerability profile over prednisone. The 24-week study was completed by 114 of 121 patients (94%). Both the high- and low-dosages showed favorable safety and tolerability profiles. No patients treated with vamorolone discontinued the study due to treatment-emergent AEs (TEAEs).

"This is an exciting time for the Duchenne community as the data generated across the clinical trial program indicate that vamorolone has the potential to address relevant aspects in patient care that could also enhance treatment outcomes," Eric Hoffman, PhD, president and chief executive officer, ReveraGen, said in a statement.1 "If approved, vamorolone will emerge as an additional treatment option in current standards of care in DMD, with the potential to address unmet medical needs and treat a majority of Duchenne patients starting at an early age."

Results from part 2 of VISION-DMD, the open-label portion, were presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference. The open-label study included 121 boys with DMD to placebo for 24 weeks (period 1) who crossed over to 2 vamorolone groups (2.0 or 6.0 mg/kg/day) for another 24-week treatment period. After 24 weeks of treatment with the agent, delayed starters demonstrated improvement on multiple efficacy outcomes including TTSTANDV (week 48 vs week 24; P <.05). Between the 2 groups, early-starters on vamorolone 6.0 mg/kg/day had increased outcome means relative to the delayed-starters for all 5 outcomes at all time points except for 10 Meter Walk Test.3

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At the end of the 48-week period, only the mean for Time to Climb Test was statistically significant between early- and delayed-starters (<.05). Although the data were not provided, investigators noted that other comparisons (vamorolone 2.0 mg/kg/day throughout vs placebo-to-vamorolone 2.0 mg/kg/day or pooled dose groups) yielded similar findings for the most part.

In September 2022, investigators from VISION-DMD continued to publish additional data that expanded on the findings presented at MDA 2022. Exploratory end points, such as NorthStar Ambulatory Assessment (NSAA) total score and time to climb 4 stairs (TTCLIMB) velocity, both showed improvement that favored both the high- and low-dose vamorolone groups compared with placebo. Between the 2 groups, patient reported outcomes such as Pediatric Outcomes Data Collection Instrument (PODCI) and Treatment Satisfaction Questionnaire (TSQM), as well as measures of muscle strength, were not statistically significantly different. Notably, in a prespecified analysis of Psychosocial adjustment and Role Skills Scale III (PARS III) limited to 4 of 5 subscales, findings suggested that treatment with low dose vamorolone showed better adjustment for anxiety and depression compared with prednisone. This finding however was not adjusted after multiple testing.4

While the number of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between groups, the total count of TEAEs was lowest in the placebo group (n = 77), highest in the prednisone group (n = 121), and intermediate in the 2 vamorolone groups (low dose: n = 97; high dose: n = 91). The only withdrawal from the study was from 1 patient in the prednisone group, owing to an AE of personality change that was viewed by the investigator as possibly related to the drug and abated after cessation of the drug.

REFERENCES
1. Santhera and ReveraGen announce FDA acceptance of new drug application for vamorolone in Duchenne muscular dystrophy. News release. January 9, 2023. Accessed February 1, 2023. https://www.globenewswire.com/news-release/2023/01/09/2584775/0/en/Santhera-and-ReveraGen-Announce-FDA-Acceptance-of-New-Drug-Application-for-Vamorolone-in-Duchenne-Muscular-Dystrophy.html
2. Santhera and ReveraGen announce positive and statistically highly significant topline results with vamorolone in pivotal VISION-DMD study. News release. Santhera. June 1, 2021. Accessed February 1, 2023. https://www.globenewswire.com/news-release/2021/06/01/2239124/0/en/Santhera-and-ReveraGen-Announce-Positive-and-Statistically-Highly-Significant-Topline-Results-with-Vamorolone-in-Pivotal-VISION-DMD-Study.html
3. Dang U, Guglieri M, Clemens PR, et al. Delayed start analysis of efficacy outcomes in placebo to vamorolone crossover participants in VBP15-004. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 89.
4. Guglieri M, Clemens PR, Perlman SJ, et al. Efficacy and safety of vamorolone vs placebo and prednisone among boys with Duchenne muscular dystrophy: a randomized clinical trial. JAMA Neurol. Published online August 29, 2022. doi:10.1001/jamaneurol.2022.2480
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