Dr Craig McDonaldCraig M. McDonald, MD
Cumulative data from the DELOS (NCT01027884) and SYROS (NCT03433807) studies of idebenone (Puldysa; Santhera Pharmaceuticals) suggest that those treated long-term with the experimental Duchenne muscular dystrophy (DMD) therapy had a lower rate and risk of bronchopulmonary adverse events (BAE), antibiotic use, and hospitalizations.1

All told, those treated with idebenone in DELOS experienced BAEs at a rate of 19.4% (82 cumulative days) compared to 51.5% for the placebo arm (222 cumulative days), and 22.6% of those in the idebenone arm using systemic antibiotics compared to 39.4% of those in the placebo arm. A single agent-treated patient was hospitalized for a total of 3 days, compared to 4 placebo patients for a total of 30 days.

Similarly, SYROS data showed an event rate per person-years (e/py) over the course of 4.2 years (range, 2.4–6.1) on treatment (n = 18). Patients were off idebenone treatment for a mean of 2.1 (range, 1.1–5.5) years during SYROS (n = 14).

While on-treatment the e/py rate for BAEs was 0.10 for the idebenone group compared to 0.33 for the off-treatment placebo group. Systemic antibiotics were used at a rate of 0.04 e/py (3 events) compared to 0.15 e/py (4 events), respectively, while hospitalizations occurred at rates of 0.29 e/py and 0.48 e/py, respectively. Hospitalizations for BAEs specifically occurred at a rate of 0.06 e/py (5 events) for idebenone patients compared to 0.15 e/py (4 events) for off-treatment patients.
 
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“Idebenone reduced the proportion of patients with a 10% decline in forced vital capacity percent predicted [FVC%p], the risk of BAEs, the total duration of systemic antibiotic usage, and the risk of hospitalizations due to BAEs,” investigator Craig M. McDonald, MD, said. “These findings were confirmed with long-term treatment in the SYROS study, and the treatment effect was maintained for up to 6 years.”

The DELOS dataset included 64 patients treated for 12 months. SYROS data included long-term, roughly 6-year follow-up for 18 of the 64 DELOS patients, of which 11 were untreated prior to joining the SYROS extension. The data were presented virtually by McDonald, who is professor and chair, Department of Physical Medicine & Rehabilitation, and director, Neuromuscular Disease Clinics and Neuromuscular Disease Program, UC Davis Health, in lieu of the planned 2020 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference.

For the 64 DELOS patients, the mean age was 14.3 years, with an FVC%p of 53.8 (standard deviation [SD], 11.8). In SYROS, the mean patient age at DELOS baseline was 13.3 years with an FVC%p of 58.7 (SD, 17.6).

SYROS data suggest that long-term idebenone treatment also delayed patients’ first 10% relative decline in FVC%p, with a median time of 1.72 years while on idebenone compared to 0.63 years while off treatment (hazard ratio [HR], 0.44). The long-term cumulative frequency of BAEs was also reduced while on treatment in SYROS (HR, 0.32). McDonald and colleagues wrote that “respiratory morbidity and hospitalization rates in patients with DMD increase as respiratory function declines,” noting that “idebenone reactivates and protects mitochondria, thus preserving muscle cell function.” In DELOS, the therapy showed an ability to reduce the rate of respiratory function decline and morbidity in steroid-naïve patients with DMD.

Following the conclusion of the ongoing SIDEROS study (NCT02814019)—which includes patients with DMD who are on steroid treatment and is expected to conclude in August 2021 (with extension data anticipated in 2024)—Santhera has announced it plans to submit a new drug application (NDA) to the FDA.2

“The initial study done—although it was a randomized, controlled trial and was really well done—had a rather modest sample size and was largely done in nonsteroidal patients,” McDonald explained when asked about the therapy’s pathway to possible FDA approval. “The FDA wanted to see a treatment effect using standard of care, so looking at the treatment effect in those patients who were on steroids. I believe the FDA’s position is that if a positive effect is seen, I think we would likely see the approval of idebenone in the US, based on the results of the SIDEROS trial in addition to the DELOS trial.”
REFERENCES
1. McDonald CM, Schar U, Klein A, Servais L, Hasham S, Buyse G. Effect of Long-Term Idebenone Treatment on Respiratory Morbidity and Hospitalization Rate in Patients with Duchenne Muscular Dystrophjy (DMD). Presented at: Presented at: 2020 MDA Clinical & Scientific Conference; March 24, 2020. Poster 56.
2. Santhera Submits Marketing Authorization Application to the European Medicines Agency for Puldysa® (Idebenone) in Duchenne Muscular Dystrophy [press release]. Pratteln, Switzerland: Santhera Pharmaceuticals; Published May 27, 2019. Accessed March 24, 2020. globenewswire.com/news-release/2019/05/27/1850103/0/en/Santhera-Submits-Marketing-Authorization-Application-to-the-European-Medicines-Agency-for-Puldysa-Idebenone-in-Duchenne-Muscular-Dystrophy.html