SIDEROS Phase 3 Trial of Puldysa in Duchenne Patients Completes Enrollment

The SIDEROS Phase 3 clinical trial, investigating if oral Puldysa (idebenone) can be added to a stable glucocorticoid regimen to more effectively slow lung function decline in boys and men with Duchenne muscular dystrophy (DMD), has completed enrollment, Santhera Pharmaceuticals announced.

A planned analysis demonstrated the study, while not enrolled up to the planned number, recruited a patient group with less variability than expected. This means that the existing number of patients is enough to determine, with very high confidence (greater than 99%), a statistical difference between Puldysa and a placebo, Santhera said.

“We are delighted to have reached such an important milestone and wish to express our sincere thanks to patients and families, caregivers, physicians and study personnel for their support and commitment,” Kristina Sjöblom Nygren, MD, chief medical officer and head of development at Santhera, said in a press release.

Given the high statistical power provided by enrolled patients, the company is considering an independent early analysis of efficacy. If results are positive, the SIDEROS trial would likely be stopped early (later this year) and requests for approval in the U.S. and Europe could be filed about one year earlier than anticipated.

If no overwhelming efficacy is demonstrated, the trial will continue as planned with currently enrolled patients.

Glucocorticoids are the only available option to slow the decline in muscle strength and function in Duchenne patients. However, their effectiveness is limited and patients often experience side effects, such as an increased risk for infections.

Puldysa is an experimental treatment that contains idebenone, a synthetic small molecule that resembles ubiquinone (coenzyme Q10), which is essential for the normal functioning of mitochondria (the cells’ powerhouses).

The treatment is designed to improve mitochondrial function, restore the production of adenosine triphosphate (ATP), and reduce the generation of damaging reactive oxygen species (ROS). These are expected to slow the progression of the respiratory symptoms experienced by patients. (ATP is a small molecule used as “fuel” by all cells in the body, while ROS are toxic free radicals that cause oxidative stress.)

In prior studies, patients given Puldysa for up to six years — but not glucocorticoids — experienced durable reductions in their annual rate of lung function decline, along with fewer respiratory problems and hospitalizations than those off therapy.

“There are currently no approved treatments to slow the rate of respiratory function decline leading to respiratory failure, which remains a leading cause of premature death in young men at the advanced stages of DMD,” said Oscar Henry Mayer, MD, medical director of the Pulmonary Function Testing Laboratory at the Children’s Hospital of Philadelphia.

“By slowing the rate of respiratory function decline, we open the possibility to delaying the time to chronic respiratory failure and the need to assisted ventilation and reducing the risk of other life-threatening respiratory complications,” added Mayer, who is the lead investigator in SIDEROS in the U.S.

The trial (NCT02814019) is assessing the benefits of Puldysa in DMD patients on a stable dose of glucocorticoids. SIDEROS includes male patients, ages 10 and older, enrolled across 62 clinical sites in the U.S., Europe and Israel, regardless of their DMD mutation or ability to walk.

Participants are randomly assigned to either Puldysa (900 mg/day, two 150 mg tablets three times a day) or a matching placebo for 18 months, while remaining on their stable glucocorticoid treatment — Emflaza (deflazacort) or prednisolone.

SIDEROS’ main goal is to assess changes in lung function, measured via forced vital capacity percent predicted (FVC %p), over the treatment period. Changes in other measures of lung function will be assessed as secondary objectives.

After completing treatment, patients may enter the SIDEROS-E open-label extension trial (NCT03603288) and either continue receiving or begin using Puldysa. To date, about half of enrolled patients have completed 18 months of treatment.

“Santhera is the only company that has dedicated its clinical development program towards finding a treatment to preserve respiratory function in DMD,” said Gunnar Buyse, MD, PhD, SIDEROS’ principal investigator and lead investigator for Europe.

“We are truly excited that SIDEROS has completed recruitment and is on track to generate a comprehensive dataset in an area of such high unmet need,” Buyse added.

Puldysa has been granted rare pediatric disease and fast track designations by the U.S. Food and Drug Administration (FDA) for the treatment of DMD. It was also named a promising innovative medicine in the U.K.

The European Medicines Agency is reviewing a request for European Union approval of Puldysa to treat respiratory problems in Duchenne patients who are not on glucocorticoids. That request, submitted in 2019, was supported partly by findings from the Phase 3 DELOS study (NCT01027884) in DMD boys not using steroids.