Puldysa (idebenone) is an experimental treatment for respiratory symptoms caused by Duchenne muscular dystrophy (DMD). Puldysa is being developed by Santhera Pharmaceuticals and has been granted rare pediatric disease designation and fast track designation by the U.S. Food and Drug Administration (FDA). In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) has designated Puldysa as a Promising Innovative Medicine.
How Puldysa works
DMD is a type of muscular dystrophy — a group of related genetic disorders characterized by muscle weakness and atrophy. DMD is caused by mutations in the DMD gene, which encodes for a protein called dystrophin. Dystrophin is a structural protein that protects muscle cells as they expand and contract with muscle movement. Mutations in DMD lead to no dystrophin protein being made, which means that muscle cells are weak and easily damaged. Over time, scar tissue forms around the damaged area, and the muscles weaken and die. In addition to problems with skeletal muscle tissue, many patients with DMD also experience symptoms of muscle weakness in the heart and diaphragm, which contribute to respiratory weakness. Many patients need ventilation as the disease progresses.
Puldysa contains idebenone, a synthetic small molecule that resembles ubiquinone (coenzyme Q10), an essential molecule in mitochondria. Mitochondria are small organelles (compartments within cells) that produce energy for the cell in the form of a molecule called ATP. The pathway that produces ATP is the electron transport chain, where chemical energy derived from sugars is converted into electrons which are transported (handed from molecule to molecule) until that energy can be converted into ATP.
Ubiquinone is a component of the electron transport chain. By increasing the presence of a ubiquinone-like molecule in the electron transport chain, idebenone is thought to increase the energy production inside cells as well as protect the mitochondria (and the cell) from damage.
Puldysa in clinical trials
DELOS (NCT01027884) was a 52-week Phase 3, double-blind, placebo-controlled study that randomly assigned 64 patients with DMD to receive either 900 mg, orally, per day of Puldysa or placebo. The study demonstrated that idebenone was able to slow the loss of respiratory function, as determined by comparing the change in peak expiratory flow (PEF, the maximum rate at which a patient can exhale) from baseline to the end of the study.
Supportive data for Puldysa were obtained in a Phase 2, double-blind, placebo-controlled clinical trial (NCT00654784, nicknamed DELPHI), and its two-year open-label extension (NCT00758225, DELPHI extension) which recruited 21 boys with DMD.
A retrospective examination of long-term respiratory function data from 18 patients who completed the DELOS study and subsequently received 900 mg per day of Puldysa under expanded access programs (NCT03433807, nicknamed SYROS) demonstrated that the previously observed beneficial effect of Puldysa in reducing the rate of respiratory function decline was maintained for up to six years during treatment. The results of the study were published in the journal Neuromuscular Disorders.
A Phase 3 clinical trial (NCT02814019, nicknamed SIDEROS) is recruiting DMD patients receiving glucocorticoid medications. Patients (266 expected) will be randomly assigned to receive 900 mg per day of Puldysa or placebo, in addition to their glucocorticoid medications. The study will compare whether Puldysa can delay the loss of respiratory function in patients with DMD receiving concomitant glucocorticoid steroids. The primary outcome measure will be the change in PEF from baseline to the end of the study at 78 weeks. The study is recruiting at 63 locations across the U.S., the U.K., and the European Union. After completion of the SIDEROS study, eligible patients will be enrolled in an open-label extension study called SIDEROS-E (NCT03603288). The SIDEROS study is estimated to be completed in August 2021 with the SIDEROS-E study estimated to continue until 2024.
Santhera announced in May 2019 that it had submitted a marketing authorization application to the European Medicines Agency (EMA) and that the EMA had validated the application for review. The submission included data from the DELOS, DELPHI, DELPHI extension, and SYROS studies. Santhera expects a decision from the EMA in mid-2020.
Following the completion of the ongoing Phase 3 SIDEROS clinical trial, Santhera plans to submit a new drug application to the US Food and Drug Administration (FDA) for Puldysa.
The most common side effects of Puldysa are mild to moderate diarrhea, cough, and back pain.
Last updated: Nov. 22, 2019
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