Global trial testing Dyne’s Z-rostudirsen for boys with DMD now underway
Results from FORZETTO expected to back FDA filing for therapy's approval
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Seeking to build on the positive results seen among boys with Duchenne muscular dystrophy (DMD) treated with its experimental exon-skipping therapy zeleciment rostudirsen — z-rostudirsen, formerly known as DYNE-251 — in an early clinical trial, Dyne Therapeutics has launched a global confirmatory study, dubbed FORZETTO.
This new Phase 3 trial is expected to enroll about 90 boys, ages 4 to 18, who can walk. Eligible participants will be DMD patients amenable to exon 51 skipping. According to Dyne, the first site is now enrolling. Details about the double-blind study, in which neither researchers nor participants will know which boys are getting the therapy and which are receiving a placebo, will be shared at a conference in July.
FORZETTO follows the ongoing Phase 1/2 DELIVER (NCT05524883) trial, which, according to a recent company announcement, met its primary goal. Treatment with Z-rostudirsen led to increased levels of dystrophin, the protein that’s lacking in people with DMD, among the trial’s participants, as well as functional improvements, along with possible stabilization of heart and lung function.
Based on early results, Dyne has said it intends to file, by the end of June, for accelerated U.S. approval of z-rostudirsen for people with DMD amenable to exon 51 skipping. Therapies granted accelerated approval by the U.S. Food and Drug Administration (FDA) can be marketed based on early evidence that they likely benefit patients. Full approval depends on additional clinical data confirming the expected benefit.
“As we approach the planned submission of our application for Accelerated Approval in the U.S. later this quarter based on the unprecedented results seen in the DELIVER trial, we are pleased to have initiated a Phase 3 trial designed to further demonstrate the potential of z-rostudirsen to enable functional improvement for people with DMD amenable to exon 51 skipping,” Doug Kerr, MD, PhD, chief medical officer of Dyne, said in a company press release.
FORZETTO is intended to serve as the confirmatory trial for U.S. approval and to support future applications outside the U.S., according to the developer.
“Z-rostudirsen is designed to enable the production of near-full length dystrophin across muscle tissues and the central nervous system in order to improve how DMD patients feel and function,” Kerr said. “By assessing multiple measures of mobility, lung health and patient-reported outcomes, we aim to demonstrate the breadth of potential benefits of z-rostudirsen.”
Exon-skipping therapies designed to target DMD’s underlying cause
A rare, progressive neuromuscular disease, DMD is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein that helps protect muscle cells from damage. Without enough working dystrophin, muscles progressively weaken and lose function.
Z-rostudirsen is designed for people whose DMD-causing mutations are amenable to exon 51 skipping. Exon skipping therapy allows cells to skip over a faulty portion of genetic instructions, in this case, exon 51, so that a shorter but functional form of dystrophin is produced.
The therapy candidate consists of a phosphorodiamidate morpholino oligomer, or PMO, linked to an antibody fragment that binds transferrin receptor 1. This design is intended to help deliver the therapy into muscle tissue and the central nervous system, which comprises the brain and spinal cord.
In the FORZETTO trial, participants will be randomly assigned to receive either z-rostudirsen at 20 mg/kg or a placebo, both given by infusion into the bloodstream once every four weeks for 72 weeks, or slightly longer than one year.
Trial assessing effects of Z-rostudirsen on muscle function
The trial’s main goal is to assess changes in rise from floor velocity, also called time to rise velocity, at week 73. This measure evaluates how quickly a patient can rise from the floor and is used in DMD studies as an indicator of muscle strength and motor coordination.
Secondary measures include changes in stride velocity, 10-meter walk/run velocity, four-stair climb velocity, and percent predicted forced vital capacity, a measure of lung function. The North Star Ambulatory Assessment of motor abilities will also be used in the evaluation, and patient-reported outcomes will be assessed.
After the placebo-controlled part of the study, participants may enter a 96-week (nearly two-year) open-label extension, in which all will receive z-rostudirsen.
Dyne said the FORZETTO trial design and protocol were aligned with the FDA. Details of the study design will be presented at the 19th International Congress on Neuromuscular Diseases, taking place July 7-11 in Florence, Italy.
The FDA has granted z-rostudirsen breakthrough therapy, fast track, rare pediatric disease, and orphan drug designations for DMD amenable to exon 51 skipping. The therapy also has orphan drug status in Europe and Japan.
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