The U.S. Food and Drug Administration has chosen Wave Life Sciences’ planned phase 2/3 study of suvodirsen, its lead experimental therapy for the treatment of Duchenne muscular dystrophy, to break new ground.

The study is the first the agency has selected for its Complex Innovative Trial Designs Pilot program. The agency announced the program in August. It was created to meet goals established by the 21st Century Cures Act and is intended to facilitate and promote the use of innovative trial designs in late-stage trials.

The Complex Innovative Trial Designs are part of a broader effort to create a new framework to allow clinical trial sponsors to take new approaches to clinical development to make studies more effective and efficient. FDA Commissioner Scott Gottlieb has called the program “an idea incubator” where the agency and participants in the program share knowledge and exchange ideas on ways to accelerate the development of products and advance the approach to designing clinical trials.

“I view it as an illustration of the FDA’s commitment of trying to accelerate development for rare diseases,” said Michael Panzara, chief medical officer of Wave Life Sciences. “They have opened the door to creative solutions for areas of high unmet need. I see this as a great step in that direction.”

Among the types of approaches the program will use are adaptive clinical trial designs to allow investigators to learn more quickly which patients are likely to benefit from a treatment or experience side effects. Innovative trial designs could also include simulations, multiple types of adaptations, or the use of natural history models to supplement or replace the use of placebo arms.

“The aim is to develop more efficient strategies to assess the safety and efficacy of medical products earlier in the development process and to adopt innovative techniques that help make clinical trials more cost efficient and flexible, enabling innovators to advance new approaches to care,” Gottlieb said in August when the agency unveiled the program.

In order to qualify for the program, companies must intend to provide substantial evidence of efficacy through a complex, novel design that incorporates innovative trial design elements, such as seamless trial designs, modeling, and simulations to assess trial operating characteristics; the use of biomarker enriched populations; complex adaptive designs; statistical models; and other benefit-risk determinations.

Wave’s study is still being finalized, but it does plan on minimizing the number of patients in the placebo arm of its study by supplementing them with patient information from natural history studies and registries. In part, Panzara said that is a response to the patient community, which does not like participating in placebo-controlled trials. “It’s something they have been trying to figure out a way to avoid as much as possible.” That should also help to reduce the cost and time of the study.

Duchenne muscular dystrophy is a rare, progressive, and fatal genetic disorder that results in muscle weakness from early childhood and leads to premature death in the mid-twenties due to heart and respiratory failure. Patients with Duchenne can lose the ability to walk as early as age 10, followed by loss of the use of their arms.

Suvodirsen is an experimental oligonucleotide that has been shown to induce skipping of exon 51 of dystrophin pre-mRNA in preclinical studies. About 13 percent of DMD patients have genetic mutations that are amenable to treatment with an exon 51 skipping therapy. Exon-skipping technology has the potential to induce the cellular machinery to skip over a targeted exon and restore the reading frame, resulting in the production of truncated, but functional dystrophin protein. Wave believes its platform technology allows for the creation of more stable and controlled oligonucleotides than competitors’.

Wave doesn’t have a start date yet for the study, although it anticipates initiating the phase 2/3 trial of suvodirsen in 2019. The trial is designed to measure clinical efficacy and dystrophin expression, and Wave intends to use the results to seek regulatory approvals globally.

One important requirement of the FDA program is that sponsors and the agency must also reach agreement on the trial design information being publicly disclosed. That’s something companies can be protective about, but the agency had the foresight to build this in as a requirement to ensure others can learn from the effort. Wave expects to present details of its phase 2/3 trial design at an upcoming scientific meeting.

Panzara said Wave understood that it would be committing to sharing details of its trial, but felt the opportunity was so great to have a high level of engagement with the FDA and make a broader contribution that it saw little downside.

“I’ve always felt the most exciting part of my job is being able to do things that change the way drugs get developed and advance the field,” said Panzara. “I believe this study will make a major contribution to the evaluation of drugs, not just in DMD, but the entire neurology space.”

In the world of biotechnology, people tend to think narrowly about innovation. The term is too often applied to platforms, modalities, and the ways drugs work. The reality is that innovation is needed throughout every part of drug discovery, development, and delivery. This will be an important program to watch to see if the agency can make an impact on the speed and cost of drug development.

January 16, 2019
Photo: Michael Panzara, chief medical officer of Wave Life Sciences

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