SMA success in Phase 3

CAMBRIDGE, Mass. & CARLSBAD, Calif.—August is starting off with good news from Biogen and Ionis Pharmaceuticals, as the companies announced this week that nusinersen, an investigational treatment for spinal muscular atrophy (SMA), has met the primary endpoint specified for the interim analysis of the Phase 3 ENDEAR trial. As a result, the study will be stopped and all participants will have the option of transitioning into the SHINE open-label study, in which all participants receive nusinersen. In addition, Biogen has exercised its option to develop and commercialize nusinersen globally and made a $75-million license fee to Ionis.

As a result of exercising its option, Biogen has now assumed full responsibility for all development, regulatory and commercialization activities and costs related to nusinersen, though Ionis will complete the Phase 3 studies and work with Biogen on regulatory filings. Ionis stands to receive tiered royalties on potential sales of nusinersen up to a percentage in the mid-teens and up to $150 million in milestone payments based on regulatory approvals. In addition to pursuing regulatory filings, Biogen is also working to launch a global expanded access program for eligible patients with infantile-onset SMA.

“We are hopeful that nusinersen, if approved, will make a meaningful difference in the lives of patients and families affected by SMA. We look forward to working with Biogen on completing the clinical program and preparing for what we hope is a positive regulatory review,” said B. Lynne Parshall, chief operating officer at Ionis Pharmaceuticals. “Nusinersen is the first antisense drug from our neurological disease franchise to advance to regulatory review, and it illustrates the potential of our antisense technology to address severe diseases that other therapeutic modalities are unable to address adequately.”

The ENDEAR trial sought to assess nusinersen in infantile-onset (consistent with type 1) SMA, and found that infants treated with nusinersen saw a statistically significant improvement in the achievement of motor milestones compared to those in the control arm. Nusinersen also demonstrated an acceptable safety profile. Participants in the sham-controlled arm of the Phase 2 EMBRACE study will also have the opportunity to receive nusinersen treatment. The two other studies of the compound—CHERISH (patients with later-onset SMA consistent with type 2) and NURTURE (pre-symptomatic infants)—will continue as planned to collect safety and efficacy data in those populations.

“We are grateful to the families participating in the clinical trials, who continue to inspire us. We want to thank them, along with the investigators who have worked tirelessly on this program and the broader SMA community, for their partnership. Without their contributions, we would not be here today,” Dr. Alfred Sandrock, executive vice president and chief medical officer at Biogen, said in a press release. “We share the community’s sense of urgency as we strive to bring the first treatment for SMA, the leading genetic cause of infant mortality, to families facing this devastating disease. We remain committed to understanding the potential of nusinersen in the broader SMA population and will continue to focus on the rapid completion of our ongoing studies.”

Nusinersen is based on findings from the lab of Prof. Adrian Krainer of Cold Spring Harbor Laboratory, which were licensed to Ionis. Krainer commented in a press release that “It’s my understanding that the results with nusinersen have been extremely impressive—to the point where, as the companies have now announced, it no longer makes sense, nor would it be ethical, to maintain a control arm in the trials involving infant-onset SMA. This is truly encouraging news for SMA families, who can now expect the companies to file for fast-track approval of the drug with the FDA in short order. I and members of my lab who have been involved in this work over the years, especially Dr. Yimin Hua, are heartened by it and proud of the role we have been privileged to play.”

Dr. Stanley Crooke, chairman and CEO of Ionis, said in a conference call that, “Nusinersen could not have happened if antisense technology had not been invented. This is a feat achievable only through antisense, and I want to thank the many people who have worked to bring this technology to a place where it might rapidly create a drug that could bring benefit to patients with SMA.”

He also commented that, “One of the remarkable observations we’ve made is, the longer we treat, the better the infants and children seem to get. The other important observation—it needs to be confirmed in our ongoing studies—is that the earlier we treat, the better the results.”

An estimated 30,000 to 35,000 children are afflicted with SMA, and it is the leading genetic cause of infant death. Type 1, the focus of this Phase 3 trial, usually affects children within six months of birth, and without treatment, these children face neuromuscular failure that affects breathing, feeding and locomotion, and generally don't live past age 2.