Clinical Trials

Date: 2017-01-13

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the British Paediatric Neurology Association (BPNA) annual conference in Cambridge,

Company: Ionis Pharmaceuticals (USA - CA)

Product: Spinraza™ -nusinersen - ISIS-SMNRx (antisense oligonucleotide targeted to the SMN2 gene)

Action mechanism:

• antisense oligonucleotide. ISIS-SMNRx is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein. The FDA granted orphan drug status and fast track designation to ISIS-SMNRx for the treatment of patients with SMA. Isis is currently in collaboration with Biogen Idec to develop and potentially commercialize the investigational compound, ISIS-SMNRx, to treat all types of SMA. Under the terms of the January 2012 agreement, Isis is responsible for global development and Biogen Idec has the option to license the compound until completion of the first successful Phase 2/3 study or the completion of two Phase 2/3 studies.

Disease: spinal muscular atrophy

Therapeutic area: Neuromuscular diseases - Rare diseases - Genetic diseases

Country: Australia, Belgium, Canada, France, Germany, Hong Kong, Italy, Japan, Republic of Korea, Spain, Sweden, Taiwan, Turkey, UK, USA

Trial details:

• This study will test the clinical efficacy and safety of IONIS-SMN Rx in patients with infantile-onset spinal muscular atrophy. (NCT02193074)

Latest news:

• • On January 13, 2017, Biogen presented new data from the Phase 3 ENDEAR study of Spinraza™ (nusinersen), which demonstrated a statistically significant reduction in the risk of death or permanent ventilation in Spinraza™-treated infants with spinal muscular atrophy (SMA) compared to untreated infants. The data were presented at the British Paediatric Neurology Association (BPNA) annual conference in Cambridge, UK, 11-13 January 2017.
• In August 2016, Biogen reported that ENDEAR met its pre-specified primary endpoint at the interim analysis, the proportion of motor milestone responders as measured by the Hammersmith Infant Neurological Examination (HINE) (see below). Following the positive interim analysis, Biogen ended the study early so that all participants could have the option to receive Spinraza™ in an open-label extension study. Biogen provided the first presentation of the pre-specified primary endpoint, time to death or permanent ventilation, from the end of study (EOS) analysis. The EOS results presented at BPNA include data from patients’ final study visit, which occurred after the announcement that the study was being stopped and was not part of the interim analysis. Spinraza™ met the pre-specified primary endpoint at the ENDEAR EOS, demonstrating a statistically significant 47% reduction in the risk of death or permanent ventilation (p<0.01). In the EOS analysis, a greater percentage of untreated infants (68%) died or required permanent ventilation compared to infants treated with Spinraza™ (39%). Spinraza™ demonstrated a favorable safety profile, with commonly reported adverse events including respiratory events and constipation, consistent with those expected in the general population of infants with SMA. Further EOS efficacy and safety results from ENDEAR will be presented at a future medical congress. ENDEAR was a randomized, double-blind, sham-controlled study in patients with infantile-onset (most likely to develop Type 1) SMA. The EOS efficacy analysis included all patients (n=121) who had their final study visit after the interim analysis (n=78) and had the opportunity to attend the six-month study visit assessment.
• • On August 1, 2016, Biogen and Ionis Pharmaceuticals announced that nusinersen met the primary endpoint pre-specified for the interim analysis of ENDEAR, the Phase 3 trial evaluating nusinersen in infantile-onset (consistent with Type 1) SMA. The analysis found that infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment. Nusinersen demonstrated an acceptable safety profile in the trial. As a result of these findings, Biogen has exercised its option to develop and commercialize nusinersen globally and paid Ionis a $75 million license fee. Biogen will initiate regulatory filings globally in the coming months. Biogen is now responsible for all nusinersen development, regulatory and commercialization activities and costs. Ionis will complete the Phase 3 studies and work with Biogen on regulatory filings. The two companies will also work together to transition the clinical programs that Ionis is conducting to Biogen. Ionis is eligible to receive tiered royalties on any potential sales of nusineren up to a percentage in the mid-teens, in addition to up to $150 million in milestone payments based on regulatory approvals.
• Based on the results of the pre-specified interim analysis, the ENDEAR study will be stopped and participants will be able to transition into the SHINE open-label study in which all patients receive nusinersen. Data from the other endpoints of ENDEAR will be analyzed when the full data set is available. Results will be presented at future medical congresses. Additionally, participants enrolled in the sham-controlled arm of EMBRACE, a Phase 2 study which also included infantile-onset patients, will have the opportunity to receive nusinersen.
• The other studies in the nusinersen program, including CHERISH (later-onset consistent with Type 2) and NURTURE (pre-symptomatic infants), will continue as planned in order to collect the data to demonstrate the safety and efficacy of nusinersen in these populations. Biogen is working to open a global expanded access program (EAP) for eligible patients with infantile-onset SMA (consistent with Type 1) in the coming months. The EAP can be initiated at existing nusinersen clinical trial sites in countries where EAPs are permitted according to local laws and regulations, can be operationalized, and where there is a path that can support long-term availability of nusinersen. Once the EAP is operational and required local approvals are in place, individual participating sites may start enrollment after they have transitioned ENDEAR study participants to the open-label extension study.

Is general: Yes