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2016 Clinical Trials Update

The following is an update on ongoing spinal muscular atrophy clinical trials, compiled by FightSMA Science Director Dr. Christian Lorson, a researcher at the University of Missouri.

1) Repligen/Pfizer – RG3039: currently no active clinical trials and the partnership for further development between Repligen and Pfizer has been terminated.

2) Roche (formerly Trophos) – Olesoxime Unlike many of the other drugs in clinical trial for SMA, this compound is not intended to increase SMN levels, rather, this drug is in a class of compounds referred to as neuroprotectants. Olesoxime has been in the clinic in Europe, however, Roche will now direct the production and future development of the compound for subsequent clinical trials.

3) Novartis – LMI070: This small molecule is being developed by Novartis and is designed to “correct” the SMN2 alternative splicing event, thereby increasing full-length SMN. The Phase I trial of approximately 22 patients will be an open-label first-in-human study of orally bioavailable LMI070 in Type 1 SMA patients. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy after 13 weeks; and to estimate the Maximum Tolerated Dose and optimal dosing regimen of orally administered LMI070 in patients with Type 1 SMA.
For additional information:
https://clinicaltrials.gov/ct2/show/NCT02268552

4a) Roche/PTC/SMAF: RG7800 – This drug is an orally bioavailable small molecule that is designed to “correct” the SMN2 alternative splicing event, thereby increasing full-length SMN. A Phase 1b/2a study called MOONFISH has initiated to assess safety, tolerability, pharmacokinetics and pharmacodynamics in adult and pediatric SMA patients. The trial will be a randomized double-blind study over 12 weeks enrolling approximately 48 patients. The trial was suspended in April due to an “unexpected eye finding” during an animal study evaluating the long term safety of the compound. At this point, internal and independent reviews found that “…no safety issues in any of the patients who were dosed with RG7800 in the trial and subsequently followed up for two months after completing treatment.” The trial remains on hold as of December 2015.
For additional information:
https://clinicaltrials.gov/ct2/show/NCT02240355

4b) Roche/PTC/SMAF: RG7916 – Similar to RG7800, another SMN2 splicing modifying drug is under development that is an orally bioavailable small molecule. A Phase 1 study in healthy volunteers has been initiated to investigate the safety, tolerability, and the pharmacokinetics/pharmacodynamics of RG7916.
For additional information: 
http://ir.ptcbio.com/releaseDetail.cfm?ReleaseID=949316
https://clinicaltrials.gov/ct2/show/NCT02633709

5) Cytokinetics/Astellas – CK-2127107: This compound is designed to improve function of skeletal muscle in SMA patients as a novel skeletal muscle troponin activator and is not intended to elevate SMN levels. Previously, CK-107 has been examined in five completed Phase 1 clinical trials in healthy volunteers, demonstrating safety, tolerability, bioavailability, pharmacokinetics, and pharmacodynamics. A Phase II trial is currently underway for SMA patients to examine efficacy. The trial will be a double-bind, randomized, placebo-controlled trial designed to investigate the pharmacodynamics of a suspension formulation of CK-2127107 following multiple oral doses in SMA patients. The trial will consist of approximately 72 patients with ascending dose cohorts (ambulatory and non-ambulatory).
For additional information: 
http://ir.cytokinetics.com/phoenix.zhtml?c=142156&p=irol-newsArticle&ID=2125742

https://clinicaltrials.gov/ct2/show/NCT02644668

6) AveXis – charisma: The lead candidate, AVXS-101, is a gene therapy product designed to deliver full-length SMN. The vector is derived from an Adeno-associated virus (AAV) serotype 9 vector and is delivered through an intravenous injection. SMN will be expressed throughout the body from the vector. An open-label Phase 1/2 trial is underway in which a dose-escalation in being performed. Dr. Jerry Mendell leads the clinical team at Nationwide Children’s Hospital (NCH) in Columbus, Ohio. Moving forward, AveXis plans to pursue an FDA approval that would allow an intrathecal delivery. Early in 2016, enrollment for the Phase I study of AVXS-101 was completed.
For additional information: 
http://www.businesswire.com/news/home/20160104005440/en/AveXis-Announces-Completed-Enrollment-Phase-1-Clinical
https://clinicaltrials.gov/ct2/show/NCT02122952

7) Ionis/Biogen – Nusinersen (formerly ISIS-SMNRx): This drug is an antisense oligonucleotide, or a short synthetic stretch of nucleic acid, that is designed to specifically bind SMN2 transcripts and “correct” SMN2 gene expression. In 2014, two Phase 3 trials were started, CHERISH and ENDEAR. The CHERISH trial is a randomized double-blind study to investigate efficacy and safety in children with later-onset SMA (ages 2-12). The trial will run approximately 15 months and will include ~120 patients. Changes in muscle function and the Hammersmith Functional Motor Scale will be used to assess efficacy. Nusinersen is delivered through an intrathecal injection. The ENDEAR study is focused upon infants with SMA and is a double-blind randomized controlled study to assess the efficacy and safety of Nusinersen in infantile-onset SMA patients. Patients up to 210 days of age are eligible. The trial will run for 13 months and will enroll approximately 110 patients.
For additional information:
https://clinicaltrials.gov/ct2/show/NCT02292537
https://clinicaltrials.gov/ct2/show/NCT02193074

Biogen is also running two clinical trials, NURTURE and EMBRACE. NURTURE is a Phase 2 study designed to examine the efficacy of Nusinersen in pre-symptomatic SMA infants. Patients will be genetically confirmed to have SMA, however, clinical manifestations will not be present. Pre-clinical animal models have suggested that early intervention results in the greatest degree of efficacy. The trial will enroll approximately 25 patients and will last ~2.5 years. The EMBRACE trial is a Phase 2 study of infantile-onset or childhood-onset SMA patients who do not meet the criteria for the ENDEAR or CHERISH trials. This is a relatively small trial of ~20 patients. Like the CHERISH and ENDEAR studies, this is a double-blind, randomized trial designed to examine efficacy of Nusinersen.
For additional information:
https://clinicaltrials.gov/ct2/show/NCT02386553
https://clinicaltrials.gov/ct2/show/NCT02462759