The Annual SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 470 attendees. The goal of the meeting is to create open communication of early, unpublished data, accelerating the pace of research. The meeting also furthers research by building collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.
We are posting a series of summaries from our 2017 researcher meeting, highlighting the most interesting new discoveries presented there. This update covers the highly anticipated closing session on SMA Therapies, where nine talks were given on drugs in preclinical or clinical development. This session was moderated by Douglas Kerr, MD, PhD, MBA, Cure SMA BOD.
Effective Treatments for All Ages, Stages and Types of SMA
Our community recently celebrated the approval of Spinraza, our first-ever FDA approval of a treatment for SMA. Spinraza. Like Spinraza, many of the other programs in the drug pipeline work to address this loss of SMN protein by replacing SMN1 or by modulating SMN2, the low-functioning SMA “backup gene.” These are called “SMN-based” or “SMN-enhancing” approaches. There are also a number of systems, pathways and processes that are affected in SMA, and there may be additional ways to treat SMA in these other areas—collectively referred to as “non-SMN” approaches. These non-SMN approaches include drugs that work on the muscles and nerves. Research strongly suggests that a combination of SMN-enhancing and non-SMN approaches is the best route to treat all ages, stages, and types of SMA. During the SMA Therapy Development Session, nine talks were given on the most advanced of these approaches.
Summary of Session Talks
The session opened with three talks on drugs designed to modulate muscle function and strength in SMA. Modulating muscle function is one the most obvious ways to development combination therapies for SMA, when given together with SMN-based therapies. The first talk was on SRK-105 from the company Scholar Rock. SRK-105 inhibits the muscle regulator myostatin to increase muscle strength. This molecule was tested in combination with SMN-based therapy in amouse model of SMA. When given with a low dose of a SMN based therapy, a 60% increase in force was observed at specific muscles. The second talk on muscle modulation was about ACE-2494 from Acceleron. ACE-2494 works to help preserve muscle strength. It was tested in a mild SMA mouse model, and was shown to increase both muscle mass and force production. CK-2127101 from Cytokinetics, currently in phase II trials, was the final muscle directed therapy discussed in the session. The trial includes two doses. The low dose cohort was completed in March 2017. The second higher dose cohort is now enrolling patients 12 years of age and older with genetically confirmed type II, III, and IV SMA, who are both ambulatory and non-ambulatory.
The second set of talks focused on the clinical development of two different orally available, small molecules that are designed to correct splicing of the SMN2 gene to increase SMN protein levels through the body. The first was given by Roche on RG7916, where they provided updates on three different clinical trials. SUNFISH (NCT02908685) assesses RG7916 in people with Type 2/3 SMA aged 2 to 25 years. In part I of this trial, the primary objectives are safety and selection of dose for Part 2. Part 2 evaluates one dose level of RG7916 versus placebo in non-ambulant patients, randomized 2:1 (RG7916: placebo). The primary endpoint for Part 2 is efficacy of RG7916 on motor function. The second trial called FIREFISH (NCT02913482) assesses RG7916 in babies with Type 1 SMA aged ≥ 1 to ≤ 7 months. FIREFISH has two parts: Part 1 explores two dose levels of RG7916; Part 2 evaluates efficacy of the most appropriate dose of RG7916. FIREFISH is open-label, i.e. there is no placebo in this study. The primary endpoint of Part 2 is the percentage of babies able to sit without support after 12 months. The third trial, JEWELFISH (NCT03032172), is an exploratory study evaluating a single dose level of RG7916 over two years in previous participants of studies with other SMN2-targeting therapies.
The next small molecule discussed was branaplam, formerly LMI070X2201, from Novartis. An open-label, first-in-human study (NCT02268552) was described for infants with Type 1 SMA with 2 SMN copies. The purpose of Part 1 of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the drug. 13 patients were treated with branaplam, and all continued into treatment extension period. Pharmacokinetic data show significant exposure with once weekly dosing. Improvements in CHOP INTEND, motor milesones using HINE, and preservation of oral feeding and breathing without mechanical support were noted in some patients. An interim analysis after a minimum of 14 months on treatment for safety, pharmacodynamic markers and clinical efficacy is being conducted.
The next three talks focused on the clinical trials results from the ENDEAR, CHERISH, AND NUTURE Trials for Spinraza (see https://curesma.wpengine.com/spinraza/ for detailed data presentations on each of these trials). At the end of the ENDEAR, there was a significantly greater proportion of nusinersen-treated motor milestone responders vs control (51% vs 0%; P=3 point increase in HFMSE score, and 17.1% vs 10.5%, respectively, achieved new WHO motor milestones. For the NURTURE study, 20 infants (SMN2 gene copies: 2, n=13; 3, n=7) were enrolled in October of 2016; 18 completed the Day 64 visit. None had met the primary endpoint of respiratory intervention or death, and 16/18 (89%) infants achieved improved milestones HINE. On the CHOP INTEND motor scales, 16 (89%) infants had a >=4-point score improvement and 7 (39%) achieved the maximum score (64). The most recent interim data from the NURTURE study show that presymptomatically treated infants are alive and are attaining appropriate age-related developmental milestones and growth.
The session closed with at talk from AveXis on the clinical development of the gene therapy AVXS-101. At data-cutoff (15 September 2016), a one-time dose of AVXS-101 appeared safe and appeared to demonstrate a positive impact on the survival in both a low (called 1) and high (called 2) dose cohort. Both cohorts demonstrated extended survival free of permanent ventilation when compared to the natural history. All patients were alive in both cohorts and only one patient, from the low dose Cohort 1, reached the pulmonary endpoint at 28.8 months of age. Cohort 2 demonstrated a rapid and sustained impact on motor function: 11/12 had head control, 11/12 sat with assistance, and 8/12 sat unassisted. Two patients who were dosed very early crawled, stood and walked independently.
Advancing Our Therapy Development Goals
The drug programs described in this session include both SMN-enhancing and non-SMN approaches. As the drug programs continue to move forward and as we continue to work through issues surrounding access to approved therapies, we also remain focused on continued growth of the SMA drug pipeline to allow for maximally effective treatment options for SMA patients of all types, ages, and stages.