2016 SMA Researcher Meeting Summary: SMA Therapy Development

The SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 350 attendees. The goal of the meeting is to create open communication of early, unpublished scientific data, accelerating the pace of research. The meeting also furthers research by building productive collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.

We will be posting a series of summaries from our 2016 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers the highly anticipated closing session on drug development for SMA. Seven talks were given about drugs both in preclinical and clinical development. Currently, there are 18 drugs in the SMA drug pipeline, with six of them in clinical trials.

This session was moderated by Cure SMA Scientific Advisory Board Member Adrian Krainer, PhD.

Kevin Hodgetts, PhD (Harvard Medical School), opened the session by describing the preclinical development of small-molecule compounds that increase SMN2 expression by stabilizing the protein, allowing it to be more functional. Derivatives of the original compounds are being optimized for eventual clinical studies, and the underlying mechanism of action is also being investigated, i.e., what the compounds interact with in cells to elicit stabilization of SMN protein.

Heidemarie Kletzl, PharmD, PhD (Roche), gave an update about RG7800, an SMN2 splicing modifier, being tested in the placebo-controlled, double-blind clinical trial called “MOONFISH” in both adult and pediatric SMA patients. Although the trial is currently on hold, due to observed eye toxicity in monkeys (at a higher dose than given to patients), no serious adverse events were seen in patients, and analysis of their blood provided important data about the drug’s accumulation in the body after oral dosing. Moreover, analysis of blood cells showed that the drug elicited the expected change in SMN2 mRNA splicing and consequent increase in SMN protein, and this effect was reversible when drug administration was discontinued. Another small-molecule compound, RG7916, was generated and characterized to overcome the eye toxicity, and is being tested for safety in a Phase 1 clinical trial.

Lawrence Charnas, MD, PhD (Novartis), presented data about LMI070, also an SMN2 splicing modulator, which is being tested in a Phase 1 open-label, dose-escalation trial by weekly oral dosing for 13 weeks in infants with SMA type I. Further recruitment was recently halted, due to observed toxicities after long-term daily dosing in rats (eye finding) and juvenile dogs (axonal, kidney, and testes findings). Patients in the trial are being closely monitored and individualized risk/benefit decisions will be made.

John Day, MD, PhD (Stanford University School of Medicine), presented data about CK-2127107 from Cytokinetics, a small molecule that activates the troponin complex involved in muscle contraction. A Phase -2 placebo-controlled, dose-escalation trial is currently recruiting individuals with SMA type II, III and IV, ages 12 and older, with weekly oral dosing. So far the drug is generally safe, and its effects on muscle function and fatigability will be determined.

Jerry Mendell, MD, PhD (Nationwide Children’s Hospital), presented interim results of the Phase 1 open-label trial of the Avexis AAV9-SMN gene therapy (AVXS-101). Fifteen infants with SMA type I were administered the virus intravenously at one of two doses, plus prednisolone, an immunosuppressant, for one month. These doses represent the largest virus doses given for any gene therapy. All infants are alive and have not required permanent ventilation; serious adverse events have been manageable. They are reaching developmental milestones, and their CHOP-INTEND, a measurement of motor function, scores are improving, especially at the higher dose and/or with earlier treatment.

Enrico Bertini, MD (Bambino Gesù Children’s Research Hospital), presented a multi-center Phase 2 open-label trial of intrathecal nusinersen in pre-symptomatic infants with SMA type I (NURTURE), sponsored by Biogen and Ionis. Nusinersen is an antisense oligonucleotide (ASO) that increases SMN protein levels in a dose-dependent manner. The study is enrolling 25 infants younger than 6 weeks, in 10 countries, for approximately 2 years; 17 patients have already enrolled. The primary outcome is prevention or delay of respiratory intervention or death, and developmental milestones and motor function will also be assessed throughout the study.

Richard Finkel, MD (Nemours Children’s Hospital), presented results of the open-label Phase 2 trial of intrathecal nusinersen in infants with SMA type I, sponsored by Ionis and Biogen. Twenty patients were treated, with 4 receiving a low dose (6 mg) and 16 receiving a high dose (12 mg). Thirteen patients remain alive without respiratory support, and their survival is significantly longer when compared to natural history data. Statistically significant improvements in CHOP-INTEND scores and CMAP amplitude (an electrical study of motor function), compared to baseline values, were observed, and patients are reaching developmental motor milestones. These improvements were dose- and time-dependent. Autopsy samples from three treated patients revealed higher levels of correctly spliced SMN2 mRNA and SMN protein in the CNS, compared to untreated controls.

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