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recommended dose (1.1 × 1014 vg/kg body weight, estimated retrospectively from the first dose of 2.0 × 1014) is delivered in a single intravenous injection (74). The relevant safety information for Zolgensma includes severe acute liver injury as the main risk; however, the recommended dose appeared to be well tolerated both short and long term in patients with SMA type I or II and presymptomatic SMA infants (reviewed in 74). Primary outcomes from the clinical trials for onasemnogene abeparvovec (AVXS-101-CL-101, NCT02122952) and nusinersen (ENDEAR, NCT02193074) were compared using frequentist and Bayesian approaches. This indirect analysis suggested that onasemnogene abeparvovec could have a superior benefit relative to nusinersen in terms of overall survival, independence from assisted ventilation, motor function, and achieved motor milestones. Onasemnogene abeparvovec also appears to offer a more favorable cost–utility procurement (74, 109). SMN-Independent Therapies A significant body of evidence has substantiated that SMA is a systemic disorder that goes beyond motor neurons. Indeed, other organs and cell types are subclinically affected in SMA patients and animal models (66 and references therein). Moreover, mouse models corroborate that the disease is a non-cell-autonomous defect of the motor neurons (76). In this context, the implementation and further development of SMN-independent therapies are extremely relevant, considering that SMN-dependent therapies reduce disease severity but do not cure the disease. Moreover, targeting only the central nervous system will not address the multiorgan impairment of SMA patients, especially those with the most severe presentation of the disease (66). SMN-independent therapies hold the key to enhancing the beneficial effects of SMN-dependent strategies if used in a combinatorial therapy approach. Neuroprotection. Enhancing motor neuron survival and function presents an attractive therapeutic target for SMA patients. Olesoxime (TRO19622) is an orally active cholesterol-like molecule that preserves mitochondrial function by targeting components of the mitochondrial permeability complex and preventing the release of proapoptotic factors that lead to motor neuron death. At the preclinical level, olesoxime-mediated restoration of mitochondrial homeostasis preserves motor neuron integrity and reduces muscle denervation, astrogliosis, and microglial activation (For personal use only. Olesoxime safety and tolerability were assessed in a phase 2, randomized, placebo-controlled clinical trial (NCT01302600) in which 165 patients with SMA type II or III and ranging in age from 3 to 25 years received a twice-daily oral administration of olesoxime (10 mg/kg) for 24 months. Although the trial did not meet the primary outcome of improved motor function, it did show that olesoxime delays the typical functional decline observed in untreated SMA patients (15, 117). However, Hoffmann–La Roche announced that it would not pursue further studies of olesoxime for the treatment of SMA, as a later phase 2 trial (OLEOS, NCT02628743) yielded a decline in motor function after 18 months of treatment. Restoration of muscle function. Skeletal muscle enhancement therapies aim to counteract muscle atrophy by improving muscle performance and increasing muscle mass. One of these enhancers is the fast skeletal muscle troponin activator reldesemtiv (CK-2127107), which not only slows down calcium release from the troponin complex but also sensitizes the sarcomere response to calcium (81). Most importantly, it amplifies the skeletal muscle force–frequency response upon nerve stimulation (7). Reldesemtiv administration (single doses up to 4,000 mg) proved to be safe and tolerable in phase 1 studies conducted in healthy individuals. A consecutive phase 2, randomized, placebo-controlled trial (NCT02644668), which enrolled 70 patients with SMA type II, III, or IV, showed a significant drug concentration–dependent increase in aerobic capacity and endurance and a significant improvement in respiratory muscle strength (S. Rudniki, unpublished update of clinical trial CY5021 presented at the
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