Novel Drug Appears Safe and Well Tolerated in Infants and Children with Spinal Muscular Atrophy

The genetic disorder that causes the most infant deaths is spinal muscular atrophy (SMA) type 1. This inherited disease is being targeted in a phase 2 clinical study of a drug that increases production of a protein critical for nerve and muscle development.

The SMN1 gene codes for production of the protein SMN, and SMA type 1 infants carry a defect in SMN1. ISIS-SMN_Rx in infants and children with spinal muscular atrophy, an intrathecally administered oligonucleotide, has shown promise for the treatment of SMA in a small open-label study, the results of which will help guide the next phase of clinical trials, said lead investigator Richard Finkel, MD, of the Nemours Children’s Hospital, during a platform session at the 2014 American Academy of Neurology annual meeting in Philadelphia, PA.

Finkel reviewed the characteristics of the disease and elucidated study methods. Type 1 spinal muscular atrophy is a devastating diagnosis; the disorder is autosomal recessive and universally fatal. SMN protein deficiency results in death of motor neurons and generalized muscular atrophy, with respiratory complications and resultant permanent ventilation commonly experienced before death in late infancy or early toddlerhood. Symptoms typically begin before two months of age. ISIS-SMN_Rx in infants and children with spinal muscular atrophyacts to alter splicing of SMN1, increasing production of SMN. In a mouse animal model the drug has been shown to increase cerebral spinal fluid and intracellular levels of SMN.

The ISIS-SMN_Rx in infants and children with spinal muscular atrophystudy enrolled 15 infants, with four receiving 6 mg of study drug and 11 receiving 12 mg of the study drug. Seven of the 11 infants received the three induction doses required by protocol and were included in the population studied for efficacy, as were all four infants in the 6 mg arm. Only the 12 mg arm is continuing to enroll infants. Age at enrollment was 18-21 weeks; median age for the 6 mg cohort was 14 months. Only two of the 6 mg cohort children are still alive and not permanently ventilated; one infant experienced accidental death and one is permanently ventilated. Median age for the 12 mg cohort infants was 9.6 months. Of the seven infants who met criteria to be evaluated for efficacy, one died and one is permanently ventilated; both events occurred in conjunction with pneumonia.

This open-label study examined safety and tolerability. The study protocol called for intrathecal administration of the study drug without sedation, a process that has been well tolerated by study subjects. Further, no adverse events related to study drug were identified. Cerebral spinal fluid and plasma pharmacokinetics indicated good uptake of ISIS-SMN_Rx in infants and children with spinal muscular atrophy. An autopsy performed on one of the subjects who died (at 2.5 months of age, after the day 85 dose) showed robust amounts of SMN in limb tissue, as well as in thoracic and cervical spinal cord tissue.

The CHOP-INTEND scale, which measures motor function and strength and was designed for infants with SMA by the Children’s Hospital of Pennsylvania, was used as one measure to track motor function in both cohorts. For both groups, scores improved over time. With a maximum 64 points possible on the CHOP-INTEND scale, the 6 mg group showed a mean increase from baseline of 5.4 points, while the 12 mg group increased a mean increase of 8.3 points from baseline testing.

Another test of neurological and motor function, the Hammersmith Infant Neurological Exam Motor Milestones test, also showed improvement in nine of the 11 children evaluated by protocol.

During questions after the presentation regarding the aims of this open label study, Finkel stressed that the goals of this phase 2 study were to establish safety and efficacy, and to gather information to help shape data acquisition and formulation of endpoints for phase 3 studies. Though functional activity was measured and improvements were seen, stabilization or improvement of motor function was not a study goal. ISIS-SMN_Rx in infants and children with spinal muscular atrophyis also being tested in children with SMA types 2 and 3, and phase 3 trials for SMA type 1 infants will be initiated this year.