ISIS-SMN Rx Shows Efficacy in Infants with SMA During Phase 2 Studies

Encouraging news from Isis Pharmaceuticals, Inc., presented at the 19th International World Muscle Society Congress in Berlin, demonstrated the efficacy of ISIS-SMN_Rx in treating spinal muscular atrophy (SMA) in infants and children. Results were from the ongoing open-label Phase 2 clinical trial. Isis is also enrolling patients in the Phase 3 trial ENDEAR, and there are now plans to initiate another Phase 3 study named CHERISH, which is not yet active on clinicaltrials.gov.

“I am encouraged with the totality of the data presented today, which show that median event-free ages for SMA infants in both the 6 mg and 12 mg cohorts compare favorably to that observed in a recent natural history study,” said Richard Finkel, MD, in a news release from Isis. Dr. Finkel was principal investigator on the preceding study, is chief of the division of neurology in the department of pediatrics at Nemours Children’s Hospital, and sees patients with SMA. “These data combined with the safety and tolerability profile observed to date support my enthusiasm to further evaluate ISIS-SMN_Rx in a Phase 3 study in infants with Type I SMA.”

Twenty infants with SMA were enrolled for treatment by the beginning of September, with four receiving 6 mg ISIS-SMN_Rx and sixteen receiving 20 mg ISIS-SMN_Rx. Both dosing cohorts have demonstrated increases in muscle function scores as defined by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Mean improvement was 9.3 points for 14 of the 16 infants who responded to treatment. A further milestone for treatment is the Motor Milestones portion of the Hammersmith Infant Neurological Examination, with 14 of the 16 infants showing increased scores.

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The 6 mg dose has proven to be slightly safer and effective in terms of events. Four respiratory-related infections led to one permanent ventilation and three deaths in the 12-mg group, while one accidental death and one permanent ventilation occurred in the 6-mg group. Median event-free ages of the two groups are 16.3 months and 13.8 months for the 6- and 12-mg groups, respectively, but the 6-mg group began treatment five months before the 12-mg group.

Compared to the preceding study, Dr. Finkel indicated, “In the PNCR natural history study, for which I was the lead investigator, in a group of untreated patients similar to those in the Isis Phase 2 study, the median event-free age was 10.5 months, with less than 20% of patients event free at 18 months. In addition to the positive data on event-free survival, substantial and persistent increases in muscle function as measured by the CHOP INTEND and Hammersmith Infant Neurological Examination were also observed in ISIS-SMN_Rx-treated infants up to 9 months on study.”

Dr. Finkel alluded to the importance of these positive results, stating, “Often infants with Type I SMA succumb to early death due to progressive weakness of the muscles responsible for breathing and feeding…. [These are] important findings because in general, infants with Type I SMA decline over time in their motor function as reflected in scores on these tests.”

Positive results may be a function of broad ISIS-SMN_Rx distribution to central nervous system tissues. Drug concentrations in the tissues are at a higher biological activity level than those identified during preclinical animal studies.