PHILADELPHIA – The latest interim results from open-label studies of the investigational antisense oligonucleotide therapy ISIS-SMNRx for the treatment of patients with type 1, 2, or 3 spinal muscular atrophy support its safety and are starting to show its potential efficacy in treating the range of severity seen in the disease.
In two ongoing studies with up to 9 months of follow-up data, no safety or tolerability concerns arose with total doses of up to 18 mg in patients with type 2 or 3 spinal muscular atrophy (SMA) and in total doses of up to 48 mg in infants with type 1 SMA. Children aged 2-15 years with type 2 or 3 SMA had a dose- and time-dependent improvement in scores on the Hammersmith Functional Motor Scale-Expanded (HFMSE) that also correlated well with levels of SMN protein in cerebrospinal fluid. Infants with type 1 SMA achieved motor milestones on the Hammersmith Infant Neurological Exam that were consistent with increases in motor function test scores, according to investigators who presented the results at the annual meeting of the American Academy of Neurology.
Dr. Claudia Chiriboga
"It’s very encouraging that we can do this safely and that the children tolerate the lumbar punctures, and there’s hope that the measures [used in the studies] are sensitive to change," said primary investigator Dr. Claudia Chiriboga, who presented the interim results of a study in patients with SMA types 2 or 3.
In that study, ISIS-SMNRx, an antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene, was administered in an intrathecal bolus via lumbar puncture at points during a 3-month period; patients were then followed for 6 months. A total of eight patients received 3 mg at each dose (total dose, 9 mg); eight received 6 mg at each dose (total dose, 18 mg); and nine received 9 mg at each dose (18 mg total). Later, investigators added a 12-mg dose cohort that currently has eight patients enrolled, but results in that cohort are not yet available, said Dr. Chiriboga of the division of child neurology at Columbia University, New York.
The SMA type 2 and 3 patients included 10 patients with type 2 and 15 with type 3. They were medically stable and 2-15 years old, with a mean age of 7.5 years. Most (20) had three copies of the SMN2 gene; 4 had four copies and 1 had two copies. A majority of the patients (16) were nonambulatory.
None of the adverse events reported were considered related to the study drug, and most of the 143 adverse events were mild or moderate, the investigators found. Two severe adverse events were back pain and myalgia. Most of the adverse events were related to the lumbar punctures.
Scores on the HFMSE improved from baseline by a mean of 1.5 points in the 3-mg group, 2.3 points in the 6-mg group, and a statistically significant 3.7 points in the 9-mg group. SMN levels in cerebrospinal fluid at day 85 increased from baseline in all groups but were significantly increased in the 9-mg group only.
Additional secondary endpoints showed nonsignificant improvement of 22.7 m at 9 months on the 6-minute walk test in those who could walk, and an improvement of 2.3 points on an 18-point scale measuring upper limb function in weaker nonambulatory patients, but the open-label nature of the study and small numbers of patients make it difficult to interpret such findings, Dr. Chiriboga said.
Dr. Richard Finkel
"The feeling is that when there’s chronicity, like end-stage type of changes – severe scoliosis, for example – that those individuals don’t do as well. ... It’s not so much the age," Dr. Chiriboga said in an interview. Patients with type 3 disease also do better because they have more SMN2 to begin with, she said.
Similarly, in the ongoing open-label study of infants with type 1 SMA, ISIS-SMNRx was administered to 4 patients in 6-mg doses at days 1, 15, 85, and 253, and in 12-mg doses to 11 patients at the same time points. These infants were all aged 7 months or younger. Their mean age at symptom onset was 7 weeks, and they were enrolled in the study at a mean age of 18-21 weeks. All but one patient had two copies of the SMN2 gene, reported primary investigator Dr. Richard S. Finkel.
None of the adverse events in the infants were deemed to be related to ISIS-SMNRx. Of 14 severe adverse events, 11 were respiratory infections, and all were considered to be consistent with severe infant SMA, said Dr. Finkel, chief of the division of neurology at Nemours Children’s Hospital and professor of neurology at the University of Central Florida, both in Orlando.