All About the Results of ISIS SMNrx Phase 1a Study

We had previously reported that the potential spinal muscular atrophy (SMA) drug SMNrx developed by ISIS Pharmaceuticals successfully completed the phase 1a clinical study and entered a phase 1b/2a study.

Results of the 1a clinical study were presented by Dr. Claudia Chiriboga, from Columbia University Medical Center, at this year's American Academy of Neurology (AAN) Annual Meeting.
ISIS-SMNRx was well tolerated when administered intrathecally as a single dose directly into the spinal fluid and that no safety concerns related to the drug were identified.  In addition, the intrathecal injection procedure was well tolerated in children with SMA. 

Concentrations of ISIS-SMNRx measured in cerebral spinal fluid were consistent with levels predicted from preclinical studies, indicating that the drug half-life in nervous system tissues is very long and that dosing once every six to nine months is feasible. 

Although the study was not designed to provide evidence of functional activity, clinically significant, dose-dependent improvements in the Hammersmith Functional Motor Scale-Expanded (HFMSE) were observed in these children.  The mean increase in the HFMSE scores observed in the highest dose cohort (9 mg) at 3 months was 3.1 points or a 17.6% increase from baseline, with six of ten patients experiencing an increase of 4 to 7 points.  Observed improvements in HFMSE scores equal to or greater than a 4 point increase were distributed by age with half (3) in children under the age of five and half in children five and older.  Children who participated in this study are allowed to either enter the ongoing multiple-dose Phase 1b/2a study or a separate re-dosing study.

The Phase 1 study of ISIS-SMNRx was an open-label, single-dose, dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile of ISIS-SMNRx in medically stable children from age 2-14.  In this study, 28 children, including 15 with Type II SMA and 13 with Type III SMA, received ISIS-SMNRx as a single dose of 1, 3, 6, or 9 mg administered intrathecally.  ISIS-SMNRx concentrations in plasma and cerebral spinal fluid were measured to provide information on the dose concentration and frequency for future studies.  In addition, exploratory analyses of changes in motor function were conducted.  Gross motor movements were measured in all children throughout the study using the Hammersmith Motor Function Scale-Expanded (HFMSE), a modified version of the Hammersmith Functional Motor Scale.  The HFMSE is used to assess responses on 33 motor function tasks, each scored on a scale from 0 to 2 and allows for assessment of any SMA patient aged 2 or older.  HFMSE has demonstrated good test-retest reliability in other studies.

"ISIS-SMNRx is our first drug to modify the splicing of RNA to increase the production of a functional SMN protein.  This Phase 1 study is the first time that we have administered an antisense drug to patients as young as 2 years of age.  We are very encouraged that the drug was safe and that intrathecal dosing was tolerated well by these children even at the highest dose level," said C. Frank Bennett, Ph.D., senior vice president of research at Isis. 

"Early evidence of activity in these children is encouraging, but it is important to note that this was an open-label study without a control arm," said Stanley T. Crooke, M.D., Ph.D., chairman of the board and chief executive officer at Isis.  "We are cautiously optimistic with the observed improvements in muscle function in the higher dose cohort, however, we will need further clinical data from a controlled study to assess the safety and activity of this drug in patients with SMA.  We plan to have additional clinical data from our ongoing multiple-dose study in children with SMA by late 2013 or early 2014.  We also plan to initiate a Phase 2/3 program in infants this year and a Phase 2/3 study in children in the first half of 2014."