Phase 3 Spinal Muscular Atrophy Study Begins For Experimental ISIS-SMN Rx Drug

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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SMA drugIsis Pharmaceuticals, Inc. has announced that it has initiated a Phase 3 clinical trial (CHERISH) that will test the safety and efficacy of their lead drug – ISIS-SMNRx – in non-ambulatory children with spinal muscular atrophy.

Spinal Muscular Atrophy (SMA) is a disease caused by mutations in the Smn1 gene that encodes SMN1 protein, a key protein for motor neuron survival. The lack of SMN protein leads to motor neuron dysfunction and death, triggering subsequent generalized muscle atrophy. SMA is the leading genetic cause of death in infants and currently there is no cure or viable FDA-approved therapy. In humans, an additional gene Smn2 is present, however, it differs in two nucleotides, in eons 7 and 8, and through a process known as alternative splicing, only a small amount of the coded protein that it produces is functional.

ISIS-SMNRx was developed to change the splicing of Smn2 gene, leading to a fully functional protein. The CHERISH study, which will enroll 120 non-ambulatory children (ages between 2 and 12 years old) with SMA, will be administered a 12 mg dose of the drug. The study outcomes will be evaluated according to changes in the Hammersmith Functional Motor Scale-Expanded (HFMSE).

The effect of ISIS-SMNRx in young infants with SMA is also currently being evaluated in another Phase 3 study, known as ENDEAR. SMA News Today reported on the ENDEAR trial back in October, which revealed the drug to be effective. In that study, both dosing cohorts demonstrated increases in muscle function scores as defined by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and mean improvement was 9.3 points for 14 of the 16 infants who responded to treatment. The Motor Milestones portion of the Hammersmith Infant Neurological Examination — the same to be used in CHERISH —  revealed 14 of the 16 infants showing increased scores.

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Lynne Parshall, chief operating officer at Isis Pharmaceuticals noted, “CHERISH is the second pivotal Phase 3 study of ISIS-SMNRx, we have initiated this year. The speed at which we have moved this drug from a preclinical development candidate to a late-stage development reflects the successful collaboration we have with Biogen Idec and the support from the SMA community. It is our hope that this study will build upon the encouraging results we observed in our open-label Phase 2 studies. Both Phase 3 studies are designed to evaluate the efficacy of ISIS-SMNRx in either infants or children with SMA and to assess further the safety profile in these patients. We are further encouraged by the FDA’s agreement on the trial design and planned analysis for both of these Phase 3 studies on ISIS-SMNRx. Together with our partner Biogen Idec, we are also in the planning stages for additional clinical studies as part of our commitment to the clinical program for ISIS-SMNRx.”

Kenneth Hobby, president of Cure SMA commented, “SMA is a devastating disease that robs people of physical strength by affecting the motor nerve cells in the spinal cord. SMA is the number-one genetic cause of death for infants. Children with SMA grow weaker as their disease progresses. Although the genetic cause of SMA is well understood, currently there are no effective drugs available for children with SMA. We applaud Isis for investing in and leading drug development efforts for SMA. We remain hopeful that potential treatments, like ISIS-SMNRx, will be able to provide therapeutic benefit.”