Update on Ongoing Clinical Trials for SMA Drug Programs

The Annual SMA Conference organized by Cure SMA was recently held this June in Kansas City. According to a news release, six representatives out of the seven drug programs currently being assessed in clinical trials presented their work at the conference.

SMA (spinal muscular atrophy) is a rare, devastating motor neuron disease and one of the leading genetic causes of pediatric mortality, occurring in approximately 1 in every 6,000 to 10,000 newborns. It is characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in muscle weakness, atrophy, paralysis and eventually death. SMA is the result of a mutation or deletion in a gene called survival of motor neuron 1 (SMN1), which causes insufficient production of the SMN protein. Currently, SMA has no approved treatment.

The SMN protein has two identical variants – SMN1 and SMN2. SMN2 is mainly produced as an unstable and shortened version of the SMN protein due to a single nucleotide difference in the exon 7 of the gene, and therefore cannot compensate for SMN1 loss. Only around 10% of all SMN2 proteins produced are full-length and these are an important determinants of disease severity. It is thought that an increase in the generation of SMN2 full-length RNA could be a therapeutic strategy for SMA.

Four of the six programs presented at the conference – gene therapy, ISIS-SMNRx, RG7800 and LMI070 – have as its main goal the treatment of the genetic causes underlying SMA. The gene therapy program developed at the Nationwide Children’s Hospital, Ohio and licensed to AveXis Inc., is a phase 1/2 clinical trial focused on correcting the SMN1 mutation through the delivery of a normal, functional copy of the SMN gene. So far, the treatment has been well tolerated by patients and preliminary results are being analyzed.

The ISIS-SMNRx, RG7800 and LMI070 programs are centered on SMN2. The ISIS-SMNRx program, developed by ISIS Pharmaceuticals and Biogen, has as a goal the increased production of full functional SMN protein through a change in the RNA maturation process (splicing) of SMN2. Two phase 3 clinical trials are currently ongoing, one called ENDEAR (NCT02193074) that involves around 110 infants with SMA and the second one, CHERISH (NCT02292537) on 120 children with SMA. Two additional trials were also initiated this year, the NURTURE where ISIS-SMNRx’s efficacy will be assessed, and the EMBRACE where the safety and efficacy of the drug will be tested in a small subset of patients with infantile or childhood-onset SMA.

The RG7800 clinical program developed by Roche, PTC Therapeutics and the SMA Foundation is based on an oral SMN2 splicing modifier. The drug is being tested in SMA patients, although the trial is currently on hold due to findings in monkeys. The LMI070 program is being developed by Novartis; it is also centered in a more efficient splicing of the SMN2 gene. LMI070 treatment in animals has been reported to prolong animal survival and increase the levels of functional SMN proteins. The First in Human study (NCT02268552) will evaluate the safety, tolerability and potential benefit of LMI070 in SMA patients between 1 and 7 months of age.

The final two programs, Olesoxime and CK-2127107, intend to protect the muscles and nerves of SMA patients. Roche is currently responsible for the development and regulatory processes of olesoxime. CK-2127107 is being developed by Cytokinetics and Astellas. The drug was found to be safe and well-tolerated by healthy volunteers, and to amplify the muscle response to nerve activation. CK-2127107 is thought to improve skeletal muscle function and the companies expect it to progress into Phase 2 clinical trials in SMA patients.