Cure SMA held its annual conference in June in Kansas City, where six representatives of the drug programs currently being assessed in clinical trials presented their work.
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 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 were presented at the conference:
- Avexis’ ChariSMA (gene therapy), focuses 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 of the phase ½ are being analysed.
The other programmes are centered on SMN2
- Biogen Isis’ ISIS-SMNRx,
- Roche’s Moonfish and
- Novartis’ LMI070
The ISIS-SMNRx program aims to increase the 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, NURTURE where ISIS-SMNRx’s efficacy will be assessed and 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 Moonfish 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 toxicity findings in monkeys (please read the Roche announcement here) .
Novartis’ LMI070 program also aims to increase the splicing efficiency 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 involved in the development and regulatory authorisation 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.