2015 SMA Researcher Meeting Summary: Drug Discovery

We will be posting a series of summaries from our 2015 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers a session on drug discovery. The session was moderated by Elliot Androphy, MD

Preclinical and Clinical Drug Development for SMA

The 2015 SMA Researcher Meeting closed with a highly anticipated session on drug development for SMA. Eight talks were given, with the first four focusing on drug programs at earlier stages in the SMA pipeline. The last four focused on drugs already being tested in human clinical trials, either in patients or healthy adult volunteers. The SMA drug pipeline currently consists of 18 drug programs, with seven of them in clinical trials.

The first several speakers were from biotechnology companies that presented different drug approaches to increase levels of the SMN (survival motor neuron) protein, which individuals with SMA don’t produce at high enough levels. BioBlast Pharma, an Israeli company, described re-purposing of an FDA-approved drug that would alter the protein originating from the SMN2 gene. The SMN2 gene typically produces a shortened form of the SMN protein that is unstable and less functional than full-length SMN protein. Their drug is intended to cause the short form of the SMA protein to become more stable and to function better.

Next, the research program at Calibr, which is supported by Cure SMA, was presented. The program has discovered novel small molecules that turn on gene expression or transcription of the SMN2 mRNA. These are currently being chemically optimized and tested in mouse models of SMA.

Next, RaNA Therapeutics discussed promising early stage studies of an antisense oligonucleotide that also turns on transcription of the SMN2 gene. RaNA Therapeutics is focused on developing a new class of medicines that target RNA to turn on gene and protein expression, enabling the body to produce more functional protein. Their strategy is different than that of Isis Pharmaceuticals, who are targeting splicing defects in the SMN2 gene.

Then, the Lorson laboratory at University of Missouri described the ability of an antisense oligonucleotide called E1 to increase exon 7 inclusion in the SMN2 mRNA, meaning it could produce full-length SMN protein. This drug also has a totally different RNA target than that of Isis Pharmaceuticals, and therefore has the potential to be used in combination with ISIS-SMNRx. Cure SMA has provided funding to Dr. Lorson in order to optimize this for testing in SMA mouse models.

To complete the session, four presentations were given by clinical investigators or companies currently engaged in clinical trials. Dr. Claudia Chiriboga from Columbia University is exploring the importance of electrical circuitry defects in ambulatory (able to walk) SMA patients. Her group has been studying the effects of Dalfampridine-ER, an FDA-approved drug marketed as Ampyra for the treatment of multiple sclerosis (MS) to see if this drug might also help SMA patients. Unfortunately, at the dosages approved for MS, they did not observe any positive effects on motor function outcomes or ambulation in adult with ambulatory type III SMA type III.

ISIS Pharmaceuticals presented an update of promising results from their Phase 2 clinical trials of their antisense oligonucleotide drug ISIS-SMNRx in infants and children with SMA. Summaries of these results for both infants and children have already been posted. Currently, Isis Pharmaceuticals is conducting two Phase 3 trials in both infants and children at dozens of sites worldwide.

Next, Drs. Kaspar and Mendell described the Avexis Pharmaceutical sponsored clinical trial of systemic viral delivery of the SMN gene therapy, called ChariSMA, in nine Type I infants treated at Nationwide Children’s Hospital. All nine infants enrolled in the trial remain alive, and none have progressed to the need for permanent ventilation (defined as the use of ventilation assistance for 16 or more hours per day). In addition, they described their CNS-delivered gene therapy program, funded by Cure SMA and NIH, that will allow gene therapy for SMA to be utilized in older and larger patients, not just infants.

Finally, the session ended with a talk from Roche Pharmaceuticals, describing a novel compound called RG7800 discovered by PTC Therapeutics, SMA Foundation, and Roche Pharmaceuticals. It is a small molecule drug that corrects the defective splicing in the SMN2 gene. It has recently been tested in a Phase 1 trial in healthy adult volunteers, where it was shown to be safe and well tolerated at all doses. Results also showed dose-dependent increases in full length SMN mRNA in the blood of the Phase 1 study participants. A phase 1b/2a study of RG7800 in adult and pediatric SMA patients was in progress, but has interrupted recruitment to assess recent non-clinical findings from a nine-month chronic toxicology study in monkeys.

Pictured above: Presenter Caroline Woo shares his research at our Family Friendly Poster Session.

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