Originally published on June 27, 2014.

The 2014 SMA Conference brought together over 1,400 families and 250 researchers from around the world. At the conclusion of the conference, families gathered for a special opportunity to hear about the latest SMA research from the leading experts.

The session addressed new advances, strategies, and challenges in SMA drug development, and leading experts on SMA drug development answered questions about their drug programs.  Below slides of the keynotes presentations and the drug company status summaries can be found.


Update on Cure SMA Research Activities, Jill Jarecki, PhD, Cure SMA Research Director
Considerations and Importance of Clinical Trial Participation, Thomas Crawford, MD, Professor Of Neurology & Pediatrics, Johns Hopkins University.

Government Panel on SMA Research and Drug Development

  • John D. Porter, PhD, Program Director, Neurogenetics Cluster, National Institute of Neurological Disorders and Stroke, NIH
  • Tiina K. Urv, PhD, Program Director, Intellectual and Developmental Disabilities Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
  • Ali Mohamadi, MD, Medical Officer, Professional Affairs & Stakeholder Engagement, Center for Drug Evaluation and Research, FDA
  • Lei Xu, MD, PhD, Medical Officer, Office of Cellular, Tissue, & Gene Therapies, Center for Biologics Evaluation and Research, FDA

Panel on SMA Drugs in Development

  • C. Frank Bennett PhD, Senior Vice President, Research, Isis Pharmaceuticals
  • Brian Kaspar, PhD, Grant Morrow III, M.D., Endowed Chair, The Research Institute at Nationwide Children’s Hospital
  • Douglas Kerr, MD, PhD, Director of Experimental Biology, Biogen Idec
  • Pannie Trifillis, PhD, Director, Alliance Management – PTC Therapeutics Inc.
  • Katherine Klinger PhD, Sr. Vice President, Genetics and Genomics and Presidential Fellow, Genzyme Corporation
  • Michael Tones PhD, Director and Research Project Leader, Rare Disease Research Unit, Pfizer Worldwide R&D
  • Rebecca Pruss, PhD, Chief Scientific Officer, Trophos
  • Brian Tseng, MD, PhD, Director, Musculoskeletal Diseases, Novartis Institute of Biomedical Research NIBR

View summary slides from each SMA drug program represented on the panel.

Written Drug Program Summaries

Isis Pharmaceuticals

ISIS-SMNRx is an antisense drug Isis is developing to treat SMA.  SMA is caused by a loss of, or defect in, the SMN1 gene leading to a decrease in the amount of SMN protein. SMN protein is critical for the health and survival of nerve cells in the spinal cord that are responsible for neuromuscular growth and function. The severity of SMA correlates with the amount of SMN protein. Isis has designed ISIS-SMNRx to potentially treat all types of SMA by altering the splicing of a closely related gene, SMN2, which leads to the increased production of SMN protein. A Phase 1 clinical study evaluating the safety of single doses of ISIS-SMNRx in children with SMA has been completed.

In this study, ISIS-SMNRx was well tolerated at all dose levels tested with no safety or tolerability concerns. The compound is delivered by an injection into the lower back (an ‘intrathecal injection’) into the space containing cerebral spinal fluid below the spinal cord in order to best distribute the drug to spinal cord motor neurons. The intrathecal injection procedure was also well tolerated in the children. ISIS-SMNRx is now being studied in Phase 2 clinical studies that are designed to examine the safety and tolerability of multiple doses of the drug given over a longer time period. These studies are being conducted in children with Spinal Muscular Atrophy aged 2 to 15 and in infants with SMA who are

AveXis / Nationwide Children’s Hospital

Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1: This study is a phase I, single-site, dose escalation study to evaluate the safety and efficacy of gene transfer for Spinal Muscular Atrophy Type 1 (SMA1). Enrollment has begun at Nationwide Children’s Hospital in Columbus, Ohio. Infants between 0 and 9 months of age with SMA1 may be eligible to take part in this first human trial. A total of nine patients will be enrolled to receive a one-time gene transfer infusion. Patients will continue to be monitored at Nationwide Children’s Hospital including physical exams and blood tests for two years after gene transfer.


  • Age: Nine months of age and younger
  • Must be diagnosed with SMA Type 1 as defined by the following features:

Inclusion Criteria

  • Mutations of the SMN1 gene with two copies of SMN2 (no more and no fewer)
  • Onset of disease at birth to 6 months of age
  • Weakness of muscles and joints demonstrated at time of enrollment

Exclusion Criteria

  • Active viral infection (includes HIV or serology positive for hepatitis B or C)
  • Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry
  • Current illness that in the opinion of the researcher creates unnecessary risks for gene transfer
  • Current use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
  • Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay.
  • Abnormal laboratory values considered clinically significant (GGT > 3XULN, Bilirubin ≥ 3.0 mg/dL , Creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
  • Participation in recent SMA treatment clinical trial that in the opinion of the researcher creates unnecessary risks for gene transfer.
  • Family does not want to disclose patient’s study participation with primary care physician and other medical providers
  • Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding

Genzyme (a Sanofi Company)

Genzyme (a Sanofi company) has an active program in SMA gene therapy, focused on AAV9-SMN gene delivery into the cerebrospinal fluid (CSF).  In studies in mouse models of SMA, we have shown that delivery of AAV9-SMN1 into the CSF results in transfer of the gene to the spinal motor neurons, and expression of SMN protein.  The treated mice show significant improvement in strength, motor function, and survival.

We have determined the lowest percentage of motor neurons that must be modified by AAV9-SMN-1 in order to make significant improvement in SMA mice.  We have also shown that this level of gene transfer can be achieved using CSF delivered gene therapy in large animals, such as juvenile pigs and non-human primates.  These findings provide the foundation for continued development of this therapeutic concept for SMA.


RG3039 (PF-06687859) is an inhibitor of the enzyme DcpS and improves survival and motor function in SMA mice. In the last year, Pfizer has completed transfer of this program from Repligen and has been actively working on the design of clinical trials, biomarker development and understanding the expected efficacious dose. Achieving a better understanding of effective dose prediction is the focus of current efforts for 3 reasons:  1) Data from a Phase 1 study already performed indicated that at doses up to and including 3 mg/kg there was significant inhibition of DcpS in the blood but no change in SMN, the protein which is deficient in SMA patients 2) We expect that efficacy will require an increase in SMN 3) A subject in one of the Phase 1 studies already performed had an unexpectedly high concentration of drug in their blood: the reason for this is currently unknown. 

No further clinical trials have been initiated in the last year.  Ongoing work will drive the decision whether and how to progress this compound in the clinic. In the past year we have developed interesting backup DcpS inhibitor compounds, which are being studied in SMA mice and are also looking for other compounds that elevate SMN via other mechanisms.


Trophos  has released data showing that  that patients treated with olesoxime were able to maintain motor function over the two-year period of the study and that typical health complications associated with SMA occurred less frequently than in patients treated with a placebo, leading to better well being. The data presented is from the recently completed international, double-blind, placebo-controlled study involving 165 type II and non-ambulatory type III SMA patients, ranging in age from 3 to 25 years old. The results show that olesoxime treatment preserved motor function for two years using the Motor Function Measure scale (MFM) D1+D2 as the primary endpoint. The MFM is a standardized neuromuscular disease-specific functional scale.

In contrast, patients in the placebo arm of the study experienced a loss of motor function starting from a mean score of 39 per cent at baseline to 37.1 per cent after two years. The mean loss of 1.9 points in motor function over the two-year study period confirms that the natural disease progression results in approximately 1 per cent per year loss of motor function in SMA patients. The difference in favor of olesoxime at 24 months is statistically significant (p equals 0.038) while the overall treatment effect on motor function measured at four visits during the study was highly significant (p equals 0.0045). Interestingly, the effect of olesoxime could be detected even within six months following initiation of treatment.

The results observed in olesoxime treated patients are consistent with the working hypothesis set up when designing the study. Data analyses considering age, gender, SMA type or country as covariates show these variables have no influence on the results.The safety of olesoxime was confirmed in the study. Moreover, even though the trial was not designed to address the point, data related to typical SMA complications showed a clear improvement and less frequent disease-associated events such as lower respiratory tract infection or spine surgery to treat scoliosis in patients treated with olesoxime.