Antisense Oligonucleotides

Example 1: nusinersen (spinal muscular atrophy)

Spinal muscular atrophy (SMA) is an inherited disorder of the nerve cells that control muscles, and a leading genetic cause of death in infants and toddlers. NINDS reports that nusinersen (Spinraza) was the first therapy approved for SMA, and works by promoting production of full-length SMN protein from a back-up gene. [1]

Evidence (human, randomized, sham-controlled, phase 3). In infants, 37 of 73 (51%) in the nusinersen group had a motor-milestone response versus 0 of 37 in the control group. Death or permanent ventilation was less likely with nusinersen (hazard ratio 0.53; P=0.005), and overall survival was higher (hazard ratio 0.37). Infants treated earlier appeared more likely to benefit. Adverse events were similar in the two groups. The trial was funded by Biogen and Ionis Pharmaceuticals. [2]

Example 2: tofersen (SOD1 ALS)

The FDA approved Qalsody (tofersen) for amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. It is an antisense oligonucleotide that targets SOD1 mRNA to reduce production of SOD1 protein, and it is given by spinal injection (intrathecally) by experienced health professionals. [3]

This is a good example of why the label matters:

• The approval rested on a biomarker. The FDA says the approval was based on a reduction in plasma neurofilament light, a blood marker of nerve injury, under the accelerated approval pathway, with a confirmatory trial ongoing. [3]


• The main clinical measure did not reach significance. In the phase 3 trial of 108 participants, the change in the ALS functional rating scale at week 28 in the faster-progression group was -6.98 with tofersen and -8.14 with placebo, a 1.2-point difference (95% CI -3.2 to 5.5; P = 0.97). Secondary clinical end points did not differ significantly. [5]


• Later data were suggestive but weaker evidence. In an open-label extension (no blinding) at 52 weeks, those who started tofersen earlier had a smaller decline than the delayed-start group (difference 3.5 points; 95% CI 0.4 to 6.7). Differences on other end points were not adjusted for multiple comparisons. [5]


• Procedure risks. Lumbar puncture-related adverse events were common. [5] The FDA lists pain, fatigue, joint pain, increased white blood cells in spinal fluid and muscle pain as the most common side effects. [3]

What this means for readers

• ASO success so far is in defined genetic conditions, with specific targets, usually in specialist centers.
• A lab change is not the same as feeling or functioning better. See Biomarkers vs Clinical Outcomes.
• Other approved and investigational examples are on Approved Gene and RNA Therapies and Investigational Gene and RNA Applications.