Nusinersen: intrathecal antisense works

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Richard Finkel, Eugenio Mercuri and colleagues (ENDEAR and CHERISH trial groups); Ionis Pharmaceuticals and Biogen. N Engl J Med 377:1723–1732 (2017) and 378:625–635 (2018).

What happened

Spinal muscular atrophy (SMA) is a childhood disease in which motor neurons die because too little SMN protein is made. Nusinersen is an antisense oligonucleotide: a short strand of DNA-like material that alters how the SMN2 gene is read so that more working SMN is made. It cannot cross the blood-brain barrier, so it is injected by lumbar puncture (intrathecally).

• ENDEAR (infants, NCT02193074). Randomised, double-blind, sham-controlled; 122 infants enrolled (registry). Interim: motor milestones improved in 41% (21 of 51) on nusinersen versus 0% (0 of 27) on sham (P<0.001), and the trial was stopped early on this result. Final: 51% (37 of 73) versus 0% (0 of 37). Death or permanent ventilation was less likely (hazard ratio 0.53; P=0.005) and so was death alone (hazard ratio 0.37; P=0.004).
• CHERISH (later-onset, NCT02292537). 126 children with onset after 6 months of age, 12 mg versus sham (2:1). Interim analysis at 15 months (HFMSE score, 0–66): +4.0 points on drug, −1.9 on sham (difference 5.9; 95% CI 3.7–8.1; P<0.001); the trial was stopped early. Final analysis (registry): +3.9 versus −1.0 (difference 4.9; 95% CI 3.1–6.7); 57% versus 26% gained at least 3 points.
• Approval. The US FDA approved nusinersen (Spinraza, NDA 209531) on 23 December 2016, as the first SMA drug, after the interim infant analysis.

Why it moved us toward a cure

Spinal-fluid drugs for LRRK2 (landmark 110) and synuclein (landmark 29) use the same route; BIIB094 and ION464 are also antisense drugs. Nusinersen showed in a sham-controlled trial that this route can change a brain and spinal cord disease, and that regulators accept it. It is a proof of delivery. It did not treat Parkinson's. SMA is a single-gene disease with a clear target.

Outcome

Advanced. Intrathecal antisense dosing is now an established method. Benefit depends on early treatment (infants treated sooner did better). The route reaches the spinal cord and surface of the brain well; deep structures such as the substantia nigra are harder to reach, which is not addressed in these sources.

Sources

• Finkel et al., N Engl J Med 2017, DOI 10.1056/NEJMoa1702752, PMID 29091570 (abstract via Europe PMC)
• Mercuri et al., N Engl J Med 2018, DOI 10.1056/NEJMoa1710504, PMID 29443664 (abstract via Europe PMC)
• Drugs@FDA, NDA 209531 (approval 12/23/2016) · ClinicalTrials.gov NCT02193074 · NCT02292537 (API, 19 Oct 2026)
• Not yet verified: the "first SMA drug" wording (from press coverage, not the FDA label); why the final ENDEAR analysis counts 110 infants against 122 enrolled; penetration of deep brain regions; the antisense field's earlier origins (e.g. earlier ALS or Huntington's work).