Antisense drug for spinal muscular atrophy nears the clinic

spinal muscular atrophy Spinraza
Max High of South Carolina was diagnosed with SMA before the age of 1. (Ron Brinson/Flickr)

Update: Nusinersen received FDA approval on December 23, 2016, and will be marketed as Spinraza.

In recent months, two Phase III clinical trials have shown a clear benefit of nusinersen in children with spinal muscular atrophy (SMA), a genetic motor neuron disease that robs children of muscle control and is the leading genetic cause of infant mortality. The ENDEAR trial, involving infants with the more severe SMA Type 1, was first to terminate randomization in August 2016. The CHERISH trial, involving older children with milder Type 2 SMA, was halted on November 8, 2016, because it also met its efficacy target.

Both trials are now open-label, and the FDA has granted nusinersen a priority review. The drug, formerly called SMNRx and now brand-named Spinraza, is an antisense oligonucleotide works by altering gene splicing (see sidebar).

Vector asked Basil Darras, MD, director of the Spinal Muscular Atrophy Program at Boston Children’s Hospital, to put these developments in perspective. Darras is site principal investigator at Boston Children’s for both trials. The hospital was the first in the world to enroll a child with SMA Type 1 in the ENDEAR study, in 2014.

Why are the nusinersen trial results so exciting?

Boosting a backup
nusinersen Spinraza antisense oligonucleotide for spinal muscular atrophySMN1, the gene mutated in spinal muscular atrophy, has a backup — SMN2 — that can also produce the SMN protein. But SMN2 has a small “letter” change (from C to T) that causes an entire coding region, exon 7, to be spliced out. As a result, the protein it makes is truncated and not fully functional. Nusinersen is an antisense oligonucleotide — a small string of nucleotides that target SMN2’s pre-messenger RNA and prevent exon 7 from being spliced out. This allows SMN2 to produce full-length SMN protein. (Neurology 2016 Mar 8; 86: 890–97doi: 10.1212/WNL.0000000000002445.)

They’re big news because spinal muscular atrophy is a disease for which there has been only supportive care and treatment of comorbidities. We haven’t had any curative treatment to offer our patients since it was first described in 1891. For the first time, we’re really on the verge of having a medication that seems to have efficacy. Not everybody responds dramatically, but there appears to be a response in many patients.

What have you observed clinically in patients during the trials?  

The patients in the SMA1 trial now range from almost 1.5 years to 3 years old. I continue to be blinded, so I don’t know what my patients are getting, but we have patients with SMA1, also known as Werdnig Hoffman disease, who have been able to acquire motor milestones, something we never see after the diagnosis is made. Usually they decline precipitously; 90 percent are dead by the age of 2 years without aggressive respiratory support. During the ENDEAR study, we have seen infants developing head control, sitting, rolling over, standing and sometimes showing some ability to walk with support. So these are substantial changes.

Patients with Type 2 SMA have a later onset; they can sit, but they never walk. The changes we saw in the CHERISH study were not as dramatic as in the infants with SMA1, but the study also met its endpoint and was interrupted a few weeks ago. Overall, it seems the earlier you give the medication, the better the outcome is going to be.

Could all SMA patients benefit from nusinersen?

When the FDA makes its decision, it will be interesting to see how broad the labeling is going to be. We’re all looking for a broad label that covers not only SMA Type 1, but also SMA 2 and SMA 3. [Update: The FDA’s approval covers all forms of SMA.]

Patients with type 3 SMA have muscular weakness, but are able to walk. Nusinersen has been studied in them, but not adequately. There are some open-label data. When we analyzed these data, it looked like these patients made progress — for example, walking longer on a six-minute walk test, and on other functional scales. But we have never had a double-blind controlled study.

How are children treated?

Nusinersen is injected intrathecally — directly into the spinal canal. We start with four loading doses. Then, in Type 1 children, we give the drug once every four months. For children with Type 2 or Type 3 SMA, we treat once every six months. We think the treatment will most probably need to be for life.

Does the success of this antisense approach bode well for other neurologic or neuromuscular disorders?

It’s hard to speculate, since the design of this drug is specific for SMA. But I think that it may make other researchers interested in this technology.

Read the story of clinical trial participant Sofia Wylie, who has SMA Type 1, and learn more about the Spinal Muscular Atrophy Program at Boston Children’s Hospital.