At the American Academy of Neurology’s 71st Annual Meeting, held May 4–10 in Philadelphia, researchers showcased their latest data on antisense oligonucleotides (ASOs). These short, synthetic, single-stranded oligodeoxynucleotides bind to target RNAs and reduce, restore, or modify protein expression in hopes of treating or preventing disease. An early trial of the SOD1-targeting tofersen, aka BIIB067, pronounced this ASO safe, and proffered a tantalizing hint of efficacy, in patients with genetic forms of amyotrophic lateral sclerosis (ALS). Nusinersen, which is approved for spinal muscular atrophy and has been studied mostly in children, was reported to have subtle treatment benefits on activities of daily living in adults with SMA, as well. What’s more, scientists claimed at AAN, presymptomatic babies develop almost normally when treated with this ASO. Lastly, a single injection of an ASO that targets prion protein was reported to delay prion disease and lengthen survival in mice.

  • An ASO against SOD1 appears safe in ALS patients, with small hints at efficacy.
  • Nusinersen is being evaluated in presymptomatic babies and adults.
  • An ASO against prion protein shows some promise in mice.

An ASO for Genetic ALS
The biggest news came from Timothy Miller, Washington University School of Medicine in St. Louis. He delivered Phase 1/2 trial data on tofersen, developed by Ionis Pharmaceuticals in Carlsbad, California, and licensed to Biogen in Cambridge, Massachusetts. This ASO targets the mRNA for superoxide dismutase 1 (SOD1), both mutant and wild-type. Binding ships the mRNA off to degradation, lowering production of the protein. At least 100 mutations in SOD1 are known to cause ALS. Just one mutant allele can cause the familial form of ALS. SOD1 mutations account for about 2 percent of all ALS cases. SOD1 is considered a target for sporadic ALS, as well.

The trial tested tofersen in ALS patients with confirmed SOD1 mutations. In Philadelphia, Miller presented its multiple-ascending-dose portion. Fifty participants were randomized to receive either 20, 40, 60, or 100 mg tofersen or placebo. There were 10, nine, nine, 10, and 12 people on each treatment, respectively. Drug or placebo was infused into the intrathecal space five times over 12 weeks. Researchers examined the safety of tofersen and tried to find the best dose.

At the end of 12 weeks, the drug appeared safe. Adverse events were mild to moderate, and included headache, pain due to lumbar puncture, and post-lumbar-puncture syndrome (Moulder et al., 2017). The 10 people on the 100-mg dose had a 37 percent reduction of the SOD1 protein in spinal fluid when compared with 12 people who received the placebo.

The study was not designed to test whether tofersen slows ALS or lessens its symptoms, but the researchers added exploratory efficacy measures anyway. They included maximum exhalation volume, change in SOD1 and neurofilament heavy chain in the cerebrospinal fluid (CSF), survival, ventilation-assistance-free survival time, change on the 48-point ALS Functional Rating Scale Revised (ALSFRS-R), muscle strength, self- and caregiver-reported health quality, fatigue severity, and work productivity.

The highest-dose group outperformed the placebo group on the ALSFRS-R, declining 1.1 from baseline compared with 5.3 points. They lost muscle strength and breathing capacity more slowly than the placebo group, and had less phosphorylated neurofilament heavy in their CSF. On the other outcome measures, people on drug did no better than those on placebo. The biggest difference between drug and placebo emerged among people whose mutations were known to cause the most rapidly progressive forms of ALS.

Participants who completed the study were invited to join an ongoing open-label extension to assess safety for up to five years, and 48 have so far.

Miller readily acknowledged that this study was too short and too small to afford statistical power. Even so, a Phase 3 trial called VALOR is already underway. It aims to enroll 60 ALS patients with a confirmed SOD1 mutation, and to evaluate efficacy, safety, and tolerability of a six-month course of the 100 mg dose. The trial is slated for completion in 2020.

“Promisingly, the tofersen data shows that it works where it should to reduce the protein levels of SOD1 in the cerebrospinal fluid, and that it seems to slow down the rate of functional decline, particularly in fast progressors,” said Jing Jing Crystal Yeo, Massachusetts General Hospital, Boston. More data are needed to show its efficacy across the spectrum of patients with SOD1 mutations and over time, Yeo pointed out. “It is exciting that we are now targeting ALS at the gene level, and this study will be a useful blueprint for the targeting of other genes associated with familial and sporadic ALS,” Yeo wrote to Alzforum.

“The tofersen study is extremely encouraging that we will be able within a few years to offer personalized treatments to patients with ALS, as well as other fatal genetic diseases, based on the understanding of basic disease mechanisms,” wrote Vivian Drory, Tel Aviv Medical Center, to Alzforum.

Trying to Broaden the Market for Nusinersen
The ASO nusinersen is already in use to treat patients with spinal muscular atrophy (SMA). In this disease, people inherit two dysfunctional copies of the SMN1 gene. The nearly identical SMN2 gene is normally spliced to exclude exon 7, rendering that protein nonfunctional. However, nusinersen modulates splicing to keep the exon, generating a functional protein that compensates for the loss of the SMN1 gene product. Nusinersen, also licensed by Ionis to Biogen, requires four loading doses in the first six weeks followed by maintenance doses every four months, all delivered via lumbar injection.

Trials in symptomatic infants and children led to FDA approval for all patients in December 2016, and since then, Biogen has added some trials in related populations.

In Philadelphia, researchers said that across the board, they are finding that nusinersen works better the sooner treatment starts. In an open-label trial, Emily Kern-Smith, Emory University School of Medicine, Atlanta, found bigger improvements in motor function in six children who started on nusinersen before their first birthday compared with four who started between 2 and 7 years of age. Twelve months into treatment, scores on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) increased from 28.7 to 43 in the younger children, but decreased from 16 to 14.8 in the older group. The scientists cited electrophysiological improvements as supporting the clinical data.

A separate open-label study at Children’s Hospital of Philadelphia reached a similar conclusion. Elizabeth Kichula found that in 61 SMA patients treated with nusinersen and followed for more than a year, those younger than 2.3 years when they started improved three times more on the CHOP-INTEND, and those under 5.5 years scored three times better on the Hammersmith Functional Motor Scale-Expanded (HFMSE) than older patients. The age benefit was most obvious in Type 1 and 2 patients, who develop symptoms before the ages of 6 months and 18 months, respectively. The onset of Type 3 SMA occurs after the age of 18 months.

Nusinersen appears to work best in presymptomatic infants. In the NURTURE clinical trial, scientists including Darryl De Vivo, Columbia University Irving Medical Center, enrolled 25 babies younger than 6 weeks, whose symptoms hadn’t started. By around 26 months, all infants were still living, and were able to sit without support; 22 walked with assistance, 17 walked alone. All were able to suck and swallow and had no problems breathing or eating. All babies had mild to moderate adverse events, which included bronchitis, choking, and post-lumbar puncture syndrome. Serious adverse events that occurred in nine babies—such as upper respiratory infection and respiratory failure—were deemed related to the illness rather than the drug. They resolved even though the babies continued to receive the drug. One baby continued to have excess protein in the urine, a sign of kidney problems, beyond the data cutoff.

“With newborn screening for SMA emerging in many states in the U.S., it is likely that more presymptomatic patients will be identified and treated,” wrote Richard Finkel, Nemours Children's Hospital, Orlando, Florida, to Alzforum.

Nusinersen’s benefits can be enhanced with intensive therapy, found Emmanuelle Tiongson, Children’s Hospital Los Angeles. Seven international patients who have lived at the hospital for the past year received intensive, daily physical, occupational, speech, respiratory, and feeding therapies on top of nusinersen. Six of them were eventually able to breathe on their own for hours at a time, and all improved neurologically and on the CHOP-INTEND functional motor scale. Some started vocalizing and eating for the first time. These benefits exceeded those seen in 40 outpatient SMA1 children treated with nusinersen alone. The results suggest that more frequent supporting therapies can further boost nusinersen’s effects, the authors wrote.

Nusinersen is approved for all SMA patients, but the trials that led to its approval included only young children. More recent data suggest the drug is beneficial in older kids aged 2 to 15 (Apr 2019 news). Far less data support use of the drug in adults with an even less aggressive form of the disease. Data presented at AAN showed that in adults, nusinersen treatment had little benefit on currently used measures. Even so, researchers claimed that the drug improved people’s daily functioning.

For instance, Aravindhan Veerapandiyan, Arkansas Children’s Hospital, Little Rock, presented a retrospective study of 12 adults treated for 13 months with nusinersen. Objective measures of upper-limb strength were unchanged or improved slightly, but patients reported qualitative improvements in endurance, hand movements, handwriting, and louder speech. Though small, these benefits were meaningful because they meant patients were able to work at a computer, move their wheelchairs, or speak more clearly, Veerapandiyan said. John Day, Stanford University School of Medicine, reported that 34 adult SMA patients treated with nusinersen improved a tad on three motor-function tests. Most also reported better strength, stamina, breathing ability, chewing and swallowing, range of motion in their jaws, and vocal strength. Drory reported that 18 adults treated with nusinersen for at least 10 months had no objective changes in their motor abilities, but reported transferring more easily between bed and wheelchair, coughing more easily, combing their own hair, or being able to stand in the restroom. More sensitive objective measures might pick up on meaningful benefits, and longer follow-up could turn up more significant gains, Drory wrote to Alzforum.

“Across all the data presented, the message is the same: intrathecal nusinersen is doable in these adults with chronic disease and it is well-tolerated,” Veerapandiyan told Alzforum. “Overall, patients had subjective benefits.”

Objective outcomes did seem to indicate some benefit for adults with milder disease. Yeo followed six adults with SMA Type 3 who didn’t have contractures, spinal or severe respiratory problems, as those conditions can limit motor performance and confound outcomes. Without treatment, these patients slowly decline over time, Yeo wrote to Alzforum. However, 18 months on nusinersen produced clinically meaningful improvements in the HFMSE and Revised Upper Limb Module. Patients also reported more energy and stamina, she wrote. 

Two up-and-coming drugs will likely compete with nusinersen. The small-molecule SMN2 splicing modifier Risdiplam from Roche Pharmaceuticals, Basel, Switzerland, is in Phase 3 trials, and the gene therapy AVXS-101 from AveXis, Inc., in Bannockburn, Illinois, owned by Novartis, is up for FDA approval this month.

An ASO for Prion Protein

Lastly, scientists from Massachusetts General Hospital in Boston, Ionis Pharmaceuticals, and the National Institute of Allergy and Infectious Disease in Bethesda, Maryland, together are exploring a prion protein-lowering ASO for prion disease. At AAN, Sonia Vallabh of The Broad Institute of MIT and Harvard presented data on mice injected in their brain ventricles with an ASO that targets the endogenous mouse prion protein, either before inoculation with infectious prions or just before disease symptoms usually appear. Given prophylactically, the ASO delayed onset of the disease, which in this model starts with weight loss, by 60 to 80 percent. Once infection was established, the ASO dose-dependently extended the time it took mice to reach the terminal stage disease by 60 percent. The authors believe their data support clinical trials of PrP-lowering ASOs.—Gwyneth Dickey Zakaib


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News Citations

  1. Older Children with Spinal Muscular Atrophy Improve on Nusinersen

Paper Citations

  1. . Factors Influencing Successful Lumbar Puncture in Alzheimer Research. Alzheimer Dis Assoc Disord. 2017 Oct-Dec;31(4):287-294. PubMed.

External Citations

  1. Phase 1/2
  2. open-label extension
  3. related populations

Further Reading


  1. . Antisense oligonucleotide therapies for Amyotrophic Lateral Sclerosis: Existing and emerging targets. Int J Biochem Cell Biol. 2019 May;110:149-153. Epub 2019 Mar 20 PubMed.
  2. . Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2018 Oct;31(5):648-654. PubMed.