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Page last updated: 15th December 2017


Nusinersen (ENDEAR Trial) and Gene Therapy (AVXS-101)

Two articles were published in the November edition of the prestigious New England Journal of Medicine. These are about two potential advances in treatment of SMA. This article summarises the findings of these two studies, and compares the two potential treatments.

The first study discussed in this article is by Finkel and colleagues¹, and is about the medication called Nusinersen, developed by Ionis Pharmaceuticals & Biogen Idec. Nusinersen is a medication that aims to modify production of the SMN2, the back-up gene which produces the protein missing in SMA – Survival of the motor neuron (SMN). Nusinersen is a drug that has to be given directly into the spine (called intra-thecal). Finkel and colleagues enrolled 122 infants with SMA Type 1 in a randomised control trial (see ‘levels of evidence’) from 31 different hospitals around the world. The infants were randomly assigned to either receive the nusinersen (two thirds) or to undergo a ‘sham procedure’ (one third). The sham procedure was designed to mimic the treatment procedure, and involved making a small mark in the skin on the back, to appear as if the patient had received the treatment. Using a sham procedure meant that parents and health professionals would not know if the medication had been given. This is called ‘blinding’.

Infants received drug (or underwent sham procedure) on day one, then on days 15, 29, 64, 183, and 302. The study chose to show whether nusinersen worked by comparing scores of participants on the “Hammersmith Infant Neurological Examination” (HINE), which is an assessment tool for physiotherapists to evaluate how an infant is objectively progressing over time. The score is based on how well the infants move and interact, as well as how they reach their developmental milestones (i.e. crawling, grasping, sitting). The other way the study assessed nusinersen was by recording the time until ‘an event’ happened. This was called ‘event – free survival’ and was the time until an infant either required ventilation for more than 16 hours a day (for >3 weeks), or died. The study also looked at other ways of assessing SMA in infants, including a second physiotherapy score (CHOP INTEND) and testing of the speed at which nerves pass information (electromyography – EMG).

All studies assess whether the drug they are giving is safe. In the case of this trial, this was done once 80 infants had been enrolled for 6 months. At this point the study was stopped as the authors felt that the potential benefits of giving nusinersen outweighed the risks significantly.


At the end of the study, infants receiving nusinersen had a significantly higher percentage of improvement in their motor milestones (51% improved, compared with those not receiving medication – none improved). In the group receiving nusinersen, 22% of infants had head control, 10% could roll over, 8% could sit without support, with 1% able to stand, compared to none in the group not receiving medication.

By the end of the study 61% of infants in the control group did not require a ventilator and were still alive, compared to 32% in the group not receiving treatment. The study quotes that the risk of death or permanent ventilator usage was almost 50% lower with treatment.

Similar increases were seen in score for the nusinersen group when looking at the second physiotherapy assessment (CHOP INTEND), with 73% of infants improving on the CHOP INTEND scale, compared to 3% in the not treated group. Testing of how well the nerves transmit information, using the EMG test, showed improvements again in the group receiving nusinersen (36% improved versus 5% not treated).

The study also found that the likelihood of survival and not requiring a ventilator was higher in infants treated earlier (less than 13.1 weeks).

The study also looked at safety of the drug. Adverse events are recorded as part of the monitoring of patient safety on the study. Serious events occurred more frequently in the group not treated, and no specific concerns were discovered for this medication.


This study is the first to show clearly positive results in a treatment for SMA. Finkel et al. used a well-designed strong study to demonstrate that nusinersen has clear positive effects on infants with SMA Type 1 in two important aspects. Firstly, nusinersen appears to improve the chances of infants achieving developmental milestones. Secondly, those treated with nusinersen survived longer on average, with fewer requiring ventilators. Another important point that was made by Finkel et al. was that a greater effect was seen in infants receiving nusinersen at an earlier age (the example they used was less than around 13.1 weeks).

The clinical implications of this study are very important. It is now possible for infants with SMA Type 1, who meet the eligibility criteria, to be enrolled in the extended access programme (EAP), and potentially receive the drug (find out more here).

The second study discussed here is about a different way of treating SMA – gene therapy. Mendell and colleagues looked at gene therapy in patients with SMA Type 1² using AVXS-101 produced by Pharmaceutical company, AveXis. The concept is that, using a virus, an infant is given the SMN gene they need to produce the protein SMN. A modified virus without the viral DNA is used to deliver the SMN gene into cells. As nerve cells are usually permanent, there should not be a need for several doses. The medication has another advantage, as it can get into all tissues once injected into the blood stream (called intravenous injection), and doesn’t involve injection into the spinal cord.

Mendell and colleagues enrolled 15 infants into the study. Three received a low dose of the gene therapy, and the rest (12) received a higher dose. There was no control group enrolled to compare against; instead Mendell and colleagues used participants from an older trial to compare against. All but one participants were given a dose of a steroid to reduce the immune response to the virus.

The study was interested in safety of gene therapy, and looked at event-free survival, defined as with the paper by Finkel et al. The study also assessed infants using the CHOP INTEND score, and looked at whether the infants achieved sitting for 5, 10 or 30 seconds. Similar again to Finkel et al, they assessed how well nerves transmit after six months of treatment.


The study found that none of the patients in the treated group had died by the end of the study. All patients had reached 20 months without needing ventilation. Significant improvements were seen in the CHOP INTEND scores and sitting unaided. 9/12 infants could sit unaided for 30 seconds. 2 of the infants were eventually able to walk independently.

The safety of the medication was assessed, with one patient having increase in blood tests which look at the liver. This was treated with steroids.


This study showed significant improvements in survival and reduction in the need for ventilation in the participants. There were stark differences between the results of this trial and infants from the old study (not receiving a drug). Similarly, comparing those treated in their CHOP INTEND score showed clear increases in muscle function, whereas those from a natural history study (a study of those not receiving any special treatment) decreased in their score.

The two infants who achieved walking were treated earlier than other participants; a fact which the authors suggest may support earlier treatment.

Looking at these two studies it is impossible not to compare the two, published as they were at the same time in the same journal. Firstly, the similarities were interesting, with both studies showing promising responses in terms of survival, reduction in dependence on ventilators, developmental milestones, and measurement of muscle function. Both drugs used different approaches, but both aimed at treating the underlying cause of SMA: a deficiency in SMN protein. Both studies pointed to early treatment having a greater effect.

Comparing the two treatments could, however, be considered premature, as both are in different stages of development. Nusinersen has been trialled before, with overall positive results. Due to this and the results of the trial done by Finkel and colleagues, nusinersen has been licenced by both American and European drug agencies 3,4. Finkel and colleagues used a very strong study design with far higher numbers. Mendell and colleagues, by contrast, had smaller numbers and didn’t employ any blinding procedure or have controls. It will need to undergo wider clinical trials to provide the same strength of evidence.

Comparing the two treatments in terms of safety: nusinersen appeared to have fewer adverse events related to the drug. The gene therapy caused rises in blood tests looking at the liver; these were, however, successfully treated with steroids and did not cause the infants to experience any symptoms. Gene therapy has the clear advantage in terms of how the drug is given, as it is a single injection. Nusinersen involves a repeated painful procedure to administer (injection of the drug into the spine). The long-term effects of the drugs are not known with the drawback for gene therapy is that the patient may develop an immune response, leading to less effective therapy with repeated doses5.

The publication of these studies and the positive findings should make it easier to progress the cause of SMA; eventually encouraging further studies into these treatments in different types of SMA. In both cases, the study publication may help to move forward licencing and supply of drugs to the NHS in the future. The other important finding from these studies was around the likely benefit in instigating earlier treatment. Newborn screening for SMA is already being explored, and with these advances it may be possible to begin treatment much earlier6.

1. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. New England Journal of Medicine. 2017;377(18):1723-32.

2. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine. 2017;377(18):1713-22.

3. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-26.

4. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86(10):890-7.

5. van der Ploeg AT. The Dilemma of Two Innovative Therapies for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1786-7.

6. Boardman FK, Young PJ, Griffiths FE. Newborn screening for spinal muscular atrophy: The views of affected families and adults. American Journal of Medical Genetics. Part a. 2017;173(6):1546-61.