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BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA. 
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
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):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
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):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
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):3017-3026.
