To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature.
In October 2013, the Myasthenia Gravis Foundation of ...America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity.
The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment.
This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.
•NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA.•All infants were ≥25 months old, and alive without permanent ventilation.•All infants achieved independent sitting ...and 88% (22/25) were walking alone.•Nusinersen demonstrated durability of effect with a median 2.9 years of follow up.•Nusinersen was well tolerated with no new safety concerns over extended follow up.
Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 25.7–45.4 months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
Introduction/Aims
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to ...bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics.
Methods
This multicenter, phase 1/2 trial enrolled 12 participants (aged 7‐21 years, who had limited ambulation or were nonambulatory) and comprised a 12‐week, double‐blind dose titration, then an open‐label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo.
Results
Participants received casimersen for a mean 139.6 weeks. Treatment‐emergent adverse events (TEAEs) occurred in all casimersen‐ and placebo‐treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen‐related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
Discussion
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
Background
Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking.
Methods
This was a retrospective study describing ...our centers' experiences in treating SMA1 patients with combination therapy.
Results
Five children received nusinersen and onasemnogene abeparvovec‐xioi (onasemnogene). Four were receiving nusinersen prior to onasemnogene. Nusinersen was continued in three. Marked liver enzyme elevations resulted in prolonged corticosteroid treatment in two patients with hospitalization and liver biopsy in one; milder liver enzyme elevations were noted in the other two. One patient received onasemnogene first, and then nusinersen. No adverse effects were noted. All patients improved.
Conclusions
Combination molecular therapy is tolerated in SMA1 patients. Further studies are needed to determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy. Prolonged corticosteroid use and liver toxicity monitoring may be necessary with onasemnogene therapy.
The differential mechanism of action of vamorolone compared to traditional corticosteroid anti-inflammatory drugs is attributed to the loss of gene transcriptional activities associated with ...glucocorticoid response element binding and activation, potent antagonist activity for the mineralocorticoid receptor, superior membrane stabilization properties, and retention of the distinct NFκB inhibitory (anti-inflammatory) activities 3,5–7). Safety endpoints (linear growth, body mass index) are also compared with data from a 12-month trial of daily prednisone (0.75 mg/kg group) in similar-aged boys with DMD 17. Methods Ethics statement All studies had appropriate approvals by ethics committees or institutional review boards, as required by the 11 participating international academic clinical recruitment sites: (Duke University, Durham, NC, US; Alberta Children’s Hospital, Calgary, AB, Canada; Nemours Children’s Hospital, Orlando, FL, US; John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Queen Silvia Children’s Hospital, Gothenburg, Sweden; Schneider Children’s Medical Center, Tel Aviv University, Petah Tikvah, Israel; Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, VIC, Australia; The Children’s Hospital at Westmead, Sydney, NSW, Australia; University of Texas Southwestern Medical Center, Dallas, TX, US; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, US; University of California Davis, Davis, CA, US). ...the total duration of corticosteroid treatment was longer than 18 months for most participants.
Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene ...abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.
STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30–60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).
From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36–100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79–100) survived free from permanent ventilation at age 14 months (vs 6 26%, 8–44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).
Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.
Novartis Gene Therapies.
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide ...drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants 41% vs. 0 of 27 0%, P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants 51% vs. 0 of 37 0%), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We ...aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 10
vector genomes vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 10
vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.
Astellas Gene Therapies.
Introduction/Aims
NURTURE (NCT02386553) is an open‐label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of ...spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow‐up (data cut: February 15, 2021) are reported.
Methods
The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety.
Results
Median age of children was 4.9 (3.8–5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies.
Discussion
These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.
Results from the ongoing NURTURE study demonstrate durability of effect and favorable safety profile of nusinersen in 25 children with two or three SMN2 copies who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). After ~5 y, all children achieved previously unattainable motor milestones, many within normal developmental timeframes, emphasizing the value of early diagnosis and early initiation of nusinersen. Subgroup analyses suggest inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.
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