Achievement Of Motor Milestones Research Articles

Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant.

Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild-type SMN (SMNWT). A severe SMA mouse model, SMA type 1.5 (Smn-/-; SMN2+/+; SMN∆7+/-) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMNWT and AAV9-SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. AAV9-SMNK186R-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMNWT-treated mice. Lifespan increased by more than 10-fold in AAV9-SMNK186R-treated mice (144.8±26.11days) as compared with AAV9-SMNWT-treated mice (26.8±1.41days). AAV9-SMNK186R-treated mice showed an ascending weight pattern, unlike AAV9-SMNWT-treated mice, which only gained weight until P20 up to 5g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9-SMNK186R-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMNWT-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMNK186R-treated mice, unlike AAV9-SMNWT-treated mice that showed clasping phenotype for more than 20 out of 30s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMNK186R-treated mice compared with AAV9-SMNWT-treated mice without prominent neurotoxicity. AAV9-SMNK186R had fewer liver defects compared with AAV9-SMNWT, as judged by increased proliferation of hepatocytes (P<0.0001) and insulin-like growth factor-1 production (P<0.0001). Especially, low-dose AAV9-SMNK186R (nine-fold) also reduced clasping time compared with SMNWT. SMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.

Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy

There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. The primary end point was the achievement of motor milestones. A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. German Clinical Trials Register: DRKS00012699.

Patient selection considerations for AADC deficiency gene therapy

AbstractBackgroundAromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality.MethodsIn response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment.ConclusionSuggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.

Dynamic Regulation of brsk2 in the Social and Motor Development of Zebrafish: A Developmental Behavior Analysis.

Both social and motor development play an essential role in an individual's physical, psychological, and social well-being. It is essential to conduct a dynamic analysis at multiple time points during the developmental process as it helps us better understand and evaluate the trajectory and changes in individual development. Recently, some studies found that mutations in the BRSK2 gene may contribute to motor impairments, delays in achieving motor milestones, and deficits in social behavior and communication skills in patients. However, little is known about the dynamic analysis of social and motor development at multiple time points during the development of the brsk2 gene. We generated a novel brsk2-deficient (brsk2ab-/-) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including that of locomotor behaviors, social behaviors, and anxiety behaviors from the larval to adult stages of development. Compared to wild-type zebrafish, brsk2ab-/- zebrafish exhibited a catch-up growth pattern of body length and gradually improved locomotor activities during the developmental process. In contrast, multimodal behavior tests showed that the brsk2ab-/- zebrafish displayed escalating social deficiency and anxiety-like behaviors over time. We reported for the first time that the brsk2 gene had dynamic regulatory effects on motor and social development. It helps us understand developmental trends, capture changes, facilitate early interventions, and provide personalized support and development opportunities for individuals.

No Delay in Age of Crawling, Standing or Walking with Pavlik Harness Treatment: A Prospective Cohort Study.

Pavlik harness treatment is the standard of care for developmental dysplasia of the hip in infants younger than 6 months. The effect of Pavlik harness treatment on the achievement of motor milestones has not previously been reported. In this prospective cohort study, 35 patients were prospectively enrolled to participate and received questionnaires with sequential clinical visits monitoring treatment of their developmental dysplasia of the hip. One-sample Student t -tests assessed differences in milestone attainment age, and the Benjamini-Hochberg procedure was conducted to decrease the false discovery rate. Post hoc power analyses of each test were conducted. The age of achievement of eight early motor milestones were recorded and compared with a previously published cohort of healthy infants. Infants treated with a Pavlik harness achieved four early motor milestones markedly later than the reported age of achievement in a historical control group. These milestones included "roll supine" (5.3 vs. 4.5 months; P = 0.039), "roll prone" (5.7 vs. 5.0 months; P = 0.039), "sit" (6.4 vs. 5.2 months; P < 0.001), and "crawl on stomach" (7.7 vs. 6.6 months; P = 0.039). However, there was no difference in time to achievement of later motor milestones of "crawl on knees," "pull to stand," and "independent walking." Several early motor milestones were achieved at a statistically significantly later time than historical control subjects not treated in a Pavlik harness. Despite statistical significance, the small delays in early motor milestones were not thought to be clinically significant. No differences were observed in the later motor milestones, including knee crawling, standing, and independent walking. Clinicians and parents may be reassured by these findings. Therapeutic Level II-prospective study.

Patient and Caregiver Outcomes After Onasemnogene Abeparvovec Treatment: Findings from the Cure SMA 2021 Membership Survey.

Onasemnogene abeparvovec (OA) is the only gene replacement therapy currently approved for spinal muscular atrophy (SMA) treatment. We sought to assess real-world patient and caregiver outcomes after OA treatment for SMA. Patients who received OA were identified from the 2021 Cure SMA Membership Survey. Those treated at 6-23months of age were matched to non-patients treated with OA on the basis of age at the time of survey and survival motor neuron2 gene copy number. Patient characteristics, motor milestones, and resource and supportive care use, as well as caregiver proxy-reported health-related quality of life (HRQOL), were described. Caregiver unmet needs and HRQOL were also assessed. Of the 614 patients in the survey, 64 received OA, and 17 were matched with 28 non-OA-treated patients. In general, a greater percentage of OA-treated patients achieved various motor milestones, including 100% sitting without support and 58.8% walking with assistance. OA-treated patients also had numerically lower rates of hospitalization and surgery. None required tracheostomy with a ventilator. The rate of using oxygen or a breathing machine for more than 16h was also lower for OA-treated patients. OA-treated patients had less frequent trouble swallowing. HRQOL was reported to be similar to non-OA-treated patients. Caregivers of OA-treated patients reported better patient mobility scores and less work impairment. The study suggests that treatment with OA is associated with greater rates of motor milestone achievements and less resource and supportive care use for patients with SMA treated at 6-23months of age in the real world. For caregivers, it may also potentially reduce unmet needs, improve HRQOL, and reduce work impairment.

Qualitative assessment in the third month of life allows for a better prognosis of the achievement of motor milestones versus assessment of pathological reflexes- prospective studies on Polish children.

The characteristic feature of primitive reflexes is that they occur early in development and must expire at a well-defined age. The study was conducted prospectively on a group of 107 children (74 boys). The study population included 83 infants born on time (weight 3,465 ± 395 g) and 24 born prematurely (weight 2,225 ± 793 g). An analysis of motor development at 3 months of age consisting of a qualitative assessment (motor performance) and a check of reflexes was performed; at 9 months, the child was checked for crawling and sitting down, and at 16 months for walking. The more abnormal reflexes, the less likely it was to achieve the assessed milestones in time. It is possible to notice that the qualitative assessment is, in each case, a better predictor of the milestones than any of the reflexes, except for walking, where the Babkin reflex was strongly predictive. However, the qualitative assessment sum still occupies the second and third positions in prone and supine positions. The occurrence of Babkin's reflex at 3 months of age impacts the achievement of sitting down and walking functions. An abnormal Galant reflex was strongly associated with the lack of occurrence of crawling on time. At the same time, a high-quality score at 3 months of age guarantees the development of crawling on time, sitting down, and walking.

Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec

Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients.

Defining Meaningful Outcomes for Patients with Spinal Muscular Atrophy in the Era of Gene Therapy

Spinal muscular atrophy (SMA) occurs due to a mutation in the SMN1 gene. It most typically has an onset in early childhood and presents as impairment in motor, bulbar, and respiratory function. In a symposium at the European Paediatric Neurology Society’s (EPNS) 2023 congress, three leading experts in SMA discussed the findings of real-world evidence (RWE) studies of the first gene therapy approved in NMD, in 2019 in the USA, and 2020 in Europe. Onasemnogene abeparvovec combines an adeno-associated virus (AAV9) vector with a functional copy of SMN complementary DNA, and is delivered in a single infusion. While clinical trials of onasemnogene abeparvovec show its efficacy and safety in populations with SMA who are symptomatic and pre-symptomatic, RWE studies have expanded the understanding of this therapy to wider SMA patient groups in the real-world clinical practice setting. Combined, such studies show how administration of onasemnogene abeparvovec in patients with symptomatic SMA can lead to motor and respiratory function improvement or stabilisation and achievement of motor milestones in naïve or pre-treated patients, while in patients who are pre-symptomatic, administration may lead to a normal development. The experts also discussed how understanding the benefit/risk profile of this gene therapy can help with decision-making over its use in patients with SMA. They highlighted how onasemnogene abeparvovec efficacy and safety can be affected by clinical status, disease severity, weight, age, and previous treatment at the time of infusion. Recently published RWE points to improvements being best predicted by baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score and age at treatment initiation, and in regard to safety and tolerability profile, liver enzyme elevation is the most predominant treatment-emergent adverse event (TEAE) with onasemnogene abeparvovec; hence, a prednisolone (or equivalent) dosing regimen is administered prior to, during, and for at least 3 months following infusion. The experts discussed how careful monitoring and adequate multidisciplinary team discussion, including colleagues from other specialities, such as hepatologists and paediatric immunologists, is advised in all cases of SMA receiving an onasemnogene abeparvovec infusion.

1044 Spinal Muscular Atrophy and Sleep: Double-Trouble

Abstract Introduction Spinal muscular atrophy (SMA) is a rare neuromuscular disorder which leads to progressive muscular weakness and respiratory impairment. Affected patients experience a variety of sleep problems including obstructive sleep apnea, nocturnal hypoventilation, and increased sleep disturbances. As of 2019, the first gene therapy was approved to treat patients with SMA under the age of 2, onasemnogene abeparvovec-xioi (ZolgensmaTM), with expedited approval due to findings of improved motor function and milestone achievement as well as survivability. We describe an unusual case of twins with SMA whom developed worsening obstructive sleep apnea after gene therapy. Report of case(s) The patients are a set of 3-year-old male twins with past medical history significant for premature lung disease related to extreme prematurity at 24-weeks and SMA type 2. They were initially referred for polysomnography (PSG) at 1 year of age for evaluation of snoring and as a precaution related to their underlying diagnosis. Physical examination findings were significant for tongue atrophy with fasciculations and generalized muscular weakness which spared the face. Neither twin achieved gross motor milestones of standing or walking to that point. Both patients would receive the gene therapy infusion at 1 year, 8 months with subsequent improvement in hypotonia and ability to ambulate independently. For twin A, baseline PSG at age 1 showed mild obstructive sleep apnea (apnea-hypopnea index (AHI)= 3.24 events per hour) without any signs of hypoxemia or hypoventilation. By comparison, the patient’s post-gene therapy PSG (around 1.5 years post-infusion) at age 3, showed progression to moderate obstruction (obstructive AHI of 6.03 events per hour). For twin B, baseline PSG showed moderate obstructive sleep apnea (AHI=9.09 events per hour) which progressed into the severe range (AHI= 11.90 events per hour) over the same time course. Conclusion Sleep-disordered breathing in SMA is a commonly diagnosed entity. While airway obstruction related to hypotonia would be an expected contributor, our case suggests that despite recovery of motor function through use of gene therapy, clinicians should maintain a high level of suspicion for sleep problems with strong consideration for PSG due to the risk of sub-clinical progression of sleep obstruction. Support (if any)

Genetic and Environmental Effects on the Early Motor Development as a Function of Parental Educational Attainment.

The contribution of genetic and environmental factors to individual differences in early motor development is still largely uncharted. This large-scale twin study establishes the genetic and environmental influences on the timing of motor milestones achievement, and it further tests whether the influences are moderated by parental education. The twins came from families registered in the Netherlands Twin Register (NTR) from 1986 to 2016. In 30,256 complete twin pairs, mother-reported ages at which each twin was able to first-time roll from back to belly, sit unassisted, hands-and-knees crawl, stand up unaided, and walk independently were used to extract an early motor development factor. Parental education was dichotomized ("both parents with low/average education" vs "at least one parent with high education" with university degree as a threshold). Additive genetics explained 52% of the variance in motor development, the remaining 39% and 9% were explained by shared and nonshared environment separately. Mean age of achieving motor milestones tended to be higher in infants with high educated parents, and a moderation of parental education on the genetic and environmental variance in motor development was seen in female twins with larger heritability in the high educated parents group (64% vs 43%) paired to a lower shared environmental influence (28% vs 48%). Only 7%-8% of the variance was accounted for nonshared environmental factors, including measurement error. The pattern of results did not change when the degree of urbanicity, a correlate of parental education, was additionally considered. Genetic factors explain most of the individual differences in the timing of motor milestone achievement, but factors related to the shared home environment also play an important role in early motor development.

The double burden of malnutrition and gross motor development in infants: A cross-sectional study

The objective of the present work was to study the relationship between the double burden of malnutrition and gross motor development in infants. ology: Sample included 5900 infants under 24 months of age, participants of the ENSANUT-ECU study. To evaluate nutritional status, we calculated z-scores for body mass index/age (BAZ) and height/age (HAZ). Six gross motor milestones were considered: sitting without-support, crawling, standing and walking with-support, standing and walking without-support. Data was analysed using logistic regression models in R. Independently form age, sex and other socio-economic factors, the probability of achieving three gross motor milestones was significantly lower among chronically undernourished infants compared to their peers: sitting without-support, crawling, and walking without-support. Compared to no malnourished infants the probability of sitting without-support at six months was 10% lower for chronically undernourished infants (0.70, 95%CI [0.64-0.75]; 0.60, 95%CI [0.52-0.67]; respectively). The probability of crawling at eight months and walking without-support at 12 months were also significantly lower among chronically undernourished infants (0.62, 95%CI [0.58-0.67]); 0.25, 95%CI [0.20-0.30]; respectively) in comparison to no malnourished infants (0.67, 95%CI [0.63-0.72]); 0.29, 95%CI [0.25-0.34]; respectively). Obesity/overweight was not associated with the achievement of gross motor milestones, except for sitting without-support. Chronically undernourished infants with low or high BMI/age were generally delayed in the achievement of gross motor milestones than their peers. Chronic undernutrition is related to delayed gross motor development. Public health measures are needed to be implemented to prevent the double burden of malnutrition and its detrimental effects on infant development.

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) (P7-9.009)

FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) (P7-9.009)

"I Am Afraid of Positioning my Baby in Prone": Beliefs and Knowledge about Tummy Time Practice.

To identify beliefs and knowledge about tummy time (TT) practice and its repercussions on motor development. Longitudinal study carried out with parents/caregivers of infants older than 30 days of life. Two assessments were performed. A structured interview was conducted, while the babies were between one and six months old to identify beliefs, knowledge about TT, and the motor milestone achievement expected for the age. At six to 12 months, the risk of motor development delay was tracked using the survey of well-being of young infant questionnaire (SWYC). 41 families responded to the SWYC questionnaire (21 were allocated to the TT group). 31.70% reported that it was not important to put the infants in a prone position while awake, and 70.70% said they are afraid their babies would become breathless when positioned in a prone position. 85.70% of infants from the TT group showed typical development, while 55% of the control group showed atypical development for their age (p = 0.01). Only three infants from the control group were at risk of delayed motor development (p = 0.10). Most of the families feel insecure about proning their babies and fear breathlessness when positioned. Acquisition of motor milestones prevailed in the TT group, suggesting an association between TT practice and motor milestone achievement.

Middle ear effusion, ventilation tubes and neurological development in childhood.

Otitis media with middle ear effusion (MEE) can be treated with ventilation tubes (VT) insertion, and it has been speculated that prolonged MEE in childhood can affect neurological development, which in turn may be important for later academic achievements. To investigate the association between middle ear effusion (MEE), treatment with ventilation tubes (VT) and childhood neurological development. We examined 663 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) unselected mother-child cohort study. Children were followed by study pediatricians with regular visits from pregnancy until 3 years of age. MEE was diagnosed using tympanometry at age 1, 2 and 3 years. Information regarding VT from age 0-3 years was obtained from national registries. We assessed age at achievement of gross motor milestones from birth, language scores at 1 and 2 years, cognitive score at 2.5 years and general development score at age 3 years using standardized quantitative tests. Children with MEE had a lower 1-year word production vs. children with no disease: (median 2, IQR [0-6] vs. 4, IQR [1-7]; p = 0.017), and a lower 1-year word comprehension (median 36; IQR [21-63] vs. 47, IQR [27-84]; p = 0.03). Children with VT had a lower 2-5-year cognitive score vs. children with no disease; estimate -2.34; 95% CI [-4.56;-0.12]; p = 0.039. No differences were found between children with vs. without middle ear disease regarding age at achievement of gross motor milestones, word production at 2 years or the general developmental score at 3 years. Our study supports the previous findings of an association between MEE and concurrent early language development, but not later neurological endpoints up to the age of 3. As VT can be a treatment of those with symptoms of delayed development, we cannot conclude whether treatment with VT had positive or negative effects on neurodevelopment.

Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%). Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam. F Hoffmann-La Roche.

New results for risdiplam in spinal muscular atrophy

Spinal muscular atrophy type 1 is a severe, progressive neuromuscular disease with symptom onset before age 6 months. Without disease modifying therapy, infants usually die of respiratory failure before age 2 years. Previous results from the FIREFISH study, an open-label clinical trial of risdiplam in patients with type 1 or infantile onset spinal muscular atrophy, have indicated that oral risdiplam might be safe and efficacious when given over 12 months to children with this type of spinal muscular atrophy. In The Lancet Neurology, Riccardo Masson and colleagues 1 Masson R Mazurkiewicz-Bełdzińska M Rose K et al. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022; (published online Oct 13.)https://doi.org/10.1016/S1474-4422(22)00339-8 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar report the results of secondary analyses from FIREFISH, including safety and efficacy data at 24 months. These analyses clearly show that patients continued to benefit from up to 24 months of treatment, with attainment of motor milestones not seen in untreated patients in natural history studies. Furthermore, the safety profile seen at 12 months was maintained at 24 months. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trialTreatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam. Full-Text PDF

P.37 Outcomes in patients with spinal muscular atrophy and four or more SMN2 copies treated with onasemnogene abeparvovec: Findings from RESTORE

Onasemnogene abeparvovec (OA) is a one-time gene replacement therapy for spinal muscular atrophy (SMA). While clinical trials of OA included patients with two or three SMN2 gene copies, patients with four or more copies may be treated in clinical practice. Natural history and outcomes following SMA treatment have not been well-characterized for these patients. We sought to describe clinical outcomes after OA monotherapy for patients with four or more SMN2 copies in RESTORE, a prospective SMA registry. We evaluated baseline characteristics, and post-treatment motor function, motor milestone achievement, use of ventilatory/nutritional support, and adverse events (AEs). Patients evaluable for motor function or milestone achievement had ≥2 assessments, with ≥1 after OA. Seven children with four SMN2 copies and five with more than four copies were included. All 12 cases were identified by newborn screening in the United States and treated presymptomatically. Median age at OA was 3 months (range, 1–11). Two of three children with evaluable motor milestone assessments achieved new milestones. All three children evaluable for CHOP INTEND maintained or achieved the maximum score of 64 points. One child was evaluable for HINE and achieved a 6-point increase. Five children with recorded AE data had ≥1 treatment-emergent AE (mainly Grade 1 LFT and/or troponin elevations without relevant clinical signs). Two children reported AEs ≥Grade 3 (one had otitis media and one with history of fetal stroke had seizure ∼3.5 months post-OA). No deaths or use of ventilatory/nutritional support were reported. Patients with four or more SMN2 gene copies attained improvements in motor function and achieved new milestones after treatment with OA. Presentation of SMA with four or more SMN2 copies is heterogeneous, and laboratory determination of SMN2 copy number may be unreliable, highlighting the importance of early identification and intervention to optimize outcomes for all SMA patients.