Setrusumab for the Treatment of Osteogenesis Imperfecta: 12-Month Results from the Phase 2b Asteroid Study.

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20 mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-month treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20 mg/kg open label. Therefore, only results from the 2, 8, and 20 mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular vBMD from baseline at Month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro finite element-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12 months, there was a significant increase in mean (SE) failure load in the 20 mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20 mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p > 0.05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20 mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.

Osteogenesis imperfecta, or OI, is a rare disorder affecting patients' bones causing pain and an increased chance of the bone breaking. Setrusumab is a possible treatment for OI being studied in a clinical trial called Asteroid. The goal of Asteroid was to determine which dose of setrusumab helped adults with OI the most: 2, 8, or 20 mg/kg. Researchers looked at the density of patients' bones and estimated how strong their bones were before setrusumab and again after 12 months of treatment to see how they improved with treatment. Researchers could compare these improvements to see which dose of setrusumab helped patients the most. Patients on the highest dose of setrusumab (20 mg/kg) experienced improvements in the density of their arm bones (radius) and leg bones (tibia) after 12 months. The strength of these bones also improved. The density of other bones including the spine, hip, and the overall skeleton (total body) also improved with treatment. Of patients who had side effects after receiving setrusumab, most were mild or moderate intensity. Overall, setrusumab improved the bones of patients with OI with no serious safety concerns. More studies will include even more patients to see how setrusumab can improve their bones.

The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder primarily characterised by skeletal deformity and fragility, and an array of secondary features. The purpose of this review was to capture and quantify the published evidence relating specifically to the clinical, humanistic, and economic impact of OI on individuals, their families, and wider society. METHODS: A systematic scoping review of 11 databases (MEDLINE, MEDLINE in-progress, EMBASE, CENTRAL, PsycINFO, NHS EED, CEA Registry, PEDE, ScHARRHUd, Orphanet and Google Scholar), supplemented by hand searches of grey literature, was conducted to identify OI literature published 1st January 1995-18th December 2021. Searches were restricted to English language but without geographical limitations. The quality of included records was assessed using the AGREE II checklist and an adapted version of the JBI cross-sectional study checklist. RESULTS: Of the identified 7,850 records, 271 records of 245 unique studies met the inclusion criteria; overall, 168 included records examined clinical aspects of OI, 67 provided humanistic data, 6 reported on the economic impact of OI, and 30 provided data on mixed outcomes. Bone conditions, anthropometric measurements, oral conditions, diagnostic techniques, use of pharmacotherapy, and physical functioning of adults and children with OI were well described. However, few records included current care practice, diagnosis and monitoring, interactions with the healthcare system, or transition of care across life stages. Limited data on wider health concerns beyond bone health, how these concerns may impact health-related quality of life, in particular that of adult men and other family members, were identified. Few records described fatigue in children or adults. Markedly few records provided data on the socioeconomic impact of OI on patients and their caregivers, and associated costs to healthcare systems, and wider society. Most included records had qualitative limitations. CONCLUSION: Despite the rarity of OI, the volume of recently published literature highlights the breadth of interest in the OI field from the research community. However, significant data gaps describing the experience of OI for individuals, their families, and wider society warrant further research to capture and quantify the full impact of OI.

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial.

Importance: Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective: To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions: Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures: The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results: A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. Conclusions and Relevance: Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Trial Registration: ClinicalTrials.gov identifier: NCT02926898.

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.

Determinación de la epidemiología, el flujo de pacientes y el tratamiento del síndrome de Dravet en España / Ascertaining the epidemiology, patient flow and disease management for Dravet syndrome in Spain

Introducción. El síndrome de Dravet (SD) es una epilepsia rara y resistente a los fármacos que comienza en etapas muy precoces de la vida con convulsiones febriles, seguidas de deterioro cognitivo y diversos tipos de crisis epilépticas. Objetivo. Generar datos objetivos sobre la epidemiología del SD, su diagnóstico, el flujo de pacientes, el tratamiento y las necesidades no cubiertas desde el punto de vista de expertos españoles. Desarrollo. Se efectuó un estudio Delphi de dos rondas en el que participaron 19 médicos. Los cuestionarios se basaron en una revisión de la bibliografía y fueron validados por expertos clínicos. Se alcanzó consenso si los temas se referían a la práctica clínica habitual y la experiencia individual, o si el coeficiente de variación entre las respuestas era <= 0,3. El número estimado de pacientes nuevos con SD es de 73 al año. La prevalencia se calcula entre 348 y 540 pacientes. El SD se diagnostica principalmente en niños. La supervivencia varía entre los 5 y los 60 años. No existe ningún seguimiento normalizado para los pacientes de más de 18 años de edad, y las tasas de mortalidad son inciertas. No existen guías normalizadas para diagnosticar o tratar el SD. Se tarda de 9 a 15 meses en confirmar el diagnóstico, y la disponibilidad de los análisis genéticos es irregular. Normalmente se utilizan el ácido valproico, el clobazam, el estiripentol y el topiramato. La escasa eficacia y la seguridad son los motivos principales de los cambios de tratamiento. Conclusiones. La epidemiología del SD en España es poco conocida, y sigue habiendo necesidades no cubiertas en algunas áreas. Las opiniones de expertos suponen un punto de partida para poder investigar la realidad del SD en España. Los estudios epidemiológicos, los criterios de consenso, el acceso fácil a las pruebas genéticas, las opciones de tratamiento, la formación y la investigación de la calidad de vida relacionada con la salud constituyen todos ellos aspectos muy necesarios

Introduction. Dravet syndrome (DS) is a rare, drug resistant epilepsy that starts very early in life with febrile seizures followed by cognitive impairment and diverse seizure types. Aim. To generate evidence on the epidemiology of DS, its diagnosis, patient-flow, treatment and unmet needs from the perspective of Spanish experts. Development. A two-round Delphi study involving 19 physicians was conducted. Questionnaires were based on literature review and validated by clinical experts. Consensus was reached when topics were subject to routine clinical practice and individual experience, or the coefficient of variation among answers was ≤ 0.3. The estimated number of new DS patients is 73 per year. Prevalence is estimated to be between 348-540 patients. DS is mostly diagnosed in children. Survival varies from 5 to 60 years. There is no standardised follow-up of patients beyond the age of 18 and mortality rates are uncertain. No standard guidelines exist for diagnosing or treating DS. It takes 9 to 15 months to confirm the diagnosis and genetic testing is unevenly available. Valproic acid, clobazam, stiripentol and topiramate are commonly used. Poor efficacy and safety are the main reasons for treatment switch. Conclusions. The epidemiology of DS in Spain is not well known and several areas of unmet needs still exist. Experts' views offer a starting point for further research into the reality of DS in Spain. Epidemiological studies, consensus criteria, easy access to genetic testing, treatment options, training and research into quality of life aspects are highly needed

Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet Syndrome.

BACKGROUND: Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy characterized by multiple seizures, frequently prolonged and treatment refractory, with significant developmental disabilities and behavioral and psychiatric disorders. Patients with DS require intensive support and supervision from a caregiver, impacting significantly on both patients' and caregivers' lives. This study aimed to identify core concepts to measure the impact on both patients and caregivers in future DS clinical trials. METHODS: Qualitative concept elicitation interviews were conducted with caregivers and healthcare professionals involved in caring for children with DS (aged 2-18years) in France to identify important concepts related to the global impact of DS. Interviews explored a range of concepts, including triggers, symptoms, impacts, and coping strategies, from which a conceptual model was developed. A Delphi consensus panel with eight international clinical experts aimed to identify important and relevant endpoints. RESULTS: Seizure was the most commonly reported symptom with DS further impacting children's cognitive and behavioral functioning. Caregivers identified impact concepts not reported by healthcare professionals. Both groups described additional impacts on wider family members and home modifications. Clinical experts agreed on the inclusion of five patient- and caregiver-relevant concepts for measurement in future DS clinical trials in a composite endpoint. The five concepts for inclusion were; seizures, expressive communication of the child, receptive communication of the child, impact on daily activities, and social functioning of the caregiver. CONCLUSIONS: This study showed the wider potential impact of DS to extend beyond that of seizures, demonstrating that there is a need for additional patient- and caregiver-relevant concepts to be measured in clinical trials to fully identify the value of therapeutic interventions.

Treatment outcomes in the STAR study: a subanalysis of solifenacin 5 mg and tolterodine ER 4 mg.

OBJECTIVE: To compare OAB symptom outcomes following initial randomised treatment with solifenacin 5 mg or tolterodine ER 4 mg at the 4-week clinic-visit and again at 12 weeks for patients choosing to remain on this treatment dose from 4 weeks. METHODS: A prospective, double blind, double-dummy, two-arm, parallel-group, 12-week study (The STAR study) was conducted to compare the efficacy and safety of solifenacin 5/10 mg and tolterodine extended release (ER) 4 mg in OAB patients. RESULTS: At 4 weeks mean improvements in OAB symptoms, including urgency, frequency (primary variable), incontinence and nocturia, were larger in patients randomised to solifenacin 5 mg; with the difference for incontinence being statistically significant (mean reduction in incontinence episodes/24 hrs in the solifenacin group of -1.30 vs. -0.90 (p=0.0181); the mean result for solifenacin 5 mg amounted to a 44% additional improvement.) There was an associated significant reduction in pad use (reduced by -1.21 vs. -0.80; p=0.0089); the mean result for solifenacin 5 mg amounted to a 51% additional improvement over that of tolterodine ER 4 mg. For patients choosing to remain on these treatments improvements in favour of solifenacin were maintained at study end (12-weeks). Treatments were well tolerated. CONCLUSIONS: Within 4 weeks solifenacin 5mg was statistically significantly better than tolterodine ER 4 mg in improving incontinence and reducing incontinence pad use. Differences in efficacy in favour of solifenacin 5 mg were maintained from 4 weeks for the duration of the study for patients choosing to remain on their starting dose.