Risdiplam in Type 1 Spinal Muscular Atrophy Baranello, Giovanni; Darras, Basil T; Day, John W ...
New England journal of medicine/The New England journal of medicine,
03/2021, Volume:
384, Issue:
10
Journal Article, Web Resource
Peer reviewed
Open access
The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status ...were reported.
In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability ...progression, and better MRI features than interferon beta-1a.
Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles.
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B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation,
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autoantibody production,
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cytokine regulation,
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and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration.
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Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .
Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received ...placebo. The drug was associated with decreased lesion activity on MRI.
Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis.
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The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur.
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Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful,
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and no disease-modifying treatments have been approved.
B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form.
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Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .
Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and ...symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy ...and safety of gantenerumab in prodromal Alzheimer's disease (AD).
In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose.
Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean 95% CI CDR-SB change from baseline 1.60 1.28, 1.91, 1.69 1.37, 2.01, and 1.73 1.42, 2.04 for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints.
The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy.
ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the ...SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).
A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale.
Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold.
Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.
ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The rising rates of autism spectrum disorder (ASD) and the lack of effective medications to treat its core symptoms have led to an increased sense of urgency to identify therapies for this group of ...neurodevelopmental conditions. Developing drugs for ASD, however, has been challenging because of a limited understanding of its pathophysiology, difficulties in modelling the disease in vitro and in vivo, the heterogeneity of symptoms, and the dearth of prior experience in clinical development. In the past few years these challenges have been mitigated by considerable advances in our understanding of forms of ASD caused by single-gene alterations, such as fragile X syndrome and tuberous sclerosis. In these cases we have gained insights into the pathophysiological mechanisms underlying these conditions. In addition, they have aided in the development of animal models and compounds with the potential for disease modification in clinical development. Moreover, genetic studies are illuminating the molecular pathophysiology of ASD, and new tools such as induced pluripotent stem cells offer novel possibilities for drug screening and disease diagnostics. Finally, large-scale collaborations between academia and industry are starting to address some of the key barriers to developing drugs for ASD. Here, we propose a conceptual framework for drug discovery in ASD encompassing target identification, drug profiling and considerations for clinical trials in this novel area.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Therapeutic approaches to multiple sclerosis (MS) are based on altering the functions of the immune system, either by using broad immunosuppressive drugs used for transplantation rejection and ...rheumatology, or by modulating them more discreetly with beta interferon and synthetic amino-acid copolymers. These strategies are only partially successful, have important safety and tolerability limitations, and have shown to be mostly effective in earlier stages of the disease, in which acute relapses dominate the clinical picture. For progressive phenotypes of MS there are currently no effective therapeutic options. As very specific and potent immunosuppressive agents, monoclonal antibodies (mAbs) may offer considerable advantages over other therapies for MS. During the last decade, anti-a4 integrin natalizumab became the first approved mAb for treatment of relapsing MS, after convincingly demonstrating clinically significant effects on two large Phase 3 trials. Moreover, the concept of disease remission was introduced for the first time, to describe patients that show no signs of clinical or imaging markers of disease activity during therapy with natalizumab. Of the mAbs under development for MS, alemtuzumab and rituximab have also shown promising evidence of effectiveness, and potentially expanded the therapeutic horizon to reversal of disease progression in early relapsing patients, and progressive patients who previously had not been studied. However, the appearance of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients, as well as in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab, and autoimmune-type complications in alemtuzumab-treated MS patients underlines the fact that extended efficacy comes with significant clinical risks. The challenge is then how best to utilize therapies that have evidently superior efficacy in a chronic disease of young adults, to obtain the best benefit-risk ratio, and how to monitor and prevent emergent safety concerns.
In two randomized trials, the use of gantenerumab (an anti-Aβ monoclonal antibody) did not lead to slower clinical decline than placebo over 116 weeks among persons with early Alzheimer’s disease.
In the last decade many studies have stated that learning based on digital games emerges as an effective way to combine teaching and learning processes with the attractiveness of digital ...technologies, because they are dynamic and playful. However, the vast majority of these digital resources - such as educational games - are still essentially visual, which prevents access to people with visual impairments. It is the duty of designers and developers not only to develop visually appealing games, but to take advantage of today's sound technologies to adapt and create inclusive solutions for non-sighted players. This paper, therefore, describes the design and evaluation processes of three new inclusive levels for Em Busca do Santo Grau, an educational, modular and customisable PC game. In addition to stating the related works, the literature review and the process of adapting a visual game to be played only by sound feedback, the design and evaluation procedures based on the EduGameAccess set of recommendations will also be described.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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