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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Risdiplam is a small-molecule SMN2 splicing modifier that increases the level of full-length SMN protein. This medication is administered daily by mouth using a syringe. The FIREFISH and SUNFISH trials demonstrated a greater number of treated patients without permanent ventilation and an improvement in the 32-item Motor Function measure score in treated individuals, respectively [33, 34].
Risdiplam as an orphan drug treatment of spinal muscular atrophy in adults and children (2 months or older)
Published in Expert Opinion on Orphan Drugs, 2022
This up to now favorable efficacy/safety profile allows risdiplam to fulfill unmet needs in this recent era of new SMA therapies. Risdiplam is orally administered and has been shown (there is at least real evidence from animals) to cross the blood brain barrier where it most probably acts on motor neurons [14]. Administration does not require hospitalization, nor invasive procedures or invasive intrathecal administration and the concomitant use of other medicines as it is the case for nusinersen, which has been shown to be a limiting factor for some patients, with for example occurrences of headache and anxiety in some children and teenagers or technical infusion difficulties in patients that have undergone spine fusion in the past [40]. The benefit of home dosing, not requiring the last, cannot be underestimated especially in the current era of a pandemic. This makes risdiplam a strong candidate to improve the quality of life of up until now untreated patients or treated patients who experience side effects of their current treatment.
Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)
Published in Expert Opinion on Investigational Drugs, 2022
Theodora Markati, Gemma Fisher, Sithara Ramdas, Laurent Servais
Prior to the approval of risdiplam, two additional drugs, targeting the root cause of SMA, were approved [10]. One is nusinersen (Spinraza®), an antisense oligonucleotide administered intrathecally that binds to SMN2 pre-mRNA to modify splicing to increase SMN protein levels [11]. It gained approval in 2016. The other is onasemnogene abeparvovec-xioi (Zolgensma®), a self-complementary adeno-associated virus-based gene therapy that aims to provide a copy of the SMN gene to neurons; it is administered intravenously [12]. It was approved in 2019 for patients younger than 2 years [13]. Risdiplam is the third drug approved for the treatment of SMA and it is the only one which is administered systemically, targeting cells beyond motor neurons. A systematic approach by considering the evidence from clinical trials and the real-world evidence for efficacy, the safety profile, the route of administration and other factors is required to identify the role of each different drug in the treatment algorithm of patients based on their age and genotype. Many more candidate therapies are in the pipeline of SMA, including therapies that aim to improve the function of the neuromuscular junction or muscle contraction and size [14]. A combination therapy between a drug that targets the SMN deficiency and a drug that targets another molecular pathway could be expected in this context.
An evaluation of onasemnogene abeparvovec for spinal muscular atrophy (SMN1)
Published in Expert Opinion on Orphan Drugs, 2021
Megan A. Waldrop, Anne M. Connolly, Jerry R. Mendell
There is unequivocal evidence that treatment at the earliest time possible provides significant advantages. Although infants with SMA are typically considered asymptomatic or presymptomatic shortly after birth, a careful exam in 2 copy (predicted type 1) and some 3 copy (predicted type 2, rarely type 1) babies may pick up subtle hypotonia or a slight reduction in reflexes that should heighten the urgency for treatment. For an infant who seems mildly symptomatic in the first weeks of life with any SMN2 copy number, treatment with onasemnogene should be considered first, and if the child is ineligible, due to AAV9 antibodies or abnormal liver function, nusinersen should be the back-up option if less than 2 months of age; risdiplam is preferred if over 2 months of age. It is important to note that treatment should begin ASAP and waiting until 2 months of age for risdiplam is not recommended in any symptomatic infant. We know that motor neuron loss can be precipitous, and treatment needs to be started prior to this phase [39]. If the child is asymptomatic with 4 copies of SMN2, there is a general consensus that there is more time available, but treatment should be initiated relatively quickly, and all options can be considered [40,41].