Spinraza Nusinersen Injection News For SMA Patients

 Medical Care

In December 2016, the FDA approved Spinraza Nusinersen Injection, the first drug approved to treat children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein.

Spinraza Nusinersen Injection approval was based on the ENDEAR trial. The ENDEAR trial (n=121) is a phase 3 randomized, double-blind, sham-controlled study in patients with infantile-onset (most likely to develop Type 1) SMA
Spinraza Nusinersen Injection

What is Spinal Muscular Atrophy (SMA)


Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.
Keywords: Spinal muscular atrophy, antisense oligonucleotides, gene therapy, outcome assessment, neonatal screening, registries

INTRODUCTION

The SMA landscape has changed considerably since the first reports more than a century ago of patients with spinal muscular atrophy (SMA) by Werdnig and Hofmann in 1891 and 1893. Decoding the disease’s genetic background, first in linkage analyses and later by identifying mutations in SMN1 as disease-causing, paved the way for targeted medical approaches. In this review we provide an overview of both the latest therapeutic options and emerging therapies for SMA. We also discuss new topics and challenges arising with the availability of drug treatments that alter the known trajectories of disease. These include changing phenotypes, new medical decisions, and newborn screening for SMA.

BACKGROUND

SMA is one of the most frequent monogenic neurodegenerative diseases with an incidence estimated to be around 1 : 6,000 to 1 : 10,000 in newborns. SMA encompasses a wide clinical continuum of disease severity and has been classified into subtypes according to age at onset and the motor milestones achieved. More than half of patients have the severe phenotype of SMA type 1 with onset of symptoms within the first 6 months of age. A ‘floppy infant’ presentation, reduced spontaneous movements and a paradoxical breathing pattern are characteristic; these infants fail to achieve the free-sitting milestone. Without drug treatment and ventilator support, SMA type 1 is the leading genetic cause of death in early infancy with a life expectancy of under 2 years. SMA type 2 is characterized by a milder course with onset of symptoms between the ages of 6 and 18 months. Per definition, these patients do manage free sitting, but not independent walking. The latter is achieved (at least temporarily) in patients with SMA type 3, whose symptoms’ onset is during infancy or adolescence. In addition, some classifications define SMA type 0 and SMA type 4 with prenatal onset or a very mild phenotype entailing an adult onset of symptoms, respectively. The disease’s hallmark is the degeneration of anterior horn cells in the spinal cord, leading to the characteristic symptom of progressive, proximal weakness involving varying degrees of muscle atrophy. Whereas all types of SMA are progressive, the rate of progression differs: SMA type 1 typically follows a rapidly progressing course, while type 3 progresses slowly.

Molecular genetics: About 95% of SMA cases are caused by homozygous deletions and less frequently point mutations in the SMN1 gene (survival of motor neuron 1) on the long arm of chromosome 5 (5q-SMA), whereas SMA mutations in other genes can also be causative (non-5q-SMA). Disease-causing mutations in SMN1 inhibit the production of functional SMN protein from this gene. SMA’s highly variable phenotypic spectrum is mainly attributable to variable copy numbers of the neighboring SMN2 gene. This gene is almost homologous to SMN1 except for few nucleotides and is of no relevance in healthy individuals. A single nucleotide transition of SMN2 causes predominant exon 7 skipping and mainly results in an unstable protein (SMNĪ”7).

In patients with SMA on the other side, small amounts of full-length and fully functional SMN-protein can be produced by SMN2, thus higher numbers of SMN2-copies are associated with milder phenotypes. Figure 1 summarizes SMA subtypes and displays typically associated SMN2 copy numbers.

THERAPEUTIC APPROACHES – SYMPTOMATIC TREATMENT

While being a monogenetic neuromuscular disease, the resulting phenotypic spectrum is complex and SMA is generally perceived as a systemic disease. Accordingly, caring for patients with SMA requires the interdisciplinary management of respiratory, nutritional and gastroenterological, orthopedic, and psychosocial issues. General treatment recommendations were published in 2007 in the first consensus statement on standards of care in SMA. Nevertheless, the implementation of standards of care is highly variable and is influenced by cultural perspectives, socioeconomic factors, and the availability of regional resources. Due to advances and improvements in care over the last decade, an updated version of recommendations on diagnosing SMA and patient care was published only recently.

THERAPEUTIC APPROACHES – DRUG TREATMENT

Several different compounds have been investigated in randomized controlled trials in the last few decades, including approaches to increase muscle strength and function by (1) hyperacetylating agents such as valproic acid or phenylbutyrate, (2) anabolic agents such as albuterol, thyreotropin-releasing hormone or growth-hormone and (3) neuroprotective agents such as gabapentin, riluzol and olesoxime. Despite negative results regarding primary endpoints, those investigations validated outcome measures and yielded key information about trial designs and the feasibility of patient recruitment.

Actual therapeutic developments can be subdivided into therapies aiming to modify the splicing of SMN2, replacing the SMN1 gene, or upregulating muscle growth. Figure 2 summarizes the therapeutic approaches discussed in the following sections and illustrates the respective molecular mechanisms of action; Table 1 illustrates the current status of development of specific drugs.

What is Spinraza Nusinersen Injection

Spinraza Nusinersen Injection is a type of medication called an antisense oligonucleotide. It is used to treat children and adults with spinal muscular atrophy (SMA), a type of motor neuron disease. It was the first drug to be approved by the US Food and Drug Administration (FDA) for this group of people.

SMA is an inherited disorder that causes skeletal muscle weakness and wasting, which worsens with age. SMA is most commonly caused by mutations in a gene called SMN1 (survival motor neuron 1), which leaves the body without enough functional SMN protein to keep motor neurons healthy and functioning.

A back-up gene called SMN2 also produces SMN protein, but only a small percentage of the protein produced by SMN2 functions properly. This is because when the protein is being made a portion of the gene called exon 7 tends to be skipped over, so the resulting protein isn’t supplied with all of the right building blocks of information it needs to function properly.

Spinraza works by fixing the protein produced by SMN2 so that it functions properly. It does this by making sure that the missing piece of information from exon 7 is included. Spinraza was approved by the FDA in 2016.

Important information

Spinraza can cause serious side effects including:
  • Increased risk of bleeding. Complications linked to an increased risk of bleeding have been observed after administration of similar medicines. Your healthcare provider will perform blood tests before you start treatment with Spinraza and before each dose to monitor for signs of these risks. Seek medical attention if unexpected bleeding occurs.
  • Increased risk of kidney damage, including potentially fatal acute inflammation of the kidney. An increased risk of kidney damage has been observed after administration of similar medicines. Your healthcare provider will perform urine testing before you start treatment with Spinraza and before each dose to monitor for signs of this risk.

What should I tell my doctor before receiving Spinraza Nusinersen Injection

Before you receive Spinraza, tell your healthcare provider about all of your medical conditions, including if you:
  • have a bleeding disorder
  • have a kidney disorder

How should I receive Spinraza Nusinersen

  • Spinraza will be administered by a qualified healthcare professional in a treatment center.
  • Spinraza is injected into the fluid of the spine (intrathecal injection) over 1 to 3 minutes.
  • Before you start treatment with Spinraza and before each dose, your doctor will order blood and urine testing to monitor for the potential risks of bleeding complications or kidney damage.
  • You will receive 4 initial loading doses of Spinraza. The first 3 doses will be given at 14-day intervals and the 4th dose will be given 30 days after the 3rd dose.
  • After your 4 loading doses, you will receive a maintenance dose of Spinraza every 4 months (3 times per year).

Spinraza Injection Storage

  • Store Spinraza in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
  • Do not freeze.
  • Spinraza should be protected from light and kept in the original carton until time of use.
  • If no refrigeration is available, Spinraza may be stored in its original carton, protected from light at or below 30°C (86°F) for up to 14 days.
  • Prior to administration, unopened vials of Spinraza can be removed from and returned to the refrigerator, if necessary. If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25°C (77°F).
  • Keep out of reach of children

Where can I buy Spinraza Nusinersen Injection

Spinraza Nusinersen Injection is available at Ozisik Eczane pharmacy

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