Spinal muscular atrophy (SMA) is a hereditary disease that causes weakness and muscle wasting because patients lose lower motor neurons (nerve cells) that control movement. This disease is caused by deletions and/or loss‐of‐function mutations in the survival of motor neuron 1 (SMN1) gene, that leads to degeneration of α‐motor neurons in the ventral horns of the spinal cord. This, in turn, leads to muscle atrophy and, depending on the type of SMA, loss of physical strength and the ability to walk, eat or breathe. A second SMN gene, SMN2, produces only low levels of full‐length SMN2 mRNA since, in the majority of transcripts, exon 7 is removed by splicing (∆7 mRNA). SMN2 therefore produces low levels of FL functional SMN protein, which are not sufficient to compensate fully for the SMN1 gene‐related deficits. Modifying SMN2 mRNA splicing to increase the inclusion of exon 7, has the potential to increase SMN2FL mRNA production and subsequently increase levels of functional SMN protein in patients with SMA.
A number of small molecule splicing modifiers with high specificity for SMN2 pre‐mRNA, were identified in the last five years. Finally in 2017, a stable derivative of its precursors was discovered and named risdiplam. IN the same year, the drug has received Orphan Drug Designation and US Food and Drug Administration Fast Track Designation. A phase 1 healthy male volunteer (n=25) single escalating dose study of the pharmacokinetics and pharmacodynamics was published in 2018. Risdiplam in the fasted or fed state was well tolerated, exhibiting a mean terminal half-life of 55 h. Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 mRNA. Now the U.S. FDA approved risdiplam as Evrysdi, to treat patients two months of age and older with SMA. This is the second drug and the first oral drug approved to treat this disease. Its efficacy for the treatment of patients with infantile-onset and later-onset SMA was evaluated in two clinical studies.
In the last clinical trial, the infantile-onset SMA study included 21 patients who had an average age of 6.7 months when the study began. In that open-label study, efficacy was established based on the ability to sit without support for at least five seconds and survival without permanent ventilation. After 12 months of treatment, 41% of patients were able to sit independently for more than five seconds, a meaningful difference from the natural progression of the disease because almost all untreated infants with infantile-onset SMA cannot sit independently. After 23 or more months of treatment, 81% of patients were alive without permanent ventilation, which is a noticeable improvement from typical disease progression without treatment. Patients with later-onset SMA were evaluated in a second randomized, placebo-controlled study. The study included 180 patients with SMA aged two to 25 years. The primary endpoint was the change from baseline in MFM32 (a test of motor function) total score at the one-year mark.
Patients on Evrysdi saw an average 1.36 increase in their score at the one-year mark, compared to a 0.19 decrease in patients on placebo (inactive treatment). The most common side effects of Evrysdi include fever, diarrhea, rash, mouth sores, joint pain and urinary tract infections. Patients with infantile-onset SMA had similar side effects as individuals with later-onset SMA. Additional side effects for the infantile-onset population include upper respiratory tract infection, pneumonia, constipation and vomiting. Patients should avoid taking Evrysdi together with drugs that are multidrug and toxin extrusion substrates because Evrysdi may increase plasma concentrations of these drugs. The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage drug development for rare diseases. The application was awarded a Rare Pediatric Disease Priority Review Voucher.
The FDA granted this approval of Evrysdi to Genentech, Inc.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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