August 10, 2020Regulatory
Spinal Muscular Atrophy refers to a group of hereditary diseases that damages and kills specialized nerve cells in the brain and spinal cord (called motor neurons). Motor neurons control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity including speaking, walking, swallowing, and breathing. The most common form of SMA is caused by an abnormal or missing gene known as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a protein essential to motor neurons. This form of SMA has four types:
1. Type l, also called Werdnig-Hoffman disease or infantile-onset SMA, is usually evident before 6 months of age. The most severely affected children will have reduced movement and chronic shortening of muscles or tendons (called contractures). Other children may have symptoms including reduced muscle tone, lack of tendon reflexes, twitching, skeletal abnormalities, and problems swallowing and feeding. Without treatment, many affected children die before age 2 years.
2. SMA Type ll is usually first noticed between the 6 and 18 months of age. Children can sit without support but are unable to stand or walk unaided. Children also may have respiratory difficulties. Life expectancy is reduced but most individuals live into adolescence or young adulthood.
3. SMA Type lll (Kugelberg-Welander disease) is seen after age 18 months. Children can walk independently but may have difficulty walking or running, rising from a chair, or climbing stairs. Other complications may include curvature of the spine, contractures, and respiratory infections. With treatment, most individuals can have a normal lifespan.
4. Individuals with SMA Type IV develop symptoms after age 21 years, with mild to moderate leg muscle weakness and other symptoms.
The FDA has approved Evrysdi (risdiplam) to treat patients two months of age and older with SMA. Evrysdi contains a survival of motor neuron 2-directed RNA splicing modifier. This is the second drug and the first oral drug approved to treat this disease.
The efficacy of Evrysdi for the treatment of patients with infantile-onset and later-onset SMA was evaluated in two clinical studies. 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. Results showed that 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, ulcers of the mouth area, joint pain (arthralgia) 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.