Genentech Enters Spinal Muscular Atrophy Market with Risdiplam’s FDA Approval
On August 7th, the USFDA announced the approval of Risdiplam (Evrysdi), the very first oral drug for the treatment of spinal muscular atrophy (SMA) of varying severity in children of two months of age and older.
By Ruchi Jhonsa, Ph.D.
Spinal muscular atrophy is an inherited disorder of the survival motor neuron (SMN) protein. Motor neurons are crucial for muscles, including the ones essential for breathing. An abnormal SMN protein affects the health and normal function of motor neurons. Therefore, most newborns affected by severe disease fail to survive beyond the first two years of their lives. At this juncture, Roche and Genentech’s Risdiplam provides hope to thousands of children and adults fighting with SMA every day. The approval came 18 days earlier than the expected date following remarkable efficacy data that significantly improved motor function in patients with varying age and disease severity.
“Given the majority of people with SMA in the U.S. remain untreated, we believe Evrysdi, with its favorable clinical profile and oral administration, may offer meaningful benefits for many living with this rare neurological disease,” said Levi Garraway, M.D., Ph. D., Roche’s Chief Medical Officer and Head of Global Product Development. “The strength and resolve of the SMA community has continually inspired us as we developed this first-of-its-kind medicine for SMA, so today we celebrate our collective accomplishment together with them.”
SMA: A Rare Genetic Disorder of the Nervous System
About 1 in 10000 children born with some form of SMA have mutations in both copies of the SMN1 gene. The embryo inside the womb survives SMN1 loss by expressing a truncated, albeit functional product of SMN2, the “backup gene.” SMN2 has a similar structure to SMN1 but produces only 10% of the functional protein. While this is enough for an embryo, dependent on its mother for nutrition and oxygen, it is insufficient for a born child that is heavily reliant on its muscles for breathing, walking, and eating.
Treating SMA with Risdiplam
Permanently inserting a normal copy of the SMN1 gene in the neuronal cells is an obvious treatment for SMA patients. Novartis’ Zolgensma targets SMA through this method. However, it is currently available for infants less than two years of age. An alternate way of treating the disease is by increasing the production of SMN protein from the SMN2 gene. It can be achieved by overcoming the splicing defect that restricts the SMN2 gene to produce only 10% of functional protein. Biogen was the first company to approach the problem through this route and got its SMA drug, Spinraza FDA approved in 2016. However, the drug’s administration is cumbersome and requires multiple visits to the hospital.
Risdiplam, an oral SMN2 splicing modifier, works the same way as Spinraza but overcomes the above-mentioned drawbacks of the two previous drugs. The medication can be taken at home at the patient’s convenience, which cuts down the need to visit hospitals for spinal or blood injections.
Trials Leading to Drug Approval
The approval of Evrysdi is based on two broad-spectrum trials that included infants and adults with varied symptoms and motor function.
In the FIREFISH trial that included symptomatic infants aged 2 to 7 months, the children gained the ability to sit independently for more than 5 seconds. Additionally, 90% of infants lost the need to ventilate at 12 months of treatment and reached 15 years of age without an external supply of oxygen. Without drug treatment, infants would fail to sit independently, and 75% of them would require permanent ventilation to survive beyond the age of 14 years.
The SUNFISH trial is the first-ever study that included adults aged 2 to 25 years with Type 2 and 3 SMA. The patients experienced an improvement in motor function of 1.55 points on a scale that evaluates 32 different motor functions compared to those who received a placebo who experienced an average increase of 1.36 points.
Both the trials showed favorable efficacy and safety profiles. The most common adverse reaction seen in the trials were diarrhea, fever, and rash in adults and upper respiratory tract infection, pneumonia, constipation, and vomiting in infants.
“Throughout their lives, many people with SMA may lose their ability to perform critical movements, which can impact the ability to independently participate in aspects of daily life and even be life-altering,” said Kenneth Hobby, president of Cure SMA. “The approval of Evrysdi is an eagerly awaited milestone for our community. We appreciate Genentech/Roche’s commitment to reflecting the full scope of the real-world SMA population in their clinical trial program and developing a treatment that can be administered at home.”
Editor: Rajaneesh K. Gopinath, Ph.D.
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