FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that the U.S. Food and Drug Administration (FDA) has approved Evrysdi™ (risdiplam) for treatment of spinal muscular atrophy (SMA) in adults and children 2 months of age and older. Evrysdi showed clinically-meaningful improvements in motor function across two clinical trials in people with varying ages and levels of disease severity, including Types 1, 2, and 3 SMA. Infants achieved the ability to sit without support for at least 5 seconds, a key motor milestone not normally seen in the natural course of the disease. Evrysdi also improved survival without permanent ventilation at 12 and 23 months, compared to natural history. A liquid medicine, Evrysdi is administered daily at home by mouth or feeding tube.

“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., 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.”

Evrysdi is being studied in more than 450 people as part of a large and robust clinical trial program in SMA. The program includes infants aged 2 months to adults aged 60 with varying symptoms and motor function, such as people with scoliosis or joint contractures, and those previously treated for SMA with another medication. The approval is based on data from two clinical studies designed to represent a broad spectrum of people living with SMA: FIREFISH in symptomatic infants aged 2 to 7 months; and SUNFISH in children and adults aged 2 to 25 years. SUNFISH is the first and only placebo-controlled trial to include adults with Types 2 and 3 SMA.

In FIREFISH, 41% (7/17) of infants treated with the therapeutic dose achieved the ability to sit without support for at least 5 seconds as measured by the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III). Additionally, 90% (19/21) of infants were alive without permanent ventilation at 12 months of treatment and reached 15 months of age or older. As described in the natural history of untreated infantile-onset SMA, infants would not be expected to be able to sit independently, and only 25% would be expected to survive without permanent ventilation beyond 14 months of age. In SUNFISH, children and adults treated with Evrysdi experienced a clinically-meaningful and statistically-significant improvement in motor function at 12 months (1.55 point mean difference; p=0.0156) compared to placebo (1.36 points [95% CI: 0.61, 2.11]; -0.19 points [95% CI: -1.22, 0.84], respectively), as measured by a change from baseline in the Motor Function Measure-32 (MFM-32) total score.

Evrysdi demonstrated a favorable efficacy and safety profile, with the safety profile established across the FIREFISH and SUNFISH trials. The most common adverse reactions were fever, diarrhea, and rash in later-onset SMA. In infantile-onset SMA, the most common adverse events were similar and also included upper respiratory tract infection, pneumonia, constipation, and vomiting. There were no treatment-related safety findings leading to withdrawal from either study.

“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’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.”

Evrysdi is designed to treat SMA by increasing production of the survival of motor neuron (SMN) protein. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and movement. Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

Evrysdi will be available in the United States within two weeks for direct delivery to patients’ homes through Accredo Health Group Inc., an Express Scripts specialty pharmacy.

Genentech is committed to helping patients access the medicines prescribed by their physician. For people with SMA, the MySMA Support program team is available to answer questions, provide product education and help families understand insurance coverage and navigate appropriate financial assistance options to start and stay on Evrysdi. Patients can call 1-833-EVRYSDI or visit http://www.Evrysdi.com or https://www.Genentech-Access.comto learn more.

About Evrysdi™ (risdiplam)

Evrysdi is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Evrysdi is administered daily at home in liquid form by mouth or by feeding tube.

Risdiplam was granted PRIME designation by the European Medicines Agency (EMA) in 2018 and Orphan Drug Designation by FDA and EMA in 2017 and 2019, respectively. At this time, risdiplam has been filed in Brazil, Chile, China, Indonesia, Russia, South Korea, and Taiwan. A Marketing Authorization Application (MAA) submission to the EMA for Evrysdi is imminent.

About the Pivotal Studies

FIREFISH (NCT02913482)

FIREFISH, an open-label, two-part pivotal study, was designed to assess Evrysdi safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) in patients aged 1 to 7 months with Type 1 SMA. Part 1 evaluated several doses of Evrysdi and determined the therapeutic dose of 0.2 mg/kg for Part 2. In Part 1, after 12 months of Evrysdi treatment:

• 41% (7/17) of infants treated with the therapeutic dose achieved the ability to sit without support for at least 5 seconds as measured by the BSID-III gross motor scale.
• 90% (19/21) of all infants were alive without permanent ventilation* and reached 15 months of age or older.
• 81% (17/21) of all patients were alive without permanent ventilation* after a minimum of 23 months of treatment and reached an age of 28 months or older (median 32 months; range 28 to 45 months).

*Permanent ventilation defined as tracheostomy or ≥16 hours of non-invasive ventilation per day or intubation for ≥21 consecutive days in the absence of, or following the resolution of, an acute reversible event.

SUNFISH (NCT02908685)

SUNFISH, a two-part placebo-controlled multicenter pivotal trial, was designed to assess Evrysdi safety, tolerability, efficacy, PK and PD in people with Type 2 or 3 SMA aged 2 to 25, including those with scoliosis (67% in Part 2) and joint contractures at baseline. In Part 2, after 12 months, Evrysdi treatment led to:

• Aclinically-meaningful and statistically significant improvement in motor function among children and adults, as measured by a change from baseline in the MFM-32 total score (1.55 point mean difference; p=0.0156), at 12 months as compared to placebo (1.36 points [95% CI: 0.61, 2.11]; -0.19 points [95% CI: 1.22, 0.84], respectively). MFM-32 assesses 32 different motor functions across a wide range of people with SMA.
• Improved upper limb motor functioncompared to baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study (1.59 point difference; p=0.0028).

Pivotal Trial Safety Data

The safety profile of Evrysdi was established across the FIREFISH and SUNFISH pivotal trials. The most common adverse reactions in later-onset SMA (incidence of at least 10% of patients treated with Evrysdi and more frequently than control) were fever, diarrhea, and rash. The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, the most common adverse reactions (incidence of at least 10%) were upper respiratory tract infection, pneumonia, constipation, and vomiting.

About the Evrysdi Clinical Trial Program

In addition to FIREFISH and SUNFISH, Evrysdi is being evaluated in a broad range of people with SMA, including in:

• JEWELFISH (NCT03032172): an open-label exploratory trial designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in people with SMA aged 6 months to 60 years who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi. Recruitment for this study is complete with 174 people enrolled.
• RAINBOWFISH (NCT03779334): an open-label, single-arm, multicenter study investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of Evrysdi in infants (~n=25), from birth to six weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study is currently recruiting.

About SMA

SMA is a severe, progressive neuromuscular disease that can be fatal. It affects approximately one in 10,000 babies and is the leading genetic cause of infant mortality. SMA is caused by a mutation of the survival motor neuron 1 (SMN1) gene, which leads to a deficiency of SMN protein. This protein is found throughout the body and is essential to the function of nerves that control muscles and movement. Without it, nerve cells cannot function correctly, leading to muscle weakness over time. Depending on the type of SMA, an individual’s physical strength and their ability to walk, eat or breathe can be significantly diminished or lost.

What is Evrysdi?

Evrysdi is a prescription medicine used to treat spinal muscular atrophy (SMA) in adults and children 2 months of age and older.

It is not known if Evrysdi is safe and effective in children under 2 months of age.

Important Safety Information

• Before taking Evrysdi, patients should tell their healthcare provider about all of their medical conditions, including if they:
  • have liver problems
  • are pregnant or plan to become pregnant. If patients are pregnant, or are planning to become pregnant, they should ask their healthcare provider for advice before taking this medicine. Evrysdi may harm one's unborn baby.
  • are a woman who can become pregnant:
    • Before patients start their treatment with Evrysdi, their healthcare provider may test them for pregnancy. Because Evrysdi may harm one's unborn baby, one's healthcare provider will decide if taking Evrysdi is right for them during this time
    • Patients should talk to their healthcare provider about birth control methods that may be right for them. Patients should use birth control while on treatment and for at least 1 month after stopping Evrysdi
  • are an adult male planning to have children: Evrysdi may affect a man’s ability to have children (fertility). If this is of concern to patients, they should make sure to ask a healthcare provider for advice
  • are breastfeeding or plan to breastfeed. It is not known if Evrysdi passes into breast milk and may harm one's baby. If patients plan to breastfeed, they should discuss with their healthcare provider about the best way to feed one's baby while on treatment with Evrysdi
• Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Patients should keep a list of them to show their healthcare provider and pharmacist when they get a new medicine
• Patients should receive Evrysdi from the pharmacy as a liquid that can be given by mouth or through a feeding tube. The liquid solution is prepared by the patient's pharmacist. If the medicine in the bottle is a powder, do not use it. The patient should contact their pharmacist for a replacement
• Avoid getting Evrysdi on one's skin or in one's eyes. If Evrysdi gets on one's skin, wash the area with soap and water. If Evrysdi gets in one's eyes, rinse one's eyes with water
• The most common side effects of Evrysdi include:
  • For later-onset SMA:
    • fever
    • diarrhea
    • rash
  • For infantile-onset SMA:
    • fever
    • diarrhea
    • rash
    • runny nose, sneezing, sore throat, and cough (upper respiratory infection)
    • lung infection
    • constipation
    • vomiting

These are not all of the possible side effects of Evrysdi. For more information on the risk and benefits profile of Evrysdi, patients should ask their healthcare provider or pharmacist.

Patients may report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Patients may also report side effects to Genentech at 1-888-835-2555.

Please see the full Prescribing Information for additional Important Safety Information.

About Genentech in neuroscience

Neuroscience is a major focus of research and development at Genentech and Roche. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases.

Genentech and Roche are investigating more than a dozen medicines for neurological disorders, including multiple sclerosis, stroke, neuromyelitis optica spectrum disorder, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Duchenne muscular dystrophy and autism spectrum disorder. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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