Genentech's Evrysdi (risdiplam) Granted FDA Priority Review for Treatment of Pre-Symptomatic Babies Under 2 Months of Age With Spinal Muscular Atrophy (SMA)

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has granted priority review of a supplemental new drug application (sNDA) for the use of Evrysdi^® (risdiplam) to treat pre-symptomatic babies under two months of age with spinal muscular atrophy (SMA). The sNDA submission incorporates interim data from the RAINBOWFISH study, which shows the majority of pre-symptomatic babies treated with Evrysdi achieved key milestones such as sitting, standing, walking and maintained the ability to swallow following 12 months of treatment.

"Treating very young babies with Evrysdi before SMA symptoms arise may help them to achieve milestones such as standing and walking within timeframes typical of healthy infants," said Levi Garraway, M.D., Ph.D., Genentech's chief medical officer and head of Global Product Development. "Extending treatment access for the youngest members of the SMA community is crucial and we look forward to working with the FDA on this application."

Evrysdi is designed to treat SMA by increasing and sustaining production of the survival motor neuron (SMN) protein in the central nervous system (CNS) and peripheral tissues. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and movement. Evrysdi's existing FDA label is for the treatment of SMA in adults, children and babies two months and older. If approved, Evrysdi would be the first medicine administered at home for pre-symptomatic babies with SMA.

Initial interim data from the RAINBOWFISH study, presented at the World Muscle Society (WMS) Virtual Congress 2021, showed that of the babies included in the interim efficacy analysis, all (5/5), maintained the ability to swallow and were able to feed exclusively orally after 12 months of treatment. Eighty percent (4/5) treated with Evrysdi for at least 12 months achieved milestones such as standing and walking independently within World Health Organization windows for healthy children. All participants (n=5) met Hammersmith Infant Neurological Examination, Section 2 (HINE-2) motor milestones of head control, sitting upright, rolling and crawling after 12 months of treatment with Evrysdi.

No treatment-related serious adverse events were reported in any of the babies treated with Evrysdi through the interim safety analysis period (n=12). Four treatment-emergent adverse events were reported, and all were resolved or were resolving with ongoing treatment with Evrysdi. The most common adverse events (AEs) were nasal congestion (33%), cough (25%), teething (25%), vomiting (25%), eczema (17%), abdominal pain (17%), diarrhea (17%), gastroenteritis (17%), papule (17%) and pyrexia (17%). The AEs were reflective of the age of the babies rather than the underlying SMA. The RAINBOWFISH study is currently recruiting.

The latest results from the RAINBOWFISH study will be presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in March 2022.

Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

About Evrysdi^® (risdiplam)

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

Evrysdi is designed to treat SMA by increasing and sustaining the production of SMN protein levels in the central nervous system (CNS) and peripheral tissues as demonstrated in animal models. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and movement.

Evrysdi was granted PRIME designation by the European Medicines Agency (EMA) in 2018 and Orphan Drug Designation by the U.S Food and Drug Administration in 2017. In 2021, Evrysdi was awarded Drug Discovery of the Year by the British Pharmacological Society as well as the Society for Medicines Research Award for Drug Discovery. Evrysdi is currently approved in 70 countries and the dossier is under review in a further 31 countries.

Evrysdi is currently being evaluated in five multicenter trials in people with SMA:

• FIREFISH (NCT02913482) ? an open-label, two-part pivotal clinical trial in infants with Type 1 SMA. Part 1 was a dose-escalation study in 21 infants with the primary objective of assessing the safety profile of Evrysdi in infants and determining the dose for Part 2. Part 2 is a pivotal, single-arm study of Evrysdi in 41 infants with Type 1 SMA treated for 2 years, followed by an open-label extension. Enrollment for Part 2 was completed in November 2018. The primary objective of Part 2 was to assess efficacy as measured by the proportion of infants sitting without support after 12 months of treatment, as assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development ? Third Edition (BSID-III) (defined as sitting without support for 5 seconds). The study met its primary endpoint.
• SUNFISH (NCT02908685) ? SUNFISH is a two part, double-blind, placebo controlled pivotal study in people aged 2-25 years with Types 2 or 3 SMA. Part 1 (n=51) determined the dose for the confirmatory Part 2. Part 2 (n=180) evaluated motor function using the total score of Motor Function Measure 32 (MFM-32) at 12 months. MFM-32 is a validated scale used to evaluate fine and gross motor function in people with neurological disorders, including SMA. The study met its primary endpoint.
• 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 (inclusion criteria) who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi. The study has completed recruitment (n=174).
• RAINBOWFISH (NCT03779334) ? an open-label, single-arm, multicenter study, investigating the efficacy, safety, PK and PD of Evrysdi in babies (~n=25), from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study is currently recruiting.
• MANATEE (NCT05115110) ? a global phase 2/3 clinical study to evaluate the safety and efficacy of GYM329 (RO7204239), an anti-myostatin molecule targeting muscle growth, in combination with Evrysdi for the treatment of SMA in patients 2-10 years of age. The FDA Office of Orphan Products Development granted GYM329 Orphan Drug Designation for the treatment of patients with SMA in December 2021. The study is commencing recruitment in Q1 2022.

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:
  • 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. 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, 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.