Late-Breaking Data for Genentech’s BTK Inhibitor Fenebrutinib Show Brain Penetration and Significant Reduction in Lesions in Patients With Relapsing Multiple Sclerosis

– New data from Phase II FENopta study in relapsing multiple sclerosis (RMS) show fenebrutinib crosses the blood-brain barrier with the potential to act directly on the chronic inflammation related to multiple sclerosis (MS) –

– More than 90% relative reduction in new/enlarging T2 lesions and new T1 gadolinium-enhancing (Gd+) lesions with fenebrutinib beginning at eight weeks –

– The safety profile of fenebrutinib was consistent with previous and ongoing clinical trials across more than 2,500 people to date –

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced new data from the Phase II FENopta study showing that investigational, oral fenebrutinib is brain penetrant and reduces brain lesions in people with relapsing multiple sclerosis (RMS), with a consistent safety profile to other fenebrutinib trials. The late-breaking data were featured in an oral presentation at the 9th Joint ECTRIMS-ACTRIMS Meeting (European and Americas Committees for Treatment and Research in Multiple Sclerosis).

“These interesting results raise the possibility that fenebrutinib slows MS disease progression in part by acting directly within the brain,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “These data, which we are currently confirming in pivotal trials of both relapsing and progressive MS, suggest that fenebrutinib may have the potential to counteract acute and chronic inflammation within the brain to reduce disease activity in people with MS.”

Brain penetrance was measured by the level of fenebrutinib in the cerebrospinal fluid (CSF) of a subgroup of 11 patients with RMS. After 12 weeks of continuous treatment, the mean fenebrutinib concentration was 43.1 ng/mL. Similar fenebrutinib concentrations can produce near-maximal inhibition (IC90) in preclinical studies. Thus, the level of fenebrutinib in the brain and central nervous system may conceivably become high enough to reduce MS disease activity and progression.

Fenebrutinib significantly reduced the total number of new T1 gadolinium-enhancing (T1 Gd+) brain lesions, which are markers of active inflammation, and the total number of new or enlarging T2-weighted (T2) brain lesions, which represent the amount of disease burden or chronic lesion load. A rapid onset of lesion reduction was observed by 4 weeks, with relative reductions of 92% and 90% in T1 Gd+ lesions and relative reductions of 90% and 95% in T2 lesions observed at 8 and 12 weeks, respectively.

Furthermore, patients treated with fenebrutinib were four times more likely to be free from any new T1 Gd+ brain lesions and new or enlarging T2 brain lesions at weeks 4, 8 and 12 combined, compared to patients who received placebo (odds ratio 4.005, p=0.0117).

The safety profile of fenebrutinib was consistent with previous and ongoing fenebrutinib clinical trials across more than 2,500 people to date. There were no new safety concerns identified in the FENopta study. Overall rates of adverse events were 38% with fenebrutinib and 33% with placebo. The most common adverse events that were higher with fenebrutinib than placebo were abnormal liver enzyme levels (5.5% fenebrutinib, 0% placebo), headache (4.1% fenebrutinib, 2.8% placebo), nasopharyngitis (2.7% fenebrutinib, 0% placebo) and upper abdominal pain (2.7% fenebrutinib, 0% placebo).

Fenebrutinib is the only non-covalent and reversible BTK inhibitor in Phase III trials for MS and was designed to be highly selective, which may be important in reducing off-target effects of a molecule and potentially contribute to long-term safety outcomes. An open-label extension of FENopta is ongoing, with Phase III studies FENhance 1 and 2 currently enrolling patients with RMS and FENtrepid fully enrolled for patients with primary progressive MS (PPMS). Genentech is committed to advancing innovative clinical research programs to broaden the scientific understanding of MS, further reduce disability worsening in RMS and PPMS and improve the treatment experiences for those living with the disease.

About fenebrutinib

Fenebrutinib is an investigational oral, reversible and non-covalent Bruton’s tyrosine kinase (BTK) inhibitor that blocks the function of BTK. BTK, also known as tyrosine-protein kinase BTK, is an enzyme that regulates B-cell development and activation and is also involved in the activation of innate immune system myeloid lineage cells, such as macrophages and microglia. Preclinical data have shown fenebrutinib to be potent and highly selective, and it is the only reversible inhibitor currently in Phase III trials for MS. Fenebrutinib has been shown to be 130 times more selective for BTK vs. other kinases. These design features may be important as the high selectivity and reversibility can potentially reduce off-target effects of a molecule.

Fenebrutinib is a dual inhibitor of both B-cell and microglia activation. This dual inhibition may be able to reduce both MS disease activity and disability progression, thereby potentially addressing the key unmet medical need in people living with MS. The Phase III program includes two identical trials in RMS (FENhance 1 and 2) with an active teriflunomide comparator and one trial in PPMS (FENtrepid) in which fenebrutinib is being evaluated against Ocrevus^® (ocrelizumab). To date, more than 2,500 patients and healthy volunteers have been treated with fenebrutinib in Phase I, II and III clinical programs across multiple diseases, including MS and other autoimmune disorders.

About the FENopta study

The FENopta study is a global Phase II, randomized, double-blind, placebo-controlled 12-week study to investigate the efficacy, safety and pharmacokinetics of fenebrutinib in 109 adults aged 18-55 years with RMS. The primary endpoint is the total number of new T1 Gd+ lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks. Secondary endpoints include the number of new or enlarging T2 lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks, and the proportion of patients free from any new T1 Gd+ lesions and new or enlarging T2 lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks. The goal of the FENopta study is to characterize the effect of fenebrutinib on MRI and soluble biomarkers of disease activity and progression, and it includes an optional substudy to measure cerebrospinal fluid biomarkers of neuronal injury. Patients who complete the double-blind period are eligible for an open-label extension study.

About multiple sclerosis

Multiple sclerosis (MS) is a chronic disease that affects more than 2.8 million people worldwide. MS occurs when the immune system abnormally attacks the insulation and support around nerve cells (myelin sheath) in the central nervous system (brain, spinal cord and optic nerves), causing inflammation and consequent damage. This damage can cause a wide range of symptoms, including muscle weakness, fatigue and difficulty seeing, and may eventually lead to disability. Most people with MS experience their first symptom between 20 and 40 years of age, making the disease the leading cause of non-traumatic disability in younger adults.

People with all forms of MS experience disease progression – permanent loss of nerve cells in the central nervous system – from the beginning of their disease even if their clinical symptoms aren’t apparent or don’t appear to be getting worse. Delays in diagnosis and treatment can negatively impact people with MS, in terms of their physical and mental health, and contribute to the negative financial impact on the individual and society. An important goal of treating MS is to slow, stop and ideally prevent disease activity and progression as early as possible.

Relapsing-remitting MS (RRMS) is the most common form of the disease and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery. Approximately 85% of people with MS are initially diagnosed with RRMS. The majority of people who are diagnosed with RRMS will eventually transition to secondary progressive MS (SPMS), in which they experience steadily worsening disability over time. Relapsing forms of MS (RMS) include people with RRMS and people with SPMS who continue to experience relapses. Primary progressive MS (PPMS) is a debilitating form of the disease marked by steadily worsening symptoms but typically without distinct relapses or periods of remission. Approximately 15% of people with MS are diagnosed with the primary progressive form of the disease. Until the FDA approval of Ocrevus, there had been no FDA-approved treatments for PPMS.

Indications and Important Safety Information

What is Ocrevus?

Ocrevus is a prescription medicine used to treat:

• Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
• Primary progressive MS, in adults.

It is not known if Ocrevus is safe or effective in children.

Who should not receive Ocrevus?

Do not receive Ocrevus if you have an active hepatitis B virus (HBV) infection.

Do not receive Ocrevus if you have had a life-threatening allergic reaction to Ocrevus. Tell your healthcare provider if you have had an allergic reaction to Ocrevus or any of its ingredients in the past.

What is the most important information I should know about Ocrevus?

Ocrevus can cause serious side effects, including:

• Infusion reactions: Infusion reactions are a common side effect of Ocrevus, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least 1 hour after each infusion of Ocrevus for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms:
  • itchy skin
  • rash
  • hives
  • tiredness
  • coughing or wheezing
  • trouble breathing
  • throat irritation or pain
  • feeling faint
  • fever
  • redness on your face (flushing)
  • nausea
  • headache
  • swelling of the throat
  • dizziness
  • shortness of breath
  • fatigue
  • fast heart beat

These infusion reactions can happen for up to 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion.

If you get infusion reactions, your healthcare provider may need to stop or slow down the rate of your infusion.

• Infection:
  • Ocrevus increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Infections are a common side effect, which can be serious. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, or a cough that does not go away. Signs of herpes include cold sores, shingles, genital sores, skin rash, pain, and itching. Signs of more serious herpes infection include: changes in vision, eye redness or eye pain, severe or persistent headache, stiff neck, and confusion. Signs of infection can happen during treatment or after you have received your last dose of Ocrevus. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with Ocrevus until your infection is gone.
  • Hepatitis B virus (HBV) reactivation: Before starting treatment with Ocrevus, your healthcare provider will do blood tests to check for hepatitis B viral infection. If you have ever had hepatitis B virus infection, the hepatitis B virus may become active again during or after treatment with Ocrevus. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop receiving Ocrevus.
  • Weakened immune system: Ocrevus taken before or after other medicines that weaken the immune system could increase your risk of getting infections.
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually leads to death or severe disability, and has been reported with Ocrevus. Symptoms of PML get worse over days to weeks. It is important that you call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms that have lasted several days, including problems with:
  • thinking
  • eyesight
  • strength
  • balance
  • weakness on 1 side of your body
  • using your arms or legs
• Decreased immunoglobulins: Ocrevus may cause a decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels.

Before receiving Ocrevus, tell your healthcare provider about all of your medical conditions, including if you:

• have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS.
• have ever had hepatitis B or are a carrier of the hepatitis B virus.
• have had a recent vaccination or are scheduled to receive any vaccinations.
  • You should receive any required ‘live’ or ‘live-attenuated’ vaccines at least 4 weeks before you start treatment with Ocrevus. You should not receive ‘live’ or ‘live-attenuated’ vaccines while you are being treated with Ocrevus and until your healthcare provider tells you that your immune system is no longer weakened.
  • When possible, you should receive any ‘non-live’ vaccines at least 2 weeks before you start treatment with Ocrevus. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with Ocrevus, talk to your healthcare provider.
  • If you have a baby and you received Ocrevus during your pregnancy, it is important to tell your baby’s healthcare provider about receiving Ocrevus so they can decide when your baby should be vaccinated.
• are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if Ocrevus will harm your unborn baby. You should use birth control (contraception) during treatment with Ocrevus and for 6 months after your last infusion of Ocrevus. Talk with your healthcare provider about what birth control method is right for you during this time.
  • Pregnancy Registry. There is a pregnancy registry for women who take Ocrevus during pregnancy. If you become pregnant while receiving Ocrevus, tell your healthcare provider right away. Talk to your healthcare provider about registering with the Ocrevus Pregnancy Registry. The purpose of this registry is to collect information about your health and your baby’s health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting https://www.ocrevuspregnancyregistry.com.
• are breastfeeding or plan to breastfeed. It is not known if Ocrevus passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Ocrevus.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What are the possible side effects of Ocrevus?

Ocrevus may cause serious side effects, including:

• Risk of cancers (malignancies) including breast cancer. Follow your healthcare provider’s instructions about standard screening guidelines for breast cancer.
• Inflammation of the colon, or colitis: Tell your healthcare provider if you have any symptoms of colitis, such as:
  • Diarrhea (loose stools) or more frequent bowel movements than usual
  • Stools that are black, tarry, sticky or have blood or mucus
  • Severe stomach-area (abdomen) pain or tenderness

These are not all the possible side effects of Ocrevus.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

For more information, go to https://www.Ocrevus.com or call 1-844-627-3887.

Please see additional Important Safety Information throughout and click here for the full Prescribing Information and Medication Guide.

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 MS, spinal muscular atrophy (SMA), neuromyelitis optica spectrum disorder (NMOSD), Alzheimer’s, Huntington’s, Parkinson’s, acute ischemic stroke, Duchenne muscular dystrophy and Angelman syndrome. 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 https://www.gene.com.

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