Pioneering the B cell approach in MS

When neurologist Dr. Kathleen Hawker did her medical training in the early 1980s, she was struck by the people she saw with multiple sclerosis (MS), a progressively disabling disease of the central nervous system. She recalls one woman, just 40 years old, who was bed-bound with cognitive confusion, her every movement and breath a labor. “There was absolutely no treatment that could help her,” says Hawker.

The damage MS does to the nervous system can accumulate rapidly or eventually impair a person’s mobility, cognition, vision and other functions. MS is an autoimmune disease, where the immune system, which usually defends against outside invaders like viruses, goes awry and attacks its own tissues. An estimated one million people in the U.S. live with MS, which usually strikes in the prime of life — between the ages of 20 and 40 — and nearly twice as many women as men.¹

Over time, researchers and clinicians have made great progress in understanding the science behind MS and developing new treatments to slow its progression. Hawker, now Medical Director Manager of Neuro-Immunology at Genentech, reflects on the decades of progress in treating MS.

Question: What changes in MS have you seen throughout your career?

Kathleen Hawker, MD:
Compared with even 20 years ago, the difference in both treatment options and outcomes for people living with MS is phenomenal. One challenge of MS is that disease progression can be seen from the start and can occur without obvious symptoms or relapses. We now recognize that this is a disease you have to treat upon diagnosis, because otherwise it will get progressively worse, and disability accumulates.^2,3 There is very limited regeneration in the brain and spinal cord, so you have to prevent the damage in the first place. When the first treatments for MS came around, they were only used for patients who had the most severe symptoms. Now, there is a broad range of MS treatment options for people living with MS, including highly efficacious disease-modifying therapies, that can be appropriate options for newly diagnosed people with MS.

Q: In your career, what have you seen as a meaningful advancement in MS?

Dr. Hawker:
A significant advance we’ve seen in the science behind MS treatment over the years has been the discovery of B cells as a critical driver in the disease. Twenty years ago, people believed MS was mainly driven by T cells, which are part of the immune system. In the late ‘90s, several researchers in neurology, discovered that B cells, which are also immune defenders, played a role in MS, too. Both B and T cells cause inflammation in the brain that damages the myelin sheath that insulates the nerves, interfering with the smooth signaling of the brain to the rest of the body. That opened up new treatment possibilities.

In the 1990’s, neurologist Dr. Stephen Hauser, now director of the University of California, San Francisco (UCSF) Weill Institute for Neurosciences, and his colleagues wanted to test whether a B cell-depleting medicine would have an impact on MS as well. In 2003, Genentech collaborated with Dr. Hauser and UCSF to explore the B cell approach in MS.

Based on the research, it was clear that B cells play a large role in causing the inflammation in MS. It created a whole new frontier in our recognition of the complexity of MS and the immune system. Following that discovery, Genentech refined a new molecule, ocrelizumab, made of humanized proteins, and completed a robust Phase III clinical program, which resulted in an FDA approval in 2017 for Ocrevus^®, the first and only treatment approved for both relapsing MS (RMS) and primary progressive MS (PPMS). Currently more than 170,000 people have been treated with Ocrevus globally in clinical trials and real-world settings. Ocrevus has side effects, which can be found in the full Prescribing Information and Medication Guide. There is potential for serious side effects including infusion reactions, infections and malignancies, so it’s important for individuals to speak with their doctor before starting any new treatment.

Q: How does the medicine work, given that we need to protect our immune system to do its job?

Dr. Hawker:
Like many medicines approved by the FDA, the way Ocrevus works is not fully known, but we do know people need their B cells to protect against infections and other invaders. B cells change over time and perform different functions in the immune system. At one point they express a protein called CD20. Ocrevus is designed to target the CD20 receptors on specific B cell subsets. It is thought that depleting some of the B cells from the body could prevent the inflammation that causes the disease. However, B cell therapies aren’t for everyone, so it’s important for people living with MS to work closely with their doctor to determine if Ocrevus is a good fit and discuss possible side effects.

MS is a chronic disease, so we’re not just treating people once or twice, but for a lifetime. One of our biggest problems in chronic treatment for MS is working with patients to optimize their ability to actually stay on treatment. In the past, when people would come to me with more brain lesions, I would always ask, “Are you taking your medicine?” Ocrevus is administered as an intravenous infusion two times a year (every six months), with the initial dose split into two separate infusions and given two weeks apart, which we know can be important to patients and their physicians. In April, the FDA also accepted a supplemental Biologics License Application for a shorter Ocrevus infusion time (two hours vs. 3.5 hours) based on data from the ENSEMBLE PLUS study, which showed comparable frequency and severity of infusion reactions to the currently approved Ocrevus dosing regimen. Shortening the infusion time may lessen the burden on patients and healthcare teams. The FDA is expected to make a decision in December 2020. The bottom line is that if B cells start coming back, the disease starts coming back. If patients are prescribed a treatment they aren’t taking as instructed — or missing a dose — it can have a negative impact on their condition.

Q: What’s next for Genentech in advancing the science of MS?

Dr. Hawker:
We have made tremendous advances in MS, but our work isn’t over. We are conducting ongoing research to identify biomarkers that may help measure new disease activity with the goal of making MS treatments even more impactful. With new data from MRIs and other sources, we’re seeing that progression starts very early in the disease course, much earlier than we had previously known. We’re also looking at digital tools and resources to help people with MS and their physicians track their disease symptoms. That way, if a person is getting worse, we can detect it earlier, and get that data to the healthcare provider to impact treatment decisions.

We’re also continuing with basic science, looking at new mechanisms of action in MS, and targeting different parts of the immune system. We’re studying small molecules that may be able to cross the blood-brain barrier and get into the brain to work on the immune system there. I’m particularly excited about some very early research on remyelination and protecting neurons. Experts believe a remyelination approach may be able to suppress the accumulation of disability and keep people healthier. More research is needed, but theoretically, if this works, we could one day offer a treatment that may even reverse some of the damage, too.

We’ve come a long way. We will continue to push the boundaries of our scientific understanding of MS, not only to bring new options to further slow the march of disease progression, but also to find a cure one day. That’s our ultimate goal.

To learn more about the importance of early treatment to delay progression in MS and how B cells play a role, visit gene.com.

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: OCREVUS can cause infusion reactions that can be serious and 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:

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. 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 and, if more serious, a severe or persistent headache, confusion, change in vision, eye redness, or eye pain. These signs can happen during treatment or after you have received your last dose of OCREVUS. If you have an active infection, your healthcare provider should delay your treatment with OCREVUS until your infection is gone.
  • Progressive Multifocal Leukoencephalopathy (PML): Although no cases have been seen with OCREVUS treatment in clinical trials, PML may happen with OCREVUS. PML is a rare brain infection that usually leads to death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These may include problems with thinking, balance, eyesight, weakness on 1 side of your body, strength, or using your arms or legs.
  • 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.

• Low Immunoglobulins: OCREVUS may cause a decrease in some types of antibodies. 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 are pregnant or planning to become pregnant talk to your doctor about vaccinations for your baby, as some precautions may be needed.
• 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.

• • If you become pregnant while taking OCREVUS, talk to your doctor about enrolling in the OCREVUS Pregnancy Registry. You can enroll in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. The purpose of this registry is to monitor the health of you and your baby.

• 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.

Most common side effects include infusion reactions and infections.

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 FDA at 1-800-FDA-1088.

For more information, go to www.OCREVUS.com or call 1-844-627-3887.

For additional safety information, please see the full Prescribing Information and Medication Guide.

¹ National MS Society. (n.d.) “Multiple Sclerosis FAQs”. https://www.nationalmssociety.org/What-is-MS/MS-FAQ-s
² MS International Federation. What is MS? Available at http://www.msif.org/about-ms/what-is-ms/.
³ National Institutes of Health-National Institute of Neurological Disorders and Stroke. (2015). Multiple Sclerosis: Hope Through Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research