Ocrelizumab - How It Works, Uses, Side Effects, Warnings, and Precautions

Overview:

Ocrelizumab, developed by Genentech, a subsidiary of the Roche Group (a multinational healthcare company), was approved by the FDA (the United States Food and Drug Administration) in March 2017 for intravenous injection. It was later approved by Health Canada in August 2017, making it the first primary progressive multiple sclerosis (PPMS) medication available in the United States and Canada. In clinical studies, treatment with Ocrelizumab reduced relapse rates and disability worsening in people with relapsing forms of multiple sclerosis compared to interferon beta-1a 5. Treatment with Ocrelizumab resulted in decreased rates of clinical and magnetic resonance imaging progression in patients with primary progressive multiple sclerosis in phase three clinical studies. Ocrelizumab is a CD20-directed cytolytic antibody used to treat patients suffering from relapsing or primary progressive multiple sclerosis. It is a humanized recombinant monoclonal IgG1 antibody of the second generation that targets B-cells that express the CD20 antigen. With repeated infusions, Ocrelizumab should be less immunogenic as a humanized molecule, improving the benefit-to-risk balance for patients with relapsing or progressive multiple sclerosis. Multiple sclerosis is a central nervous system autoimmune disease that causes neurological impairments and a considerable reduction in quality of life. Relapses with deteriorating function are common in multiple sclerosis patients, who are followed by recovery periods or remissions. Primary progressive multiple sclerosis (PPMS) affects 10 to 15 % of multiple sclerosis patients and entails a slow worsening of neurologic impairment from the outset of symptoms, frequently without early relapses or remissions.

How Does Ocrelizumab Work?

Through the stimulation of pro-inflammatory T-cells and the release of pro-inflammatory cytokines, B lymphocytes are known to have a part in the pathogenesis of multiple sclerosis. B cells can develop into plasma cells, which can create autoantibodies against myelin and attack the myelin sheath via complement. Pre-B cells, naive and mature B cells, and memory B cells all have CD20 on their cell surfaces. However, hematopoietic stem cells, pro-B cells (precursors), and developed plasma cells do not exhibit this activated glycosylated phosphoprotein. While the specific mechanism by which Ocrelizumab causes B-cell depletion is uncertain, various theories have been offered. Ocrelizumab enhances antibody-dependent cellular cytotoxicity and complement-mediated cell lysis when it binds to CD20-expressing B cells on the cell surface. The capacity for B-cell reconstitution and pre-existing humoral immunity, such as IgG and IgM antibody levels in the blood and cerebrospinal fluid, are conserved. Ocrelizumab may cause cell death by antibody-dependent cellular cytotoxicity involving macrophages, natural killer cells, and cytotoxic T-cells. Apoptosis is another method that can be triggered by cross-linking membrane CD20 on the target cell surface.

Uses of Ocrelizumab:

Ocrelizumab is used to treat the following conditions:

• Adults with primary progressive multiple sclerosis.

• Multiple sclerosis (MS) in adults with relapsing forms, such as clinically isolated syndrome, relapsing-remitting illness, and active secondary progressive disease.

Dosage:

Evaluations That Need to Be Done Before Administering the First Dose of Ocrelizumab:

1) Hepatitis B Virus Screening- Perform an HBV or a Hepatitis B virus screening test before starting Ocrelizumab. Ocrelizumab is not recommended for patients who have active hepatitis B virus, as evidenced by positive HBsAg and anti-HBV testing. Patients who test negative for surface antigen but positive for hepatitis B core antibody or who are hepatitis B virus carriers should seek advice from a liver disease specialist before beginning treatment and during it as well.

2) Vaccinations- Because live-attenuated or live vaccines are not indicated during treatment or after termination until B-cell repletion, all necessary immunizations should be given at least six weeks before starting Ocrelizumab.

Preparation Which Needs to Be Done Before Every Infusion of Ocrelizumab:

1) Infection assessment before each infusion preparation - Assess if there is a current infection prior to each Ocrelizumab infusion. In the event of an active infection, defer Ocrelizumab infusion until the infection has cleared.

2) Pre-medication is strongly advised- To minimize the severity and frequency of infusion responses, pre-medication of patients with 100 mg of Methylprednisolone or an equivalent corticosteroid given intravenously 30 minutes before each Ocrelizumab infusion is highly recommended. Premedication with an antihistamine 30 to 60 minutes before each Ocrelizumab infusion reduces infusion reaction risks. An antipyretic, such as Acetaminophen, may also be used to further lower the risks.

Dose Administration:

To address severe responses such as significant infusion reactions, Ocrelizumab should be administered under the direct supervision of a qualified healthcare practitioner with access to adequate medical support. The initial dosage of 300 mg of the drug is given by intravenous infusion (IV), followed by the second dosage of 300 mg intravenous infusion two weeks later. A subsequent dose of Ocrelizumab 600 mg is given in a single intravenous infusion every six months.

Warnings and Precautions:

1) Reactions to Infusion- Pruritus, urticaria, rash, bronchospasm, erythema, throat irritation, oropharyngeal discomfort, flushing, dyspnea, laryngeal or pharyngeal edema, hypotension, pyrexia, weariness, headache, nausea, dizziness, and tachycardia are all possible infusion effects. The proportion of infusion reactions in Ocrelizumab-treated patients who got Methylprednisolone or an equivalent steroid and potentially other pre-medication to minimize the risk of infusion reactions before each infusion was 34 to 40 % in multiple sclerosis clinical trials, with the peak incidence recorded with the first infusion. Although there were no severe infusion events, 0.3 % of Ocrelizumab-treated multiple sclerosis patients had significant infusion responses, some of which necessitated hospitalization. During the intravenous infusion and for at least an hour following the infusion, monitor patients who have received Ocrelizumab for infusion responses. Patients should be informed that infusion responses might happen up to 24 hours following the injection. To lessen the frequency and severity of infusion responses, administration of pre-medication may be added. The nature and degree of infusion reactions affect the treatment recommendations. Stop Ocrelizumab promptly and permanently if a life-threatening infusion reaction occurs, and offer appropriate supportive therapy. Management of less serious infusion reactions may include temporarily pausing the infusion or lowering the infusion rate.

2) Malignancies- With Ocrelizumab, there may be an elevated risk of cancer. Malignancies, such as breast cancer, were more common in Ocrelizumab-treated individuals in controlled trials; hence breast cancer screening guidelines must be followed by patients.

3) Risk of Infections- In comparison to patients taking a placebo, a larger proportion of Ocrelizumab-treated patients developed infections. In relapsing multiple sclerosis studies, 58 % of Ocrelizumab treated patients had one or more infections, in comparison to 52 % of placebo patients. In the primary progressive multiple sclerosis experiment, 70 % of Ocrelizumab-treated patients had one or more infections, compared to 68 % of placebo-treated patients. In multiple sclerosis patients, Ocrelizumab was not linked to a higher risk of serious infections. In individuals with an active infection, defer Ocrelizumab treatment until the infection has cleared.

4) Herpes- Herpes infections, such as herpes zoster, herpes simplex, oral herpes, genital herpes, and herpes virus infection, were reported more frequently in Ocrelizumab-treated patients in active-controlled relapsing multiple sclerosis clinical trials. The majority of infections were mild to moderate in intensity. Oral herpes was observed more frequently in Ocrelizumab-treated patients than in placebo-treated patients in the placebo-controlled primary progressive multiple sclerosis clinical trial.

5) Infections of the Respiratory Tract- When compared to those taking a placebo, Ocrelizumab-treated individuals had a greater rate of respiratory tract infections. In relapsing multiple sclerosis studies, 40 % of Ocrelizumab-treated patients had upper respiratory tract infections, compared to 33 % of placebo patients, and 8 % of Ocrelizumab-treated patients had lower respiratory tract infections, compared to 5 % of placebo-treated patients. In the primary progressive multiple sclerosis experiment, 49 % of Ocrelizumab-treated patients had upper respiratory tract infections versus 43 % of placebo-treated patients, and 10 % of Ocrelizumab-treated patients had lower respiratory tract infections as compared to 9 % of placebo-treated patients. Upper respiratory tract infections and bronchitis were the most common infections, mostly mild to moderate.

6) Reactivation of the Hepatitis B Virus- Hepatitis B reactivation has not been reported in multiple sclerosis patients treated with Ocrelizumab. Hepatitis B virus reactivation has resulted in fulminant hepatitis, hepatic failure, and death in patients treated with different anti-CD20 antibodies. Before starting Ocrelizumab medication, one has to make sure all patients have been tested for hepatitis B virus. Ocrelizumab should not be given to patients who have active hepatitis B virus, as evidenced by positive HBsAg and anti-HB testing. Patients who test negative for surface antigen but positive for HB core antibody or who are HBV carriers should seek advice from a liver disease specialist before beginning treatment and throughout it.

7) Progressive Multifocal Leukoencephalopathy (PML)- This is an opportune viral infection caused by the John Cunningham or JC virus in the brain, which mainly affects immunocompromised patients and results in death or severe disability. John Cunnigham virus infection leading to progressive multifocal leukoencephalopathy has been found in individuals treated with various anti-CD20 antibodies and other multiple sclerosis medications and has been linked to some risk factors. Withhold Ocrelizumab and do an adequate diagnostic examination at the first sign or symptom suggestive of progressive multifocal leukoencephalopathy. Clinical indications and symptoms may appear before MRI (magnetic resonance imaging) findings.

8) Vaccinations- All vaccines should be given at least six weeks before starting Ocrelizumab, according to immunization standards. Following Ocrelizumab medication, the safety of immunizing with live or live-attenuated vaccines has not been evaluated, and vaccination using live or live-attenuated vaccines is not indicated during treatment or until B-cell repletion.

9) Immunosuppressive Effects- The possibility of enhanced immunosuppressive effects when starting Ocrelizumab after an immunosuppressive therapy or starting an immunosuppressive therapy after Ocrelizumab dosage should be considered.

For Patients:

What Is Multiple Sclerosis?

Multiple sclerosis is a central nervous system illness that affects people of all ages. The immune system destroys nerve fibers and myelin sheath (a fatty substance that surrounds and protects healthy nerve fibers) present in the brain and spinal cord, resulting in multiple sclerosis. Inflammation occurs as a result of the attack, which affects nerve cell processes and myelin, changing electrical messages in the brain. Multiple sclerosis is unexpected and affects each patient differently - some people may experience only minor symptoms while others lose their ability to write, speak, or walk.

What Causes Multiple Sclerosis?

Experts are still unsure about what triggers multiple sclerosis. The hunt for the disease's cause is still going on. Multiple sclerosis can be triggered by a number of factors, including:

• According to some studies, certain infections (such as the Epstein-Barr virus) can cause multiple sclerosis later in life.

• There are much greater rates of the disease in some places of the world than in others. Multiple sclerosis is more commonly observed in areas farthest from the equator. The reason behind this could be due to the fact that the sun is less powerful in certain areas. Vitamin D levels are lower in people who get less sun, which is a risk factor for multiple sclerosis.

• Having a relative with multiple sclerosis raises the chances of developing the condition. However, which genes and how the genes have a role in the onset of multiple sclerosis are still unknown.

Learn More About Ocrelizumab

Who Can Take Ocrelizumab?

Ocrelizumab is a drug that is used to treat relapse multiple sclerosis that is still active. Its license also allows it to be used in the early stages of primary progressive multiple sclerosis. Patients must have relapsing multiple sclerosis that is 'active.' This indicates that they have had relapses or that MRI scans of the brain or spinal cord reveal new lesions. If the patient qualifies for another drug, but it is not right for them, they should be offered Ocrelizumab. So, if patients cannot take other drugs available for multiple sclerosis for some reason or are concerned about its side effects and hazards, Ocrelizumab is an option. On the Expanded Disability Status Scale (EDSS), if the patient has a score between 3.0 and 6.5, requires two walking aids (canes or crutches) to walk 20 meters without stopping, or if a person has been using a wheelchair for at least six months, they are not administered disease-modifying therapies, including Ocrelizumab. This is due to a lack of proof that disease-modifying therapies will make a significant difference in multiple sclerosis. The neurologist will determine if a patient has primary progressive multiple sclerosis and how much disability it has caused them depending on how long they have had symptoms. The neurologist will apply the following rule to classify primary progressive multiple sclerosis as 'early' and hence qualify the patient for Ocrelizumab. If the expanded disability status scale score is greater than five and the multiple sclerosis symptoms must have begun within the last 15 years. If a patient gets a score of five or less, their symptoms must have begun no more than ten years ago. The expanded disability status scale assesses how much multiple sclerosis affects an individual, with a focus on their ability to walk.

Who Cannot Take This Drug?

• Patients are already on a disease-modifying therapy that is effectively regulating their multiple sclerosis.

• If a patient has an active hepatitis B virus infection, they should not receive Ocrelizumab.

• If a patient had a life-threatening allergic response to Ocrelizumab, do not take it. If they have ever had an adverse response to Ocrelizumab or any of its constituents, let your doctor know.

• If the patient has cancer or has already had cancer in the past, the doctor may opt not to give them this drug or delay it. Tell the multiple sclerosis expert everything about your medical history, including any other health issues you are dealing with and any drugs you are taking.

• If the patient has a weaker immune system.

• If the patient is a woman and they are thinking about getting pregnant, do not use this medication. Women using Ocrelizumab should utilize a reliable form of contraception, such as condoms or contraceptive pills.

How to Take Ocrelizumab?

Ocrelizumab is administered by a drip (sometimes known as an "infusion") in the hospital. Patients will be given steroids and antihistamines before the infusion to help prevent any responses that the infusion might cause. It will take two hours or three and a half hours to complete the infusion. The doctor will be able to tell the patient about the infusion pace they will employ. After that, the patient will be watched for an hour. Patients will be admitted to the hospital for the infusion, but they will not be required to stay overnight. They will receive two infusions separated by two weeks for their initial therapy. Following that, they will have an infusion every six months. Ocrelizumab is slowly injected into the patient's bloodstream using a needle inserted into a vein, generally in your arm. They usually sit on a chair or lie on the bed. Any vaccines the patient may require must be administered to them at least six weeks before they begin taking this medication.

What Side Effects Might One Get?

Ocrelizumab, like all medicines, can cause adverse effects, but not everyone experiences them. Few people stop taking this medication due to its negative effects. There were no major negative effects in the studies, unlike with other, more powerful disease-modifying therapies. Some immune system cells are killed by Ocrelizumab. However, because it does not target all types of immune cells, the patient will still be protected against infections. However, taking this medication increases an individual's chances of contracting some (usually minor) infections. Ocrelizumab has the potential to damage unborn children. If a woman might become pregnant, they should use effective contraception while taking this medication and for at least 12 months following their last infusion. If a patient gets pregnant, they must immediately notify the neurologist and stop taking this medication. Up to one out of every four patients has a minor reaction to the infusion. These responses can occur during or within 24 hours of receiving the infusion and vanish quickly. Steroids and antihistamines are administered to reduce the likelihood of a response. During the infusion and for an hour later, patients will be monitored. Reactions to infusions can include:

• Feeling ill or dizzy.

• Headache.

• Exhaustion.

• Shortness of breath.

• Hives (an itchy skin rash).

• The skin turns red, especially on the chest or face (flushing).

• A fast heartbeat.

• Low blood pressure.

• A fever or high temperature.

• Throat pain or irritation or swelling of the throat.

This is most likely to happen when a patient receives their first infusion. With subsequent infusions, they become less common. If patients experience a reaction, the infusion may need to be slowed or halted until the problem is resolved.

It is possible that the patient will be more susceptible to infections. The most common ones are colds and flu. Other common infections include:

• Herpes infections (cold sores, shingles, etc.).

• Sinus infections (infections of the regions behind your cheeks, forehead, and nose).

• Bronchitis and coughs.

• Gastroenteritis (infections of the stomach and intestines).

• Illnesses such as sore throats and tonsillitis.

• Viral infections.

• Infections of the skin.

More Serious Side Effects Seen Are:

1) Blood-related effects such as a decline in the levels of immunoglobulin M and G. These are proteins in our blood that serve to defend us from infection. Neutropenia is another prevalent condition. When a patient has low numbers of a type of white blood cell that fights infections, they have this condition. A fever is one of the signs of this.

2) In clinical trials, more people who took this medicine developed cancer, particularly breast cancer. However, the figure remained within the normal range. So it is unclear whether this is a pharmacological side effect.

3) Progressive multifocal leukoencephalopathy is an extremely rare but deadly brain infection. If a patient has been infected with the John Cunnigham virus, they are at risk. This virus is seen in more than half of multiple sclerosis patients. Progressive multifocal leukoencephalopathy symptoms are comparable to those of multiple sclerosis or a relapse: clumsiness, poor balance, and a lack of strength.

When Should One Stop Taking Ocrelizumab?

• Ocrelizumab is a long-term treatment. It is hoped that if it is controlling multiple sclerosis well and causing no adverse effects, patients will be able to take it for years. Their neurologist will advise them to discontinue using Ocrelizumab if patients experience negative side effects or if the treatment is not controlling their multiple sclerosis.

• The neurologist can switch a patient to another therapy if the patient has been taking it for relapsed multiple sclerosis. After six months on a medicine, patients are usually ready to switch. If patients have been taking this medicine for early primary progressive multiple sclerosis and need to quit, there are currently no other therapies that can be used in its place.

• If the patient is a woman, she must stop taking Ocrelizumab if they have become pregnant or decided to become pregnant.

• If the patient has relapsing multiple sclerosis and it turns to secondary progressive multiple sclerosis, and they stop having relapses, their neurologist may decide that it is best to stop taking Ocrelizumab for a period.

• People with progressive multiple sclerosis who do not have relapses or active inflammation would not benefit from the current therapies. Other medications are being tested in clinical trials to treat progressive, non-relapsing multiple sclerosis.

• If the patient acquires a serious infection.

What Tests Are Needed Before Starting the Drug?

• A patient will get one or two MRI (magnetic resonance imaging) scans of the brain before starting this medication. They will get vaccinated against hepatitis, tetanus, polio, and the human papillomavirus (HPV) six weeks before their first infusion.

• Before a patient starts taking Ocrelizumab, they should get tested to check if they have hepatitis B or if they have ever had it. They would not be allowed to start Ocrelizumab if they have an active hepatitis B infection since it could make it worse. If a patient previously had this infection, Ocrelizumab may make it aggressive again. As a result, it is needed to keep a close eye on things to make sure this does not happen. Patients could also be prescribed a medicine to help in stopping hepatitis from coming back.

• Patients would not require any additional testing or monitoring while using this medication. However, the neurologist will most likely want an MRI (magnetic resonance imaging) scan once a year to check on the drug's effectiveness.

For Medical Professionals:

Indications for Ocrelizumab: Individuals with relapsing or primary progressive forms of multiple sclerosis are indicated for the use of this medication.

Chemical Taxonomy:

Pharmacology:

Mechanism of Action:

Ocrelizumab's precise mechanism of action in multiple sclerosis is uncertain. However, it is thought to include its binding to CD20, a cell surface antigen found on pre-B and mature B lymphocytes. Ocrelizumab causes antibody-dependent cellular cytolysis and complement-mediated lysis after binding to B lymphocytes on the cell surface.

Pharmacodynamics:

Since the presence of Ocrelizumab interferes with the CD20 assay, assays for CD19+ B-cells are employed for B-cell counts. Ocrelizumab treatment lowers CD19+ B-cell numbers in the blood 14 days after infusion. Between infusions of Ocrelizumab at least once, B-cell counts climbed to above the lower limit of normal or above baseline numbers in patients in clinical investigations. After the last Ocrelizumab injection, the median time for B-cell counts to return to baseline was 72 weeks in a clinical study. In 90 % of patients, B-cell counts returned to baseline or LLN within 2.5 years following the last treatment.

Pharmacokinetics:

In multiple sclerosis clinical investigations, the pharmacokinetics of Ocrelizumab fits a two-compartment model with time-dependent clearance. Maintenance dosages of Ocrelizumab in multiple sclerosis patients were either 600 mg every six months (relapsing multiple sclerosis patients) or two 300 mg infusions spaced by 14 days every six months (primary progressive multiple sclerosis patients) in clinical investigations.

Distribution:

The central volume of distribution was estimated by the population PK to be 2.78 L. The intercompartmental clearance and peripheral volume were calculated to be 2.68 L and 0.29 L/day, respectively.

Elimination:

Initial time-dependent clearance was estimated at 0.05 L/day, with a half-life of 33 weeks, and the constant clearance was estimated at 0.17 L/day. The terminal half-life of elimination was 26 days.

Metabolism:

Because antibodies are removed mostly through catabolism, the metabolism of Ocrelizumab has not been investigated in depth.

Non-clinical Toxicology:

To examine the carcinogenic potential of Ocrelizumab, no carcinogenicity studies have been conducted. Ocrelizumab's mutagenic potential has not been investigated in any studies. Ocrelizumab is not predicted to bind directly with DNA like an antibody. In male monkeys given Ocrelizumab intravenously for eight weeks, no effects on reproductive organs were found. Female monkeys given Ocrelizumab across three menstrual cycles with the same dose regimen had no influence on their estrus cycle. On an mg/kg basis, the doses examined in monkeys are 2 and 10 times the recommended human intake of 600 mg.

Experience From Clinical Trials:

Since clinical trials are performed under such a broad range of conditions, adverse reactions seen in the clinical trial of one drug cannot be directly compared to what is seen in another clinical trial of another drug and might not reflect rates seen in real practice. Ocrelizumab safety was assessed in 1311 people in multiple sclerosis clinical trials, including 825 participants in active-controlled trials in patients with relapsing forms of multiple sclerosis and 486 patients in a placebo-controlled study in patients having primary progressive multiple sclerosis (PPMS). Upper respiratory tract infections and infusion responses were the most prevalent adverse effects in relapsing multiple sclerosis studies. Upper respiratory tract infections, infusion responses, skin infections, and lower respiratory tract infections were the most prevalent adverse reactions in the primary progressive multiple sclerosis trials. Ocrelizumab reduced total immunoglobulins, with IgM levels dropping the most. There was no evident link between decreased immunoglobulin levels and the risk of severe infections in multiple sclerosis therapeutic trials. Reduced neutrophil counts occurred in Ocrelizumab-treated patients in the primary progressive multiple sclerosis clinical trial.

Immunogenicity:

Immunogenicity is a possibility with all therapeutic proteins. The specificity and sensitivity of the test methods utilized have a significant impact on immunogenicity statistics. Furthermore, various factors, such as sample handling, sample collection timing, drug interference, concurrent therapy, and the underlying condition, may influence the observed incidence of a positive result in a test method. As a result, comparing the incidence of Ocrelizumab antibodies to the incidence of antibodies to other medications could be deceptive. Out of the 1311 patients who received Ocrelizumab tested positive for anti-drug antibodies, with two of them also testing positive for neutralizing antibodies. These data are insufficient to assess the influence of anti-drug antibodies on Ocrelizumab safety and efficacy.

Drug Interactions:

The use of Ocrelizumab in combination with other immune-modulating or immunosuppressive medications, such as immunosuppressive corticosteroid dosages, is likely to enhance the risk of immunosuppression. When taking immunosuppressive medications with Ocrelizumab, keep in mind the possibility of additive immune system effects. Consider the length and mechanism of action of these medications when switching from drugs with extended immunological effects, such as Daclizumab, Fingolimod, Natalizumab, Teriflunomide, or Mitoxantrone, because of additive immunosuppressive effects after starting Ocrelizumab.

Usage of Ocrelizumab in Specific Populations:

Ocrelizumab Usage in Pregnant Individuals:

There is little information on the developmental risk of Ocrelizumab use in pregnant women. However, infants delivered to women who were exposed to different anti-CD20 antibodies during pregnancy have shown transitory peripheral B-cell depletion and lymphocytopenia.

Ocrelizumab Usage in Lactating Females:

There is no information on Ocrelizumab's presence in human milk, its effects on a breastfed newborn, or its effects on milk production. Human IgG is expelled in human milk; thus, there is no way of knowing whether Ocrelizumab absorption would cause B-cell depletion in the baby. Breastfeeding's developmental and health benefits should be weighed against the mother's clinical requirement for the drug and any potential or underlying maternal condition-related detrimental effects on the breastfed infant.

Ocrelizumab Usage in Humans With Reproductive Potential:

Contraception should be employed by women of reproductive potential while receiving Ocrelizumab and for six months following the final infusion.

Ocrelizumab Usage in Pediatric Patients:

Ocreliozumab's safety and efficacy in pediatric patients have yet to be determined.

Ocrelizumab Usage in Geriatric Patients:

Ocrelizumab clinical trials did not involve a large enough number of patients aged 65 and over to assess whether they would respond differently than younger people