Ocrelizumab

Article Author:
James Flynn
Article Editor:
Valerie Gerriets
Updated:
12/14/2019 4:10:33 PM
PubMed Link:
Ocrelizumab

Indications

Ocrelizumab is an FDA approved CD20-directed humanized monoclonal antibody indicated for the treatment of adult patients with primary progressive or relapsing multiple sclerosis; it received approval from the FDA on March 28, 2017. 

FDA-approved indications (with clinical trial summaries):

Multiple Sclerosis(MS):

Primary-Progressive MS

  • ORATORIO study: In this double-blinded study, 732 patients were randomly assigned 2 to 1 to either ocrelizumab (two intravenous 300 mg doses given 14 days apart every 24 weeks) or placebo for at least 120 weeks until a prespecified number of disability events occurred. The study's primary endpoint was the percentage of patients with 12-week confirmed disability progression.  Ocrelizumab showed a 12-week confirmed disability progression of 32.9% whereas the placebo arm showed a 39.3% rate (hazard ratio = 0.76, p=0.03).[1]

Relapsing MS:

  • OPERA I study: In this double-blinded study, 821 patients were randomly assigned 1 to 1 to either ocrelizumab (two intravenous 300 mg doses given 14 days apart and then a single 600 mg doses every 24 weeks) or interferon beta-1a (subcutaneous 44 microgram dose three times weekly) for 96 weeks with a primary endpoint of annualized relapse rate. Results showed that ocrelizumab has a statistically significantly lower annualized relapse rate at 0.16 vs. interferon beta-1a at 0.29 (46% reduction, p<0.001).[2]
  • OPERA II study: In this double-blinded study, 835 patients were randomly assigned 1:1 to either Ocrelizumab(two intravenous 300mg doses given 14 days apart and then a single 600mg dose every 24 weeks) or interferon beta-1a (subcutaneous 44 microgram dose three times weekly) for 96 weeks with a primary endpoint of annualized relapse rate. Results showed that ocrelizumab has a statistically significantly lower annualized relapse rate at 0.16 vs. Interferon beta-1a at 0.29 (47% reduction, p<0.001).[2]

At the time of launch, ocrelizumab had a list price of $65000 annually. It is generally covered by commercial insurance and by Medicare. The manufacturer provides patient payment assistance in the forms of a co-pay program and also referrals to a patient payment assistance foundation.

Mechanism of Action

Ocrelizumab is a second-generation anti-CD20 recombinant monoclonal antibody with a molecular mass of 145kDa. It is a follow up to the anti-CD20 monoclonal antibody rituximab, but with a humanized IgG1 tail.[3] Humanization of the antibody is expected to reduce antigenicity and improve CD20 binding.[4] CD20 is a phosphoprotein expressed on a broad range of human B-cells. However, it is not present in the early lineage (stem cells and pro-B-cells) or late lineage (plasmablasts and plasma cells).[5] Ocrelizumab binds to CD20 on B-lymphocytes leading to antibody-dependent cellular cytolysis and complement-mediated lysis.[6] While the precise method by which ocrelizumab exerts its effect on multiple sclerosis is unknown, it depletes B-cells which are thought to affect the pathogenesis of multiple sclerosis using cytokine regulation, antigen presentation, autoantibody production.[2]

Administration

Ocrelizumab is FDA approved for intravenous infusion. It is supplied in 300 mg/mL single-dose vials. The initial dose is given as a 300 mg intravenous infusion over 2.5 hours, followed up with an additional 300 mg intravenous infusion 14 days later. Subsequent doses are given every six months as a 600 mg intravenous infusion over 3.5 hours.  Maintenance doses of ocrelizumab should be at a minimum five months apart. Some argue that dosing should not be on a fixed schedule but based on CD19/20 counts to optimize dosing to minimize unnecessary patient exposure and allow for significant cost savings.[7] For mild to moderate adverse events, a reduction in infusion rate is indicated, if tolerated. Severe and life-threatening reactions indicate interruption or discontinuation of the drug. 

Adverse Effects

Adverse reactions in relapsing multiple sclerosis with an incidence of more than 5% and higher than interferon beta-1a[2]:

  • Back pain
  • Depression
  • Herpes virus-associated infections
  • Infusion reactions
  • Lower respiratory infections
  • Pain in extremities
  • Upper respiratory infections 

Adverse reactions in primary progressive multiple sclerosis with an incidence of more the 5% and higher than placebo[1]:

  • Cough
  • Diarrhea
  • Edema peripheral
  • Herpes virus-associated infections
  • Infusion reactions
  • Lower respiratory tract infections
  • Skin reactions
  • Upper respiratory tract infections

Contraindications

Ocrelizumab is contraindicated in the following patients:

  • Those with a history of life-threatening infusion reactions to ocrelizumab
  • Patients with active hepatitis-B infection

Before initiating ocrelizumab:

  • Hepatitis B virus screening is necessary. There have been reports of ocrelizumab leading to reactivation of latent HBV in a previously resolved patient.[8] 
  • All necessary immunizations should be given at least six weeks before initiating ocrelizumab given the expected B-cell depletion.
  • Consider previous immunosuppressive therapy for potential increased immunosuppressive effects.

Before every ocrelizumab infusion:

  • Determine if there is an active infection, if yes, delay infusion until resolution
  • Premedicate with 100 mg of methylprednisolone and an antihistamine 30 minutes before infusion.
  • Consider premedication with an antipyretic
  • A regiment of cetirizine (10 mg), ranitidine (75 mg), increased hydration, IV diphenhydramine (50 mg), IV methylprednisolone (125 mg) and oral acetaminophen (650 mg) has been shown to reduce infusion reactions by 60% in one study.[9]

Monitoring

Before initiating ocrelizumab therapy, hepatitis B virus screening is indicated. 

Patients receiving an ocrelizumab infusion will require monitoring for at least the next hour for the following signs and symptoms of refusion reactions:

  • Coughing or wheezing
  • Dizziness
  • Fast heart rate
  • Fatigue
  • Feeling faint
  • Fever
  • Flushing
  • Headache
  • Hives
  • Itchy skin
  • Nausea
  • Rash
  • Shortness of breath
  • Swelling of throat
  • Throat irritation or pain
  • Tiredness
  • Trouble breathing

In clinical trials, there was an incidence of life-threatening bronchospasm (which recovered with treatment) with the initial infusion of ocrelizumab.[2]

Toxicity

Pregnancy:

  • There is inadequate data on the fetal risk associated with ocrelizumab use in pregnancy.
  • Ocrelizumab is an antibody of immunoglobulin G1 subtype, which is known to cross the placental barrier.
  • Administration of ocrelizumab to pregnant monkeys at 2 to 10 times the recommended human dose has shown increased perinatal mortality and depletion of B-cell populations. Offspring were observed to have bone marrow, renal, and testicular toxicities not seen in the mother. 
  • While data on ocrelizumab exposure during pregnancy is sparse, rituximab use (as a proxy) has shown B-cell depletion in delivered babies. [10]

Other:

  • No data shows the existence of ocrelizumab in human milk; animal studies have shown its presence in monkey milk. However, large molecules like monoclonal antibodies are unlikely to be excreted into human breast milk or absorbed into the baby’s circulation in any significant amount. [11]
  • Ocrelizumab’s safety and efficacy have not been established in pediatric patients
  • Ocrelizumab’s safety and efficacy have not been established in patients over 65 years old
  • In clinical studies of ocrelizumab, there were six cases of breast cancer as compared to none in the placebo or Interferon beta-1a groups [1][2]

Enhancing Healthcare Team Outcomes

Ocrelizumab is a new biological agent, and even though it has shown a positive risk/benefit trade-off in clinical trials, it does require close monitoring for safety; thus, besides the prescribing clinician, both nurses and pharmacists are responsible for educating the patient on the potential side effects of the drug.

During IV administration, the drug has shown infusion-reactions in more than one-third of patients, therefore it is essential to monitor side effects such as coughing, dizziness, fast heart rate, fatigue, feeling faint, fever, flushing, headache, hives, itchy skin, nausea, rash, shortness of breath, swelling of throat, throat irritation or pain, tiredness, trouble breathing and wheezing. In clinical trials, there was an incidence of life-threatening bronchospasm (which recovered with treatment) during the initial infusion of ocrelizumab.[2] Therefore, because the drug can trigger a life-threatening infusion reaction, the interprofessional team needs to have the necessary medications and equipment in the room to ensure safe outcomes.

Since some of the adverse effects are delayed-onset, including opportunistic infections and malignancies, an outpatient neurology nurse should continue to follow the patients and coordinate additional surveillance between infusions. The nurses and pharmacists should regularly check immune titers to monitor immunosuppression. While there are no reported cases of progressive multifocal leukoencephalopathy (PML) to date (which has happened in other anti-CD20 antibodies and immunosuppressant therapies) it is crucial for the entire healthcare team to be on the lookout for clinical signs and symptoms including hemiparesis, clumsiness, visual changes, memory/thinking changes, and personality changes.[12] The clinical trial experience showed a higher rate of breast malignancy in the ocrelizumab treated group.  However, patients are not advised to undergo increased surveillance and instead to continue to undergo routine breast cancer screening as age-appropriate.[13]

Pharmacists should also work with the prescriber and nursing to ensure proper dosing, preclude drug interactions, and educate the patient and nursing staff on potential adverse reactions. This information will allow nursing to administer the drug effectively, as well as monitor for any adverse reactions, and inform the ordering clinician should they encounter any concerns. This collaborative paradigm exemplifies the kind of interprofessional teamwork the healthcare team requires to administer ocrelizumab effectively to achieve optimal patient outcomes while minimizing patient risks. [Level V]

Finally, the drug is prohibitively expensive, and insurance health plans do not always cover the cost. Without long term data available, clinicians should always consider other similar cost-effective agents first.

Interprofessional communication between the primary treatment team and the patient’s PCP or OBGYN is essential to make sure such screenings occur as estimates are that roughly one-third of women do not get an appropriate annual screening.[14]


References

[1] Montalban X,Hauser SL,Kappos L,Arnold DL,Bar-Or A,Comi G,de Seze J,Giovannoni G,Hartung HP,Hemmer B,Lublin F,Rammohan KW,Selmaj K,Traboulsee A,Sauter A,Masterman D,Fontoura P,Belachew S,Garren H,Mairon N,Chin P,Wolinsky JS, Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. The New England journal of medicine. 2017 Jan 19;     [PubMed PMID: 28002688]
[2] Hauser SL,Bar-Or A,Comi G,Giovannoni G,Hartung HP,Hemmer B,Lublin F,Montalban X,Rammohan KW,Selmaj K,Traboulsee A,Wolinsky JS,Arnold DL,Klingelschmitt G,Masterman D,Fontoura P,Belachew S,Chin P,Mairon N,Garren H,Kappos L, Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. The New England journal of medicine. 2017 Jan 19;     [PubMed PMID: 28002679]
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[5] Stashenko P,Nadler LM,Hardy R,Schlossman SF, Characterization of a human B lymphocyte-specific antigen. Journal of immunology (Baltimore, Md. : 1950). 1980 Oct;     [PubMed PMID: 6157744]
[6] Anderson DR,Grillo-López A,Varns C,Chambers KS,Hanna N, Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma. Biochemical Society transactions. 1997 May;     [PubMed PMID: 9191187]
[7] Avasarala J, Anti-CD20 Cell Therapies in Multiple Sclerosis-A Fixed Dosing Schedule for Ocrelizumab is Overkill. Drug target insights. 2017;     [PubMed PMID: 29123374]
[8] Ciardi MR,Iannetta M,Zingaropoli MA,Salpini R,Aragri M,Annecca R,Pontecorvo S,Altieri M,Russo G,Svicher V,Mastroianni CM,Vullo V, Reactivation of Hepatitis B Virus With Immune-Escape Mutations After Ocrelizumab Treatment for Multiple Sclerosis. Open forum infectious diseases. 2019 Jan;     [PubMed PMID: 30697576]
[9] Conte WL,Arndt N,Cipriani VP,Dellaria A,Javed A, Reduction in ocrelizumab-induced infusion reactions by a modified premedication protocol. Multiple sclerosis and related disorders. 2019 Jan;     [PubMed PMID: 30508784]
[10] Fragoso YD,Adoni T,Brooks JBB,Finkelsztejn A,da Gama PD,Grzesiuk AK,Marques VD,Parolin MFK,Sato HK,Varela DL,Vasconcelos CCF, Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children. Neurology and therapy. 2018 Dec;     [PubMed PMID: 30167914]
[11] Langer-Gould AM, Pregnancy and Family Planning in Multiple Sclerosis. Continuum (Minneapolis, Minn.). 2019 Jun;     [PubMed PMID: 31162316]
[12] Berger JR, The clinical features of PML. Cleveland Clinic journal of medicine. 2011 Nov;     [PubMed PMID: 22123935]
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