Ocrevus Drug Information
Generic name: OCRELIZUMAB
CD20-directed Cytolytic Antibody [EPC]
Uses of Ocrevus
is indicated for the treatment of: 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 Relapsing-remitting MS, in pediatric patients 10 years of age and older who weigh 25 kg or more. OCREVUS is a CD20-directed cytolytic antibody indicated for the treatment of: 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 Relapsing-remitting MS, in pediatric patients 10 years of age and older who weigh 25 kg or more
Dosage & Administration of Ocrevus
| Infusion 1 | |
| Infusion 2 (2 weeks later) | 300 mg in 250 mL |
| Option 1 Infusion of approximately 3.5 hours duration | |
| OR | |
| Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) | 600 mg in 500 mL |
Side Effects of Ocrevus
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The safety of OCREVUS has been evaluated in 1311 adult patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS). Adverse Reactions in Adult Patients with Relapsing Forms of MS In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received OCREVUS 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2). The overall exposure in the 96-week controlled treatment periods was 1448 patient-years. The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions.
Table 4 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2). Table 4 Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIF Adverse Reactions Studies 1 and 2 OCREVUS 600 mg IV Every 24 Weeks The first dose was given as two separate 300 mg infusions at Weeks 0 and 2. (n=825) % REBIF 44 mcg SQ 3 Times per Week (n=826) % Upper respiratory tract infections 40 33 Infusion reactions 34 10 Depression 8 7 Lower respiratory tract infections 8 5 Back pain 6 5 Herpes virus- associated infections 6 4 Pain in extremity 5 4 Adverse Reactions in Adult Patients with Primary Progressive MS In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of OCREVUS (600 mg of OCREVUS administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years. The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections.
Table 5 summarizes the adverse reactions that occurred in the PPMS trial (Study 3). Table 5 Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo Adverse Reactions Study 3 OCREVUS 600 mg IV Every 24 Weeks One dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart) Placebo (n=486) % (n=239) % Upper respiratory tract infections 49 43 Infusion reactions 40 26 Skin infections 14 11 Lower respiratory tract infections 10 9 Cough 7 3 Diarrhea 6 5 Edema peripheral 6 5 Herpes virus associated infections 5 4 Adverse Reactions in Adult Patients who Received 2-hour Infusions Study 4 was designed to characterize the safety profile of OCREVUS infusions administered over 2 hours in patients with Relapsing-Remitting Multiple Sclerosis who did not experience a serious infusion reaction with any previous OCREVUS infusion. In this study, the incidence, intensity, and types of symptoms of infusion reactions were consistent with those of infusions administered over 3.5 hours . Laboratory Abnormalities in Adults Decreased Immunoglobulins OCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels; however, a decrease in IgG levels was associated with an increased rate of serious infections. In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in OCREVUS-treated patients was 0.5%, 1.5%, and 0.1%, respectively.
Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively. In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in OCREVUS-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.
The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of IgG and increased rates of serious infections. The type, severity, latency, duration, and outcome of serious infections observed during episodes of immunoglobulins below LLN were consistent with the overall serious infections observed in patients treated with OCREVUS. Decreased Neutrophil Levels In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with OCREVUS and were between LLN - 1.5 × 10 9 /L and 1.0 × 10 9 /L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 × 10 9 /L and these were not associated with an infection.
Pediatric Patients Adverse Reactions in Patients 10 to Less Than 18 Years of Age with Relapsing-Remitting MS The safety of OCREVUS in pediatric patients with relapsing-remitting MS was evaluated in one randomized, double-blind clinical study in 185 patients, 93 of whom received OCREVUS and 92 of whom received fingolimod . In the controlled pediatric trial (Study 5), the safety profile in pediatric patients was consistent with that observed in adult patients. Infusion Reactions Infusion reactions were the most common adverse reactions in patients treated with OCREVUS with an incidence of 48%, compared to an incidence of 24% in fingolimod-treated patients (placebo infusion). The incidence of infusion reactions was highest at 31% with infusion 1 of the initial dose (on day 1), and decreased to 9% with infusion 2 of the initial dose (on day 15). At the first subsequent dose (at 6 months), 16% of patients had an infusion reaction. The incidence and severity of infusion reactions decreased with additional subsequent infusions.
The majority of infusion reactions were mild to moderate. One infusion reaction with infusion 1 of the initial dose was reported as serious because it required hospitalization. Infections Infections were observed in 73% of patients treated with OCREVUS (1.5 infections per patient-year) and 59% of patients treated with fingolimod (1.2 infections per patient-year). Serious infections occurred in 3% of patients treated with OCREVUS (0.03 serious infections per patient-year) compared to 3% of fingolimod-treated patients (0.03 serious infections per patient-year). Laboratory Abnormalities Decreased Immunoglobulins OCREVUS decreased total immunoglobulins over the controlled period of Study 5, with the greatest decline seen in IgM levels.
Similar to the pattern observed in the adult population, reduction in IgM occurred earlier and in a higher proportion of patients compared to IgG and IgA.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Immune-mediated colitis Hepatobiliary Disorders: Liver injury Infections and Infestations: Serious herpes infections , progressive multifocal leukoencephalopathy , and babesiosis Skin: Pyoderma gangrenosum
Warnings & Cautions for Ocrevus
Infusion Reactions
OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. These reactions are more commonly reported with the first infusion. In multiple sclerosis (MS) clinical trials, all adult and pediatric patients who were treated with OCREVUS received premedication with methylprednisolone (or an equivalent steroid), and may have also received an antihistamine (all pediatric patients) and/or an analgesic/antipyretic to reduce the risk of infusion reactions prior to each infusion.
In adults, the incidence of infusion reactions in patients treated with OCREVUS was 34 to 40%. There were no fatal infusion reactions, but 0.3% of patients with MS who were treated with OCREVUS experienced infusion reactions that were serious, some requiring hospitalization. In pediatric patients, the incidence of infusion reactions in patients treated with OCREVUS was 48%, compared with an incidence of 24% in patients who received placebo infusion (fingolimod-treated patients). There were no fatal infusion reactions, but one pediatric patient (1.1%) treated with OCREVUS experienced an infusion reaction that was serious because it required hospitalization . Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.
Reducing the Risk of Infusion Reactions and Managing Infusion Reactions Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. Management recommendations for infusion reactions depend on the type and severity of the reaction.
For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic and fungal infections
have been reported in patients receiving OCREVUS. An increased risk of infections (including serious and fatal bacterial, fungal, and new or reactivated viral infections) has been observed in patients during and following completion of treatment with anti-CD20 B-cell depleting therapies. A higher proportion of adult patients treated with OCREVUS experienced infections compared to patients taking REBIF or placebo. In RMS trials in adults, 58% of patients treated with OCREVUS experienced one or more infections compared to 52% of patients treated with REBIF. In the PPMS trial, 70% of patients treated with OCREVUS experienced one or more infections compared to 68% of patients on placebo.
OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. In the pediatric study, infections occurred in 73% of patients treated with OCREVUS (1.5 infections per patient-year) and 59% of patients treated with fingolimod (1.2 infections per patient-year) . Upper respiratory tract infections, nasopharyngitis, and influenza, all of which were mild to moderate, were more frequently reported in patients treated with OCREVUS compared to patients treated with fingolimod. Delay OCREVUS administration in patients with an active infection until the infection is resolved.
Respiratory Tract Infections A higher proportion of adult patients treated with OCREVUS experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials in adults, 40% of patients treated with OCREVUS experienced upper respiratory tract infections compared to 33% of patients treated with REBIF, and 8% of patients treated with OCREVUS experienced lower respiratory tract infections compared to 5% of patients treated with REBIF. In the PPMS trial, 49% of patients treated with OCREVUS experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of patients treated with OCREVUS experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.
Herpes In active-controlled (RMS) clinical trials in adults, herpes infections were reported more frequently in patients treated with OCREVUS than in patients treated with REBIF, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the patients treated with OCREVUS than in the patients on placebo (2.7% vs 0.8%). Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving OCREVUS. Serious herpes virus infections may occur at any time during treatment with OCREVUS. Some cases were life-threatening. If serious herpes infections occur, OCREVUS should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered.
Hepatitis B Virus (HBV) Reactivation Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests.
For patients who are negative for surface antigen and positive for HB core antibody or are carriers of HBV, consult liver disease experts before starting and during treatment. Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effects. OCREVUS has not been studied in combination with other MS therapies.
Vaccinations Administer all age-appropriate immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion . Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19 + B-cells.
Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. If indicated, non-live vaccines may be administered prior to recovery from B-cell depletion, but assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to assess whether a protective immune response was mounted.
Progressive Multifocal Leukoencephalopathy Cases of progressive multifocal leukoencephalopathy (PML) have been reported
in patients with MS treated with OCREVUS in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in OCREVUS-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any immunosuppressive or immunomodulatory medications associated with the risk of PML prior to or concomitantly with OCREVUS, and did not have any known ongoing systemic medical conditions resulting in compromised immune system function.
JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis.
It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients. If PML is confirmed, treatment with OCREVUS should be discontinued.
Reduction in Immunoglobulins As expected with any B-cell depleting therapy, decreased immunoglobulin
levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) in adults and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins . An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in patients treated with OCREVUS. Breast cancer in adults occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines. form of colitis, has been reported in patients receiving OCREVUS in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during OCREVUS treatment, and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur. been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including OCREVUS. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from weeks to months after administration. Patients treated with OCREVUS found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3× the upper limit of normal (ULN) with serum total bilirubin greater than 2× ULN are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with OCREVUS and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue OCREVUS.Malignancies
Immune-Mediated Colitis Immune-mediated colitis, which can present as a severe and acute-onset
Liver Injury Clinically significant liver injury, without findings of viral hepatitis, has
Drug Interactions with Ocrevus
Immunosuppressive or Immune-Modulating Therapies
The concomitant use of OCREVUS and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with OCREVUS. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS.
Vaccinations
A Phase 3b randomized, open-label study examined the concomitant use of OCREVUS and several non-live vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects undergoing treatment with OCREVUS at the time of vaccination and 34 subjects not undergoing treatment with OCREVUS at the time of vaccination). Concomitant exposure to OCREVUS attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and seasonal inactivated influenza vaccines. The impact of the observed attenuation on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with OCREVUS have not been assessed .
Pregnancy Safety for Ocrevus
Pregnancy Risk Summary OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy.
B-cell levels in infants following maternal exposure to OCREVUS have not been studied in clinical trials. The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown . Following administration of ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data Animal Data Following intravenous administration of OCREVUS to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses. Intravenous administration of OCREVUS (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections.
Reduced testicular weight was observed in neonates at the high dose. A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
Pediatric Use of Ocrevus
Pediatric Use The safety and effectiveness of OCREVUS for the treatment of relapsing-remitting MS have been established in pediatric patients 10 years of age and older who weigh 25 kg or more. Use of OCREVUS for this indication is supported by evidence from one randomized, double-blind clinical study in 187 pediatric patients (93 of whom received OCREVUS) and additional pharmacokinetic data in pediatric patients . The overall safety profile in pediatric patients 10 years of age and older receiving OCREVUS was generally consistent with that observed in adult patients . Safety and effectiveness of OCREVUS have not been established in pediatric patients less than 10 years of age or who weigh less than 25 kg.
Contraindications for Ocrevus
is contraindicated in patients with: Active HBV infection A history of life-threatening infusion reaction to OCREVUS Active hepatitis B virus infection History of life-threatening infusion reaction to OCREVUS
Clinical Studies of Ocrevus
Relapsing Forms of Multiple Sclerosis in Adults
The efficacy of OCREVUS was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in adult patients with relapsing forms of multiple sclerosis (RMS) treated for 96 weeks (Study 1 and Study 2). The dose of OCREVUS was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV infusions administered 2 weeks apart, and subsequent doses were administered as a single 600 mg IV infusion) and placebo subcutaneous injections were given 3 times per week. The dose of REBIF, the active comparator, was 44 mcg given as subcutaneous injections 3 times per week and placebo IV infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Patients with primary progressive forms of multiple sclerosis (MS) were excluded.
Neurological evaluations were performed every 12 weeks and at the time of a suspected relapse. Brain MRIs were performed at baseline and at Weeks 24, 48, and 96. The primary outcome of both Study 1 and Study 2 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of 1 point or more from the baseline EDSS score attributable to MS when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening.
The primary population for analysis of confirmed disability progression was the pooled population from Studies 1 and 2. In Study 1, 410 patients were randomized to OCREVUS and 411 to REBIF; 11% of OCREVUS-treated and 17% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female.
The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of patients had one or more T1 Gd-enhancing lesions (mean 1.8). In Study 2, 417 patients were randomized to OCREVUS and 418 to REBIF; 14% of OCREVUS-treated and 23% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups.
At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of OCREVUS-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9). In Study 1 and Study 2, OCREVUS significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study 1 and Study 2 are presented in Table 6 and Figure 1. Table 6 Key Clinical and MRI Endpoints in Adult RMS Patients from Study 1 and Study 2 Endpoints Study 1 Study 2 OCREVUS 600 mg every 24 weeks REBIF 44 mcg three times a week OCREVUS 600 mg every 24 weeks REBIF 44 mcg three times a week N=410 N=411 N=417 N=418 Clinical Endpoints Annualized Relapse Rate (Primary Endpoint) 0.156 0.292 0.155 0.290 Relative Reduction 46% (p<0.0001) 47% (p<0.0001) Proportion Relapse-free 83% 71% 82% 72% Proportion of Patients with 12-week Confirmed Disability Progression Defined as an increase of 1.0 point or more from the baseline Expanded Disability Status Scale (EDSS) score for patients with baseline score of 5.5 or less, or 0.5 or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96. 9.8% OCREVUS vs 15.2% REBIF Risk Reduction (Pooled Analysis Data prospectively pooled from Study 1 and Study 2. ) 40%; p=0.0006 MRI Endpoints Mean number of T1 Gd-enhancing lesions per MRI scan 0.016 0.286 0.021 0.416 Relative Reduction 94% (p<0.0001) 95% (p<0.0001) Mean number of new and/or enlarging T2 hyperintense lesions per MRI 0.323 1.413 0.325 1.904 Relative Reduction 77% (p<0.0001) 83% (p<0.0001) Figure 1 Kaplan-Meier Plot Pre-specified pooled analysis of Study 1 and 2 of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Pooled Studies 1 and 2 in Adult Patients with RMS (Pooled ITT Population) In exploratory subgroup analyses of Study 1 and Study 2, the effect of OCREVUS on annualized relapse rate and disability progression was similar in male and female patients.
Figure 1
Primary Progressive Multiple Sclerosis in Adults Study 3 was a randomized, double-blind
placebo-controlled clinical trial in patients with primary progressive multiple sclerosis (PPMS). Patients were randomized 2:1 to receive either OCREVUS 600 mg or placebo as two 300 mg intravenous infusions 2 weeks apart every 24 weeks for at least 120 weeks. Selection criteria required a baseline EDSS of 3 to 6.5 and a score of 2 or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurological assessments were conducted every 12 weeks.
An MRI scan was obtained at baseline and at Weeks 24, 48, and 120. In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment.
Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume. Study 3 randomized 488 patients to OCREVUS and 244 to placebo; 21% of OCREVUS-treated patients and 34% of placebo-treated patients did not complete the trial. The baseline demographic and disease characteristics were balanced between the two treatment groups.
At baseline, the mean age of patients was 45; 49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with a non-steroid treatment for MS. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for OCREVUS-treated patients than for placebo-treated patients (see Figure 2 ). Results for Study 3 are presented in Table 7 and Figure 2. Table 7 Key Clinical and MRI Endpoints in Adult PPMS Patients for Study 3 Endpoints Study 3 OCREVUS 600 mg (two 300 mg infusions two weeks apart every 24 weeks) Placebo N=488 N=244 Clinical Outcomes Proportion of patients with 12-week Confirmed Disability Progression Defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or an increase of 0.5 or more when the baseline score is more than 5.5 32.9% 39.3% Risk reduction 24%; p=0.0321 MRI Endpoints Mean change in volume of T2 lesions, from baseline to Week 120 (cm 3 ) -0.39 0.79 p<0.0001 Figure 2 Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Adults in Study 3 All patients in this analysis had a minimum of 120 weeks of follow-up. The primary analysis is based on all disability progression events accrued including 21 without confirmatory EDSS at 12 weeks.
In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in OCREVUS-treated patients compared to 59% in placebo-treated patients (25% risk reduction). In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in OCREVUS-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in OCREVUS-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored OCREVUS numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions. Figure 2
Safety Study of 2-Hour Infusions in Adults
The safety of the 2-hour OCREVUS infusion was evaluated in Study 4 (NCT03085810), a prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy in adult patients with Relapsing-Remitting Multiple Sclerosis who were naïve to other non-steroid therapies for MS and did not experience a serious infusion reaction with any previous OCREVUS infusion. The first dose of OCREVUS was administered as two 300 mg infusions (600 mg total) separated by 14 days. After enrollment in the substudy, patients were randomized in a 1:1 ratio to receive infusions over approximately 3.5-hours or 2-hours, after appropriate premedication , every 24 weeks.
The randomization was stratified by region and the dose at which patients were first randomized. The primary endpoint of the substudy was the proportion of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion of OCREVUS. The primary analysis was performed when 580 patients were randomized, at which time 469/579 (81%) of the treated patients had received only a single randomized infusion of OCREVUS. The proportions of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion in this substudy were similar between the 2-hour and 3.5-hour infusion groups (24.4% versus 23.3%, respectively). Overall, in all randomized doses, 27.1% of the patients in the 2-hour infusion group and 25.0% of the patients in the 3.5-hour infusion group reported mild or moderate infusion reactions; two infusion reactions were severe in intensity, with one severe infusion reaction (0.3%) reported in one patient in each group in this substudy . There were no life-threatening, fatal, or serious infusion reactions in this substudy.
Relapsing-Remitting MS in Pediatric Patients 10 Years to less than 18 Years
of Age The efficacy and safety of OCREVUS in pediatric patients 10 years to less than 18 years of age with relapsing-remitting multiple sclerosis (RRMS) was established in a randomized, double-blind, double-dummy clinical study (Study 5; NCT05123703 with a follow-up time of at least 24 weeks. Patients were randomized 1:1 to receive either OCREVUS intravenously according to the recommended dosage regimen or 0.5 mg fingolimod daily by mouth. Both treatment groups received placebo, either by mouth or via infusion, respectively.
The primary outcome of Study 5 was ARR. Secondary outcome measures included the annualized rate of new or enlarging T2 hyperintense MRI lesions, and the mean number of T1 gadolinium (Gd)-enhancing MRI lesions at Week 12. In Study 5, 93 patients were randomized to the OCREVUS arm and 94 patients to the fingolimod arm. The duration of the study was variable for each patient, but all patients received double-blind treatment for at least 24 weeks. Patients were treated until the last randomized patient completed 24 weeks of double-blind treatment.
The median (range) treatment duration for patients treated with OCREVUS was 72.1 (24.0-158.9) weeks and for patients treated with fingolimod was 70.9 (0.0-141.7) weeks. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the median age was 15 years (range: 11–17 years). Patients were predominantly female (69%); 66% were White, 5% were Black or African American, 5% were multiracial, and race was unknown for 19%. The median weight of patients was 63.1 kg (range: 42.3–154.2 kg). The median EDSS score was 1.5 in both arms.
In Study 5, OCREVUS demonstrated non-inferiority to fingolimod in reducing the ARR and superiority in reducing the annualized rate of new/enlarging T2 lesions during the double-blind period and reducing the number of Gd-enhancing T1 lesions at Week 12. Results for Study 5 are presented in Table 8. Table 8 Key Clinical and MRI Endpoints in Pediatric Patients with RRMS from Study 5 Endpoints Study 5 OCREVUS Intravenous Infusion Based on body weight N = 93 Fingolimod 0.5 mg By Mouth N = 94 Two patients were randomized to the fingolimod arm, but were not treated and did not contribute follow-up time to the estimate of the annualized relapse rate. Clinical Endpoints Annualized Relapse Rate (Primary Endpoint) During the double-blind treatment period 0.070 0.135 Relative Reduction 48.3% Rate Ratio 0.517 (95% Cl: 0.193-1.329) Based on the prespecified non-inferiority criteria, non-inferiority of ocrelizumab to fingolimod was demonstrated. MRI Endpoints Annualized rate of new and/or enlarging T2 hyperintense lesions per MRI scan 3.778 7.235 Relative Reduction 47.8% (p=0.001) Mean number of T1 Gd-enhancing lesions at Week 12 0.031 0.243 Relative Reduction 87.2% (p=0.001)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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