New Indication for Amgen's Fifth FDA-approved Biosimilar

Now Approved to Treat All Available Rituxan® Indications

THOUSAND OAKS, Calif., June 6, 2022 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved RIABNI™ (rituximab-arrx), a biosimilar to Rituxan®, in combination with methotrexate for adults with moderate to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. RIABNI is already approved for the treatment of adult patients with Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Granulomatosis with Polyangiitis (GPA) (also called Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

"The approval of RIABNI is an important advancement for adults living with moderate to severe rheumatoid arthritis, a chronic inflammatory joint disease, who now have access to a proven and affordable treatment option," said Murdo Gordon, executive vice president of Global Commercial Operations at Amgen. "Our fully integrated portfolio of innovative and biosimilar medicines for inflammatory diseases reinforces our commitment to providing patients with high-quality and affordable treatment options that deliver substantial value to our healthcare system."

RIABNI, a CD20-directed cytolytic antibody, was proven to be highly similar to, with no clinically meaningful differences in safety or efficacy from, Rituxan (rituximab) based on totality of evidence, which included comparative analytical, non-clinical and clinical data.

The randomized, double-blind, comparative clinical study compared the efficacy, safety, pharmacokinetics and immunogenicity of RIABNI versus rituximab reference product (RP) in patients with moderate to severe RA. Overall, 311 patients were randomized and treated with RIABNI, rituximab RP approved in the EU (rituximab-EU) or rituximab RP approved in the US (rituximab-US). The rituximab-US group transitioned to RIABNI in period 2 of the study. The primary efficacy endpoint, the change in disease activity score 28 using C-reactive protein (DAS28-CRP) from baseline at week 24, was within the predefined equivalence margin indicating equivalence in clinical efficacy between RIABNI and rituximab RP. Safety, pharmacokinetics and immunogenicity of RIABNI were similar to rituximab RP.

Amgen has a total of 11 biosimilars in its portfolio including potential treatments for chronic inflammatory diseases and cancer. There are currently five biosimilars approved in the U.S. and three approved in the European Union (EU) in Amgen's portfolio.  

About RIABNI™ (rituximab-arrx) in the U.S.RIABNI is a biosimilar to Rituxan, an anti-CD20 monoclonal antibody. The active ingredient of RIABNI is a monoclonal antibody that has the same amino acid sequence as Rituxan. RIABNI also has the same strength as Rituxan, and the dosage form and route of administration are identical to Rituxan. RIABNI is not currently indicated as a treatment for children with mature B-cell Non-Hodgkin's lymphoma, mature B-cell acute leukemia, MPA, or GPA. RIABNI is not indicated in adult patients with moderate to severe pemphigus vulgaris (PV), for which Rituxan has orphan status.

In the U.S., RIABNI is approved for:

Non-Hodgkin's Lymphoma (NHL)RIABNI (rituximab-arrx) is indicated for the treatment of adult patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

Chronic Lymphocytic Leukemia (CLL)RIABNI, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.

Rheumatoid Arthritis (RA)

RIABNI, in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)RIABNI, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS:  FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Infusion-Related Reactions: Rituximab product administration can result in serious, including fatal, infusion-related reactions.  Deaths within 24 hours of rituximab infusion have occurred.  Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion.  Monitor patients closely.  Discontinue RIABNITM infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions.

• Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products.  Discontinue RIABNITM in patients who experience a severe mucocutaneous reaction.  The safety of readministration of RIABNITM to patients with severe mucocutaneous reactions has not been determined.

• Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RIABNITM. Discontinue RIABNITM and concomitant medications in the event of HBV reactivation.

• Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products.  Discontinue RIABNITM and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Warnings and Precautions

Infusion-Related Reactions (IRR)

• Rituximab products  can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes.

• Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. 

• Premedicate patients with an antihistamine and acetaminophen prior to dosing. For patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA), methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.  Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RIABNI.TM Resume infusion at a minimum of 50% reduction in  rate after symptoms have resolved.

• Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3).

Severe Mucocutaneous Reactions

• Mucocutaneous reactions, some with fatal outcome, can occur in patients receiving rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. 
• The onset of these reactions has been variable and includes reports with onset on the first day of rituximab  exposure. Discontinue RIABNI in patients who experience a severe mucocutaneous reaction. The safety of readministration of rituximab products to patients with severe mucocutaneous reactions has not been determined.

Hepatitis B Virus (HBV) Reactivation 

• Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive). 

• HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases, increase in bilirubin levels, liver failure, and death can occur.

• Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RIABNI.TM For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RIABNI treatment.

• Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RIABNITM therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.

• In patients who develop reactivation of HBV while on RIABNITM, immediately discontinue RIABNITM and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming rituximab product  treatment in patients who develop HBV reactivation. Resumption of RIABNITM treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

Progressive Multifocal Leukoencephalopathy (PML)  

• JC virus infection resulting in multifocal leukoencephalopathy (PML) and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML  received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab. 

• Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue RIABNITM and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Tumor Lysis Syndrome (TLS)

• Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of RIABNITM in patients with non–Hodgkin's Lymphoma (NHL). A high number of circulating malignant cells (≥25,000/mm3), or high tumor burden, confers a greater risk of TLS. 

• Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated.

Infections

• Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure).

• New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RIABNITM for serious infections and institute appropriate anti-infective therapy.

• RIABNITM is not recommended for use in patients with severe, active infections.

Cardiovascular Adverse Reactions

• Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RIABNITM for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

Renal Toxicity

• Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RIABNITM is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RIABNITM in patients with a rising serum creatinine or oliguria.

Bowel Obstruction and Perforation

• Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1−77) days in patients with NHL.  Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

Immunization

• The safety of immunization with live viral vaccines following rituximab product therapy has not been studied, and vaccination with live virus vaccines is not recommended before or during treatment.

• For patients treated with RIABNITM, physicians should review the patient's vaccination status and patients should, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating RIABNI and administer non-live vaccines at least 4 weeks prior to a course of RIABNI.TM

• The effect of rituximab products on immune responses was assessed in a randomized, controlled study in patients with RA treated with rituximab and methotrexate (MTX) compared to patients treated with MTX alone.

• A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with rituximab plus MTX as compared to patients treated with MTX alone (19% vs 61%). A lower proportion of patients in the rituximab plus MTX group developed detectable levels of anti-keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs 93%). 
• A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar in patients treated with rituximab plus MTX compared to patients on MTX alone (39% vs 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on rituximab plus MTX vs 70% of patients on MTX alone).

• Most patients in the rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known.

Embryo-Fetal Toxicity

• Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed  in utero. Advise pregnant women of the potential risk to a fetus.  Advise females of reproductive potential to use effective contraception with RIABNITM and for 12 months after the last dose.

Concomitant Use with Biologic Agents and DMARDs Other Than MTX

• Limited data are available on the safety of the use of biologic agents or DMARDs other than MTX in RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA, MPA, or PV patients exhibiting peripheral B-cell depletion following treatment with rituximab products.

Use in Patients With RA Who Had No Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists

• While the efficacy of rituximab was supported in 4 controlled trials in patients with RA with prior inadequate responses to nonbiologic DMARDs and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not been established in these populations. The use of RIABNITM in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended.

Additional Important Safety Information

Adverse Reactions

Clinical Trials Experience in NHL and CLL

• The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and chronic lymphocytic leukemia (CLL) were infusion-related reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections.  Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials.

• The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion-related reactions.  Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials.

Clinical Trials Experience in RA

• Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion-related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis.

• In placebo-controlled studies, adverse reactions reported in ≥5% of patients were hypertension (8% vs 5%), nausea (8% vs 5%), upper respiratory tract infection (7% vs 6%), arthralgia (6% vs 4%), pyrexia (5% vs 2%), and pruritus (5% vs 1%) of rituximab-treated vs placebo, respectively.

Infusion-Related Reactions

• In the rituximab RA pooled, placebo-controlled studies, incidence of any adverse event within 24 hours of an infusion was 32% vs 23% after the first infusion, and 11% vs 13% after the second infusion in the rituximab-treated patients and placebo group, respectively. Incidence of acute infusion-related reactions was 27% vs 19% after the first infusion, 9% vs 11% after the second infusion in the rituximab-treated patients and placebo group, respectively.

• Serious acute infusion-related reactions were experienced by