Biosimilar Development

Demonstrating clinical comparability1

A robust and complex process ensuring structural and clinical comparability is used to demonstrate a biosimilar’s clinical comparability to the reference product.

Data on pharmacokinetics, pharmacodynamics, immunogenicity, safety profile, and efficacy are collected.

Adapted from: FDA. Biosimilar product regulatory review and approval. 2018.1

Replicating complex biologics2

Developing biosimilars has been made possible due to modern analytical advances in characterization and development of biologics1:

Accurate analytics allow assessment of critical quality attributes in the molecule that may impact clinical activity.  These methods contribute to building a fingerprint of quality attributes for the reference drug.

Graphic depicting biosimilar IL-6 monoclonal antibody
Graphic depicting biosimilar IL-6 monoclonal antibody
Graphic depicting biosimilar IL-6 monoclonal antibody

Developing Biosimilars3

Biosimilars are assessed for similarity to the reference medicine based upon3:

  • Structure
  • Biological activity
  • Efficacy
  • Safety profile
  • Immunogenicity profile
  • Pharmacokinetics/Pharmacodynamics

Indications already studied in a reference product can also be approved for the biosimilar of that product through a process called “extrapolation”1

A biosimilar must show no clinically meaningful differences from its reference biologic in terms of safety profile, purity, and potency4

Adapted from: Wolff-Holz, et al. 2018.

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References
  1. FDA. Biosimilar product regulatory review and approval. 2018. https://www.fda.gov/files/drugs/published/Biosimilar-Product-Regulatory-Review-and-Approval.pdf. Accessed November 2024.
  2. CFDA. Scientific considerations in demonstrating biosimilarity to a reference product: Guidance for industry. 2015. https://www.fda.gov/media/82647/download. Accessed October 2024
  3. Wolff-Holz E, Garcia Burgos J, Giuliani R, et al. Preparing for the incoming wave of biosimilars. ESMO Open. 2018;3(6):e000420.
  4. FDA. Biological product definitions. 2020. https://www.fda.gov/files/drugs/published/Biological-Product-Definitions.pdf. Accessed September 2024.
  5. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-3196.
Click HERE for the TOFIDENCE IV Dosing Calculator

TOFIDENCE™ (tocilizumab-bavi) injection, for intravenous use

INDICATIONS

Rheumatoid Arthritis (RA)
TOFIDENCE™ (tocilizumab-bavi) 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 Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Giant Cell Arteritis (GCA)
TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of giant cell arteritis in adult patients.

Polyarticular Juvenile Idiopathic Arthritis (PJIA)
TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

Systemic Juvenile Idiopathic Arthritis (SJIA)
TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

Coronavirus Disease 2019 (COVID-19)
TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with tocilizumab products including TOFIDENCE are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate (MTX) or corticosteroids.

If a serious infection develops, interrupt TOFIDENCE until the infection is controlled.

Reported infections include:

  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before TOFIDENCE use and during therapy. Treatment for latent infection should be initiated prior to TOFIDENCE use.
  • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
  • Bacterial, viral and other infections due to opportunistic pathogens.

The risks and benefits of treatment with TOFIDENCE should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with TOFIDENCE, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.


CONTRAINDICATIONS

TOFIDENCE is contraindicated in patients with known hypersensitivity to tocilizumab products.


WARNINGS AND PRECAUTIONS

Serious Infections: see Boxed Warning

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TOFIDENCE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

Hepatotoxicity

Serious cases of hepatic injury have been observed in patients taking intravenous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (>5 times upper limit of normal [ULN]), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.

During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab.

It is not recommended to initiate TOFIDENCE treatment in RA, GCA, PJIA and SJIA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue TOFIDENCE.

Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer TOFIDENCE should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST above 10x ULN.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury. If the patient is found to have abnormal liver tests, TOFIDENCE treatment should be interrupted. TOFIDENCE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.

Changes in Laboratory Parameters

Laboratory monitoring is recommended due to potential consequences of treatment-related laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications may be required.

Neutropenia

Treatment with tocilizumab products was associated with a higher incidence of neutropenia. It is not recommended to initiate TOFIDENCE treatment in RA, GCA, PJIA and SJIA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm3 . In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended.

It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with an ANC less than 1000 per mm3.

Thrombocytopenia

Treatment with tocilizumab products was associated with a reduction in platelet counts. It is not recommended to initiate TOFIDENCE treatment in RA, GCA, PJIA and SJIA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended.

In COVID-19 patients with a platelet count less than 50,000 per mm3 , treatment is not recommended.

Elevated Liver Enzymes

It is not recommended to initiate TOFIDENCE treatment in patients with elevated transaminases ALT or AST >1.5x ULN. In patients who develop ALT or AST >5x ULN, treatment is not recommended.

It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST >10x ULN.

Lipid Abnormalities

Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.

Immunosuppression

The impact of treatment with tocilizumab products on the development of malignancies is not known but malignancies were observed in clinical studies. TOFIDENCE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products. TOFIDENCE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If a hypersensitivity reaction occurs, immediately discontinue TOFIDENCE; treat promptly and monitor until signs and symptoms resolve.

Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab and 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation.

Demyelinating Disorders

The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of TOFIDENCE in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment

Treatment with TOFIDENCE is not recommended in patients with active hepatic disease or hepatic impairment.

Vaccinations

Avoid use of live vaccines concurrently with TOFIDENCE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products or on the effectiveness of vaccination in patients receiving tocilizumab products. Patients should be brought up to date on all recommended vaccinations prior to initiation of TOFIDENCE therapy, if possible.


ADVERSE REACTIONS

Rheumatoid Arthritis

The most common serious adverse reactions were serious infections. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. In the tocilizumab-IV monotherapy clinical study, the rate of serious infections was 3.6 per 100 patient years in the tocilizumab group and 1.5 per 100 patient years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab plus DMARD group was 4.4 and 5.3 events per 100 patient years, respectively, compared to 3.9 events per 100 patient years in the placebo plus DMARD group.

The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).

In the 5 Phase III clinical trials, the most common adverse reactions (≥5% of patients treated with tocilizumab-IV) in the 24-week Phase 3 Controlled Study Population were:

 

 

Tocilizumab 8 mg per kg
MONOTHERAPY

Methotrexate

Tocilizumab 4 mg per kg
+DMARDs

Tocilizumab 8 mg per kg
+DMARDs


Placebo +DMARDs

 

N = 288

%

N = 284

%

N = 774

%

N = 1582

%

N = 1170

%

Upper
Respiratory
Tract Infection



7



5



6



8



6

Nasopharyngitis

7

6

4

6

4

Headache

7

2

6

5

3

Hypertension

6

2

4

4

3

ALT increased

6

4

3

3

1

 

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Giant Cell Arteritis

The overall safety profile observed for tocilizumab administered intravenously in GCA patients was generally consistent with the known safety profile of tocilizumab.

Polyarticular Juvenile Idiopathic Arthritis

Infections

The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab-IV (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab-IV (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab-IV (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab-IV (8%).

Infusion Reactions

In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients.

Systemic Juvenile Idiopathic Arthritis

The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

Infections

In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient years and 287 per 100 patient years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient years.

In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

Macrophage Activation Syndrome

In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV. One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.

Infusion Reactions

In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia, and headache. One of these events, urticaria, was considered serious.

Anaphylaxis

Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study.

Coronavirus Disease 2019 (COVID-19)

The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA.

The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab.

 

Adverse Reaction

Tocilizumab 
8 mg per kg
N = 974

(%)


Placebo
N = 483

(%)

Hepatic Transaminases increased

10%

8%

Constipation

9%

8%

Urinary tract infection

5%

4%

Hypertension

4%

1%

Hypokalaemia

4%

3%

Anxiety

4%

2%

Diarrhea

4%

2%

Insomnia

4%

3%

Nausea

3%

2%

 

In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo.

Laboratory Abnormalities

In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received tocilizumab and 0.5% of patients who received placebo. Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received tocilizumab and 1.5% of patients who received placebo. ALT or AST at or above 5x ULN occurred in 11.7% of patients who received tocilizumab and 9.9% of patients who received placebo.


DRUG INTERACTIONS

In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.

Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates.

Exercise caution when coadministering TOFIDENCE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc.


USE IN PREGNANCY

Based on animal data, there may be a potential risk to the fetus. The limited available data with tocilizumab products in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Biogen MA Inc. at 1-877-422-8360.

Please see full Prescribing Information, including Boxed Warning.

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