bimekizumab: prescribing information – dosing, contraindications, interactions, side effects

Plaque psoriasis

Bimzelx is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.

Psoriatic arthritis

Bimzelx, alone or in combination with methotrexate, is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (DMARDs).

Axial spondyloarthritis

Non-radiographic axial spondyloarthritis (nr-axSpA)

Bimzelx is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) who have responded inadequately or are intolerant to non- steroidal anti-inflammatory drugs (NSAIDs).

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)

Bimzelx is indicated for the treatment of adults with active ankylosing spondylitis who have responded inadequately or are intolerant to conventional therapy.

Hidradenitis suppurativa (HS)

Bimzelx is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adults with an inadequate response to conventional systemic HS therapy (see section 5.1).

This medicinal product is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which it is indicated.

Posology

Plaque psoriasis

The recommended dose for adult patients with plaque psoriasis is 320 mg (given as 2 subcutaneous injections of 160 mg or 1 subcutaneous injection of 320 mg) at week 0, 4, 8, 12, 16 and every 8 weeks thereafter.

Psoriatic arthritis

The recommended dose for adult patients with active psoriatic arthritis is 160 mg (given as 1 subcutaneous injection of 160 mg) every 4 weeks.
For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, the recommended dose is the same as for plaque psoriasis [320 mg (given as 2 subcutaneous injections of 160 mg or 1 subcutaneous injection of 320 mg) at week 0, 4, 8, 12, 16 and every 8 weeks thereafter]. After 16 weeks, regular assessment of efficacy is recommended and if a sufficient clinical response in joints cannot be maintained, a switch to 160 mg every 4 weeks can be considered.

Axial spondyloarthritis (nr-axSpA and AS)

The recommended dose for adult patients with axial spondyloarthritis is 160 mg (given as 1 subcutaneous injection of 160 mg) every 4 weeks.

Hidradenitis suppurativa

The recommended dose for adult patients with hidradenitis suppurativa is 320 mg (given as 2 subcutaneous injections of 160 mg or 1 subcutaneous injection of 320 mg) every 2 weeks up to week 16 and every 4 weeks thereafter.

For above indications, consideration should be given to discontinuing treatment in patients who have shown no improvement by 16 weeks of treatment.

Special populations

Overweight patients with plaque psoriasis

For some patients with plaque psoriasis (including psoriatic arthritis with coexistent moderate to severe psoriasis) and a body weight ≥120 kg who did not achieve complete skin clearance at week 16, 320 mg every 4 weeks after week 16 may further improve treatment response (see section 5.1).

Elderly (≥65 years)

No dose adjustment is required (see section 5.2).

Renal or hepatic impairment

Bimekizumab has not been studied in these patient populations. Dose adjustments are not considered necessary based on pharmacokinetics (see section 5.2).

Paediatric population

The safety and efficacy of bimekizumab in children and adolescents below the age of 18 years have not yet been established. No data are available.

Method of administration

This medicinal product is administered by subcutaneous injection. A 320 mg dose can be given as 2 subcutaneous injections of 160 mg or 1 subcutaneous injection of 320 mg.

Suitable areas for injection include thigh, abdomen and upper arm. Injection sites should be rotated and injections should not be given into psoriasis plaques or areas where the skin is tender, bruised, erythematous, or indurated. Administration in the upper arm may only be performed by a healthcare professional or caregiver.
The pre-filled syringe or pre-filled pen must not be shaken.
After proper training in subcutaneous injection technique, patients may self-inject Bimzelx with a pre- filled syringe or pre-filled pen if their physician determines that it is appropriate and with medical follow-up as necessary. Patients should be instructed to inject the full amount of Bimzelx according to the instructions for use provided in the package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

Summary of the safety profile

The most frequently reported adverse reactions were upper respiratory tract infections (14.5%, 14.6%, 16.3%, 8.8% in plaque psoriasis, psoriatic arthritis, axial spondyloarthritis (axSpA) and hidradenitis suppurativa respectively) and oral candidiasis (7.3%, 2.3%, 3.7%, 5.6% in PSO, PsA, axSpA and HS respectively).

Tabulated list of adverse reactions

Adverse reactions from clinical studies and post-marketing reports (Table 1) are classified by MedDRA System Organ Class and frequency, using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

A total of 5862 patients have been treated with bimekizumab in blinded and open-label clinical studies in plaque psoriasis (PSO), psoriatic arthritis (PsA), axial spondyloarthritis (nr-axSpA and AS) and

hidradenitis suppurativa (HS) representing 11468.6 patient-years of exposure. Of these, over 4660 patients were exposed to bimekizumab for at least one year. Overall, the safety profile of bimekizumab is consistent across all indications.

Table 1: List of adverse reactions
System Organ Class
Frequency
Adverse reaction

Infections and infestations
Very common
Upper respiratory tract infections
Common
Oral candidiasis,
Tinea infections,
Ear infections,
Herpes simplex infections,
Oropharyngeal candidiasis,
Gastroenteritis,
Folliculitis,
Vulvovaginal mycotic infection (including vulvovaginal candidiasis)
Uncommon
Mucosal and cutaneous candidiasis
(including oesophageal candidiasis),
Conjunctivitis
Blood and lymphatic system disorders
Uncommon
Neutropenia
Nervous system disorders
Common
Headache
Gastrointestinal disorders
Uncommon
Inflammatory bowel disease
Skin and subcutaneous tissue disorders
Common
Rash, dermatitis and eczema,
Acne
General disorders and administration site conditions
Common
Injection site reactionsa,
Fatigue a) Includes: injection site erythema, reaction, oedema, pain, swelling, haematoma.

Description of selected adverse reactions

Infections

In the placebo-controlled period of Phase III clinical studies in plaque psoriasis, infections were reported in 36.0% of patients treated with bimekizumab for up to 16 weeks compared with 22.5% of patients treated with placebo. Serious infections occurred in 0.3% of patients treated with bimekizumab and 0% treated with placebo.

The majority of infections consisted of non-serious mild to moderate upper respiratory tract infections such as nasopharyngitis. There were higher rates of oral and oropharyngeal candidiasis in patients treated with bimekizumab consistent with the mechanism of action (7.3% and 1.2% respectively compared to 0% for placebo-treated patients). More than 98% of cases were non-serious, mild or moderate in severity, and did not require treatment discontinuation. A slightly higher incidence of oral candidiasis was reported in patients <70 kg (8.5% versus 7.0% in patients ≥70 kg).

Over the entire treatment period of Phase III studies in plaque psoriasis, infections were reported in 63.2% of patients treated with bimekizumab (120.4 per 100 patient-years). Serious infections were reported in 1.5% of patients treated with bimekizumab (1.6 per 100 patient-years) (see section 4.4).

Infection rates observed in PsA and axSpA (nr-axSpA and AS) Phase III clinical studies were similar to those observed in plaque psoriasis apart from oral and oropharyngeal candidiasis rates in patients treated with bimekizumab, which were lower at 2.3% and 0% respectively in PsA and 3.7% and 0.3% respectively in axSpA compared to 0% with placebo.

Infection rates observed in HS Phase III clinical studies were similar to those observed in other

indications. In the placebo-controlled period, oral and oropharyngeal candidiasis rates in patients treated with bimekizumab were 7.1% and 0% respectively compared to 0% with placebo.

Neutropenia

Neutropenia was observed with bimekizumab in Phase III clinical studies in plaque psoriasis. Over the entire treatment period of Phase III studies, neutropenia grade 3/4 were observed in 1% of patients treated with bimekizumab.

The frequency of neutropenia in PsA, axSpA (nr-axSpA and AS) and HS clinical studies was similar to that observed in plaque psoriasis studies.

More than 80% of the cases were transient and did not require treatment discontinuation. No serious infections were associated with neutropenia.

Hypersensitivity

Serious hypersensitivity reactions including anaphylactic reactions have been observed with IL-17 inhibitors (see section 4.4).

Immunogenicity

Plaque psoriasis

Approximately 45% of plaque psoriasis patients treated with bimekizumab up to 56 weeks at the recommended dosing regimen (320 mg every 4 weeks up to week 16 and 320 mg every 8 weeks thereafter) developed anti-drug antibodies. Of the patients who developed anti-drug antibodies, approximately 34% (16% of all patients treated with bimekizumab) had antibodies that were classified as neutralising.

Psoriatic arthritis

Approximately 31% of patients with psoriatic arthritis treated with bimekizumab at the recommended dosing regimen (160 mg every 4 weeks) up to 16 weeks had anti-drug antibodies. Of the patients with anti-drug antibodies, about 33% (10% of all patients treated with bimekizumab) had antibodies that were classified as neutralising. By week 52, approximately 47% of biologic disease-modifying anti- rheumatic drug (bDMARD) treatment naïve patients with psoriatic arthritis in the BE OPTIMAL study treated with bimekizumab at the recommended dosing regimen (160 mg every 4 weeks) had anti-drug antibodies. Of the patients with anti-drug antibodies, about 38% (18% of all patients in the BE OPTIMAL study treated with bimekizumab) had antibodies that were classified as neutralising.

Axial spondyloarthritis (nr-axSpA and AS)

Approximately 57% of patients with nr-axSpA treated with bimekizumab up to 52 weeks at the recommended dosing regimen (160 mg every 4 weeks) had anti-drug antibodies. Of the patients with anti-drug antibodies, approximately 44% (25% of all patients treated with bimekizumab) had antibodies that were classified as neutralising.

Approximately 44% of patients with AS treated with bimekizumab up to 52 weeks at the recommended dosing regimen (160 mg every 4 weeks) had anti-drug antibodies. Of the patients with anti-drug antibodies, approximately 44% (20% of all patients treated with bimekizumab) had antibodies that were classified as neutralising.

Hidradenitis suppurativa

Approximately 59% of HS patients treated with bimekizumab up to 48 weeks at the recommended dosing regimen (320 mg every 2 weeks up to week 16 and 320 mg every 4 weeks thereafter) developed anti-drug antibodies. Of the patients who developed anti-drug antibodies, approximately 63% (37% of all patients treated with bimekizumab) had antibodies that were classified as neutralising.

Across indications, no clinically meaningful impact on clinical response was associated with anti- bimekizumab antibodies development, and an association between immunogenicity and treatment emergent adverse events has not been clearly established.

Elderly patients (≥65 years)
Exposure is limited in elderly subjects.

Elderly patients may be more likely to experience certain adverse reactions such as oral candidiasis, dermatitis and eczema when using bimekizumab.

In the placebo-controlled period of Phase III clinical studies in plaque psoriasis, oral candidiasis was observed in 18.2% of patients ≥65 years versus 6.3% in <65 years, dermatitis and eczema in 7.3% of patients ≥65 years versus 2.8% in <65 years.

In the placebo-controlled period of Phase III clinical studies in psoriatic arthritis, oral candidiasis was observed in 7.0% of patients ≥65 years versus 1.6% in <65 years, dermatitis and eczema in 1.2% of patients ≥65 years versus 2.0% in <65 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Bimekizumab may increase the risk of infections such as upper respiratory tract infections and oral candidiasis (see section 4.8).

Caution should be exercised when considering the use of bimekizumab in patients with a chronic infection or a history of recurrent infection. Treatment with bimekizumab must not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated (see section 4.3).

Patients treated with bimekizumab should be instructed to seek medical advice if signs or symptoms

suggestive of an infection occur. If a patient develops an infection, the patient should be carefully monitored. If the infection becomes serious or is not responding to standard therapy, treatment should be discontinued until the infection resolves.

Pre-treatment evaluation for tuberculosis (TB)

Prior to initiating treatment with bimekizumab, patients should be evaluated for TB infection.
Bimekizumab should not be given in patients with active TB (see section 4.3). Patients receiving bimekizumab should be monitored for signs and symptoms of active TB. Anti-TB therapy should be considered prior to initiating bimekizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.

Inflammatory bowel disease

Cases of new or exacerbations of inflammatory bowel disease have been reported with bimekizumab (see section 4.8). Bimekizumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, bimekizumab should be discontinued and appropriate medical management should be initiated.

Hypersensitivity

Serious hypersensitivity reactions including anaphylactic reactions have been observed with IL-17 inhibitors. If a serious hypersensitivity reaction occurs, administration of bimekizumab should be discontinued immediately and appropriate therapy initiated.

Vaccinations

Prior to initiating therapy with bimekizumab, completion of all age-appropriate immunisations according to current immunisation guidelines should be considered.

Live vaccines should not be given in patients treated with bimekizumab.

Patients treated with bimekizumab may receive inactivated or non-live vaccinations. Healthy individuals who received a single 320 mg dose of bimekizumab two weeks prior to vaccination with an inactivated seasonal influenza vaccine had similar antibody responses compared to individuals who did not receive bimekizumab prior to vaccination.

Excipients with known effect

Polysorbate 80
This medicinal product contains 0.4 mg of polysorbate 80 in each 1 mL solution. Polysorbates may cause allergic reactions.

Sodium
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium free”.

No interaction studies have been performed.
There is no direct evidence for the role of IL-17A or IL-17F in the expression of CYP450 enzymes.
The formation of some CYP450 enzymes is suppressed by increased levels of cytokines during chronic inflammation. Thus, anti-inflammatory treatments, such as with the IL-17A and IL-17F inhibitor bimekizumab, may result in normalisation of CYP450 levels with accompanying lower exposure of CYP450-metabolised medicinal products. Therefore, a clinically relevant effect on CYP450 substrates with a narrow therapeutic index, in which the dose is individually adjusted (e.g.

warfarin) cannot be excluded. On initiation of bimekizumab therapy in patients being treated with these types of medicinal products, therapeutic monitoring should be considered.

Population pharmacokinetic (PK) data analyses indicated that concomitant administration of conventional disease modifying antirheumatic drugs (cDMARDs) including methotrexate or prior exposure to biologics have no clinically relevant impact on the clearance of bimekizumab.

Live vaccines should not be given concurrently with bimekizumab (see section 4.4).

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception during treatment and for at least 17 weeks after treatment.

Pregnancy

There is a limited amount of data on the use of bimekizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Bimzelx during pregnancy.

Breast-feeding

It is unknown whether bimekizumab is excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Bimzelx therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of bimekizumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Bimzelx has no or negligible influence on the ability to drive and use machines.

Single doses of 640 mg intravenously or 640 mg subcutaneously, followed by 320 mg subcutaneously every two weeks for five doses have been administered in clinical studies without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs and symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC21

Mechanism of action

Bimekizumab is a humanised IgG1/κ monoclonal antibody that selectively binds with high affinity to IL-17A, IL-17F and IL-17AF cytokines, blocking their interaction with the IL-17RA/IL-17RC receptor complex. Elevated concentrations of IL-17A and IL-17F have been implicated in the pathogenesis of several immune-mediated inflammatory diseases including plaque psoriasis, psoriatic arthritis, axial spondyloarthritis and hidradenitis suppurativa. IL-17A and IL-17F cooperate and/or synergise with other inflammatory cytokines to induce inflammation. IL17-F is produced in significant amount by innate immune cells. This production can be independent of IL-23. Bimekizumab inhibits the proinflammatory cytokines, resulting in the normalisation of skin inflammation and substantial

decrease of local and systemic inflammation, and as a consequence improvement in clinical signs and symptoms associated with psoriasis, psoriatic arthritis, axial spondyloarthritis and hidradenitis suppurativa. From in vitro models, bimekizumab was shown to inhibit psoriasis-related gene expression, cytokine production, the migration of inflammatory cells and pathological osteogenesis to a greater extent than inhibition of IL-17A alone.

Clinical efficacy and safety

Plaque psoriasis

The safety and efficacy of bimekizumab was evaluated in 1,480 patients with moderate to severe plaque psoriasis in three Phase 3 multicentre, randomised, placebo and/or active comparator- controlled studies. Patients were at least 18 years of age, had a Psoriasis Area and Severity Index (PASI) score ≥12 and Body Surface Area (BSA) affected by psoriasis (PSO) ≥10%, an Investigators Global Assessment (IGA) score ≥3 on a 5-point scale and were candidates for systemic psoriasis therapy and/or phototherapy. The efficacy and safety of bimekizumab were evaluated versus placebo and ustekinumab (BE VIVID – PS0009), versus placebo (BE READY – PS0013) and versus adalimumab (BE SURE - PS0008).

The BE VIVID study evaluated 567 patients for 52 weeks where patients were randomised to receive either bimekizumab 320 mg every 4 weeks, ustekinumab (45 mg or 90 mg, depending on patient weight, at baseline and week 4 and then every 12 weeks), or placebo for an initial 16 weeks, followed by bimekizumab 320 mg every 4 weeks.

The BE READY study evaluated 435 patients for 56 weeks. Patients were randomised to receive bimekizumab 320 mg every 4 weeks or placebo. At week 16, patients who achieved a PASI 90 response entered the 40-week randomised withdrawal period. Patients initially randomised to bimekizumab 320 mg every 4 weeks were re-randomised to either bimekizumab 320 mg every 4 weeks or bimekizumab 320 mg every 8 weeks or placebo (i.e. withdrawal of bimekizumab). Patients initially randomised to placebo continued to receive placebo provided they were PASI 90 responders.

The pharmacokinetic (PK) properties of bimekizumab were similar in patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis (nr-axSpA and AS).

Based on population PK analyses and using a reference bodyweight of 90 kg, the bimekizumab apparent clearance and volume of distribution, respectively, in patients with hidradenitis suppurativa were estimated to be approximately 31 and 18 % higher than for the aforementioned indications, with an estimated half-life in HS of 20 days. Consequently, the median steady state trough concentration at a dose of 320 mg every 4 weeks was approximately 40 % lower in HS compared to other indications.

Absorption

Based on population pharmacokinetic analysis, following a single subcutaneous dose of 320 mg in plaque psoriasis patients, bimekizumab reached a median (2.5th and 97.5th percentile) peak plasma concentration of 25 (12 -50) μg/mL, between 3 and 4 days post dose.

Population pharmacokinetic analysis showed that bimekizumab was absorbed with an average absolute bioavailability of 70.1% in healthy volunteers.

Based on simulated data, the median (2.5th and 97.5th percentile) peak and trough concentration at steady-state following subcutaneous administration of 320 mg every 4 weeks are 43 (20-91) µg/mL and 20 (7-50) µg/mL respectively and steady-state is reached after approximately 16 weeks with every 4 weeks dosing regimen. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 1.74-fold increase in peak plasma concentrations and area under the curve (AUC) following repeated four weekly dosing.

After switching from the 320 mg every 4 weeks dosing regimen to 320 mg every 8 weeks dosing regimen at week 16, steady-state is achieved approximately 16 weeks after the switch. Median (2.5th and 97.5th percentile) peak and trough plasma concentrations are 30 (14 -60) μg/mL and 5 (1- 16) μg/mL respectively.

Distribution