Bimekizumab

BIMZELX is a humanized interleukin-17A and F antagonist indicated for the treatment of: Moderate to severe plaque psoriasis (PSO) in adults who are candidates for systemic therapy or phototherapy. ( 1.1 ) Adults with active psoriatic arthritis (PsA) . ( 1.2 ) Adults with active non-radiographic axial spondyloarthritis ( nr-axSpA ) with objective signs of inflammation. ( 1.3 ) Adults with active ankylosing spondylitis ( AS ). ( 1.4 ) Adults with moderate to severe hidradenitis suppurativa (HS) . ( 1.5 )

1.1 Plaque Psoriasis BIMZELX is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

1.2 Psoriatic Arthritis BIMZELX is indicated for the treatment of adults with active psoriatic arthritis.

1.3 Non-Radiographic Axial Spondyloarthritis BIMZELX is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation.

1.4 Ankylosing Spondylitis BIMZELX is indicated for the treatment of adults with active ankylosing spondylitis.

1.5 Hidradenitis Suppurativa BIMZELX is indicated for the treatment of adults with moderate to severe hidradenitis suppurativa.

Injection : 160 mg/mL in a single-dose prefilled syringe or single-dose prefilled autoinjector. ( 3 ) Injection : 320 mg/2 mL (160 mg/mL) in a single-dose prefilled syringe or single-dose prefilled autoinjector. ( 3 ) Injection (1 mL): 160 mg/mL clear to slightly opalescent, and colorless to pale brownish-yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. Injection (2 mL): 320 mg/2 mL (160 mg/mL) clear to slightly opalescent, and colorless to pale brownish-yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector.

None. None. ( 4 )

Suicidal Ideation and Behavior (SI/B) : May increase risk of SI/B. Advise patients, their caregivers, and families to monitor for the emergence or worsening of depression, suicidal ideation, or other mood changes. If such changes occur, instruct patients to promptly seek medical attention or call the National Suicide and Crisis Lifeline at 988. Carefully weigh risks and benefits of treatment with BIMZELX in patients with a history of severe depression and/or suicidal ideation or behavior. ( 5.1 ) Infections : May increase risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If such an infection develops, do not administer BIMZELX until the infection resolves. ( 5.2 ) Tuberculosis (TB) : Avoid use in patients with active TB. Initiate treatment of latent TB prior to BIMZELX treatment. ( 5.3 ) Liver Biochemical Abnormalities : Elevated serum transaminases were reported in clinical trials. Test liver enzymes, alkaline phosphatase, and bilirubin at baseline and according to routine patient management. Permanently discontinue use of BIMZELX in patients with causally – associated combined elevations of transaminases and bilirubin. ( 5.4 ) Inflammatory Bowel Disease (IBD) : Cases of IBD were reported in clinical trials with IL-17 inhibitors, including BIMZELX. Avoid use of BIMZELX in patients with active IBD. Monitor patients for signs and symptoms of IBD and discontinue treatment if new onset or worsening of signs and symptoms occurs. ( 5.5 ) Immunizations : Avoid the use of live vaccines in patients treated with BIMZELX. ( 5.6 )

5.1 Suicidal Ideation and Behavior An increased incidence of new onset or worsening suicidal ideation and behavior was observed in subjects treated with BIMZELX. A causal association between treatment with BIMZELX and increased risk of suicidal ideation and behavior has not been definitively established. Suicidal ideation and behavior were prospectively monitored using the Columbia Suicide Severity Rating Scale (C-SSRS) in clinical trials. The C-SSRS is an interview-based instrument used to monitor for the presence and severity of suicidal ideation (ranging from "none" to "active suicidal ideation with specific plan and intent") and behaviors (rating the injury and potential lethality of self-injury, if present). Plaque Psoriasis During the two 16-week, placebo-controlled periods of Trials Ps-1 and Ps-2, higher rates of suicidal ideation as assessed by C-SSRS were reported in BIMZELX-treated subjects than in subjects receiving placebo. Pooled analysis of C-SSRS data indicated that 12/670 (1.8%) BIMZELX-treated subjects and 1/169 (0.6%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 3.0 (95% confidence interval: 0.39, 22.74). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new onset suicidal ideation on the C-SSRS than subjects receiving placebo (1.3% vs 0.6%). During the open-label extension trial, one completed suicide was reported in a BIMZELX-treated subject [see Adverse Reactions (6.1) ]. Psoriatic Arthritis Pooled analysis of C-SSRS data from the two 16-week, placebo-controlled periods of Trials PsA-1 and PsA-2 indicated that 2/698 (0.3%) BIMZELX-treated subjects and 3/413 (0.7%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 0.35 (95% confidence interval: 0.05, 2.29) [see Adverse Reactions (6.1) ] . Non-Radiographic Axial Spondyloarthritis Analysis of C-SSRS data from a 16-week, placebo-controlled period of Trial nr-axSpA-1 indicated that no subjects, being treated either with BIMZELX or placebo, reported suicidal ideation [see Adverse Reactions (6.1) ] . Ankylosing Spondylitis Analysis of C-SSRS data from a 16-week, placebo-controlled period of Trial AS-1 indicated that no subjects, being treated either with BIMZELX or placebo, reported suicidal ideation [see Adverse Reactions (6.1) ] . Hidradenitis Suppurativa During the two 16-week, placebo-controlled periods of Trials HS-1 and HS-2, higher rates of suicidal ideation as assessed by C-SSRS were reported in BIMZELX-treated subjects than in subjects receiving placebo. Based on a pooled analysis of the first 16 weeks of the placebo controlled clinical trials, 16/861 subjects in the BIMZELX group (1.9 %) reported suicidal ideation on the C-SSRS compared to 1/146 subjects in the placebo group (0.7%) with an estimated relative risk of 2.70 (95% confidence interval: 0.36, 20.12). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new-onset suicidal ideation on the C-SSRS than subjects treated with placebo (0.9% vs. 0%). [see Adverse Reactions 6.1 ]. Consider the potential risks and benefits before prescribing BIMZELX to patients with a history of severe depression or suicidal ideation or behavior. Advise patients, their caregivers, and families to monitor for the emergence or worsening of depression, suicidal ideation, or other mood changes. If such changes occur, instruct patients to promptly seek medical attention or call the National Suicide and Crisis Lifeline at 988 [see Patient Counseling Information (17) ] . Refer BIMZELX-treated patients with new or worsening symptoms of depression or suicidal ideation and/or behavior to a mental health professional, as appropriate. Re-evaluate the risks and benefits of continuing treatment with BIMZELX if such events occur.

5.2 Infections BIMZELX may increase the risk of infections, including serious infections. Do not initiate treatment with BIMZELX in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing BIMZELX. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and discontinue BIMZELX until the infection resolves.

5.3 Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with BIMZELX. Avoid the use of BIMZELX in patients with active TB infection. Initiate treatment of latent TB prior to administering BIMZELX. Consider anti-TB therapy prior to initiation of BIMZELX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients treated with BIMZELX for signs and symptoms of active TB during and after treatment.

5.4 Liver Biochemical Abnormalities Treatment with BIMZELX was associated with increased incidence of liver enzyme elevations compared to treatment with placebo in randomized clinical trials. Liver serum transaminase elevations > 3 times the upper limit of normal were reported in subjects treated with BIMZELX [see Adverse Reactions (6.1) ] . Elevated liver serum transaminases resolved after discontinuation of BIMZELX. Test liver enzymes, alkaline phosphatase, and bilirubin at baseline, periodically during treatment with BIMZELX and according to routine patient management. If treatment-related increases in liver enzymes occur and drug-induced liver injury is suspected, interrupt BIMZELX until a diagnosis of liver injury is excluded. Permanently discontinue BIMZELX in patients with causally associated combined elevations of transaminases and bilirubin. Patients with acute liver disease or cirrhosis may be at increased risk for severe hepatic injury; avoid use of BIMZELX in these patients.

5.5 Inflammatory Bowel Disease Cases of inflammatory bowel disease (IBD) have been reported in patients treated with IL-17 inhibitors, including BIMZELX [see Adverse Reactions (6.1) ]. Avoid use of BIMZELX in patients with active IBD. […]

The following adverse reactions have been observed with BIMZELX and are discussed in greater detail in other sections of the labeling: Suicidal Ideation and Behavior [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Liver Biochemical Abnormalities [see Warnings and Precautions (5.4) ] Inflammatory Bowel Disease [see Warnings and Precautions (5.5) ] Most common adverse reactions are: Psoriasis and Hidradenitis Suppurativa (incidence ≥ 1%): upper respiratory tract infections, oral candidiasis, headache, injection site reactions, tinea infections, gastroenteritis, Herpes simplex infections, acne, folliculitis, other candida infections, and fatigue. ( 6.1 ) Psoriatic Arthritis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, and urinary tract infection. ( 6.1 ) Non-Radiographic Axial Spondyloarthritis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, cough, fatigue, musculoskeletal pain, myalgia, tonsilitis, transaminase increase, and urinary tract infection. ( 6.1 ) Ankylosing Spondylitis (incidence ≥ 2%): upper respiratory tract infections, oral candidiasis, headache, diarrhea, injection site pain, rash and vulvovaginal mycotic infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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 practice. Plaque Psoriasis Clinical Trials In clinical trials, a total of 1,789 subjects with plaque psoriasis were treated with BIMZELX. Of these, 1,073 subjects were exposed to BIMZELX for at least one year. The safety of BIMZELX was evaluated in two placebo-controlled trials (Ps-1 and Ps-2), an active-controlled trial (Ps-3), and an open-label extension trial. Data from Trials Ps-1 and Ps-2 in 839 subjects (mean age 45 years, 72% male, 84% White) were pooled to evaluate the safety of BIMZELX in comparison to placebo up to 16 weeks after treatment initiation. A total of 670 subjects were treated during this initial period with BIMZELX 320 mg at Weeks 0, 4, 8, 12, and 16. Table 1 summarizes the adverse reactions that occurred at a rate of 1% or greater and at a higher rate in the BIMZELX group than the placebo group. Table 1: Adverse Reactions Occurring in ≥1% of Subjects with Plaque Psoriasis in the BIMZELX Group and More Frequently than in the Placebo Group in Trials Ps-1 and Ps-2 BIMZELX N=670 n (%) Placebo N=169 n (%) URI Upper Respiratory Infections include nasopharyngitis, upper respiratory tract infection, pharyngitis, rhinitis, viral upper respiratory tract infection, tonsillitis, sinusitis, pharyngitis streptococcal, pharyngitis bacterial, peritonsillar abscess, viral rhinitis, and influenza 102 (15) 24 (14) Oral Candidiasis Oral Candidiasis includes oral candidiasis, oropharyngeal candidiasis, oral fungal infection, fungal pharyngitis, and oropharyngitis fungal 61 (9) 0 (0) Headache 22 (3) 0 (0) Injection Site Reactions Injection Site Reactions include injection site reaction, injection site erythema, injection site pain, injection site edema, injection site bruising, and injection site swelling 19 (3) 2 (1) Tinea Infections Tinea Infections include tinea pedis, fungal skin infection, tinea versicolor, tinea cruris, tinea infection, body tinea, and onychomycosis 18 (3) 1 (1) Gastroenteritis Gastroenteritis includes Enterovirus infection, gastroenteritis, gastroenteritis bacterial, and gastroenteritis viral 12 (2) 0 (0) Herpes Simplex Infections Herpes Simplex Infections include herpes simplex and oral herpes 9 (1) 0 (0) Acne 8 (1) 0 (0) Folliculitis 8 (1) 0 (0) Other Candida Infections Other Candida Infections include vulvovaginal candidiasis, vulvovaginal mycotic infection, skin candida, and genital candidiasis. 7 (1) 1 (1) Fatigue 7 (1) 0 (0) Adverse reactions that occurred in < 1% but > 0.1% of subjects in the BIMZELX group and at a higher rate than in the placebo group through Week 16 were neutropenia, eczema, otitis externa, otitis media, and pyrexia. The safety of BIMZELX was evaluated in another active-controlled trial (Ps-4) in 743 adult subjects who received BIMZELX 320 mg every 4 weeks or every 8 weeks through Week 48. Specific Adverse Reactions Suicidal Ideation and Behavior : The study populations of Trial Ps-1, Trial Ps-2, Trial Ps-3 and Trial Ps-4 excluded subjects with active suicidal ideation, suicidal ideation within the month prior to screening, a history of suicide attempt within the past 5 years prior to screening, or moderately severe to severe major depression (i.e., score of ≥15 on the screening Patient Health Questionnaire-9 (PHQ-9)). Analysis of pooled C-SSRS data from the first 16 weeks of placebo-controlled clinical trials indicated that 12/670 (1.8%) BIMZELX-treated subjects and 1/169 (0.6%) subjects receiving placebo reported passive suicidal ideation with an estimated relative risk of 3.0 (95% confidence interval: 0.39, 22.74). Subjects without a prior history of SI/B treated with BIMZELX also reported a higher rate of new onset suicidal ideation on the C-SSRS than subjects receiving placebo (1.3% vs 0.6%). During the course of the clinical trials for plaque psoriasis, there was 1 completed suicide in the open label extension trial after 718 days of treatment (1/2,480; 0.01/100 patient-years). The completed suicide was reported in a subject without a past reported psychiatric history. There were also 3 suicide attempts (3/2,480; 0.04/100 patient-years); 2 of these subjects had a history of prior suicide attempts. Infections : During the placebo-controlled period of Trials Ps-1 and Ps-2, infections were reported in 36% of subjects (141.7 per 100 patient-years) treated with BIMZELX compared with 23% of subjects (84.6 per 100 patient-years) receiving placebo. Serious infections occurred in 0.3% of subjects (1.0 per 100 patient-years) treated with BIMZELX and 0% subjects receiving placebo . The most common infections were upper respiratory tract infections and Candida infections, including oral candidiasis (oral candidiasis, oropharyngeal candidiasis, oral fungal infection, fungal pharyngitis, and oropharyngitis fungal) occurring in 9% (30.6 per 100 patient-years) of subjects treated with BIMZELX and other Candida infections (vulvovaginal candidiasis, vulvovaginal mycotic infection, skin candida, and genital candidiasis) in 1% (3.4 per 100 patient-years) of subjects treated with BIMZELX compared to 0% and 1%, respectively, of subjects receiving placebo. During the combined initial, maintenance, and open-label extension treatment periods of trials Ps-1, Ps-2, Ps-3, and the open-label extension trial, infections were reported in 63% of subjects treated with BIMZELX (120.4 per 100 patient-years). Serious infections were reported in 1.5% of subjects treated with BIMZELX (1.6 per 100 patient-years). Inflammatory Bowel Disease : In clinical trials in subjects with plaque psoriasis, subjects with active inflammatory bowel disease were excluded. In these trials, which included 2,480 subjects exposed to BIMZELX accounting for 5,830 patient-years, adjudicated cases of new onset of inflammatory bowel disease (including ulcerative colitis (UC), Crohn's disease (CD) and IBD-undetermined) occurred in seven subjects (0.12 per 100 patient-years); the majority of these cases were serious and resulted in discontinuation of therapy. Liver Biochemical Abnormalities : During the placebo-controlled period of Trials Ps-1 and Ps-2, liver serum transaminase elevations (> 3 times the upper limit of normal [ULN]) occurred in 1.0% of subjects treated with BIMZELX versus 0.6% of subjects receiving placebo. […]

CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Treatment with BIMZELX may modulate serum levels of some cytokines. Therefore, upon initiation or discontinuation of BIMZELX in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate. Population pharmacokinetic (PK) data analyses indicated that the clearance of BIMZELX was not impacted by concomitant administration of cDMARDs including methotrexate, or by prior exposure to biologics.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIMZELX during pregnancy. For more information, healthcare providers or patients can contact the Organization of Teratology Information Specialists (OTIS) AutoImmune Diseases Study at 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/. Risk Summary Available data from case reports on BIMZELX use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, BIMZELX may be transmitted from the mother to the developing fetus (see Clinical Considerations ) . In an enhanced pre- and postnatal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of bimekizumab-bkzx during the period of organogenesis through parturition at doses up to 38 times the maximum recommended human dose (MRHD) (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions: Because bimekizumab-bkzx may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to BIMZELX in utero. There are no data regarding infant serum levels of bimekizumab-bkzx at birth and the duration of persistence of bimekizumab-bkzx in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 4 months after birth may be considered because of the half-life of the product. Data Animal Data: An enhanced pre- and postnatal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered subcutaneous doses of bimekizumab-bkzx of 20 or 50 mg/kg/week from gestation day 20 to parturition and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology or neurobehavioral development. The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week (38 times the MRHD, based on mg/kg comparison of 1.33 mg/kg/week administered as a 320 mg dose to a 60 kg individual once every 4 weeks).

8.2 Lactation Risk Summary There are no data on the presence of bimekizumab-bkzx in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Endogenous IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to bimekizumab-bkzx are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BIMZELX and any potential adverse effects on the breastfed infant from BIMZELX or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of BIMZELX in pediatric patients have not been established.

8.5 Geriatric Use Of the 1,789 subjects with plaque psoriasis that were exposed to BIMZELX, a total of 153 subjects were 65 years of age or older, and 18 subjects were 75 years of age or older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in PSO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects . Of the 1,197 subjects with PsA that were exposed to BIMZELX, a total of 148 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in PsA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects . Of the 244 subjects with nr-axSpA that were exposed to BIMZELX, a total of 6 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, the clinical trial in nr-axSpA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects . Of the 330 subjects with AS that were exposed to BIMZELX, a total of 11 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, the clinical trial in AS did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects . Of the 995 subjects with hidradenitis suppurativa that were exposed to BIMZELX, a total of 18 were 65 years of age and older. Although no differences in safety or effectiveness were observed between subjects 65 years of age or older and younger adult subjects, clinical trials in HS did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects .

Bimekizumab-bkzx is a humanized immunoglobulin IgG1/ κ monoclonal antibody with two identical antigen binding regions that selectively bind to human interleukin 17A (IL-17A), interleukin 17F (IL-17F), and interleukin 17-AF cytokines, and inhibits their interaction with the IL-17 receptor complex. IL-17A and IL-17F are naturally occurring cytokines that are involved in normal inflammatory and immune responses. Bimekizumab-bkzx inhibits the release of proinflammatory cytokines and chemokines.