Continuing Education Activity
Brodalumab is a monoclonal antibody approved by the United States Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adult patients who have failed treatment with topical and other systemic therapy. In addition to plaque psoriasis, brodalumab has been explored as a potential treatment for other auto-inflammatory diseases, including psoriatic arthritis and rheumatoid arthritis. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of brodalumab, pertinent for members of the interprofessional team for the treatment of patients with indicated inflammatory pathologies.
- Identify the indications for brodalumab.
- Summarize the mechanism of action of brodalumab.
- Review the adverse events and toxicities of brodalumab.
- Outline the importance of improving care coordination among the interprofessional team to improve outcomes for patients using brodalumab therapy for indicated conditions.
Brodalumab is a monoclonal antibody approved by the United States Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adult patients who have failed treatment with topical and other systemic therapy. Results from phase 3 randomized, double-blinded studies have demonstrated that patients treated with brodalumab can achieve significant clinical improvement as compared to those treated with placebo. By week 12 on brodalumab, 83% of patients were able to achieve a 75% reduction in psoriasis area and severity score (PASI 75) score compared to 3% of patients on placebo, and almost 42% were able to achieve a PASI 100 response rate. Similarly, 76% of patients were able to achieve a static Physician’s Global Assessment sPGA success (defined as an sPGA score of 0 or 1).
Phase 3 studies comparing brodalumab with ustekinumab showed that at standard dosing, brodalumab was able to achieve higher rates of PASI 100, 44% and 37% versus 22% and 19% of patients treated with ustekinumab. Brodalumab is also more effective than ustekinumab in biologic-experienced patients: 40% of patients previously treated with a biologic medication were able to achieve PASI 100, while only 17% of biologic-experienced patients treated with ustekinumab were able to achieve the same level of efficacy. Additionally, brodalumab had a more rapid onset of action with PASI 75 responders reaching this benchmark in a median of 4.2 weeks compared to 9.4 weeks for ustekinumab.
In addition to plaque psoriasis, researchers have explored brodalumab as a potential treatment for other auto-inflammatory diseases. A phase 2 randomized control trial examining the efficacy of brodalumab for the treatment of psoriatic arthritis (PsA) showed that by week 12 almost 40% of patients treated with brodalumab (at either 140 mg or 280 mg doses) were able to achieve 20% improvement in the American College of Rheumatology response criteria (ACR 20) compared to 18% in the placebo group. By 24 weeks, 51% of patients in the 140 mg brodalumab group and 64% of those in the 280 mg group achieved improved ACR 20 response. The research revealed no statistical difference in response among patients who had received prior treatment with a biologic medication.
While results from PsA trials have been promising, phase 1b and phase 2 data evaluating brodalumab efficacy in subjects with rheumatoid arthritis who have had an inadequate response to methotrexate have not demonstrated evidence of clinical response. There is no evidence of significant improvement in ACR or disease activity scores for patients treated with brodalumab compared to placebo. Similarly, though implications point to interleukin-17 (IL-17) pro-inflammatory pathways in airway hypersensitivity reactions, brodalumab has not demonstrated effectiveness in the treatment of moderate to severe asthma.
Mechanism of Action
Brodalumab is a human monoclonal IgG2 antibody directed at the IL-17 receptor. The IL-17 protein family is a group of six pro-inflammatory cytokines (IL17A-F) produced by T-helper cells (Th17) thought to play an important role in autoinflammatory diseases such as psoriasis, PsA, rheumatoid arthritis, and multiple sclerosis. Unlike other IL-17 inhibitors, such as ixekizumab and secukinumab, which primarily target IL-17A and bind to the protein itself, brodalumab targets the IL-17RA receptor. The IL-17RA receptor is used not only by IL-17A, but also by IL-17C, IL17-E, and IL-17F. By blocking the IL-17RA receptor, brodalumab prevents the release of IL-17 mediated pro-inflammatory protein kinases and chemokines, such as nuclear factor kappa light chain enhancer of activated B cells (NF-kappa-B), IL-6, IL-8, cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMPs), and granulocyte-macrophage colony-stimulating factor (GM-CSF).
Brodalumab administration is by subcutaneous injection. Patients may self-inject the 210 mg/1.5 ml prefilled syringe at weekly intervals for weeks 0, 1, and 2, followed by an injection every two weeks. Prefilled syringes should be stored at 2 degrees C to 8 degrees C, but require approximately 30 minutes to reach room temperature before injection. Syringes may be stored at room temperature for up to 2 weeks, but should not be re-refrigerated. If there is an inadequate response by weeks 12 to 16 of treatment, discontinue brodalumab as therapy past 16 weeks is unlikely to result in more significant disease improvement.
As brodalumab is an immune-modulating medication, most adverse reactions to therapy relate to increased risk of infection. The most common adverse events reported at week 120 of an open-label extension study in patients receiving brodalumab included:
- Nasopharyngitis (27%)
- Upper respiratory tract infections (20%)
- Arthralgia (16%)
- Back pain (11%)
- Gastroenteritis (10%)
- Influenza (9%)
- Oropharyngeal pain (9%)
- Sinusitis (9%)
Researchers noted mild to moderate oral candidiasis in five patients (3%), and there were reports of injection site reactions in fifteen patients (8%). Additionally, a total of 15 patients (8%) reported serious adverse events. Four patients had to withdraw treatment due to infection. Transient grade-2 absolute neutrophil abnormalities occurred in four patients (2%), but all cases resolved without modification in treatment. There are also several reported cases of grade-3 neutropenia.
Furthermore, while not directly establishing a causal relationship, four completed suicides, including one case ruled as indeterminate, were reported in patients receiving brodalumab during phase 3 clinical trials. Therefore, package inserts for brodalumab include a boxed warning for increased risk of suicidal ideation and behavior. Patients must be informed about this increased risk and should receive a referral to a mental health professional in the event of new or increasing thoughts of suicide or depression. Brodalumab is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.
Inflammatory Bowel Disease
- Brodalumab is contraindicated in patients with Crohn disease. Researchers terminated a randomized, placebo-controlled trial examining the safety and efficacy of brodalumab in patients with Crohn disease due to disproportionate Crohn disease progression in those patients treated with brodalumab: 31% experienced worsening of disease versus 9% in the placebo group. Additionally, though patients with Crohn disease met the exclusion criteria from the psoriasis clinical trials, during one phase 3 study, one patient developed new-onset Crohn disease. If a patient develops Crohn disease while taking brodalumab, they should discontinue therapy.
- Risks and benefits of treatment with brodalumab require thoughtful evaluation before administration in patients with chronic or recurrent infections. If a patient develops a non-resolving infection, the clinician should discontinue the medication.
Children and Pregnancy
- Though no contraindication exists, researchers have not investigated the efficacy and safety of brodalumab as a potential treatment in children or pregnant women with psoriasis or breastfed infants of mothers taking brodalumab. However, monoclonal antibodies are generally known to actively be transported through the placenta, especially in the third trimester and get excreted in modest amounts in breast milk. Risks and benefits to the mother require assessment before initiation or discontinuation of brodalumab.
Due to the increased risk of infection in patients prescribed brodalumab, all patients require screening for tuberculosis (TB) before initiation of the medication. If a patient has an active TB infection, the clinician should not administer the drug. For patients with latent TB or a history of latent or active TB with unconfirmed treatment, therapy for TB infection should start before the initiation of brodalumab as there is a risk for latent TB reactivation.
Patients should be informed of the increased risk of neutropenia and will need monitoring for any new or non-resolving infections. Additionally, live vaccines should be avoided in patients while they are taking brodalumab.
Enhancing Healthcare Team Outcomes
The management of patients with psoriasis is usually by the primary care provider, nurse practitioner, dermatologist, infectious disease consultant, internist, and a rheumatologist. When the disease is moderate to severe, one option for treatment is brodalumab. This new agent was approved by the United States Food and Drug Administration for the treatment of moderate to severe plaque psoriasis in adult patients who have failed treatment with topical and other systemic therapy. The drug is effective and does provide rapid symptom relief, but monitoring of patients is necessary.
Due to the increased risk of infection in patients prescribed brodalumab, all patients require screening for tuberculosis (TB) prior to initiation of the medication. If a patient has an active TB infection, they should not receive the drug. For patients with latent TB or a history of latent or active TB with unconfirmed treatment, therapy for TB infection should start before the initiation of brodalumab as there is a risk for latent TB reactivation.
Patients should be informed of the increased risk of neutropenia and must have ongoing monitoring for any new or non-resolving infections. Additionally, live vaccines should be avoided in patients while they are taking brodalumab. Pharmacists should carefully verify dosing and perform complete medication reconciliation for patients commencing therapy on brodalumab, and report any concerns to the healthcare team.
Nursing staff can assist in all the above monitoring activities, help evaluate the effectiveness of ongoing treatment, and also confirm patient compliance. Should they note any issues, these must be reported to the prescribing physician immediately.
Because of its adverse event profile and potential for increased infections, brodalumab treatment requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]