Brodalumab

Article Author:
Nicole Golbari
Article Editor:
Mark Pellegrini
Updated:
10/27/2018 12:32:08 PM
PubMed Link:
Brodalumab

Indications

Brodalumab (Siliq) 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 (Stelara) 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, brodalumab has been explored 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. No statistical difference in response was seen among patients who had been previously treated 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 the interleukin-17 (IL-17) pro-inflammatory pathways have been implicated in airway hypersensitivity reactions, brodalumab has not been shown to be effective for 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 auto-inflammatory diseases such as psoriasis, PsA, rheumatoid arthritis, and multiple sclerosis. Unlike other IL-17 inhibitors, such as ixekizumab (Taltz) and secukinumab (Cosentyx) 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 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-?B), IL-6, IL-8, cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMPs), and granulocyte-macrophage colony stimulating factor (GM-CSF).

Administration

Brodalumab is administered by subcutaneous injection. Patients may self-inject the 210mg/1.5ml prefilled syringe at intervals of week 0, 1, and 2, followed by an injection every two weeks. Prefilled syringes should be stored at 2°C to 8°C, but should be given 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 12-16 of treatment, brodalumab should be discontinued as therapy past 16 weeks is unlikely to result in greater disease improvement.

Adverse Effects

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%)

Mild to moderate oral candidiasis was noted in five patients (3%) and injection site reactions were reported in fifteen patients (8%) reported. 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 were reported in four patients (2%), but all cases resolved without modification in treatment. Several cases of grade-3 neutropenia have also been reported.

Furthermore, while a causal relationship has not been established, 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 be referred 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.

Contraindications

Inflammatory Bowel Disease

  •  Brodalumab is contraindicated in patients with Crohn's disease. A randomized, placebo control trial examining the safety and efficacy of brodalumab in patients with Crohn’s disease was terminated due to disproportionate Crohn’s disease progression in those patients treated with brodalumab: 31% experienced worsening of disease versus 9% in placebo group. Additionally, though patients with Crohn’s were excluded from the psoriasis clinical trials, during one phase 3 study, one patient developed new-onset Crohn’s disease. If a patient develops Crohn’s disease while taking brodalumab, therapy should be discontinued.

Infection

  • Risks and benefits of treatment with brodalumab should be thoughtfully evaluated prior to administration in patients with chronic or recurrent infections. If a patient develops a non-resolving infection, the medication should be discontinued.

Children and Pregnancy

  • Though no contraindication exists, it should be noted that the efficacy and safety of brodalumab have not yet been investigated 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 be excreted in modest amounts in breast milk. Risks and benefits to the mother should be assessed prior to initiation or discontinuation of brodalumab.

Monitoring

Due to increased risk of infection in patients prescribed brodalumab, all patients should be screened for tuberculosis (TB) prior to initiation of the medication. If a patient has an active TB infection, medication should not be administered. For patients with latent TB or a history of latent or active TB with unconfirmed treatment, therapy for TB infection should be administered prior to initiation of brodalumab as there is a risk for latent TB reactivation.

Patients should be informed of the increased risk of neutropenia and should be monitored for any new or non-resolving infections. Additionally, live vaccines should be avoided in patients while they are taking brodalumab.