The document addresses the indications for interleukin-17A (IL-17A) monoclonal antibody drugs used in the treatment of adults with active ankylosing spondylitis, moderate to severe plaque psoriasis, or active psoriatic arthritis.
The U.S. Food and Drug Administration (FDA) has approved the following IL-17A receptor antagonists for use in specific indications:
Note: Please see the following related documents for additional information:
Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in DRUG.00077, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.
Brodalumab is considered medically necessary for the treatment of plaque psoriasis when each of the following criteria are met:
Not Medically Necessary:
Brodalumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Brodalumab is considered investigational and not medically necessary when the criteria above are not met and for all other conditions including, but not limited to:
Ixekizumab is considered medically necessary for the treatment of plaque psoriasis when each of the following criteria are met:
Not Medically Necessary:
Ixekizumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Ixekizumab is considered investigational and not medically necessary when the criteria above are not met and for all other conditions including, but not limited to:
Not Medically Necessary:
Secukinumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Secukinumab is considered investigational and not medically necessary when the criteria above are not met and for all other conditions including, but not limited to:
Brodalumab for Moderate to Severe Plaque Psoriasis
Brodalumab is a human immunoglobulin G2 (IgG2) IL-17A monoclonal antibody that selectively binds and blocks signaling to the interleukin 17 receptor A (IL-17RA). On February 15, 2017, the FDA approved brodalumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies (Siliq Product Information [PI] Label, 2017). Labeling for brodalumab includes a Boxed Warning for suicidal ideation and behavior and the drug is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Siliq REMS Program. Brodalumab is a 210 milligram (mg) subcutaneous injection administered at weeks 0, 1, and 2 followed by 210 mg every 2 weeks thereafter.
AMAGINE-1 Clinical Trial
The safety and efficacy of brodalumab was evaluated in three multicenter, prospective, double-blind, placebo and comparator controlled phase III clinical trials (AMAGINE-1, AMAGINE-2, AMAGINE-3) of adults 18-75 years of age with stable moderate to severe plaque psoriasis ≥ 6 months, ≥ 10% BSA involvement, a Psoriasis Area and Severity Index (PASI) ≥ 12 and static Physician's Global Assessment (sPGA) ≥ 3, and no known history of active tuberculosis and were negative for tuberculosis during screening (or received prophylactic treatment). Individuals with a history of psychiatric disorders were not specifically excluded from the trials. AMAGINE-I (Papp, 2016) was a 12-week placebo controlled study and included an induction period followed by a withdrawal and retreatment period up to 52 weeks. Participants who responded at week 12 were re-randomized to receive placebo or to continue their induction dose in a blinded manner. AMAGINE-2 and AMAGINE-3 (Lebwohl, 2015) were identical in study design and included both a placebo and an active control (ustekinumab [Stelara], Janssen Biotech, Inc, Horsham, PA). Participants originally randomized to receive brodalumab during the induction phase were re-randomized at week 12 to receive one of four maintenance regimens of brodalumab. The sPGA success (0 or 1) and the PASI 75 at week 12 were co-primary efficacy endpoints in all three phase III studies for brodalumab and placebo comparisons. PASI 100 was a coprimary endpoint for comparison of brodalumab 210 mg every 2 weeks to ustekinumab at week 12. At week 52, the maintenance endpoint across all three studies was sPGA success (0 or 1) for brodalumab versus placebo in AMAGINE-1, and comparison of the four maintenance regimens for AMAGINE-2 and AMAGINE-3.
During the induction phase of AMAGINE-1 (Papp, 2016), 661 participants were randomized to receive brodalumab 210 mg (n=222), brodalumab 140 mg (n=219), or placebo (n=220) every 2 weeks, with an additional dose at week 1. During the withdrawal phase, participants originally randomized to brodalumab 210 or 140 mg every 2 weeks with sPGA score 0 or 1 (sPGA success) at week 12 were re-randomized to receive induction doses of brodalumab or placebo. Beginning at week 16, re-randomized participants who experienced return of disease (sPGA ≥ 3) were eligible for retreatment and received induction doses of brodalumab. After at least 12 weeks of retreatment with inadequate response (sPGA 2 over at least a 4-week period or sPGA ≥ 3), participants qualified for rescue therapy and received open-label brodalumab 210 mg every 2 weeks. At week 12, participants originally randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg every 2 weeks. The coprimary endpoints were the percentage of participants with ≥ 75% improvement in PASI 75 and sPGA success at week 12. At week 12, 132 (60.3%) and 185 (83.3%) participants in the brodalumab 140 mg and 210 mg arms, respectively versus 6 (2.7%) participants in the placebo group achieved PASI 75. A total of 118 (53.9%) and 168 (75.7%) participants in the brodalumab 140 mg and 210 mg arms, respectively, versus 3 (1.4%) participants in the placebo group achieved sPGA success (p<0.001 between both brodalumab arms and placebo). Participants who achieved sPGA success at week 12 were re-randomized to their induction doses of brodalumab or placebo during the withdrawal phase (12-52 weeks). At week 52, the percentages of participants randomized to 210 mg in the induction phase with sPGA success were 83% and 0% for the re-randomized 210 mg and placebo groups, respectively. The percentages of participants randomized to 140 mg in the induction phase with sPGA success were 70% and 5% for the re-randomized 140 mg and placebo groups, respectively (p<0.001 for both brodalumab doses). The percentages of participants with PASI 90 and PASI 100 were maintained through week 52 among responders at week 12 who were re-randomized to their induction dose of brodalumab. Participants who experienced return of disease (sPGA ≥ 3 after week 16) during the withdrawal phase were eligible for retreatment with their induction dose of brodalumab. Among those participants evaluable after 12 weeks of retreatment, 97% (31 participants) and 84% (16 participants) receiving 210 mg and 140 mg brodalumab, respectively, regained sPGA success after 12 weeks of retreatment; 84% (27 participants) and 68% (13 participants) in the 210 mg and 140 mg arms, respectively achieved sPGA 0. The median time to regain sPGA success for both 210 mg and 140 mg was 4 weeks.
At least one adverse event reported during the induction phase occurred in 59%, 58%, and 51% of participants in the 210 mg, 140 mg, and placebo groups, respectively. Serious adverse events were reported in 1.8%, 2.7% and 1.4% in the 210 mg, 140 mg, and placebo groups, respectively. The most frequent adverse events (≥ 5% in any group) were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia. Depression was reported in 3 participants (1 in each group), neutropenia in 1 participant (140 mg) and suspected Candida infection in 9 participants (3 in placebo, 1 in 140 mg and 5 in 210 mg). There were no major adverse cardiac events (MACE) or fatal adverse events. However, four fatal adverse events occurred through week 52: sudden death in a participant receiving constant 210 mg brodalumab; an intentional illicit drug overdose considered by the coroner to be suicide in a participant receiving placebo (induction phase) and 210 mg (withdrawal phase); esophageal varices hemorrhage in a participant with a history of cirrhosis receiving constant 210 mg brodalumab; and, cerebrovascular accident in a participant receiving 210 mg brodalumab (induction phase), placebo (withdrawal phase) and 210 mg brodalumab (retreatment phase). There was one additional suicide after week 52 (day 415) during the uncontrolled open-label extension in a participant receiving 210 mg brodalumab (induction phase), placebo (withdrawal phase) and 210 mg brodalumab (retreatment phase) (Papp, 2016).
AMAGINE-2 and AMAGINE-3 Clinical Trials
Study participants in AMAGINE-2 (n=1831) and AMAGINE-3 (n=1881) (Lebwohl, 2015) were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for participants with a body weight ≤ 100 kg and 90 mg for those > 100 kg), or placebo. At week 12, participants receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; participants receiving ustekinumab continued to receive ustekinumab every 12 weeks, and participants receiving placebo received 210 mg of brodalumab every 2 weeks. Response rates were statistically higher comparing brodalumab to placebo and to ustekinumab with respect to the primary endpoints in both studies. At week 12, the primary co-endpoint for PASI 75 response rates was higher with brodalumab at the 210 mg and 140 mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; p<0.001). The rates of sPGA scores of 0 or 1 were also higher with brodalumab (p<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3]; p<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (p=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (p=0.007). Other secondary endpoints and efficacy response rates were significantly higher in the brodalumab groups than with use of ustekinumab, with the exception of 210 mg of brodalumab use in AMAGINE-2 (p=0.08). The median time to a response in both studies was significantly shorter with either brodalumab dose than with ustekinumab (p<0.001). In the maintenance phase of AMAGINE-2, 1174 participants were assigned in the re-randomization process to receive brodalumab, and 297 switched from placebo; 1331 participants (90%) remained in the study at week 52. In AMAGINE-3 study, 1200 participants were assigned in the re-randomization process to receive brodalumab, and 298 participants switched from placebo, with 1370 participants (91%) remaining in the study at week 52. A total of 55 of 300 participants in the AMAGINE-2 study who were assigned to receive ustekinumab were given rescue therapy with brodalumab at week 16; 69 of 313 participants (22%) received rescue therapy in the AMAGINE-3 study. The proportion of participants with an sPGA score of 0 or 1 at week 52 was significantly higher among those who had received 210 mg or 140 mg of brodalumab every 2 weeks than among those who had received the other brodalumab maintenance regimens (p<0.001). Most participants who were given rescue therapy with brodalumab after ustekinumab treatment had PASI 75 and sPGA 0 or 1 responses, and more than 40% had PASI 100 responses.
Specific safety concerns with use of brodalumab were identified, including infections, malignancy, neutropenia, worsening of Crohn's disease, immunogenicity (anti-brodalumab antibodies), suicide ideation and behavior (SIB), and cardiac disorders (including MACE). Rates of neutropenia were higher and mild or moderate candida infections were more frequent with brodalumab and with ustekinumab than with placebo. Serious adverse events overall occurred with similar frequency in the placebo, ustekinumab and brodalumab groups by 12 weeks, including cellulitis, appendicitis, gastroenteritis, and acute pancreatitis. By week 52, serious adverse events occurred with similar rates in the brodalumab and ustekinumab groups, including cellulitis, myocardial infarction, and cholelithiasis. The rates of serious adverse events per 100 patient-years through week 52 were 8.3 with brodalumab and 13.0 with ustekinumab in the AMAGINE-2 study and 7.9 and 4.0, respectively in the AMAGINE-3 study. One case of Crohn's disease occurred during the maintenance phase. In the AMAGINE-2 study, one death from stroke occurred during the induction phase in the 210 mg brodalumab group, 20 days after the last dose. Five deaths occurred through week 52 in both studies: three deaths from cardiac arrest in brodalumab-treated participants, one death from pancreatic carcinoma in a ustekinumab-treated participant, and one accidental death in a motor vehicle accident. Three deaths occurred after exposure to brodalumab, including one suicide (27 days after the last dose of brodalumab in the AMAGINE-2 study). In the AMAGINE-3 study, one death occurred from hematophagic histiocytosis syndrome and one death from cardiomyopathy. There was one additional suicide after week 52 during the open-label extension of the AMAGINE-2 study (Lebwohl, 2015).
Summary of Safety Information for Brodalumab
From the clinical trials data, the known adverse events with use of brodalumab include exacerbation of existing Crohn's disease, infections, and neutropenia. Through the end of the clinical trials, the long term rate of fatal events occurring during or after use of brodalumab was reported as 23 deaths: 12 cardiovascular, 4 completed suicides, 2 accidental deaths, and 4 other single events. There were insufficient numbers of MACE events in the studies for meaningful comparison to placebo. While the MACE rate was highest in brodalumab-treated participants, MACE rates were similar with use of other biologic drugs for the treatment of moderate to severe plaque psoriasis. In addition, it is uncertain from the study data if there is a potential relationship between brodalumab and completed suicide, and other SIB and adverse events; therefore, no conclusions can be drawn whether or not these serious adverse events were drug-related. According to the FDA (2017),
…brodalumab users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior compared to users without this history. A causal association between treatment with Siliq and increased risk of suicidal ideation and behavior has not been established.
Because of the observed risk of suicidal ideation and behavior, the FDA is requiring additional labeling for brodalumab including a Boxed Warning and availability of the drug only through the restricted Siliq REMS Program.
Other Proposed Uses of Brodalumab
Brodalumab has been investigated for use in the treatment of asthma, Crohn's disease, generalized pustular psoriasis and psoriatic erythroderma, psoriatic arthritis, and rheumatoid arthritis. To date, the FDA has not approved the use of brodalumab for any of these indications.
Busse and colleagues (2013) attempted to determine the efficacy and safety of brodalumab in a randomized, double-blind, placebo-controlled study of 302 individuals with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids. Subjects were randomized to brodalumab (140 mg, 210 mg, or 280 mg) or placebo. The primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to week 12. For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. A change of nominal significance was only observed in the ACQ score in the high-reversibility subgroup (post-bronchodilator forced expiratory volume [FEV]1 improvement ≥ 20%; n=112). ACQ responses were nominally significant in the 210 mg brodalumab group (estimated treatment difference, 0.53) but not significant in the higher 280 mg brodalumab group (estimated treatment difference, 0.38). The investigators concluded that brodalumab did not produce a treatment effect in subjects with asthma and the results of the high-reversibility subgroup analysis were of uncertain significance.
Targan and colleagues (2016) performed a randomized, double-blind, placebo-controlled, phase II dose-ranging study in individuals with moderate to severe Crohn's disease and evidence of active inflammation. Participants were randomized to receive brodalumab (210 mg, 350 mg, or 700 mg at baseline and week 4) or placebo. The primary endpoint was the proportion of participants achieving Crohn's disease activity index (CDAI) remission (≤ 150) at week 6. According to the study authors, "the study was terminated early based on an imbalance in worsening CD in active treatment groups."
Generalized Pustular Psoriasis and Psoriatic Erythroderma
Yamasaki and colleagues (2017) evaluated the efficacy and safety of brodalumab in a 52-week, open-label, multicenter, phase III study in individuals with rare and severe types of psoriasis including generalized pustular psoriasis (n=12) and psoriatic erythroderma (n=18). Participants received brodalumab 140 mg at day 1 and weeks 1 and 2, and then every 2 weeks until week 52. The primary endpoint was the Clinical Global Impression of Improvement (CGI). Evaluation of safety included treatment-emergent adverse events and changes in laboratory parameters. A total of 26 participants completed the study at week 52: 10 and 16 participants in the generalized pustular psoriasis and psoriatic erythroderma groups, respectively. CGI remission or improvement was achieved in 11 and 18 participants with generalized pustular psoriasis and psoriatic erythroderma, respectively. The most commonly reported adverse event was nasopharyngitis (33.3%). Five serious adverse events occurred during the study; however, none was considered treatment-related.
Mease and colleagues (2014) evaluated the efficacy and safety of brodalumab in a phase II, randomized, double-blind, placebo-controlled study involving individuals with psoriatic arthritis. Participants with active psoriatic arthritis were randomly assigned to receive brodalumab (140 mg or 280 mg) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, those who had not discontinued study participation were offered open-label brodalumab (280 mg) every 2 weeks. The primary endpoint was American College of Rheumatology (ACR) response (ACR20) improvement at week 12. A total of 159 of the 168 subjects who underwent randomization (57 in the brodalumab 140 mg group, 56 in the brodalumab 280 mg group, and 55 in the placebo group), completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140 mg and 280 mg groups had higher rates of ACR20 response than the placebo group (37% [p=0.03] and 39% [p=0.02], respectively, vs. 18%); higher rates of 50% improvement (ACR50) were also reported (14% [p=0.05] and 14% [p=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among subjects who were previously treated with biologic therapy and those who had not received such therapy. At week 24, ACR20 response rates in the brodalumab 140 mg and 280 mg groups were 51% and 64%, respectively, compared with 44% among subjects who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events occurred in 3% of subjects in the brodalumab groups and in 2% of those in the placebo group. Additional study of larger populations and longer duration are necessary to determine the clinical efficacy and safety of brodalumab in the treatment of individuals with active psoriatic arthritis.
In a randomized, double-blind, phase Ib multiple ascending dose study, Martin and colleagues (2014) evaluated the safety, pharmacokinetics, and early clinical response of brodalumab in methotrexate-resistant rheumatoid arthritis. with moderate to severe rheumatoid arthritis. Subjects with moderate to severe disease (≥ 6 of 66 swollen and ≥ 8 of 68 tender joints) were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every 2 weeks for six doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. The study was not designed to assess efficacy. The primary endpoints included incidence of adverse events and pharmacokinetics. A total of 40 subjects were randomized to brodalumab; 1 subject in the placebo group discontinued treatment due to worsening of rheumatoid arthritis-related symptoms. Adverse events were reported by 70% (7 of 10) of placebo subjects and 77% (22 of 30) of brodalumab subjects. Three serious adverse events were reported in 2 subjects; there were no opportunistic infections. No treatment effects were observed with individual measures of rheumatoid arthritis disease activity. On day 85 (week 13) 37% (11 of 30) of brodalumab subjects and 22% (2 of 9) of placebo subjects achieved ACR20; 7% (2 of 30) of brodalumab subjects and 11% (1 of 9) of placebo subjects achieved ACR50; and 0% (0 of 30) of brodalumab subjects and 0% (0 of 9) of placebo subjects achieved ACR70. Although multiple dose administration of brodalumab was tolerated in the study subjects, there was no evidence of a clinical response to brodalumab-treated subjects with moderate to severe rheumatoid arthritis.
Pavelka and colleagues (2015) evaluated the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis who had an inadequate response to methotrexate. A total of 252 subjects were randomized to receive subcutaneous injections of brodalumab (70 mg, 140 mg, or 210 mg) or placebo. The primary endpoint was ACR50 response at week 12. At week 12, nonsignificant responses were observed in all subjects in the evaluation of ACR50 response (16% [70 mg], 16% [140 mg], 10% [210 mg], and 13% [placebo]). No significant treatment effects were observed for the secondary endpoints, including ACR20, ACR70, and Disease Activity Score (DAS) in 28 joints. Incidences of all adverse events, including serious adverse events, were similar across treatment groups. A total of 7 subjects reported serious adverse events during the study (2 in the placebo group and 5 in the brodalumab groups), none of which was treatment related. There was one death (cardiopulmonary failure) approximately 1 week after the last dose in the 140 mg group. The investigators conclude that the study "…failed to find evidence of meaningful clinical efficacy with brodalumab treatment" in individuals with rheumatoid arthritis who had an inadequate response to methotrexate. "These preliminary results do not support further evaluation of brodalumab as a treatment for rheumatoid arthritis [RA]."
Ixekizumab for Moderate to Severe Plaque Psoriasis
Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) anti-IL-17A monoclonal antibody with neutralizing activity against IL-17A, a naturally occurring cytokine involved in normal inflammatory and immune responses and found in high concentration in skin affected by plaque psoriasis. On March 22, 2016, the FDA approved ixekizumab subcutaneous injection for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy (Taltz PI Label, 2017).
The FDA approval of ixekizumab was based on findings from three multicenter, double-blind, placebo-controlled and/or biologic-active phase III clinical studies (UNCOVER-1, UNCOVER-2, UNCOVER-3) that enrolled a total of 3866 individuals, 18 years of age or older, with moderate to severe plaque psoriasis (Gordon, 2014; Griffiths, 2015; Gordon, 2016). Participants had a minimum BSA involvement of 10%, a sPGA score of ≥ 3 in the overall assessment of psoriasis (on a severity scale of "0" to "5"), a PASI score of ≥ 12, and were candidates for phototherapy or systemic therapy. All three studies evaluated different dosing regimens of ixekizumab, administered at 80 milligram (mg) every 2 to 4 weeks following a 160 mg starting dose, compared to placebo after 12 weeks. UNCOVER-2 and UNCOVER-3 included an additional comparator arm in which participants received etanercept (Enbrel® , Immunex Corporation, Thousand Oaks, CA) 50 mg twice a week for 12 weeks. In UNCOVER-1 and UNCOVER-2, the safety and efficacy of ixekizumab was further evaluated through 60 weeks.
The primary efficacy endpoints at 12 weeks were a 75% improvement in the composite PASI score and sPGA score of 0 or 1 and at least a 2-point improvement from baseline. In all three studies at week 12, 87% to 90% of ixekizumab-treated participants experienced significant improvement in their psoriasis plaques. A total of 81% to 83% of ixekizumab-treated participants achieved a sPGA score of 0 or 1. The majority of ixekizumab-treated participants (68% to 71%) achieved virtually clear skin (PASI 90) and 35% to 42% saw complete resolution of their psoriasis plaques (PASI 100, sPGA 0) when compared to minimal improvement in placebo-treated participants. In UNCOVER-1 and UNCOVER-2, 75% of participants who responded to ixekizumab (sPGA 0 or 1 and at least a 2-point improvement from baseline) at 12 weeks consistently maintained that response at the 60-week endpoint.
The most common (≥ 1%) adverse events in the studies were reported as injection site reactions, upper respiratory tract infections, nausea, and fungal infections. Serious adverse events were reported in 14 (1.9%) of 734 participants given ixekizumab every 2 weeks, 14 (1.9%) of 729 participants given ixekizumab every 4 weeks, 7 (1.9) of 360 participants given placebo, and 14 (1.9%) of 739 participants given etanercept.
Ixekizumab is administered by subcutaneous injection at a recommended dose of 160 mg (two 80 mg injections given via a single-dose prefilled autoinjector or prefilled syringe) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. Ixekizumab is intended for use under the guidance and supervision of a physician. Persons may self-inject only after trained in subcutaneous injection technique using an autoinjector or prefilled syringe.
Blauvelt and colleagues (2017) performed a post-hoc analysis of the UNCOVER-2 and UNCOVER-3 phase III trials to assess response to ixekizumab in those participants with moderate to severe plaque psoriasis who had an inadequate response to etanercept. In this subanalysis, non-response was defined by either failure to have an sPGA of 0/1 in UNCOVER-2 or failure to have at least 75% improvement in PASI 75 in UNCOVER-3 at week 12 of each study. Non-responders treated with twice-weekly etanercept 50 mg in the first 12 weeks received two injections of placebo at week 12 (4-week wash-out period), followed by ixekizumab every 4 weeks for weeks 16-60. Non-responders to placebo in the first 12 weeks were administered ixekizumab 160 mg at week 12, followed by ixekizumab every 4 weeks for weeks 16-60. After switching to an ixekizumab subcutaneous injection every 4 weeks, a substantial proportion of participants who were unresponsive to etanercept experienced rapid and sustained improvement in all efficacy evaluations. Among sPGA 0/1 (UNCOVER-2) and PASI 75 (UNCOVER-3) non-responders to etanercept, 73.0% achieved sPGA 0/1 and 78.2% achieved PASI 75, respectively, after 12 weeks of ixekizumab treatment. Safety profiles in participants who switched from etanercept to ixekizumab were similar to those in participants who switched from placebo to ixekizumab. A limitation of this analysis is that the original studies were not designed to directly compare outcomes in etanercept non-responders versus placebo non-responders who switched to every 4-week ixekizumab. In addition, while participants and investigators in UNCOVER-2 remained blinded through week 60, participants and investigators in UNCOVER-3 were not blinded after the first 12 weeks of treatment, potentially resulting in higher responses after week 12 in that trial. Another potential limitation cited by the investigators is that some persons may require more than 12 weeks to achieve sPGA 0/1 or PASI 75 in response to etanercept; "therefore, it is conceivable that with longer exposure to etanercept, some of the non-responders might have become responders."
Other Proposed Uses of Ixekizumab
Ixekizumab has been studied in phase III clinical trials for use in active psoriatic arthritis (Mease, 2017; Nash, 2017) and moderate to severe plaque psoriasis in individuals naïve to systemic treatment. Additional data in the peer-reviewed published medical literature suggests a potential treatment benefit of ixekizumab in individuals with rheumatoid arthritis who are naïve to biologic agents or experienced an inadequate response to tumor necrosis factor (TNF) antagonists (Genovese, 2014; Genovese, 2016). To date, the FDA has not approved ixekizumab for use in the treatment of any of these conditions.
Mease and colleagues (2017) evaluated the efficacy and safety of ixekizumab in the treatment of biologic-naïve individuals with active psoriatic arthritis in a 24-week randomized, double-blind, placebo-controlled and active (adalimumab)-controlled period phase III clinical trial (SPIRIT-P1). Participants were randomized to subcutaneous injections of placebo (n=106), adalimumab 40 mg once every 2 weeks (active reference; n=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (n=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (n=107). Participants randomized to IXEQ4W or IXEQ2W were administered a starting dose of 160 mg given as two injections at week 0. Because the different randomized treatments used distinct schedules and distinguishable prefilled syringes, a double-dummy design with every 2-week dosing was used to conceal treatment allocation. The study was not powered to test equivalence or non-inferiority of ixekizumab versus adalimumab. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of participants who achieved an ACR20 response at week 24. Efficacy analyses were conducted on the intent-to-treat population (all randomized participants). The adalimumab 40 mg every 2-week treatment arm acted as active reference for comparison with placebo. The primary efficacy endpoint of ACR20 response at week 24 was met with both IXEQ4W (57.9%) and IXEQ2W (62.1%); response rates in both ixekizumab groups were significantly greater than in the placebo group (30.2%) (p≤0.001). The adalimumab group (active reference) also had a significantly greater ACR20 response at week 24 (57.4%) compared with placebo (p≤0.001). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at week 12. In addition, there was significantly less progression of structural damage at week 24 as measured by changes from baseline in mTSS (that is, the van der Heijde modified total Sharp score) in both ixekizumab groups (IXEQ4W, 0.17; IXEQ2W, 0.08) and adalimumab (0.10) groups compared with the placebo group (0.49) (p≤0.01). Among participants with psoriasis at baseline affecting ≥ 3% BSA, a significantly greater percentage of participants achieved PASI 75 at week 12 for the IXEQ4W (75.3%), IXEQ2W (69.5%) and adalimumab (33.8%) groups compared with the placebo group (7.5%) (p<0.001). A greater percentage of participants receiving ixekizumab (66%) and adalimumab (64%) reported at least one treatment-emergent adverse event compared with participants receiving placebo (47.2%) (p<0.05). Adverse events were mostly mild or moderate, and the most common were injection site reaction, injection site erythema and nasopharyngitis. The safety profile of ixekizumab for use in active psoriatic arthritis was consistent with the safety profile in the studies of moderate to severe plaque psoriasis.
Nash and colleagues (2017) evaluated the efficacy and safety of ixekizumab in individuals with active psoriatic arthritis who had an inadequate response to prior TNF antagonist drugs. In this double-blind, multicenter, randomized, placebo-controlled, phase III clinical trial (SPIRIT-P2), participants (n=363) ages 18 years or older with a confirmed diagnosis of psoriatic arthritis for at least 6 months, and a previous inadequate response (that is, refractory to therapy or had loss of efficacy, or were intolerant) to TNF antagonists were randomly assigned to receive 80 mg subcutaneous ixekizumab every 4 weeks (n=122) or every 2 weeks (n=123) after a 160 mg starting dose, or placebo (n=118). The primary endpoint was the proportion of participants who attained at least an ACR20 response at week 24. At week 24, a higher proportion of participants achieved an ACR20 response with ixekizumab every 4 weeks (n=65 [53%] participants; effect size vs. placebo 33.8% [95% CI, 22.4-45.2]; p<0.0001) and ixekizumab every 2 weeks (n=59 [48%] participants; 28.5% [17.1-39.8]; p<0.0001) than did participants with placebo (n=23 [20%] participants). Up to week 24, serious adverse events were reported in 3 (3%) participants with ixekizumab every 4 weeks, 8 (7%) participants with ixekizumab every 2 weeks, and 4 (3%) placebo-treated participants; no deaths were reported. Infections were reported in 47 (39%) participants with ixekizumab every 4 weeks, 47 (38%) participants with ixekizumab every 2 weeks, and 35 (30%) placebo-treated participants. A total of 3 (2%) serious infections were reported in participants in the ixekizumab every 2 weeks group. This safety profile is consistent with previous studies investigating the use of ixekizumab.
Secukinumab is a fully human immunoglobulin (Ig)-G1κ monoclonal antibody that selectively binds to IL-17A cytokine and inhibits its interaction with the IL-17 receptor. The FDA has approved secukinumab for use in the treatment of adults with active ankylosing spondylitis, moderate to severe plaque psoriasis, and active psoriatic arthritis (Cosentyx PI Label, 2016).
Secukinumab for Active Ankylosing Spondylitis
On January 15, 2016, the FDA approved secukinumab subcutaneous injection for the treatment of adults with active ankylosing spondylitis. The clinical efficacy and safety of secukinumab for this indication was evaluated in two phase III, double-blind, randomized controlled trials (MEASURE 1, n=371; MEASURE 2, n=219) (Baeten, 2013; Baeten, 2015). MEASURE 1 is a 2-year study followed by a 3-year extension study; and, MEASURE 2 is a 5-year study.
In the MEASURE 1 study, 371 participants were randomly assigned to receive an intravenous loading dose of secukinumab (10 mg per kilogram) followed by subcutaneous secukinumab at a dose of 150 mg (n=125), an intravenous loading dose of secukinumab (10 mg per kilogram) followed by subcutaneous secukinumab at a dose of 75 mg (n=124), or placebo (n=122). At week 16, 351 (95%) participants remained in the study; 20 participants discontinued study protocol, with 10 participants from the placebo arm and 10 participants total from the two intervention arms (placebo, n=5, total intervention, n=3, due to adverse events).
A total of 219 participants in the MEASURE 2 trial received subcutaneous secukinumab at a dose of 150 mg (n=72), subcutaneous secukinumab at a dose of 75 mg (n=73), or matched placebo (n=74) at baseline and at weeks 1, 2, 3, and every 4 weeks starting at week 4. At week 16, 200 participants (91%) remained in the study; 19 participants discontinued the study, with 8 participants from the placebo arm and 11 participants total from the two intervention arms (placebo, n=4, total intervention, n=7, adverse events). At week 16, participants in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg.
The primary endpoint, the proportion of participants with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16, was met in both secukinumab groups in MEASURE 1, and in the group that received 150 mg of secukinumab subcutaneously in MEASURE 2 (61% vs. 29%, MEASURE 1; 61% vs. 28%, MEASURE 2). ASAS40 response was also significant with secukinumab 150 mg in both studies as compared to placebo (42% vs. 13%; 36% vs. 11%). The response rates were maintained in a 52-week follow-up analysis and similar in participants regardless of concomitant therapies. Participants treated with secukinumab showed improvement compared to placebo-treated participants in health-related quality of life assessed by the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) at week 16.
During the 16-week placebo controlled period of the trials, the overall proportion of participants with adverse events was higher in the secukinumab groups than the placebo groups (66% and 59%, respectively). The adverse events that occurred at a proportion of at least 2% and at a higher proportion in the secukinumab groups than the placebo groups during the 16-week placebo-controlled period were nasopharyngitis, nausea, and upper respiratory tract infection. The safety profile of secukinumab was consistent with that in prior studies of its use for ankylosing spondylitis and moderate to severe plaque psoriasis. The incidence of infection was higher in secukinumab-treated participants than with placebo (30% vs. 12% in MEASURE 1; 32% vs. 27% in MEASURE 2). There were 8 cases of inflammatory bowel disease (IBD) during the entire treatment period (n=5, Crohn's disease; n=3, ulcerative colitis). Other adverse events included grade 3 or 4 neutropenia and candida infections.
Braun and colleagues (2016) reported on the long-term effects of secukinumab on clinical signs and symptoms and radiographic changes at 2-year follow-up in individuals with ankylosing spondylitis who participated in the phase III MEASURE 1 study. Clinical efficacy assessments included ASAS20 response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Of the 371 participants originally randomized to treatment, a total of 97 of 125 (77.6%) and 103 of 124 (83.1%) participants in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. No placebo treatment was given beyond week 24. Adverse events (6.4%), lack of efficacy (4.4%) and patient/guardian decision (5.8%) were the primary reasons from discontinuation among secukinumab-treated participants. In the full intent-to-treat analysis set, ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among participants with evaluable x-rays who were originally randomized to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30 ± 2.53. Serious adverse events were reported in 12.2% and 13.4% of participants in the 150 mg and 75 mg groups, respectively. Limitations of this analysis include the lack of comparator group beyond week 16 and as noted by the investigators, even though there was "…use of accepted statistical methods to account for missing data during the continuation period of the study, there remains a possible bias from the fact that patients who stay on study are those who do well on study treatment."
In September 2015, the ACR, in conjunction with the Spondylitis Association of America and the Spondyloarthritis Research and Treatment Network (Ward, 2015), released recommendations for both pharmacologic and non-pharmacologic treatment of AS and non-radiographic axial spondyloarthritis (SpA). The recommendations include treatment of individuals with active or stable ankylosing spondylitis (pharmacologic and rehabilitation) and treatment of those with ankylosing spondylitis and specific impairments or comorbidities (for example, acute iritis, advanced hip arthritis, severe kyphosis, and IBD). The recommendations also address the treatment of individuals with non-radiographic axial SpA and education and preventive care recommendations for ankylosing spondylitis and SpA. For treatment of an individual with active ankylosing spondylitis, strong recommendations include use of non-steroidal anti-inflammatory drugs (NSAIDs), TNF antagonists when activity persists despite NSAID treatment, and no use of systemic glucocorticoids; non-pharmacologic treatments include use of physical therapy and hip arthroplasty in individuals with advanced hip arthritis.
Secukinumab for Moderate to Severe Plaque Psoriasis
On January 23, 2015, the FDA approved secukinumab subcutaneous injection for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The clinical efficacy and safety of secukinumab was evaluated in two phase III, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis) (Langley, 2014). The proportion of participants who met the criterion for PASI reduction of at least 75% (PASI75) at week 12 was higher with each secukinumab dose than with placebo or etanercept. The proportion of participants with a response of 0 or 1 on the modified Investigator's Global Assessment (mIGA) at week 12 was higher with each secukinumab dose than with placebo or etanercept. Changes in the Dermatology Quality of Life Index (DLQI) at week 12 were greater in secukinumab-treated participants than in placebo- or etanercept-treated participants. The proportions of participants meeting other secondary endpoints were also higher in the secukinumab-treated arms of the trials. The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept in FIXTURE. Serious adverse events were low in both trials and there were no treatment-related deaths. Discontinuations due to adverse events were slightly more frequent in the etanercept group than in either secukinumab group in the FIXTURE study. The most common adverse events in the secukinumab groups during induction and the entire treatment period were nasopharyngitis, headache, and diarrhea.
The route of administration of secukinumab was evaluated in two additional phase III studies (FEATURE; JUNCTURE) using a prefilled syringe and autoinjector/pen dosage forms for self-administration (Blauvelt, 2015; Paul, 2014). The recommended dose for secukinumab is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3 and 4 followed by 300 mg every 4 weeks. For some individuals, a dose of 150 mg may be acceptable (Cosentyx PI Label, 2016).
Secukinumab for Active Psoriatic Arthritis
On January 15, 2016, the FDA approved secukinumab subcutaneous injection for the treatment of adults with active psoriatic arthritis. The clinical efficacy and safety of secukinumab for this indication was evaluated in two phase III, double-blind, randomized, placebo-controlled trials (FUTURE 1, n=606; FUTURE 2, n=397) (Mease, 2015; McInnes, 2015) of 1003 individuals, 18 years of age or older, with active psoriatic arthritis (> three swollen and > three tender joints) despite NSAID, corticosteroid, or disease-modifying antirheumatic drug (DMARD) therapy.
In FUTURE 1, 606 participants were randomized 1:1:1 to receive intravenous secukinumab 10 mg/kg at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 75 mg or 150 mg, or placebo every 4 weeks. Participants receiving placebo were re-randomized to receive secukinumab (either 75 mg or 150 mg every 4 weeks) at week 16 or week 24 based on responder status. The primary endpoint was the proportion of participants achieving ACR20 response rates at week 24. Results for the intervention groups were significantly higher than in the placebo group with 50.0% achieving ACR20 in the group receiving secukinumab at doses of 150 mg and 50.5% achieving ACR20 at the 75 mg dose compared to17.3% at ACR20 for the placebo group (p<0.001 for both comparisons with placebo). While there were no major adverse events in the placebo group, two myocardial infarcts and four strokes occurred in the treatment groups. The authors report that these findings are consistent with previous studies.
In FUTURE 2, 397 participants were randomized 1:1:1:1 to receive subcutaneous secukinumab at 75 mg (n=99), 150 mg (n=100), 300 mg (n=100), or placebo (n=98) once a week from baseline and then every 4 weeks from week 4. Participants receiving placebo were re-randomized to receive secukinumab (either 150 mg or 300 mg every 4 weeks) at week 16 or week 24 based on responder status. The primary endpoint was the percentage of participants achieving at least 20% improvement in the ACR20 response criteria at week 24. In FUTURE 2, a significantly higher proportion of participants achieved ACR20 response at week 24 with secukinumab 300 mg (n=54, 54%), 150 mg (n=51, 51%), and 75 mg (n=29, 29%) versus placebo (n=15, 15%) (p<0.0001). Additionally, the proportion of participants receiving secukinumab 300 mg and 150 mg significantly improved with least a 75% and 90% participants respectively achieving improvement on the PASI 75 and PASI 90 score, a change from baseline in the 28-point DAS using C-reactive protein (DAS28-CRP), and the Medical Outcomes Study 36-item Short Form Health Survey Physical Component Summary (SF36-PCS) score. At week 16 in FUTURE 2, the estimated mean change from baseline function as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) was -0.23 in the placebo group compared with -0.45 in the secukinumab 150 mg group and -0.55 in the secukinumab 300 mg group. During the 16-week placebo-controlled period of the trials, the overall proportion of participants with adverse events was similar in the secukinumab and placebo-treatment groups (59% and 58%, respectively); in addition, adverse events that occurred at a proportion of at least 2% and at a higher proportion in the secukinumab groups than the placebo groups were nasopharyngitis, upper respiratory tract infection, headache, nausea, and hypercholesterolemia. There were an increased proportion of participants with infections in the secukinumab groups (29%) compared to the placebo group (26%).
Kavanaugh and colleagues (2017) assessed the long-term efficacy and safety of secukinumab at 2-year follow-up in individuals with active psoriatic arthritis who participated in the phase III FUTURE 1 study. A total of 476 participants (78.5%) completed 104 weeks of treatment. Exploratory analysis of all primary and secondary endpoints continued to week 104 on an intent-to-treat basis. Secukinumab showed sustained efficacy in control of disease activity, quality of life, physical function, skin symptoms, dactylitis, and enthesitis. ACR20 response rates were 66.8% with secukinumab 150 mg and 58.6% with secukinumab 75 mg at week 104; PASI 75 improvement response rates were 74.6% and 63.0%, respectively. Based on observed data, 84.3% of participants in the secukinumab 150 mg group and 83.8% in the secukinumab 75 mg group showed no radiographic disease progression. No new or unexpected adverse events were reported during 2 years of treatment.
Other Proposed Uses of Secukinumab
Secukinumab is being studied in ongoing phase III trials for use in other skin disorders including moderate to severe palmoplantar psoriasis (GESTURE trial; Gottlieb, 2017), moderate to severe nail psoriasis, and palmoplantar pustulosis. Additional data in the peer-reviewed published medical literature suggests a potential treatment benefit for the use of secukinumab for non-infectious uveitis (Dick, 2013; Letko, 2015), and rheumatoid arthritis (Genovese, 2013; Genovese, 2014). However, in a proof-of-concept trial, Hueber and colleagues (2013) found that use of secukinumab was ineffective in the treatment of Crohn's disease and higher rates of adverse events were noted compared with placebo. Other ongoing clinical trials are posted in the ClinicalTrials.gov database. To date, the FDA has not approved secukinumab for use in the treatment of any of these conditions.
Ankylosing Spondylitis and Spondyloarthropathy
Spondyloarthritis (SpA) is a family of inflammatory rheumatic diseases that can affect the spine and peripheral joins, ligaments, and tendons. There are two main types of clinical presentation of SpA: axial (axSpA) (symptoms predominantly related to the spine) and peripheral SpA (symptoms predominantly related to the peripheral joints). Ankylosing spondylitis is the most familiar and severe form of SpA, classified with a group of spondyloarthritides comprised of Reiter's syndrome, reactive arthritis, and psoriatic arthritis. Ankylosing spondylitis is characterized not by the inflammation of the synovium, as seen in rheumatoid arthritis, but inflammation of the enthesis, the site where ligaments, tendons, and joint capsules insert into bone. Inflammation around the spine/vertebrae, joints and feet can lead to fibrosis, ossification, deformity, and ankylosis. It can also cause inflammation in or injury to other organs, such as the eyes, heart, lungs, and kidneys. The disease most often begins between ages 20 and 40, but it may begin before age 10. It affects more males than females. Conventional therapy for ankylosing spondylitis consists primarily of NSAIDs, corticosteroids, and nonbiologic DMARDs, including methotrexate and sulfasalazine.
Plaque Psoriasis and Psoriatic Arthritis
According to the American Academy of Dermatology (AAD, 2008) plaque psoriasis is a multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. The major manifestation of plaque psoriasis is chronic inflammation of the skin, characterized by "disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritic and may cause significant quality of life issues." Treatments available to help manage the symptoms of plaque psoriasis include topical therapy, phototherapy, systemic therapy, and biologic DMARDs.
The AAD has published a set of evidence-based guidelines, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis (AAD, 2008), intended to assist physicians in managing the complexities of the treatment of individuals with plaque psoriasis. The first guideline, Section 1: Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis with Biologics (AAD, 2008) provides an overview of psoriasis classification, co-morbidities, assessment tools, and the use of biologics to treat psoriasis. The work group states that approximately 80% of individuals affected with psoriasis have mild to moderate disease, with 20% having moderate to severe psoriasis, defining the extent of BSA involvement as:
…affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals…The areas of involvement and types of psoriasis should be considered in evaluating severity of disease because the impact of these types of psoriasis may be quite substantial.
Individuals with more than 5% to 10% BSA affected are typically candidates for systemic or biologic therapy. Treatment planning for use of ixekizumab or secukinumab (and other FDA-approved biologic agents) for moderate to severe plaque psoriasis considers this definition of the extent of BSA involvement. In addition, for individuals with plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (for example, palms, soles of feet, head, neck, or genitalia), ≤ 5% BSA involvement is considered as moderate to severe disease.
Psoriatic arthritis is condition associated with plaque psoriasis. Psoriatic arthritis is characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons. Symptoms of psoriatic arthritis can range from mild to very severe. Approximately 15% of people with plaque psoriasis develop psoriatic arthritis (National Psoriasis Foundation [NPF], 2017).
Contraindications, Precautions, and Warnings with Use of Brodalumab, Ixekizumab and Secukinumab
The FDA PI label for brodalumab (Siliq, 2017) includes the following Boxed Warning:
WARNING: SUICIDAL IDEATION AND BEHAVIOR
The FDA PI labels for brodalumab (Siliq, 2017), ixekizumab (Taltz, 2017), and secukinumab (Cosentyx, 2016) include the following Contraindications, Warnings and Precautions:
Warnings and Precautions for Cosentyx and Taltz
Warnings and Precautions for Cosentyx, Siliq, and Taltz
Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines or chemokines suppressing IL-Ra, IL-1ß, IL-6, IL-12, IL-17A, and/or IL-23, or by directly suppressing lymphocytes.
Conventional therapy: Treatments that are widely accepted and practiced by the medical community.
Immunosuppressant drugs: A class of immunomodulatory drugs including 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus that reduce inflammation by affecting the immune system.
Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).
Monoclonal antibody: A laboratory-produced substance that can locate and bind to specific cells wherever they are in the body. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to their target cell.
Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown; includes azathioprine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds, penicillamine, and sulfasalazine.
Nonsteroidal anti-inflammatory drugs (NSAIDs): A class of drugs used to treat pain, redness, swelling, and inflammation from conditions including different types of arthritis; includes over-the-counter (OTC) and prescription medicines, such as celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen, sulindac, tolmetin, and valdecoxib.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|J3490||Unclassified drug [when specified as brodalumab (Siliq), ixekizumab (Taltz), or secukinumab (Cosentyx)]|
|J3590||Unclassified biologics [when specified as brodalumab (Siliq), ixekizumab (Taltz). or secukinumab (Cosentyx)]|
|L40.0||Psoriasis vulgaris (plaque psoriasis)|
|L40.50-L40.59||Arthropathic psoriasis [secukinumab (Cosentyx) only]|
|L40.8-L40.9||Other, unspecified psoriasis|
|M45.0-M45.9||Ankylosing spondylitis [secukinumab (Cosentyx) only]|
When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above for the indications listed in the Position Statement section as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
T-SPOT.TB test (T-Spot)
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||08/03/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Added Note to Description section regarding CG-ADMIN-02. Updated Rationale, References, and Websites for Additional Information sections.|
|Revised||05/04/2017||MPTAC review. Added psoriatic arthritis to the INV and NMN statement for ixekizumab. Updated Rationale, Background, References, and Websites for Additional Information sections.|
|Revised||03/01/2017||MPTAC review. Updated formatting in Position Statement section. Added MN statement for FDA approval of brodalumab (Siliq) for moderate to severe plaque psoriasis when criteria are met. Added NMN and INV and NMN statements for brodalumab when criteria are not met. Separated MN, NMN, and INV and NMN statements into sections specific to ixekizumab and secukinumab. Revised NMN statement for use of ixekizumab in combination with other biologic drugs (added brodalumab and secukinumab). Revised NMN statement for use of secukinumab in combination with other biologic drugs (added brodalumab and ixekizumab). Updated Description, Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections.|
|Revised||05/05/2016||MPTAC review. Added MN criteria for the FDA approval of ixekizumab (Taltz) for moderate to severe plaque psoriasis in individuals 18 years of age or older when criteria are met. Updated NMN and INV and NMN statements to include ixekizumab when criteria are not met. Updated Subject (title), Description, Rationale, Background, Coding, References, and Websites for Additional Information sections.|
|Revised||02/04/2016||MPTAC review. Revised medically necessary criteria to include FDA approval of secukinumab for the treatment of active ankylosing spondylitis or active psoriatic arthritis in individuals 18 years or age or older when criteria are met. Revised investigational and not medically necessary statement, removing ankylosing spondylitis and psoriatic arthritis. Updated Subject (title), Description, Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.|
|New||08/06/2015||MPTAC review. Initial document development.|