Biologics for Psoriasis: A Status Update

The field has grown substantially from the early 2000s to include now a dozen innovator systemic agents, a host of biosimilars, and soon JAK Inhibitors. BY NEAL BHATIA, MD

Biologic therapies—once novel and exciting in the field analysis of data show that 59 percent of patients who >> of dermatology—are now well-established for some, received 200mg achieved a PGA response of scary to others, but still as exciting as ever. The field had grown “clear” or “minimal,” compared with 48 percent for etaner- substantially from the early 2000s to include now a dozen cept (P = 0.0031).2 innovator systemic agents (counting apremilast, which is not Research Note: There is a risk with any biologic therapy technically a biologic) and a host of biosimilars approved for for development of neutralizing or anti-drug antibodies psoriasis or psoriatic arthritis, as well as the JAK inhibitors for (ADA). Researchers investigated the rate of ADA develop- atopic dermatitis. And more agents are on the horizon. ment with tildrakizumab treatment for 52-64 weeks, and it To help keep you up to date on the field, here is a closer was low. Approximately three percent of subjects developed look at the efficacy data for the drugs approved for plaque TE-POS NAb POS ADA and showed lower serum concentra- psoriasis in the last five years, as well as some emerging tions and corresponding reduced efficacy. No relationship research on each agent. It should be noted that while these between ADA and safety was observed.3 newer agents demonstrate impressive efficacy, they, like the generation of biologics that preceded them, will require BRODALUMAB some time to establish a long-term safety profile. Siliq (brodalumab, Ortho Dermatologics) binds to IL-17RA; by binding the receptor, it acts differently from TILDRAKIZUMAB other agents that block IL-17. It is indicated for the treat- Ilumya (tildrakizumab-asmn100mg/mL, Sun ment of moderate to severe plaque psoriasis in adult Pharmaceuticals) is an injectable IL-23 inhibitor approved patients who are candidates for systemic therapy or pho- by the FDA for the treatment of moderate to severe plaque totherapy and have failed to respond or have lost response psoriasis in adults. Ilumya injections are administered by a to other systemic therapies. The agent is contraindicated healthcare provider every 12 weeks, following starter doses in patients with Crohn’s disease. Brodalumab has a Boxed at Week 0 and Week 4. Warning and a Risk Evaluation and Mitigation Strategy A pooled analysis of Phase 3 trial data in which tildraki- (REMS) due to observed suicidal ideation and behavior in zumab 100mg or tildrakizumab 200mg was compared to clinical trials. A safety assessment of brodalumab based on placebo, found significantly greater proportions of Psoriasis publically available adverse event data from Phase 2 and 3 Area and Severity Index (PASI) 75 responders at week 12 clinical trials determined that the most common adverse for tildrakizumab 100mg (62.3 percent) and tildrakizum- events associated with treatment were nasopharyngitis, ab 200mg (64.8 percent), compared to placebo (5.6 percent; upper respiratory tract infection, and candidiasis. Current P < 0.0001). Similarly, the proportion of responders for PASI evidence, therefore, suggests that brodalumab has a similar 90, PASI 100, and Physician’s Global Assessment (PGA) of safety profile to other IL-17 antagonists used to treat moder- “clear” or “minimal” were all significantly higher for active ate to severe plaque psoriasis.4 Results from the Phase 3, ran- treatment vs. placebo. Responses increased from weeks 12 domized, controlled AMAGINE-1 suggest that to 28. Data indicate that week 8 PASI 50 response predicted treatment with brodalumab reduced anxiety and depres- long-term PASI 90 response.1 sion in patients with moderate to severe plaque psoriasis. The Phase 2 and Phase 3 trials also compared treatment In the study, patients receiving brodalumab had decreases with tildrakizumab to treatment with etanercept. Pooled in depression and hospital anxiety and depression scale

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(HADS) scores (by 2.1 and 1.8, respectively) at 12 weeks, compared with no change among those receiving placebo. Data suggest that brodalumab may have the most rapid Just Approved: onset of action of available antipsoriatic therapies.5 Pooled analysis of data from six clinical trials involving more than 4,100 patients favored brodalumab over placebo in terms of the Psoriasis Area and Severity Index (PASI) 75 and PASI Skyrizi (risankizumab, AbbVie), an IL-23 inhibitor for psoria- 100. Analysis of secondary outcomes showed that broda- sis, was approved by the FDA on April 23, 2019 for patients lumab was superior to placebo in terms of static physician’s with moderate to severe plaque psoriasis, and is specifically global assessment and psoriasis symptoms inventory scores. aimed at anyone who is a candidate for systemic therapy or Meta-regression analysis indicated that there is a significant phototherapy. linear association between brodalumab dose and the effect size on PASI and psoriasis symptoms inventory scores.6 Two Phase 3 trials compared the efficacy of risankizum- Few studies have assessed the efficacy of biologic treat- ab 150mg to 45mg or 90mg, or placebo. At ments in specific racial groups. A recent 52-week study has week 16, 75.3 percent and 74.8 percent of subjects receiv- shown that brodalumab 210mg is well tolerated and effica- ing risankizumab, respectively, acheived PASI 90. PASI cious across diverse racial and ethnic subgroups in patients 90 response rates at week 16 were 4.9 percent and two with psoriasis, including black, Asian, white, and Hispanic/ Latino patients. Across all racial and ethnic subgroups, percent, respectively, of placebo-treated patients, and 42 patients receiving brodalumab had higher rates of 75 per- percent and 47 percent, respectively, for those receiving cent, 90 percent, and 100 percent improvement in PASI ustekinumab. from baseline and sPGA score ≤ 1, than did patients who received ustekinumab.7 Research Note: Data analysis suggests that brodalumab for adults with moderate to severe plaque psoriasis is 400mg was associated with the lowest cost per PASI 75, 90 and (given as two subcutaneous injections of 200mg each) every 100 among the biologics evaluated. Total annual costs to other week. For some patients (with body weight ≤ 90 kg), a health plan per patient with , brodalumab, certolizumab 400mg (given as two subcutaneous injections , and ustekinumab were estimated of 200mg each) initially and at weeks 2 and 4, followed by at $51,246, $38,538, $65,484, $57,510 and $57,013.8 200mg every other week can be considered.10,11 In clinical trials, the incidence of adverse events was generally similar CERTOLIZUMAB between subjects receiving certolizumab 400mg and those Cimzia (, UCB) is the first Fc-free, receiving placebo and somewhat lower in subjects receiving PEGylated anti-TNF treatment option for psoriasis. The 200mg, versus placebo.9 absence of the Fc component helps to minimize potential Research Note: The FDA approved a label update that Fc-mediated cytotoxicity from complement or other anti- includes pharmacokinetic data showing negligible to low body dependent mechanisms. It is also hypothesized that transfer of certolizumab through placenta and minimal the absence of the Fc region may be influential in the pre- transfer to breast milk from mother to infant. Although there vention of active transfer of certolizumab pegol across the is evidence that therapeutic monoclonal antibodies do not placenta during pregnancy.9 increase clinical risk of congenital anomalies during concep- Three Phase 3 clinical trials in psoriasis enrolled more than tion or early pregnancy, there has been concern historically 1,000 patients; nearly one-third of these had prior biologic about placental transfer of drug during the third trimester. exposure. A statistically significant proportion of patients Research shows that the amount of certolizumab that trans- receiving active treatment achieved PASI 75 or PASI 90 by fused through the placenta was less than one percent of the week 16 in two trials and by week 12 in the third. Active other biologics and less than the control in one study.12 treatment was also associated with a statistically significantly greater proportion of sujects achieving at least a two-point IXEKIZUMAB improvement on a five-point PGA scale to a final score repre- Ixekizumab (Taltz, Eli Lilly and Company), is an IL-17a inhib- senting clear or almost clear skin at week 16, versus placebo. itor for treatment of moderate to sever plaque psoriasis. In The labeling for certolizumab for psoriasis offers flexibility Phase 3 trials, subjects were randomized 2:2:2:1 to 80mg ixeki- based on weight. The recommended dose of certolizumab zumab every two or four weeks, 50mg etanercept twice

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weekly, or placebo. At week 12, patients switched to ixeki- 1 and 70.0 percent in VOYAGE 2. remained effica- zumab every four weeks during a long-term extension (LTE) cious through 48 weeks of treatment. Guselkumab maintained period. Analysis of 12 week data show that, among patients a satisfactory safety profile with the most frequently reported treated with ixekizumab two-week dosing, 81.8 percent adverse events being nasopharyngitis, headache, and upper had an sPGA score of 0 or 1 and 89.1 percent had a PASI 75 respiratory tract infection. response. In the four-week dosing group, the respective rates Recently reported results from the open-label extension were 76.4 percent and 82.6 percent, compared to 3.2 percent of the Phase 3 VOYAGE 1 study showed that at week 100, and 3.9 percent, respectively, in the placebo groups. 82.4 percent of patients initially randomized to guselkumab In the UNCOVER-1 and UNCOVER-2 trials, among treatment achieved an IGA score of 0/1 (cleared or minimal the patients who were randomly reassigned at week 12 disease) and 82.1 percent achieved a PASI 90 score, while to receive 80mg of ixekizumab every four weeks, 80mg 53.8 percent of patients achieved an IGA score of 0 and 49 of ixekizumab every 12 weeks, or placebo, 73.8 percent, 39.0 percent achieved PASI 100.16 percent, and 7.0 percent of the patients, respectively, main- Research Note: The FDA recently approved Tremfya One- tained an sPGA score of 0 or 1. Adverse events reported Press, a single-dose, patient-controlled injector for adults during ixekizumab use included neutropenia, candidal infec- with moderate to severe plaque psoriasis. In the Phase 3, tions, and inflammatory bowel disease.13 multicenter, randomized ORION study of One-Press, the Analysis of data out to 108 weeks, (n = 385), among mean score for “Satisfaction with Self Injection” was 9.18 patients receiving ixekizumab every two weeks for weeks 0-12 (with 10 indicating “Very Satisfied”) and the mean score for and every four weeks during LTE, the 108-week as-observed, “Ease of Use” was 9.24 (with 10 indicating “Very Easy”). In MI, and mMI response rates were 93.4 percent, 88.3 percent, the study, 81 percent and 76 percent of patients, respec- and 83.6 percent, respectively, for patients achieving ≥75 per- tively, achieved an IGA score of 0 or 1 or a PASI 90 response cent improvement from baseline in PASI, and the 108-week at week 16; scores for placebo were both zero. as-observed, MI, and mMI response rates were 82.6 percent, 78.3 percent, and 74.1 percent, respectively, for patients with SECUKINUMAB a static PGA score of 0 or 1. During LTE, 1,077 (84.5 percent) Secukinumab (Cosentyx, Novartis) is an IL-17 inhibitor patients reported ≥1 treatment-emergent adverse event, and dosed at 300mg by subcutaneous injection at Weeks 0, 1, 2, 85 percent were mild or moderate in severity. Discontinuation 3, and 4 followed by 300mg every four weeks. because of adverse events occurred in 6.4 percent of Among 738 patients in one study, 81.6 percent of those patients.14 receiving secukinumab 300mg, 71.6 percent of subjects receiv- Research Note: The FDA has approved a label update ing secukinumab 150mg, and 4.5 percent of controls achieved for Taltz injection 80mg/mL to include data in psoriasis PASI 75 at week 12. In a second study involving 1,306 subjects, involving the genital area. Taltz is the first treatment FDA 77.1 percent of subjects receiving secukinumab 300mg, 67 approved for moderate to severe plaque psoriasis that percent of subjects receiving secukinumab 150mg, 44 percent includes such data in its label. In a randomized, double- of subjects receiving etanercept, and 4.9 percent of controls blind, placebo-controlled study in moderate to severe pso- achieved PASI 75 at week 12. The proportion of patients with riasis involving the genital area, 149 patients with plaque a response of 0 or 1 on the modified investigator’s global psoriasis affecting the genital area were treated with Taltz assessment at week 12 was higher with each secukinum- or placebo. The majority of patients treated with Taltz ab dose than with placebo or etanercept.The rates of infec- achieved clear or almost clear genital skin at week 12. tion were higher with secukinumab than with placebo in both studies and were similar to those with etanercept.17 GUSELKUMAB Research Note: The FDA approved a label update for Guselkumab (Tremfya, Janssen) is a subcutaneously Novartis’ Cosentyx to include data in moderate to severe administered that targets the p19 scalp psoriasis. The label update was based on 12-week cytokine subunit in IL-23 and IL-39. It is administered as a primary endpoint results from the US study of moderate 100mg subcutaneous injection once every 8 weeks, after to severe scalp psoriasis patients where Cosentyx (300mg) starter doses at weeks 0 and 4. In clinical trials, it was effec- demonstrated superior efficacy compared to placebo. tive in treating psoriasis in patients who were unresponsive to adalimumab or ustekinumab.15 APREMILAST In Phase 3 trials of guselkumab, at week 16, the proportion of Apremilas (Otezla, Celgene) is not a biologic. It is a small patients attaining at least PASI 90 was 73.3 percent in VOYAGE molecule that inhibits phosphodiesterase 4 (PDE-4) in

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Patient Focus: Women with Psoriasis

Psoriasis treatment is highly individualized, taking into selection of an effective treatment must be weighed against account a variety of factors including but not limited to the potential impact on any planned or unintentional pregnancy. degree of impact of the disease, the patient’s willingness Interestingly, pregnancy may have a positive effect on or desire to use certain therapies, and the patient’s overall psoriasis. More than half of patients who were not treated for health and potential comorbidities. For women—especially psoriasis reported that the disease improved during pregnan- those of childbearing age—there may be additional consider- cy, while 21 percent reported no change; 23 percent reported ations, including the impact of psoriasis and its treatment on worsening. However, in the postpartum period, 65 percent of a potential pregnancy. patients reported worsening of psoriasis, 26 percent had no The potential impact of psoriasis on an individual’s quality change, and nine percent reported improvement of psoria- of life cannot be overstated. Among men and women with sis.22 A review of multiple studies and case reports concludes psoriasis and psoriatic arthritis, 88 percent of patients say that overall, there is no clear evidence of increased adverse the conditions affected overall wellbeing, and 82 percent said outcomes in pregnant women with psoriasis.23 they interfered with enjoyment of life.18 Among women undergoing biologic therapy for psoriasis, Twelve percent of surveyed patients were unemployed, and those who continued on therapy during pregnancy had low 92 percent cited psoriasis and/or psoriatic arthritis as the sole levels of disease activity and few flares during pregnancy, reasons for not working.19 while those who discontinued treatment with biologics There is evidence that women may bear the impact of pso- before pregnancy had higher rates of flares during pregnan- riasis differently than men do. An analysis of data from German cy and the postpartum period.24 and Swiss psoriasis registries shows that women rated 20 Taken together, the data suggest that women with psoria- (out of 25) items reflecting patient needs as significantly more sis who are candidates for biologic therapy should remain important than men did. The greatest differences related to on therapy through pregnancy and the post-partum period. depression, sleep quality, and everyday productivity. In terms of therapeutic selection among the biologic agents, Another analysis shows that severity of psoriasis (assessed dermatologists have limited data to inform treatment selec- in this case as a function of BSA) was less influential on tion. depression among patients with psoriasis than factors related There is some suggestion in the data that TNF inhibitors to gender and body image perceptions.20 Researchers con- may be associated with increased risk of congenital malfor- cluded that the main contributors to depression were female mations and preterm birth and may alter the gender, beliefs about appearance and its relationship to one’s of infants towards hypersensitivity and reduced response to self-worth, greater psychological distress, and lower levels of infections.25 Nonetheless, adalimumab in the US and Europe emotional social support. In the US specifically, data confirm and etanercept in Europe have updated labeling suggesting that women with psoriasis—and particularly those with con- they may be used during pregnancy, although there is evi- comitant PsA—are at increased risk for depression compared dence that they cross the placenta. to women without psoriasis.21 Certolizumab has not been shown to cross the placenta. The potential impact of psoriasis on a patient’s quality of It has labeling to suggest minimal to no fetal exposure when life and functioning indicates a need to offer efficient treat- used during pregnancy and to show little to no transfer to ment. For the female patient of childbearing potential, the human breast milk of nursing mothers.

inflammatory cells, keratinocytes, vascular endothelium, and cent and 45 percent of patients, respectively, achieved PASI synovium. 50, compared to 17 percent and 19 percent, respectively, in In two Phase 3 controlled trials, at 16 weeks, 33 percent the placebo group. Among subjects that continued treat- and 29 percent of subjects, respectively, treated with apre- ment for 52 weeks, 61 percent achieved PASI 75. milast achieved PASI 75, compared to five and six percent, Regarding safety, the most common adverse events were respectively, of those in the placebo group. Fifty-nine per- (Continued on page 36)

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(Continued from page 32) diarrhea, nausea, and vomiting; only one patient had to dis- continue from the clinical trials due to these adverse events. Use of a titration pack during the first week of treatment seems to diminish the incidence of these adverse events. There was a 1.3 percent incidence of depression compared to 0.6 percent of patients receiving placebo, so there is a recom- mendation to evaluate and monitor individuals with a his- tory of depression. n

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