A Review of Brodalumab, an IL-17 Receptor Antagonist, for Moderate-to-Severe Plaque Psoriasis

Yun Tong, MD; Andrew J. Peranteau, MD; Zeena Nawas, MD; Stephen K. Tyring, MD, PhD

Disclosures

Skin Therapy Letter. 2017;22(1) 

In This Article

Clinical Trials

Several clinical trials have been undertaken to evaluate the efficacy and safety of brodalumab. Fairly standard inclusionary and exclusionary items were used in the study to screen for adults with moderate-to-severe plaque psoriasis.

Phase 1 Trials

Significant improvements in the major clinical parameters were seen involving 25 patients who were followed for 85 days in a phase 1[19,20] clinical study assessing the safety and clinical response of brodalumab; 20 of the 25 subjects received a single dose of brodalumab and the remaining 5 received placebo. None of the 5 placebo patients achieved Psoriasis Area and Severity Index (PASI) 50. Significant PASI improvement occurred in the brodalumab higher dosing arms (350 mg SC and 700 mg IV). Six (of the 8) administered 350 mg achieved PASI 50, and 5 also achieved PASI 75. All 8 subjects in the 700 mg arm achieved PASI 50 by day 29, and all but 1 also achieved PASI 75 or greater (3 achieved PASI 90) at week 6 (Table 1). Decreases in IL-17 A, C, and F mRNA levels and improvements in histopathological parameters of epidermal thickness, Ki-67, keratin-16 gene expression, and infiltrating leukocyte subsets were observed.

Safety and adverse event profiles of brodalumab and placebo were similar. Two subjects (1 each from 350 mg and 700 mg arms) receiving brodalumab tested positive for non-neutralizing antibodies against brodalumab at week 12.

A Japanese phase 1 study[21] evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics in 8 healthy and 13 psoriatic patients, who received a single dose of brodalumab, added evidence that IL-17RA is a viable option against psoriasis. Three of the 6 patients who received a single dose of 140 mg SC achieved PASI 75 or greater. All 7 patients in the 350 mg SC arm achieved PASI 50, with 6 achieving PASI ≥75 (Table 1). In both healthy and psoriatic patients, brodalumab was well tolerated at the studied doses with respect to adverse events (AE), and safety profiles were similar to western trials. No anti-brodalumab antibodies were detected. Mean serum brodalumab concentration and PK parameters were comparable between psoriasis patients and healthy volunteers during the study. PK and occupancy data showed brodalumab is at maximum with a serum brodalumab concentration of approximately 1 ug/ml at 2 weeks after dosing 140 mg, implying 2-week interval SC dosing could maintain maximal IL-17RA occupancy.

Phase 2 Trials

A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study assessing short-term efficacy and safety of brodalumab was significant for PASI reductions at week 12 (primary endpoint).[22] Secondary endpoints of PASI 75, 90, and static physician global assessment (sPGA) at week 12 were also met. Statistically significant PASI improvement was seen as early as week 2. Dose response effect was seen in the study involving 198 patients who received either placebo, brodalumab at 70 mg, 140 mg, or 210 mg at weeks 0, 1, 2, and then every 2 weeks or monthly dosing of brodalumab 280 mg at weeks 0, 4, and 8; 188 patients completed through week 16. Primary endpoint was PASI improvement at week 12; 16% of patients in the placebo arm achieved significant (p<0.001) PASI improvement, whereas mean PASI improvements at week 12 for each brodalumab arm were as follows: bimonthly 70 mg (45%), 140 mg (85.9%), 210 mg (86.3%), and monthly 280 mg (76%). Seventy-two percent and 75% of the 140 mg and 210 mg recipients achieved PASI 75 or greater with 38% of the 140 mg arm and 62% of the 210 mg arm achieving PASI 100 (Table 1). At week 12, significant decreases of body surface area (BSA), sPGA, and Dermatology Quality of Life Index (DLQI) were also seen.

More AEs were reported in patients receiving brodalumab than placebo. Nasopharyngitis, upper respiratory infection, and arthralgia were the most common. Four serious adverse events (SAE) were reported during the trial including 2 cases of grade 3 asymptomatic neutropenia that normalized after withdrawal of brodalumab. Non-neutralizing antibodies were identified in all brodalumab arms (5–9.8%), which is similar to phase 1 observations.

A subanalysis of the data demonstrated patients with moderateto- severe plaque psoriasis received similar levels of benefit whether they had a history of prior biologic use or psoriatic arthritis.[23]

Of the original 198 patients, 181 (33 placebo and 148 brodalumab) enrolled in a 5-year (264 weeks) open-label extension (OLE) study and were initially administered brodalumab 210 mg every 2 weeks.[24] At week 52, a protocol modification switched patients <100 kg to 140 mg dosing every 2 weeks, while patients >100 kg were maintained at 210 mg every 2 weeks. During the OLE, 72% of patients maintained a sPGA of 0 or 1 (clear or almost clear) in comparison to 90% at week 12. Interim analysis at week 120 showed sustained clinical response and acceptable safety profiles through week 120. Non-neutralizing anti-brodalumab antibodies were discovered in 19 patients (11%) during the OLE, but only 2 of the 19 continued to show antibodies at final specimen collection. At interim analysis, 95% of patients reported an AE at some point during weeks 0–120 with nasopharyngitis being the most commonly reported AE at 26.5%. Fifteen SAEs were reported and 5 patients reported depression during the OLE.

A Japanese phase 2 study[25] was conducted with dosing regimens of 70 mg, 140 mg, 210 mg, or placebo SC at weeks 0, 1, 2, 4, 6, 8, and 10. Efficacy was similar to the western phase 2 study22 (Table 1). At week 12, the primary endpoint of mean percentage improvements in the PASI scores were 37.7%, 82.2%, 96.8%, and 9.4% in the 70 mg, 140 mg, 210 mg, and placebo groups, respectively (p<0.001). Similarly, more patients in the brodalumab arms achieved sPGA of 0 or 1 than in the placebo group at week 12. PASI 90 response rates in the 140 mg and 210 mg brodalumab groups were 64.9% and 91.9%, respectively.

Phase 3 Trials

Three phase 3 trials were conducted: AMAGINE-1 evaluated the efficacy, safety, and withdrawal and retreatment effect of brodalumab compared with placebo. AMAGINE-2 and AMAGINE-3, 12-week induction trials followed by rerandomization at week 12, evaluated the efficacy and safety of induction and maintenance of brodalumab compared with both ustekinumab and placebo.

AMAGINE-1. AMAGINE-1 was a phase 3, randomized, double-blind, placebo-controlled trial composed of a 12-week induction phase followed by a withdrawal/retreatment phase from weeks 12 through 52.[26,27] Using a 1:1:1 randomization, 661 patients were randomized to biweekly injections of 210 mg (n=222), 140 mg (n=219), and placebo (n=220) for 12 weeks. Re-randomization occurred at week 12 for patients with sPGA of 0/1 in the 210 mg and 140 mg arms to either continue their current dose or switch to placebo. Those re-randomized to placebo and subsequently lost disease control were restarted on their original dose. Subjects originally in the placebo arm and any patient with sPGA greater than 2 received brodalumab 210 mg every 2 weeks at week 12.

Co-primary endpoints of PASI 75 and sPGA 0/1 at week 12 were statistically significant for either dosage groups compared with placebo. At week 12, PASI 75 for placebo, brodalumab 140 mg, and brodalumab 210 mg were 2.7%, 60.3%, and 83.3%, respectively (Table 1), indicating a majority of brodalumab patients achieved 75% improvement of their psoriasis while only 2.7% of patients on placebo did so. Similarly, only 1.4% of patients on placebo compared to 53.9% on brodalumab 140 mg and 75.7% on brodalumab 210 mg had a treatment response of sPGA 0/1. Following withdrawal, most subjects were able to recover treatment sPGA response with retreatment.

No meaningful or dose effect on AE rates were observed through 52 weeks. Most reported AEs included nasopharyngitis, upper respiratory tract infection, and headache. Three SAEs were reported: cellulitis (n=2) and diverticulitis (n=1). Hospital Anxiety and Depression Scale was analyzed at week 12. Statistically significant decreases (p<0.001) in mean depression were observed for 210 mg (5.5% to 3.4%) and 140 mg (5.2% to 3.5%) doses at week 12. The placebo arm was unchanged (5.3% at baseline and 5.5% at week 12).

AMAGINE-2 and AMAGINE-3. Most recently, AMAGINE-2 and AMAGINE-3, two large, parallelgroup, double-blind, placebo-controlled, active comparatorcontrolled, multinational phase 3 trials were conducted involving a 12-week induction phase and 40-week maintenance phase.[28] During the 12-week induction phase, patients were randomized utilizing a 2:2:1:1 ratio to receive brodalumab 210 mg or 140 mg every 2 weeks, ustekinumab (45 mg for subjects <100 kg in weight and 90 mg for subjects >100 kg) every 4 weeks, or placebo.

All primary endpoints for all brodalumab doses against placebo and ustekinumab were met. Multiple endpoints were evaluated including primary endpoints of PASI 75 and sPGA 0/1 at week 12 of brodalumab compared to placebo. Another primary endpoint compared brodalumab to ustekinumab for PASI 100. Brodalumab 210 mg was superior (p<0.001) to ustekinumab at week 12 (AMAGINE-2: 44% vs 22%; AMAGINE-3 37% vs 19%). Brodalumab 210 mg was superior for maintenance of clinical responses.

Regarding secondary endpoints, both doses of brodalumab were superior to placebo at all secondary endpoints including PASI 100 and sPGA 0. While brodalumab 210 mg was superior to ustekinumab in both studies for PASI 100; brodalumab 140 mg was superior to ustekinumab in the AMAGINE-3 study (p<0.007) but not in the AMAGINE-2 trial (p=0.08); however, the nominal p-value was significant (p<0.001). The median time to PASI 75 of brodalumab 210 mg was 4 weeks vs. approximately 2 months for ustekinumab.

At week 12, patients on brodalumab were re-randomized to receive brodalumab 210 mg every 2 weeks, 140 mg every 2 weeks, 140 mg every 4 weeks, or 140 mg every 8 weeks. Placebo patients were switched to brodalumab 210 mg every 2 weeks. Patients on ustekinumab continued to receive ustekinumab; 55 (18%) and 69 (22%) subjects assigned to ustekinumab received rescue therapy with brodalumab at week 16. Patients on 210 mg or 140 mg of brodalumab every 2 weeks maintained or achieved a sPGA 0/1 at a higher rate than 140 mg every 4 weeks or 8 weeks (p<0.001). The majority of placebo patients who switched to brodalumab achieved PASI 100 at week 52; 40% of patients on ustekinumab who received brodalumab rescue therapy were able to achieve PASI 100.

Anti-brodalumab antibodies that were non-neutralizing and did not cause a loss in efficacy or AE, were detected in 1.8% and 2.3% in patients in AMAGINE-2 and AMAGINE-3, respectively. Four patients had antibodies detected at baseline. Six patients were positive for non-neutralizing anti-brodalumab antibodies after initiating ustekinumab.

Higher percentages of patients on brodalumab or ustekinumab reported an AE during the first 12 weeks than placebo patients. Most common AEs were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia. Non-serious and reversible neutropenia events were more frequent among brodalumab and ustekinumab. No clinically apparent differences were noticed among all study groups throughout the study. One patient (placebo followed by 210 mg of brodalumab) in AMAGINE-2 committed suicide 27 days after the last dose. An additional patient from AMAGINE-2 in the OLE receiving 210 mg of brodalumab every 2 weeks committed suicide 19 days after the last dose.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....