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A Phase 2b, Multicenter, Randomized, Placebo- and Active-comparator-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Bermekimab (JNJ-77474462) for the Treatment of Participants with Moderate to Severe Atopic Dermatitis

A Study of Bermekimab (JNJ-77474462) in the Treatment of Participants with Moderate to Severe Atopic Dermatitis (GENESIS)

198

The participants had a mean (SD) age of 36.0 (13.65) years, a mean (SD) body weight of 77.9 (18.00) kg, and a mean (SD) BMI of 26.3 (5.18) kg/m2. There were more male participants compared to female participants (111 [56.1%] versus 87 [43.9%]) and majority of the participants were White (142 [71.7%]). The most common medical histories were allergic/immunologic in nature (106 [53.5%] participants): food allergy, allergy to animals, allergic rhinitis, and seasonal allergy. Asthma was also a common history reported in 51 (25.8%) participants. Most participants in the study had previously used topical agents (197 [99.5%] participants). Systemic or intralesional corticosteroids were used by 82 (41.4%) participants.

A total of 268 participants with moderate to severe atopic dermatitis (AD) from 45 sites across Canada, Germany, Japan, Poland, and the United States of America were screened; of which, 57 (21.3%) participants were screen failures. Of these, 198 participants were randomized and received at least 1 dose of the assigned study intervention: 33 participants in the placebo treatment group, 100 participants in the combined bermekimab group (33 participants: 350 mg; 67 participants: 700 mg), and 65 participants in the dupilumab treatment group.

Summaries of AEs and other safety data are based on 198 participants who received at least 1 dose of double-blind study intervention. Adverse Events Through Week 16 - Eighteen (54.5%) participants from the placebo treatment group, 66 (66.0%) participants from the combined bermekimab treatment groups, and 33 (50.8%) participants from the dupilumab treatment group reported >=1 AEs through Week 16. - The highest number of TEAEs were reported in the SOC of Infections and infestations followed by Skin and subcutaneous tissue disorders. The most commonly reported TEAEs were dermatitis atopic, injection site erythema, and nasopharyngitis. - Two (6.1%) participants from the placebo treatment group, 6 (6.0%) participants from the combined bermekimab treatment group, and 2 (3.1%) participants from the dupilumab treatment group reported AEs that were assessed as severe through Week 16. The majority of these AEs were AD followed by single reports of eczema herpeticum, viral infection, AST increase, and toothache. - Five (15.2%) participants from the placebo treatment group, 24 (24.0%) participants from the combined bermekimab treatment group, and 11 (16.9%) participants from the dupilumab treatment group reported AEs that were assessed as related to the study intervention. Through Week 36 - 18 (54.5%) participants from the placebo treatment group, 84 (64.6%) participants from the combined bermekimab treatment groups, and 40 (61.5%) participants from the dupilumab treatment group reported>=1 AE. - The highest number of AEs were reported in the SOC of Infections and infestations followed by Skin and subcutaneous tissue disorders. The most commonly reported AEs were COVID-19 infection (25 events) and nasopharyngitis (27 events). - AEs of severe intensity were reported in 2 (6.1%) participants from the placebo group, 7 (5.4%) participants from the bermekimab combined treatment group, and 3 (4.6%) participants from the dupilumab treatment group. The most frequently reported severe AE was AD (9 participants). - AEs that were assessed as related to the study intervention were reported in 5 (15.2%) participants from the placebo group, 28 (21.5%) participants from the bermekimab combined treatment group, and 12 (18.5%) participants from the dupilumab treatment group. - Injection site erythema and upper respiratory tract infection (14 events each) and AD (12 events) were the most commonly reported AEs that were assessed as related to their respective study interventions. Deaths: There were no deaths reported during the study. SAEs: Through Week 16 Three (3.0%) participants from the combined bermekimab treatment group reported SAEs during the study; 2 cases of worsening AD, 1 case of severe AST increased, and 1 case of auricular haematoma most likely due to traumatic origin (exercise); none of these SAEs were assessed by the investigator as related to the study intervention. No SAEs were reported in the placebo and dupilumab treatment groups. Through Week 36 No new SAEs were reported after Week 16. At the time of this report, all reported SAEs had resolved. Discontinuations due to AEs: Through Week 16 One (3.0%) participant from the placebo treatment group and 4 (6.0%) participants from the bermekimab 700 mg treatment group discontinued study intervention due to AEs. The primary reason for discontinuation was AD. One (1.5%) participant from the bermekimab 700 mg treatment group discontinued study intervention due to moderate folliculitis. No discontinuations were reported in dupilumab treatment group. Through Week 36 One (3.0%) participant from the placebo treatment group, 1 (1.5%) participant from the dupilumab treatment group, and 5 (7.5%) participants from the bermekimab 700 mg treatment group discontinued study intervention due to AEs. The primary reason for discontinuation was AD. One (1.5%) participant from the bermekimab 700 mg treatment group discontinued study intervention due to moderate folliculitis while the 1 (1.5%) participant from the dupilumab treatment group discontinued due to COVID-19 infection. Other Adverse Events: - Injection Site Reactions (ISRs): Overall, 4 (3.1%) participants from the placebo treatment group, 10 (10.0%) participants from the combined bermekimab treatment group and 2 (3.1%) participants from the dupilumab treatment group reported ISRs. These events were all mild in intensity. The most common ISRs were erythema, swelling, and pruritis. - Anaphylactic or Serum Sickness Reactions: No anaphylactic or serum sickness reactions were reported during the study. - COVID-19 Associated AEs: 4 (12.1%) participants from the placebo treatment group, 19 (14.6%) participants from the combined bermekimab treatment group, and 5 (7.7%) participants from the dupilumab treatment group reported COVID-19 associated AEs. Of these, 2 (1.5%) participants from the combined bermekimab treatment group were asymptomatic while 1 (1.5%) participant from the dupilumab treatment group had suspected COVID-19 infection. The majority of the events were assessed as mild or moderate in severity and not related to the study intervention. Clinical Laboratory Evaluations: - Hematology: There were no clinically significant findings. Through Week 16: two instances of CTCAE Grade 2 neutropenia in the bermekimab 700 mg group were reported. Through Week 36: Apart from the 2 participants with neutropenia reported through the Week 16 timepoint, an additional case of Grade 2 neutropenia was observed in a participant who subsequently had switched from the placebo treatment group to the bermekimab 700 mg treatment group. The participant had Grade 1 neutropenia (1.79 x 10^9/L) on Study Day 85 followed by Grade 2 neutropenia (1.39 x 10^9/L) on Study Day 203. No infection associated with any of these instances of neutropenia were reported. The participant had recovered whilst continuing to receive the study intervention. - Clinical Chemistry: There were no clinically significant findings. Other Safety Evaluations There were no clinically meaningful findings in the vital sign measurements and ECG data in this study. The assessments and observations were comparable across intervention groups.

Efficacy Results: The primary efficacy analysis set was planned to be based upon the FAS, defined as randomized participants (n=199) who received at least 1 dose of study intervention (n=198). Due to the early termination of this study, a large number of participants discontinued treatment prior to Week 16. The mFAS was defined as those FAS participants who could have reached a visit by the time of the decision was made to terminate the study on 02 February 2022. The main analyses for the primary and major secondary endpoints are based on the mFAS through Week 16 (excluded participants with projected Week 16 visit occurring after study termination date). The mFAS through Week 16 included a total of 130 participants: 21 participants in the placebo treatment group, 24 participants in the bermekimab 350 mg treatment group, 42 participants in the bermekimab 700 mg treatment group, and 43 participants in the dupilumab group treatment group. Primary Efficacy Endpoint: EASI-75 The treatment difference observed in the bermekimab treatment groups (350 mg and 700 mg) versus the placebo group at Week 16 was similar ie, 7.1% (95% CI: -12.1%, 26.2%; p-value: 0.489) and 7.1% (95% CI: -9.4%, 23.7%; p-value: 0.448), respectively. The treatment difference observed in the dupilumab treatment group versus the placebo group was similar ie, 42.0% (95% CI: 22.9%, 61.1%; p-value: 0.001) as previously reported. Secondary Efficacy Endpoints: EASI-90 The treatment difference observed in the bermekimab treatment groups (350 mg and 700 mg) versus the placebo group at Week 16 was low and similar ie, 2.9% (95% CI: -15.1%, 20.9%; p-value: 0.758) and 2.4% (95% CI: 13.2%, 18.0%; p-value: 0.780), respectively. The treatment difference for the dupilumab group versus the placebo group was similar to results previously reported ie, 25.4% (95% CI: 6.5%, 44.2%; p-value: 0.034). vIGA AD of 0 or 1 and a Reduction from Baseline of >=2 Points The treatment difference observed in the bermekimab treatment groups (350 mg and 700 mg) versus the placebo group at Week 16 was low and similar ie, 2.9% (95% CI: -15.1%, 20.9%; p-value: 0.758) and 2.4% (95% CI: 13.2%, 18.0%; p-value: 0.780), respectively. The treatment difference for the dupilumab group versus the placebo group was similar to results previously reported ie, 18.0% (95% CI: -0.1%, 36.1%; p-value: 0.103). Proportion of Participants with Improvement (Reduction) of Eczema-Related Itch NRS >=4 The treatment difference observed in the bermekimab treatment groups (350 mg and 700 mg) versus the placebo group at Week 16 was 9.3% (95% CI: -13.3%, 31.8%; p-value: 0.434) and -4.6% (95% CI: -21.0%, 11.7%; p-value: 0.559), respectively. The response rate in dupilumab group was numerically higher (21.8% [95% CI: 1.1%, 42.5%; p-value: 0.083]) than the placebo group but not statistically significant. A small number of participants who had NRS >=4 at the baseline may have impacted this analysis. Proportion of Participants Achieving EASI-75 and EASI-90 Through Week 16 The dupilumab treatment group showed clear separation from placebo starting from Week 2 in EASI-75 but the bermekimab treatment groups (350 mg and 700 mg) did not show clear separation from placebo over time. The number of participants who achieved EASI-90 response through Week 16 was low for the bermekimab treatment arms. Proportion of Participants Achieving EASI-75 and EASI-90 from Week 16 Through Week 36 At Week 16, participants in the placebo group crossed over to receive bermekimab 700 mg weekly. At Week 16, participants who achieved an EASI-75 response in bermekimab 700 mg group were rerandomized in a 1:1 ratio either to continue to receive bermekimab 700 mg weekly, or to receive bermekimab 350 mg weekly. Participants who did not achieve an EASI-75 response continued to receive bermekimab 700 mg weekly. Participants who switched from the placebo treatment group to the bermekimab 700 mg treatment group showed some improvement based on EASI-75. The number of EASI-75 responders in the bermekimab treatment group were low and maintained over time. The number of participants who reached Week 36 was small and the number of participants in each group was small, therefore the results were difficult to interpret. Pharmacokinetic Results: Concentrations over time: - For the bermekimab 350 mg qw group, the trough serum bermekimab concentration reached steady-state by approximately Week 12. The mean and median steady-state trough serum bermekimab concentrations for this group were 46.90 and 49.67 mcg/mL, respectively, at Week 12 and were maintained through Week 32 (mean: 48.68 mcg/mL; median: 47.28 mcg/mL). - For the bermekimab 700 mg, steady-state trough serum bermekimab were achieved by Week 4. The mean and median trough serum bermekimab concentrations for this group at Week 4 were 83.07 and 91.37 mcg/mL, respectively. - For the placebo to bermekimab 700 mg qw crossover group, the mean and median steady-state trough serum bermekimab concentrations at Week 20 were 86.49 and 96.93 mcg/mL, respectively, and were maintained through Week 28 (mean: 99.41 mcg/mL; median: 122.01 mcg/mL). Immunogenicity Results: Antibodies to Bermekimab The overall incidence of antibodies to bermekimab was 6.2% (6/97) through Week 16 and 12.1% (14/116) through Week 36. Among the 14 participants who were positive for antibodies to bermekimab through Week 36, 1 (5.3%), 9 (27.3%) and 4 (6.3%) participants were in the placebo to bermekimab 700 mg qw crossover group, bermekimab 350 mg qw group and bermekimab 700 mg qw treatment group, respectively. The highest titer of antibodies to bermekimab observed was 1:2880. Most of the participants (10 out of 14 participants) who were positive for antibodies to bermekimab had low titers (<1:100). Antibodies to Bermekimab and Serum Bermekimab Concentrations In the bermekimab 700 mg qw treatment group, participants with lower mean and median serum bermekimab concentrations were positive for antibodies to bermekimab. However, the number of participants who were positive for antibodies to bermekimab was very small (n=1 to 4 at different visits). No apparent difference in mean serum bermekimab concentrations was observed between participants who were positive and negative for antibodies to bermekimab in the 700 mg qw group through Week 36. Only 1 participant in the placebo to bermekimab 700 mg qw crossover group was positive for antibodies to bermekimab. Hence effect on serum bermekimab concentrations cannot be evaluated.

The results of EASI, IGA, and itch NRS suggests that there may not have been substantial additional benefit for participants with AD from bermekimab. Hence, following the interim analysis, this study was terminated. Based on the available safety data, bermekimab 700 mg and 350 mg qw were well tolerated in participants with AD and no new safety concerns were observed with the study participants.. All ISRs were mild in intensity and there were no serious cases or discontinuations due to ISR.

Mar. 31, 2023

Yes

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

https://jrct.mhlw.go.jp/latest-detail/jRCT2011210006

Nishikawa Kazuko

Janssen Pharmaceutical K.K.

3-5-2 Nishikanda, Chiyoda-ku, Tokyo

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Medical Information Center

Janssen Pharmaceutical K.K.

3-5-2 Nishikanda, Chiyoda-ku, Tokyo

+81-120-183-275

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Complete

June. 04, 2021

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

- Be otherwise healthy on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiograms (ECGs) performed at screening. Any abnormalities, must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator
- Have atopic dermatitis (AD) for at least 1 year (365 days) prior to the first administration of study intervention as determined by the investigator through participant interview and/or review of the medical history
- Have a history of inadequate response to treatment for AD with topical medications or for whom topical treatments are otherwise medically inadvisable (example [eg], due to important side effects or safety risks)
- Be considered, in the opinion of the investigator, a suitable candidate for dupilumab (DUPIXENT) therapy according to their country's approved DUPIXENT product labeling
- Have an eczema area and severity index (EASI) score greater than or equal (>=) to 16 at screening and at baseline
- Have an investigator global assessment (IGA) score >=3 and involved body surface area (BSA) >=10 percent (%) at screening and baseline

- Has a current diagnosis or signs or symptoms of severe, progressive, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances
- Has unstable cardiovascular disease, defined as a recent clinical deterioration (eg, unstable angina, rapid atrial fibrillation) in the last 3 months or a cardiac hospitalization within the last 3 months
- Has or has had a serious infection (eg, sepsis, pneumonia, or pyelonephritis), or has been hospitalized or received intravenous (IV) antibiotics for an infection during the 2 months before screening
- Has or has had herpes zoster within the 2 months before screening
- Has a history of being human immunodeficiency virus (HIV) antibody-positive, or tests positive for HIV at screening

Both

Dermatitis, Atopic

Placebo :
Placebo will be administered subcutaneously.
Group 1: Placebo
Group 4: Dupilumab

Bermekimab
Bermekimab will be administered subcutaneously.
Group 1: Placebo
Group 2: Bermekimab
Group 3: Bermekimab
Group 4: Dupilumab

Dupilumab
Dupilumab will be administered subcutaneously.
Group 4: Dupilumab

Percentage of Participants With Eczema Area and Severity Index (EASI)-75 (Greater Than or Equal to [>=] 75 Percent (%) Improvement From Baseline) for Efficacy of Bermekimab at Week 16

- Percentage of Participants With Both Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) Score of 0 or 1 and a Reduction From Baseline of >=2 Points for Additional Assessments of Bermekimab at Week 16
- Percentage of Participants With Improvement (Reduction) of Eczema-Related Itch Numeric Rating Scale (NRS) Value of >=4 From Baseline to Week 16 Among Participants With a Baseline Itch Value >=4 for Additional Assessments of Bermekimab
- Percentage of Participants With EASI-90 (>=90% improvement in EASI from Baseline) for Additional Assessments of Bermekimab at Week 16
- Percentage of Participants With EASI-75 (Greater Than or Equal to [>=] 75 Percent (%) Improvement From Baseline) for Efficacy of Bermekimab Relative to Dupilumab at Week 16
- Percentage of Participants With EASI-90 (>=90% improvement in EASI from Baseline) for Efficacy of Bermekimab Relative to Dupilumab at Week 16
- Percentage of Participants With Both vIGA-AD Score of 0 or 1 (on a 5-point scale) and a Reduction From Baseline of >=2 Points for Efficacy of Bermekimab Relative to Dupilumab at Week 16
- Percentage of participants With Improvement (Reduction) of Eczema-Related Itch NRS Value of >=4 From Baseline to Week 16 Among Participants With a Baseline Itch Value >=4 for Efficacy of Bermekimab Relative to Dupilumab
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
- Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
- Serum Bermekimab Concentration
- Number of Participants with Anti-Bermekimab Antibodies

+81-11-221-8807

Mar. 24, 2021

Canada/Germany/Poland/United States of America