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A Phase 3, placebo-controlled, double-blind comparative study of KHK4827 with an open-label extension period in subjects with systemic sclerosis who have moderate to severe skin thickening

A Phase 3 study of KHK4827 in patients with systemic sclerosis

100

In the KHK4827 group and the placebo group, females accounted for 43 of 50 participants (86.0%) and 44 of 50 participants (88.0%), respectively. The mean age +/- standard deviation (SD) (hereinafter the same) was 50.7 +/- 12.20 years old in the KHK4827 group and 50.1 +/- 12.66 years old in the placebo group. In both treatment groups, the majority of participants were younger than 65 years of age, accounting for 43 participants (86.0%) in the KHK4827 group and 42 participants (84.0%) in the placebo group. Mean body weight was 57.26 +/- 11.405 kg in the KHK4827 group and 54.97 +/- 7.786 kg in the placebo group. Mean body mass index (BMI) was 22.69 +/- 4.231 kg/m2 in the KHK4827 group and 21.58 +/- 2.750 kg/m2 in the placebo group. The two treatment groups were balanced with respect to sex (proportion of females), age, body weight, height, and BMI. The mean duration of systemic sclerosis was 16.18 +/- 16.234 months in the KHK4827 group and 19.32 +/- 16.638 months in the placebo group. Participants with a disease duration of <=1 year accounted for 30 (60.0%) and 26 (52.0%) participants in the KHK4827 group and placebo group, respectively, while participants with a disease duration of >1 year accounted for 20 (40.0%) and 24 (48.0%) participants, respectively. Approximately half of the participants in both treatment groups had a disease duration of <=1 year.

In this study, 100 participants were randomized to either the KHK4827 group or the placebo group. All participants in the KHK4827 group (n=50) and the placebo group (n=50) received the study treatment. (Hereinafter, participants administered KHK4827 will be referred to as "KHK4827 Pooled".) During the double-blind treatment period (up to Week 52), 13 participants (6 in the KHK4827 group and 7 in the placebo group) discontinued the study, and 87 participants (44 in the KHK4827 group and 43 in the placebo group) completed the Week 52 assessment. A total of 86 participants, excluding 1 participant in the placebo group, entered the extension treatment period after Week 52. The number of participants who switched to active treatment after Week 24 was markedly higher in the placebo group, with 1 participant (2.0%) in the KHK4827 group compared with 38 participants (76.0%) in the placebo group. Overall, 81 participants (81.0%) experienced self-administration by Week 52. Of the 86 participants who entered the extension treatment period, 35 subsequently discontinued the study.

During the double-blind treatment period, Treatment-Emergent Adverse Events (TEAEs) were reported in 42 of 50 participants (84.0%) in the KHK4827 group and 41 of 50 participants (82.0%) in the placebo group. Drug-related TEAEs were reported in 11 participants (22.0%) in the KHK4827 group and 2 participants (4.0%) in the placebo group. By preferred term, the most frequently reported TEAE in the KHK4827 group was oral candidiasis was the most frequently reported TEAE, occurring in 8 participants (16.0%), followed by upper respiratory tract infection in 6 participants (12.0%), and pharyngitis, pyrexia, contact dermatitis, asteatotic eczema, and stomatitis in 4 participants each (8.0%). In the placebo group, upper respiratory tract infection, which occurred in 7 participants (14.0%), followed by pharyngitis in 6 participants (12.0%), pyrexia and eczema in 5 participants each (10.0%), and arthropod bite and back pain in 4 participants each (8.0%). Oral candidiasis, the most frequently reported TEAE in the KHK4827 group, was reported in 1 participant (2.0%) in the placebo group. In addition, asteatotic eczema and stomatitis were reported in 4 participants (8.0%) in the KHK4827 group, whereas no cases were reported in the placebo group. In participants who received KHK4827 during the entire study period (hereinafter referred to as "KHK4827 pooled"), a total of 95 participants received KHK4827 (total exposure: 361.0 subject-years; maximum treatment duration: up to Week 302). At least one TEAE was reported in 91 of 95 participants (95.8%). For exposure-adjusted TEAEs, 772 events (213.9 events per 100 subject-years) were reported. By event rate, vaccination complication was the most frequently reported event at 19.4 events per 100 subject-years, followed by nasopharyngitis (15.8 events per 100 subject-years), COVID-19 (9.4 events per 100 subject-years), and oral candidiasis (8.3 events per 100 subject-years). No TEAEs leading to death were reported during the study. Other serious TEAEs were reported in 1 participant (2.0%) each in the KHK4827 group and the placebo group during the double-blind treatment period. These events were systemic lupus erythematosus in 1 participant in the placebo group and upper gastrointestinal haemorrhage in 1 participant in the KHK4827 group. A causal relationship to study treatment was ruled out for both events. For exposure-adjusted serious TEAEs, 16 events (4.4 events per 100 subject-years) were reported in 9 participants in the KHK4827 pooled population. By event type, upper gastrointestinal haemorrhage and pneumothorax were each reported twice (0.6 events per 100 subject-years), while all other events were reported once each (0.3 events per 100 subject-years). In addition, one case of Grade 3 cellulitis was reported as a serious drug-related TEAE.

The least squares (LS) mean change from baseline in modified Rodnan's total skin thickness score (mRSS) at Week 24, estimated using a mixed-effects model for repeated measures (MMRM), which was the primary endpoint, was -16.8 (95% CI: -18.7, -14.8) in the KHK4827 group and 4.4 (95% CI: 2.5, 6.4) in the placebo group. The difference in the change from baseline in mRSS between the KHK4827 group and the placebo group was -21.2 (95% CI: -23.9, -18.5) (p<0.0001). For the primary endpoint, a statistically significant difference was observed between the KHK4827 group and the placebo group. In addition, subgroup analyses of the primary endpoint were performed according to demographic characteristics (age, sex, and body weight), baseline disease characteristics (baseline mRSS, oral corticosteroid use, concomitant use of bosentan, disease duration, disease subtype, and antinuclear antibody status), and self-administration status. In the subgroups evaluated (excluding subgroups based on self-administration status), the LS mean change from baseline in mRSS at Week 24 showed a markedly greater improvement in the KHK4827 group than in the placebo group, and the magnitude of the treatment difference was generally consistent with that observed in the overall population. In the KHK4827 group, mRSS at Week 24 was markedly lower than that in the placebo group across all subgroups evaluated.

The following results were obtained for the secondary endpoints. - The least squares (LS) mean change from baseline in mRSS at Week 52, estimated using a mixed-effects model for repeated measures (MMRM), was -18.9 (95% CI: -20.7, -17.2) in the KHK4827 group and 0.1 (95% CI: -2.5, 2.7) in the placebo group. The difference in the change from baseline in mRSS between the KHK4827 group and the placebo group was -19.1 (95% CI: -22.0, -16.1) (p<0.0001). - Regarding the change from baseline in mRSS at each assessment time point, mRSS increased from Week 2 onward in the placebo group. At Week 24 (n=47), the change and percent change from baseline in mRSS were 4.8 +/- 5.32 (mean +/- standard deviation [SD], hereinafter the same) and 22.66 +/- 24.803%, respectively. In the KHK4827 group, a decrease in mRSS was observed from Week 2, and mRSS decreased over time through Week 24. At Week 24 (n=47), the change and percent change from baseline were -17.1 +/- 7.10 and -79.66 +/- 26.648%, respectively. In addition, from Week 12 onward, some participants had a percent change from baseline in mRSS of -100% (mRSS = 0). Furthermore, in the KHK4827 group, mRSS continued to decrease after Week 24, and at Week 52 (n=43), the change and percent change from baseline in mRSS were -19.2 +/- 6.69 and -87.72 +/- 21.735%, respectively. In contrast, in the placebo group, mRSS increased from Week 2 onward. In the KHK4827 group, the decrease in mRSS observed by Week 24 was maintained through Week 52. - Regarding improvement from baseline in mRSS, in the placebo group, up to 6 participants showed an improvement of >=5 points or >=20% from baseline in mRSS at each assessment time point through Week 52, and up to 2 participants showed an improvement of >=40%; however, no participants showed an improvement of >=60%. Through Week 24 (n=47 to 50), the proportion of participants who showed an improvement of >=5 points or >=20% from baseline in mRSS ranged from 2.0% to 12.8%. In the KHK4827 group, by Week 4, participants who showed an improvement of >=5 points or >=20% from baseline in mRSS each accounted for 67.3% (33/49 participants), indicating improvement early after the start of study treatment. In addition, at Week 24, 89.4% (42/47 participants) showed an improvement of >=60%, and the high rate of improvement was maintained through Week 52. - Regarding worsening from baseline in mRSS, the proportion of participants who experienced worsening from baseline in mRSS of >=5 points and >=20% at least once through Week 52 exceeded 80% in the placebo group, whereas it was markedly lower in the KHK4827 group at 14.0%. - The number of new digital ulcers at each assessment time point was evaluated. The number of new digital ulcers at Week 24 was 3.6 +/- 5.47 in the placebo group (n=47) and 0.0 +/- 0.20 in the KHK4827 group (n=47). At Week 52, the number of new digital ulcers was 0.1 +/- 0.38 in the placebo group (n=7) and 0.1 +/- 0.39 in the KHK4827 group (n=43). The proportion of participants with no cumulative new digital ulcers was 27.7% (13/47 participants) and 57.1% (4/7 participants) in the placebo group at Week 24 and Week 52, respectively, and 91.5% (43/47 participants) and 88.4% (38/43 participants) in the KHK4827 group, respectively. In the KHK4827 group, many participants did not develop any new digital ulcers from the start of study treatment through Week 52. - Regarding pulmonary function, FEV1, %DLCO, and %FVC decreased or tended to decrease after the start of study treatment in the placebo group, whereas these parameters showed no change from baseline and were maintained through Week 52 in the KHK4827 group. TLC showed little change from baseline in either treatment group. - Regarding the severity of lung lesions, the proportions of participants whose condition worsened at Week 24 compared with baseline were 17.0% and 2.1% in the placebo and KHK4827 groups, respectively, while the proportions of participants whose condition improved were 2.1% and 10.6%, respectively. Worsening was more frequent in the placebo group, whereas improvement was more frequent in the KHK4827 group. - For Patient Global Assesment (PGA) and Clinician Global Assesment (CGA), the placebo group showed a tendency toward worsening at Week 24, whereas the KHK4827 group showed changes toward improvement (decreased values). In particular, the mean CGA value decreased further at Week 52 compared with Week 24. - For Composite Response Index in dcSSc (CRISS), the values in the placebo group were 0.091 +/- 0.2442 at Week 24 (n=47) and 0.509 +/- 0.3509 at Week 52 (n=7). In the KHK4827 group, the values were 0.926 +/- 0.2517 at Week 24 (n=47) and 0.949 +/- 0.2035 at Week 52 (n=43). - The proportion of participants who experienced worsening of the underlying disease at least once after the start of study treatment through Week 52, defined as a >10% decrease in %FVC from baseline or an increase in mRSS of >=5 points and >=20% from baseline, was 43/50 (86.0%) in the placebo group and 7/50 (14.0%) in the KHK4827 group. The proportion of participants with worsening of the underlying disease was markedly lower in the KHK4827 group than in the placebo group. - Regarding the J-HAQ-DI score, in the placebo group, the number of participants with a score >=0.5, the threshold for functional remission, more than doubled from baseline by Week 24, indicating worsening in many participants. In contrast, in the KHK4827 group, the number of participants with a score >=0.5 at Week 24 (8/47 participants, 17.0%) decreased compared with baseline (14/50 participants, 28.0%). - Regarding FACIT-Fatigue, the FACIT-Fatigue subscale score decreased at Week 24 in the placebo group, indicating worsening. Among participants observed through Week 52, the FACIT-Fatigue subscale score subsequently increased. In contrast, no marked changes in the FACIT-Fatigue subscale score were observed after the start of study treatment in the KHK4827 group, although the score tended to increase from baseline. - Regarding the Total FSSG score, the mean score increased in the placebo group at Week 24, and the number of participants with a score >=8 increased compared with baseline. In contrast, the mean score decreased in the KHK4827 group, and the number of participants with a score >=8 decreased markedly compared with baseline.

For the primary efficacy endpoint, change from baseline in mRSS at Week 24 was significantly improved with KHK4827 versus placebo (p<0.0001). Regarding safety, TEAE incidence during the double-blind treatment period was similar between placebo (82.0%) and KHK4827 (84.0%). Among participants receiving KHK4827 throughout the study, TEAEs were reported in 91/95 participants (95.8%), with 772 events in total (213.9 events per 100 subject-years).

Yes

The datasets generated and/or analyzed during the study sponsored by Kyowa Kirin will be available in the Vivli repository, https://vivli.org/ourmember/kyowa-kirin/ as long as conditions of data disclosure specified in the policy section of the Vivli website are satisfied.

Kyowa Kirin Co., Ltd.

1-9-2, Otemachi , Chiyoda-ku, Tokyo, 100-0004, Japan

clinical.info.jp@kyowakirin.com

Kyowa Kirin Co., Ltd.

1-9-2, Otemachi , Chiyoda-ku, Tokyo, 100-0004, Japan

+81-3-5205-7200

clinical.info.jp@kyowakirin.com

completed

May. 23, 2019

Interventional

Double-blind, placebo-controlled and open-label extension study

treatment purpose

3

- Patient meets the diagnostic criteria defined in the guidelines for systemic sclerosis (Japanese Dermatological Association 2016) at screening
- Patient with onset of skin phenomenon within 60 months before enrollment
- Patient with moderate to severe skin thickening defined by a modified Rodnan total skin thickness score (mRSS) of 10 to < 30 at screening and enrollment and with progressing skin thickening.

1)Any of the following significant concomitant diseases:
- Type 1 diabetes
- Poorly controlled type 2 diabetes (HbA1c > 8.5%)
- Congestive heart failure (Class II to IV of the New York Heart Association Functional Classification)
- Myocartial infarction, unstable angina, or stroke occurring within 12 months before the first dose of investigational product
- Poorly controlled hypertension (systolic pressure > 150 mm Hg or diastolic pressure > 90 mg Hg at screening)
- Severe chronic lung disease (%FVC < 60% and %DLco < 40%, calculated according to the Reference Values for Spirometry, Including Viral Capacity, in Japanese Adults Calcluated with the LMS Method and Compared with Previous Values [Japanese Respiratory Society])
- Major chronic inflammatory diseases or connective tissue diseases other than scleroderma
2) Patient has a history or evidence of a psychiatric disorder, alcohol and/or substance abuse, or any other mental health disorder that, in the opinion of the investigators, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
3) Patient has a history or evidence of suicidal ideation (severity of 4 or 5) or any suicidal behavior based on an assessment with the Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment
4) Patient has severe depression based on a total score of >= 15 on the Patient Health Questionnaire-8 (PHQ-8) at enrollment

Both

Systemic sclerosis

investigational material(s)
Generic name etc : KHK4827
INN of investigational material : Brodalumab
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : 210 mg Q2W, SC

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : 210 mg Q2W, SC

efficacy
Change from baseline in mRSS at Week 24

efficacy
Change from baseline in mRSS at Week 52

Jan. 28, 2019