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A Phase IIb, Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Dose Ranging Study of a Subcutaneous Anti-OX40L Monoclonal Antibody (KY1005) in Moderate-to-Severe Atopic Dermatitis

Study Testing Response Effect of KY1005 Against Moderate-to-Severe Atopic Dermatitis, The STREAM-AD Study (STREAM-AD) (STREAM-AD)

390

Overall Population: Overall, the mean (standard deviation [SD]) age of the participants enrolled was 37.8 (14.36) years and 20 [5.1%] participants were aged 65 years or older. The majority of participants were male (219 [56.2%]), White (307 [78.7%]) and not Hispanic or Latino (376 [96.4%]). A total of 60 (15.4%) participants were Asian, 20 (5.1%) participants were Black or African American, and 3 (0.8%) participants were of another race. The mean (SD) duration of AD from first diagnosis to randomization was 22.27 (16.499) years. Mean (SD) EASI score was 28.9 (10.65). A total of 279 (71.5%) participants had an EASI score of >21 (severe) and 111 (28.5%) participants had an EASI score of <=21(moderate). A total of 280 (71.8%) participants had IGA 3 (moderate) and 110 (28.2%) participants had IGA 4 (severe). Mean (SD) baseline weekly average pruritus NRS was 7.32 (1.327).

Baseline to Week 24 (Overall Population): - Randomized: 390 (KY1005 250 mg with 500 mg loading dose [LD]: 77, KY1005 250 mg no LD: 78, KY1005 125 mg: 77, KY1005 62.5 mg: 79, Placebo: 79) (hereinafter in the same group order) - Randomized and treated: 388 (77, 78, 77, 78, 78) - Completed treatment from baseline to Week 24: 323 (68, 62, 69, 67, 57) - Discontinued from study prior to Week 24: 51 (8, 12, 8, 7, 16) From Week 24 Onwards (Responders Population): - Re-randomized: 190 (KY1005 250 mg with 500 mg LD: 13, KY1005 250 mg no LD: 12, KY1005 125 mg: 12, KY1005 62.5 mg: 7, KY1005 250 mg with 500 mg LD to placebo: 34, KY1005 250 mg no LD to placebo: 28, KY1005 125 mg to placebo: 33, KY1005 62.5 mg to placebo: 35, Placebo to placebo: 16) (hereinafter in the same group order) - Re-randomized and treated: 186 (13, 11, 12, 7, 34, 28, 32, 34, 15) - Completed the study: 171 (13, 12, 10, 7, 31, 27, 30, 29, 12) - Discontinued from study: 19 (0, 0, 2, 0, 3, 1, 3, 6, 4) - Completed safety follow-up: 70 (5, 5, 8, 4, 9, 10, 12, 14, 3)

No treatment-emergent adverse event (TEAE) led to death during the study. Baseline to Week 24 (Overall safety Population): Overall, 65.7% of participants (255/388 participants) reported at least one TEAE and the incidence of TEAEs was similar across the treatment groups (51 [66.2%], 52 [66.7%], 52 [67.5%], 53 [67.9%], and 47 [60.3%] participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg KY1005 groups and placebo group, respectively). The TEAEs by preferred term (PT) with total incidence of >=5% in any treatment group, and numerically more frequent over the placebo group were nasopharyngitis, COVID-19, headache, upper respiratory tract infection, blood creatine phosphokinase increased, and hypertension. A total of 3 (3.9%), 8 (10.3%), 6 (7.8%), and 6 (7.7%) participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg KY1005 groups, respectively, and 6 (7.7%) participants placebo group had treatment-related TEAEs reported by the investigator. No serious TEAE was reported in the 250 mg no LD group. Two (2.6%) participants in the 250 mg with 500 mg LD group reported 4 serious TEAEs (metabolic acidosis, alcohol withdrawal syndrome, and supraventricular tachycardia in the first participant and tension headache in the second participant); 1 (1.3%) participant in the 125 mg group reported 1 serious TEAE of dermatitis bullous; 5 (6.4%) participants in the 62.5 mg group reported 5 serious TEAEs (appendicitis, pharyngitis, haemorrhoidal haemorrhage, osteoarthritis, and forearm fracture); and 1 (1.3%) participant in the placebo group reported 1 serious TEAE of atrial fibrillation. Only 1 (1.3%) participant in the 125 mg KY1005 group reported a serious TEAE (dermatitis bullous) that was considered as related to the treatment by the investigator. A total of 14 participants in the KY1005 dose groups (3 [3.9%], 5 [6.4%], 1 [1.3%], 5 [6.4%] participants in the KY1005 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups) experienced 16 TEAEs leading to study treatment discontinuation and 5 (6.4%) participants experienced 5 TEAEs leading to study treatment discontinuation in the placebo group. No participant in the 125 mg and 62.5 mg KY1005 groups had TEAEs leading to study discontinuation. Overall, 3 participants discontinued the study due to TEAEs: face oedema in 1 participant in the KY1005 250 mg with 500 mg LD group, anaemia in 1 participant in the KY1005 250 mg no LD group, and hypersensitivity vasculitis in 1 participant in the placebo group. From Week 24 Onwards (Responders Safety Population): The incidence of TEAEs was 11 (84.6%), 7 (63.6%), 8 (66.7%), and 4 (57.1%) participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg KY1005 groups, respectively; 23 (67.6%), 22 (78.6%), 28 (87.5%), 23 (67.6%) in the corresponding withdrawal (placebo transition) groups, respectively; and 10 (66.7%) in the placebo to placebo group. The TEAEs by PT with total incidence of >=15% in any treatment group and TEAEs by PT numerically more frequent over placebo to placebo group were nasopharyngitis, headache and viral upper respiratory tract infection. Among the KY1005 groups, only 1 treatment-related TEAE (mild viral upper respiratory tract infection) was reported by the investigator in the KY1005 250 mg no LD group. All other TEAEs reported as treatment-related (10 TEAEs in 9 participants) occurred in participants during their time in the treatment withdrawal (placebo transition) groups. One participant in 250 mg no LD to placebo group reported a treatment-related serious adverse event (SAE) (abnormal loss of weight). One (7.7%) participant in the KY1005 250 mg with 500 mg LD group reported 1 SAE of umbilical hernia; 1 (2.9%) participant in the KY1005 250 mg with 500 mg LD to placebo group reported 1 SAE of tendon rupture; 2 (7.1%) participants in the KY1005 250 mg no LD to placebo group reported 3 SAEs (abnormal loss of weight and spinal osteoarthritis in 1 participant and rotator cuff syndrome in other); and 1 (8.3%) participant in the KY1005 125 mg group reported 1 SAE of ankle fracture. One (8.3%) participant in the 125 mg group reported 4 nonserious TEAEs leading to treatment discontinuation. One (2.9%) participant in the 62.5 mg KY1005 to placebo group reported a nonserious TEAE of dermatitis atopic (moderate) leading to study discontinuation.

Primary Efficacy Endpoint: Percentage Change in EASI From Baseline to Week 16 The statistical analysis results of the primary estimand showed a statistically significant improvement in the percent change in EASI score from baseline at Week 16 in all the KY1005 groups of 250 mg with 500 mg LD (P<0.0001), 62.5 mg (P<0.0001), 250 mg no LD (P<0.0001), and 125 mg (P=0.0002) as compared with placebo. The mean (SD) percent change in EASI score from baseline to Week 16 was highest in 250 mg with 500 mg LD group (-62.35 [32.322]), followed by 62.5 mg (-61.51 [31.663]), 250 mg no LD (-56.98 [37.444]), and 125 mg (-52.50 [40.820]). No clear dose response proportionality was observed. Secondary Efficacy Endpoints: The following focuses on the results of the key secondary efficacy endpoints. Percentage Change from Baseline in EASI at Day 169 (Week 24): A greater improvement in the percent change in EASI score from baseline was observed at Week 24 in all the KY1005 dose groups of 250 mg with 500 mg LD (P<0.0001), 62.5 mg (P<0.0001), 125 mg (P=0.0001), and 250 mg no LD (P=0.0002) groups as compared with placebo. The mean (SD) percent change in EASI score from baseline was highest in the 250 mg with 500 mg LD group (-68.01 [36.052]), followed by the 62.5 mg (-57.37 [40.225]), 125 mg (-56.72 [44.271]), and 250 mg no LD (-55.84 [40.299]) groups. Percentage of Participants With At Least a 75% Reduction from Baseline in EASI (EASI 75): At Week 16, all KY1005 dose groups showed greater proportions of participants reaching EASI 75 (31 [40.3%], 30 [38.5%], 33 [42.9%], and 32 [40.5%] participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups, respectively) as compared with placebo (9 [11.4%] participants). While all KY1005 dose groups showed similar response rates, the 125 mg group showed the greatest numerical proportionate difference (0.31) at Week 16 followed by the 62.5 mg (0.29), the 250 mg with 500 mg LD (0.29), and the 250 mg no LD (0.27) groups versus the placebo group. At Week 24, all KY1005 dose groups showed greater proportions of participants reaching EASI 75 (42 [54.5%], 30 [38.5%], 38 [49.4%], and 32 [40.5%] participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups, respectively) compared with placebo (14 [17.7%] participants). The 250 mg with 500 mg LD group showed the greatest numerical proportionate difference (0.36) at Week 24 followed by the 125 mg (0.31), 62.5 mg (0.23), and 250 mg no LD (0.21) groups versus the placebo group. Percentage of Participants with a Response of IGA 0 (clear) or 1 (almost clear) and a Reduction from Baseline of >=2 points: At Week 16, all KY1005 dose groups, except the 250 mg no LD group (11 [14.1%], P=0.0562), showed greater proportions of participants reaching IGA 0 (clear) or 1 (almost clear) (17 [22.1%], 15 [19.5%], and 20 [25.3%] participants in 250 mg with 500 mg LD, 125 mg, and 62.5 mg groups, respectively) compared with the placebo group (4 [5.1%] participants). The 62.5 mg group showed the greatest numerical proportionate difference (0.20) at Week 16 followed by 250 mg with 500 mg LD (0.17), 125 mg (0.14), and 250 mg no LD (0.09) groups versus the placebo group. At Week 24, all KY1005 dose groups showed greater proportions of participants reaching IGA 0 (clear) or 1 (almost clear) (35 [45.5%], 26 [33.3%], 31 [40.3%], and 23 [29.1%] participants in 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups, respectively) compared with the placebo group (9 [11.4%] participants). The 250 mg with 500 mg LD group showed the greatest numerical proportionate difference (0.34) at Week 24, followed by the 125 mg (0.29), 250 mg no LD (0.22), and 62.5 mg (0.18) groups versus the placebo group. Proportion of Participants With Improvement (reduction) of Weekly Average of Pruritus NRS >=4 With a Baseline Pruritus NRS of >=4: At Week 16, all KY1005 dose groups showed greater proportions of participants reaching a >=4-point reduction of weekly average of pruritus NRS (19 [24.7%], 15 [19.2%], 16 [20.8%], and 18 [22.8%] participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups, respectively) compared with placebo (4 [5.1%] participants). While all KY1005 dose groups showed similar response rates, the 250 mg with 500 mg LD group showed the greatest numerical proportionate difference (0.19) at Week 16 followed by the 62.5 mg (0.18), 125 mg (0.16), and 250 mg no LD (0.14) groups versus the placebo group. At Week 24, all KY1005 dose groups showed greater proportions of participants reaching a >=4-point reduction of weekly average of pruritus NRS (24 [31.2%], 19 [24.4%], 22 [28.6%], and 22 [27.8%] participants in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg groups, respectively) compared with placebo (6 [7.6%] participants). The 250 mg with 500 mg LD group showed the greatest numerical proportionate difference (0.23) at Week 24 followed by the 125 mg (0.21), 62.5 mg (0.20), and 250 mg no LD (0.17) groups versus the placebo group. Pharmacokinetics: Pharmacokinetic steady state was reached by Week 4 in the 250 mg with 500 mg LD group and by Week 12 in the group with no LD. Trough concentrations increased in the range of dose proportionality. Steady-state conditions were maintained up to Week 52 in the 250 mg with 500 mg LD, 250 mg no LD, 125 mg, and 62.5 mg KY1005 groups. Serum concentrations consistently decreased from Week 28 onwards reaching concentrations close to lower limit of quantification at Week 52 in all treatment withdrawal (placebo transition) groups.

A total of 390 participants were randomized to receive KY1005 or placebo subcutaneously. Of these, 190 were re-randomized at Week 24. There was a statistically significant improvement in the percent change in EASI score from baseline to Week 16 in all the KY1005 groups as compared with placebo. Almost all KY1005 groups showed greater improvement in the key secondary efficacy endpoints compared with placebo. No significant dose-dependent response was observed in the incidence of TEAEs.

Nov. 08, 2024

https://www.sciencedirect.com/science/article/pii/S0091674924011758?via%3Dihub

Yes

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

https://jrct.mhlw.go.jp/latest-detail/jRCT2011210072

Obara Kentaro

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp-2@sanofi.com

Clinical Study Unit

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp-2@sanofi.com

Complete

Mar. 16, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Adults (18 to < 75 years of age) with AD (Atopic dermatitis) as defined by the American Academy of Dermatology Consensus Criteria for 1 year or longer at Baseline.
- EASI (Eczema Area and Severity Index) of 12 or higher at the Screening Visit and 16 or higher at Baseline.
- IGA (Investigator Global Assessment) of 3 or 4 at Baseline.
- AD involvement of 10% or more of body surface area (BSA) at Baseline.
- Baseline worst / maximum pruritus NRS of >= 4.
- Documented history, within 6 months prior to Baseline, of either inadequate response or inadvisability of topical treatments.
- Must have applied a stable dose of topical bland emollient (simple moisturizer, no additives [e.g., urea]) at least twice daily for a minimum of 7 consecutive days before Baseline.
- Able to complete patient questionnaires
- Able and willing to comply with requested study visits / telephone and procedures.
- Able and willing to provide written informed consent.
- For patients who decide to join the biopsy sub-study be able and willing to provide skin biopsies.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

- Treatment within specific time windows before the baseline visit for the management of atopic dermatitis such as topical or systemic corticosteroids, biologic or investigational therapies and/or phototherapy.
- Known history of, or suspected, significant current immunosuppression, including history of invasive opportunistic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration.
- Weight < 40 kg or > 150 kg at Baseline.
- Treatment with a live (attenuated) immunization within 12 weeks prior to Baseline.
- Men and women (of reproductive potential) unwilling to use birth control and women who are pregnant or breastfeeding.
- Any malignancies or history of malignancies prior to Baseline (except for non-melanoma skin cancer that has been excised and cured for more than 3 years prior to Baseline; in situ cervical carcinoma that has been excised and cured).
- Positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C at the screening visit.
-Severe concomitant illness that would in the Investigator's opinion inhibit the patient's participation in the study, including for example, but not limited to, hypertension, renal disease, neurological conditions, heart failure and pulmonary disease.
-In the Investigator's opinion, any additional clinically significant laboratory results from the clinical chemistry, haematology or urinalysis tests at the Screening Visit.
-Concurrent participation in any other clinical study, including non-interventional studies.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Both

Atopic Dermatitis

Drug: KY1005
Pharmaceutical Form: Injection solution, Route of Administration: Subcutaneous
Drug: Placebo
Pharmaceutical Form: Injection solution,Route of Administration: Subcutaneous

1. Percentage change in EASI (Eczema Area and Severity Index) from Baseline [ Time Frame: Baseline to Day 113 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.

1. Incidence of treatment-emergent adverse event [ Time Frame: Baseline through Day 477 ]
2. Serum KY1005 concentration assessed throughout the study [ Time Frame: Baseline through Day 477 ]
3. Percentage change in EASI (Eczema Area and Severity Index) from baseline to Day 169 [ Time Frame: Baseline to Day 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
4. Percentage of patients with at least a 75% reduction from Baseline in EASI (EASI 75) [ Time Frame: At Days 113 and 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
5. Percentage of patients with a response of IGA (Investigator Global Assessment) 0 or 1 and a reduction from baseline >= 2 points [ Time Frame: At Days 113 and 169 ]
The IGA is a five-point scale that provides a global clinical assessment of AD severity ranging from 0 to 4, where 0 indicates clear, 2 is mild, 3 is moderate, and 4 indicates severe AD.
6. Proportion of patients with improvement (reduction) of weekly average of pruritus NRS (Numerical Rating Scale) >= 4 with a baseline pruritus of >= 4 from baseline [ Time Frame: Days 113 and 169 ]
The pruritus NRS is a simple assessment tool to report the intensity of their pruritus (itch) ranges from 0 to 10 with 0 being <no itch> and 10 being the <worst itch imaginable> .
7. Absolute change from Baseline in EASI (Eczema Area and Severity Index) [ Time Frame: At Days 15, 29, 57, 85, 113, 141 and 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
8. Percentage change from Baseline in EASI (Eczema Area and Severity Index) [ Time Frame: At Days 15, 29, 57, 85 and 141 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
9. Percentage of patients with at least a 50% reduction from Baseline in EASI (EASI 50) [ Time Frame: At Days 15, 29, 57, 85, 113, 141 and 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
10. Percentage of patients with at least a 75% reduction from Baseline in EASI (EASI 75) [ Time Frame: At Days 15, 29, 57, 85, and 141 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
11. Percentage of patients with at least a 90% reduction from Baseline in EASI (EASI 90) [ Time Frame: At Days 15, 29, 57, 85, 113, 141 and 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
12. Percentage of patients with a 100% reduction from Baseline in EASI (EASI 100) [ Time Frame: At Days 15, 29, 57, 85, 113, 141 and 169 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicate worse condition.
13. Change in IGA (Investigator Global Assessment) from baselin [ Time Frame: Baseline to day 113 and over time up to Day 365 ]
The IGA is a five-point scale that provides a global clinical assessment of AD severity ranging from 0 to 4, where 0 indicates clear, 2 is mild, 3 is moderate, and 4 indicates severe AD
14. Percentage of patients with a score of IGA (Investigator Global Assessment) 0 or 1 and a reduction from Baseline of >= 2 points [ Time Frame: At Days 15, 29, 57, 85, and 141 ]
The IGA is a five-point scale that provides a global clinical assessment of AD severity ranging from 0 to 4, where 0 indicates clear, 2 is mild, 3 is moderate, and 4 indicates severe AD
15. Absolute and Percentage change in SCORAD (SCORing Atopic Dermatitis) Index from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
SCORAD was used to assess the extent and severity of AD (Atopic Dermatitis). Extent and severity of eczema as well as subjective assessment of symptoms were assessed and scored. SCORAD total score ranges from 0 (absent disease) to 103 (severe disease).
16. Absolute and Percentage change in affected BSA from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
17. Absolute and Percentage change in Patient Oriented Eczema Measure (POEM) from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
POEM is a 7-item (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) questionnaire to assess frequency of disease symptoms with a scoring system of 0 to 28. The higher score indicating higher severity
18. Absolute and Percentage change in Dermatology Life Quality Index (DLQI) from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
DLQI is a questionnaire with a score system of 0 to 30 the high score is indicative of poor QoL (Quality of life).
19. Absolute and Percentage change in Atopic Dermatitis Control Tool (ADCT) from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
ADCT is a questionnaire to assess patient-self-perceived control of their eczema with a total score from 0 to 24; higher scores indicate lower AD control
20. Absolute and Percentage change in Hospital Anxiety and Depression Scale (HADS) from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
HADS is a fourteen-item scale with seven items each for anxiety and depression subscales. Scoring for each item ranges from zero to three. A subscale score >8 denotes anxiety or depression
21. Absolute and Percentage change in weekly average of pruritus Numerical Rating Scale (NRS) from Baseline [ Time Frame: Baseline to Day 169 and over time up to Day 365 ]
The pruritus NRS is a simple assessment tool to report the intensity of their pruritus (itch) ranges from 0 to 10 with 0 being <no itch> and 10 being the <worst itch imaginable> .
22. Proportion of patients with improvement (reduction) of weekly average of pruritus NRS (Numerical Rating Scale) >= 3 with a baseline pruritus NRS >= 3 from baseline [ Time Frame: Baseline to Days 113 and 169 ]
The pruritus NRS is a simple assessment tool to report the intensity of their pruritus (itch) ranges from 0 to 10 with 0 being <no itch> and 10 being the <worst itch imaginable>.
23. Incidence of positive anti-Ky1005 antibody response [ Time Frame: Baseline through Day 477 ]
24. Time to loss of EASI 75 [ Time Frame: Week 24 to Day 365 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicates worse condition.
25. Time to loss of IGA 0/1 (Patients with a response of 0 or 1 in IGA) [ Time Frame: Week 24 to Day 365 ]
The IGA is a five-point scale that provides a global clinical assessment of AD severity ranging from 0 to 4, where 0 indicates clear, 2 is mild, 3 is moderate, and 4 indicates severe AD.
26. Time to loss of EASI 50 [ Time Frame: Week 24 to Day 365 ]
The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicates worse condition.

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Mar. 02, 2022

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