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A Two-cohort, Open-label, Single-arm, Multicenter Study to Evaluate Efficacy, Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of Emapalumab in Children and Adults with Macrophage Activation Syndrome (MAS) in Still's Disease (Including Systemic Juvenile Idiopathic Arthritis and Adult Onset Still's Disease) or with MAS in Systemic Lupus Erythematosus (EMERALD)

Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still's or SLE

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Cohort 1 (systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still's diseases [AOSD]): Of 25 participants, 4 participants (16.0%) were males and 21 (84.0%) were females, and the mean (standard deviation [StDev]) age was 15.8 (15.54) years. Eight participants (32.0%) were adults (>=17 years old); 14 (56.0%) were pediatric patients (2 to <17 years old); and 3 (12.0%) were pediatric patients (<2 years old). The majority of participants (18 participants, 72.0%) were White, and 4 (16.0%) were Asian. Three participants (12.0%) were enrolled in North America; 19 participants (76.0%) in the UK and EU; 2 participants (8.0%) in Japan; and 1 participant (4.0%) in China. The mean (StDev) body weight of 25 participants was 44.48 (21.777) kg. Cohort 2 (systemic lupus erythematosus [SLE]): Of 8 participants, 3 participants (37.5%) were males and 5 (62.5%) were females, and the mean (StDev) age was 14.6 (6.78) years. Four participants (50.0%) were adults (>=17 years old) and 4 (50.0%) were pediatric patients (2 to <17 years old). Half of the participants (4 participants, 50.0%) were Asian. Five participants (62.5%) were enrolled in North America; 2 participants (25.0%) in China; and 1 participant (12.5%) in the EU. The mean (StDev) body weight of 8 participants was 49.46 (33.990) kg.

Cohort 1 (sJIA and AOSD): A total of 25 participants were enrolled and treated in Cohort 1. Of these, 2 participants discontinued the study (one due to an adverse event [AE] and the other due to death), and 23 participants completed the study. Cohort 2 (SLE): A total of 8 participants were enrolled and treated in Cohort 2. Of these, 1 participant discontinued the study due to an AE, and 7 participants completed the study. *Enrollment in Cohort 2 was discontinued by the Sponsor after 8 (of 16 planned) participants were enrolled in June 2024 due to enrollment challenges in this patient population.

Cohort 1 (sJIA and AOSD): - Of 25 participants, 2 participants (8.0%) experienced AEs leading to death. - Eighteen participants (72.0%) experienced serious adverse events (SAEs). The most frequently reported SAEs were Still's disease (6 participants [24.0%]), pneumonia (5 participants [20.0%]), and condition aggravated (4 participants [16.0%]); all other SAEs were reported in 1 participant (4.0%) each, except Cytomegalovirus infection, herpes zoster, and pulmonary arterial hypertension (2 participants [8.0%] each). - Nonserious AEs were experienced by 24 participants (96.0%). The most frequently reported nonserious AEs were Still's disease (8 participants [32.0%]); anaemia (7 participants [28.0%]); condition aggravated and pyrexia (6 participants [24.0%] each); and thrombocytopenia, Cytomegalovirus infection reactivation, and cough (5 participants [20.0%] each). Cohort 2 (SLE): - Of 8 participants, no participant experienced AEs leading to death. - Four participants (50.0%) experienced SAEs. All SAEs occurred in 1 participant (12.5%) each and included condition aggravated, abscess limb, prothrombin level decreased, and lupus nephritis. - All of the 8 participants experienced nonserious AEs. Nonserious AEs that occurred in 2 or more participants were upper respiratory tract infection (3 participants [37.5%]) and constipation, Cytomegalovirus infection, sinusitis, Epstein-Barr virus infection, systemic lupus erythematosus, lupus nephritis, and rash (2 participants [25.0%] each).

Cohort 1 (sJIA and AOSD): [Primary Efficacy Endpoint] - Of 25 participants, 11 participants (44.0%) achieved complete response (CR) at Week 8 after first administration of emapalumab. [Secondary Endpoints] - Fifteen participants (60.0%) achieved glucocorticoids (GCs) tapering to a dose <50% of prednisolone (PDN) equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of macrophage activation syndrome (MAS), whichever occurs first at any time within the first 8 weeks from start of emapalumab treatment. - Nineteen participants (90.5%) achieved GCs tapering to <=1 mg/kg/day of PDN equivalent at any time until end of study (EOS). - Median time to achieve GCs tapering to a dose <50 % of PDN equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS (in patients already treated for the underlying condition), or to <=1mg/kg/Day of PDN equivalent, whichever occurs first at any time during the study was 5 weeks (95% confidence interval [CI]: 2.0, 10.0). - Median time to first CR was 8.4 weeks (95% CI: 5.0, 20.9). - Sixteen participants (64.0%) achieved overall response as defined by CR or partial response (PR). - Median time to first overall response as defined by CR or PR was 2.9 weeks (95% CI: 1.4, 8.4). - Four participants (19.0%) had MAS recurrence at anytime after achievement of CR. - No participant withdrew from the study due to lack of response as per investigator decision. - Twenty-three participants (92.0%) were alive at the end of study. - Twenty-four participants (96.0%) experienced at least one AE (serious or non-serious). - One participant (4.0%) withdrew from the study treatment due to safety reasons. - No clinically meaningful changes in hematology and chemistry laboratory parameters from baseline were observed. - Mean (StDev) scores of the Pediatric Quality of Life Inventory (PedsQL (TM)) parent report (age from 2 years) at baseline, Week 8, and EOS were 43.18 (21.488), 67.88 (21.617), and 80.79 (18.020), respectively. - Based on the Clinician Global Impression of Severity, at baseline, the overall severity status was mild for 1 (4.0%), moderate for 15 (60.0%), and severe for 9 (36.0%) participants. At Week 8, the severity status was none for 11 (57.9%), mild for 5 (26.3%), and moderate for 3 (15.8%) participants. At EOS, the severity status was none for 17 (85.0%) and mild for 3 (15.0%) participants. - Based on the Patient/Parent Global Impression of Severity, at baseline, the overall severity of the patient's status was mild for 1 (4.0%), moderate for 15 (60.0%) and severe for 9 (36.0%) participants. At Week 8, the severity status was none for 11 (57.9%), mild for 5 (26.3%), and moderate for 3 (15.8%) participants. At EOS, the severity status was none for 17 (85.0%) and mild for 3 (15.0%) participants. - For the pharmacokinetic (PK) profile, the mean emapalumab concentrations increased over time, with a mean (StDev) concentration of 112,541.47 (43 924.399) ng/mL on Study Day (SD) 1 and peaking at 273,966.58 (201,869.698) ng/mL by SD28, then decreasing, with the concentration of 44,314.88 (59,798.354) ng/mL 60 days after end of treatment (EOT). At EOS, the mean (StDev) emapalumab concentration was 889.11 (3921.266) ng/mL. - For the pharmacodynamic (PD) markers, the mean (StDev) values for chemokine (C-X-C motif) ligand 9 (CXCL9) were high at baseline (21,344.26 [79,546.837] ng/L), below 1500 ng/L at SD7 (735.90 [2045.783] ng/L), and remained below 700 ng/L after SD7, during, and after EOT at most timepoints. The mean (StDev) CXCL9 values were 96.43 (128.617) ng/L at Week 8 and 293.05 (441.078) ng/L at EOS. The mean (StDev) levels of soluble CD25 (sCD25) were high at baseline (21,287.45 [34,921.520)] ng/L) and remained high until SD19 (8964.75 [6345.701] ng/L), before decreasing progressively to reach 3915.58 (2251.457) ng/L by Week 8 and remained at that level after EOT. At EOS, the mean (StDev) sCD25 values were 3456.40 (3630.806) ng/L. - For immunogenicity, of the 23 participants analyzed for antidrug antibodies (ADAs), no participant was ADA positive at baseline. Five participants (21.7%) were treatment-induced ADA positive. Cohort 2 (SLE): [Primary Efficacy Endpoint] - Of 8 participants, 4 participants (50.0%) achieved CR at Week 8 after first administration of emapalumab. [Secondary Endpoints] - Seven participants (87.5%) achieved GCs tapering to a dose <50% of PDN equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS, whichever occurs first at any time within the first 8 weeks from start of emapalumab treatment. - Six participants (85.7%) achieved GCs tapering to <=1 mg/kg/day of PDN equivalent at any time until EOS. - Median time to achieve GCs tapering to a dose <50 % of PDN equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS (in patients already treated for the underlying condition), or to <=1mg/kg/Day of PDN equivalent, whichever occurs first at any time during the study was 1 week (95% CI: 1.0, 5.0). - Median time to first CR was 5.9 weeks (95% CI: 3.4, not evaluable [NE]). - Six participants (75.0%) achieved overall response as defined by CR or PR. - Median time to first overall response as defined by CR or PR was 3.7 weeks (95% CI: 0.6, NE). - One participant (14.3%) had MAS recurrence at anytime after achievement of CR. - No participant withdrew from the study due to lack of response as per investigator decision. - All 8 participants (100.0%) were alive at the end of study. - All of the 8 participants (100.0%) experienced at least one AE (serious or non-serious). - One participant (12.5%) withdrew from the study treatment due to safety reasons. - No clinically meaningful changes in hematology and chemistry laboratory parameters from baseline were observed. - Mean (StDev) scores of the PedsQL (TM) parent report (age from 2 years) at baseline, Week 8, and EOS were 51.45 (25.955), 79.35 (NE), and 97.83 (NE), respectively. - Based on the Clinician Global Impression of Severity, at baseline, the overall severity status was mild for 1 (12.5%), moderate for 1 (12.5%), and severe for 6 (75.0%) participants. At Week 8, the severity status was none for 6 (85.7%) and mild for 1 (14.3%) participants. At EOS, the severity status was none for 4 (80.0%) and moderate for 1 (20.0%) participants. - Based on the Patient/Parent Global Impression of Severity, at baseline, the overall severity of the patient's status was mild for 1 (12.5%), moderate for 1 (12.5%), and severe for 6 (75.0%) participants. At Week 8, the severity status was none for 6 (85.7%) and mild for 1 (14.3%) participants. At EOS, the severity status was none for 4 (80.0%) and moderate for 1 (20.0%) participants. - For the PK profile, the mean emapalumab concentrations increased over time, with a mean (StDev) concentration of 167,990.22 (77,376.997) ng/mL on SD1 and peaking at 314,699.04 (386,826.422) ng/mL by SD16, then decreasing, with the concentration of 19,532.33 (23,182.423) ng/mL 60 days after EOT. At EOS, the mean (StDev) emapalumab concentration was 74,817.54 (167,195.974) ng/mL. - For the PD markers, the mean (StDev) values for CXCL9 were high at baseline (2352.57 [3674.773] ng/L), below 100 ng/L at SD7 (70.88 [35.704] ng/L), and fluctuated during and after EOT. The mean (StDev) CXCL9 values were 134.70 (149.996) ng/L at Week 8 and 123.12 (62.820) ng/L at EOS. The mean (StDev) levels of sCD25 were high at baseline (4893.50 [2113.562] ng/L) and remained at that level after EOT. At EOS, the mean (StDev) sCD25 values were 3515.40 (2809.668) ng/L. - For immunogenicity, of the 6 participants analyzed for ADAs, no participant was ADA positive at baseline. Also, no participant was treatment-induced ADA positive.

This study evaluated the efficacy and safety of emapalumab for the treatment of MAS in patients with Still's disease (Cohort 1) or SLE (Cohort 2). In both cohorts, high response rates were observed across multiple efficacy endpoints, including tapering of GCs and abnormal laboratory values, supporting the utility of emapalumab in this difficult-to-treat patient population. Emapalumab was well-tolerated, with the most common AEs being infections and infusion-related reactions.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220187

Ochiai Kazuya

ICON Clinical Research GK

Kyutaromachi 4-chome 1-3, Chuo-ku, Osaka city, Osaka 541-0056, Japan

ICONCR-Chiken@iconplc.com

Clinical Trial Contact

ICON Clinical Research GK

Kyutaromachi 4-chome 1-3, Chuo-ku, Osaka city, Osaka 541-0056, Japan

+81-6-4560-2001

ICONCR-Chiken@iconplc.com

Complete

Aug. 01, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

- Run-in phase in all cohorts
1. Informed consent provided by the patient or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as required by local law.
2. Male and female patients aged between 6 months and 80 years of age at the time of diagnosis of active MAS.
3. MAS defined as per the criteria defined below for each cohort and requiring treatment with GCs as per standard of care.

- Interventional phase in all cohorts
1. Informed consent provided by the patient or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as required by local law.
2. Male and female patients aged between 6 months and 80 years of age at the time of diagnosis of active MAS.
3. Patients who have shown an inadequate response to high dose i.v. GCs administered for at least 3 days according to local standard clinical practice, including but not limited to pulses of 30 mg/kg mPDN on 3 consecutive days. High i.v. GCs dose is recommended not be lower than 2 mg/kg/day PDN equivalent (or at least 60 mg/day in pediatric patients of 30 kg or more and at least 1 g/day in adult/MAS patients). In case of rapid worsening of the patient's condition and/or laboratory parameters, as per Investigator judgment, inclusion may occur within less than 3 days from starting high dose GCs.
4. Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the following:
a. Febrile patients presenting with ferritin > 684 ng/mL
b. and any 2 of:
i. Platelet count <= 181 x10^9/L
ii. AST-level > 48 U/L
iii. Triglycerides > 156 mg/dL
iv. Fibrinogen level <= 360 mg/dL
5. Female patients of childbearing potential (sexually or nonsexually active). Female patients who are sexually active must be willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug.

- Specific inclusion criteria for Cohort 1 and Cohort 2
1. Cohort 1:
a. Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility.
b. Confirmed diagnosis of AOSD as per Yamaguchi criteria.
2. Cohort 2:
a. Confirmed diagnosis of SLE as per SLICC 2012 criteria.

1. Primary hemophagocytic lymphohistiocytosis(pHLH) documented by either the presence of a known causative genetic mutation or abnormal perforin expression or CD107a degranulation assay as described with pHLH or by the presence of family history.
2. Confirmed malignancy. Note: patients with a suspected malignancy should have mononuclear cells typed by flow cytometry and/or tissue biopsy, as applicable, to rule out malignancy.
3. Treatment with canakinumab, JAK inhibitors, TNF inhibitors, and tocilizumab at the time of emapalumab initiation.
4. Ongoing treatment with anakinra at a dose above 4 mg/kg/day at time of emapalumab initiation.
5. Patients treated with etoposide for MAS in the last 1 month.
6. Presence of any medical or psychological condition or laboratory result that in the opinion of the Investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with emapalumab.
7. Foreseeable inability to cooperate with given instructions or study procedures.
8. Clinically active mycobacteria (typical and atypical), Histoplasma capsulatum, or Salmonella infections.
9. Evidence of leishmania infection.
10. Evidence of latent tuberculosis.
11. History of hypersensitivity or allergy to any component of the study drug.
12. Receipt of a Bacillus Calmette-Guerin(BCG) vaccine within 12 weeks prior to Screening.
13. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to Screening.
14. Pregnancy or lactating female patients.

Both

Macrophage Activation Syndrome, Secondary Hemophagocytic Lymphohistiocytosis, Still Disease, SLE

Emapalumab iv infusion
initial dose: 6 mg/kg
Subsequent doses: 3 mg/kg

Proportion of subjects with complete response (CR) at Week 8 after first administration of emapalumab

- GCs tapering to a dose below 50% of prednisolone (PDN) equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS whichever occurs first
- GCs tapering to <=1mg/kg/day of PDN equivalent at any time during the study.
- Time to achieve GCs tapering as defined above.
- Time to first Complete Remission (CR)
- Proportion of subjects with overall response (OR) as defined by CR or Partial Remission (PR)
- Time to first OR as defined by CR or PR
- MAS recurrence at anytime after achievement of CR
- Withdrawal from the study due to lack of response as per Investigator decision
- Survival time

+81-44-977-8111

June. 15, 2022

Belgium/Canada/China/Czechia/France/Germany/Italy/Netherlands/Poland/Spain/Sweden/United Kingdom/United States