臨床研究等提出・公開システム

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy (VIS649-201)

Phase 2 Study of VIS649 for IgA Nephropathy (VIS649-201)

155

155 participants were enrolled in the trial, randomized to trial intervention, and received at least one dose of trial intervention. Participants were randomized to each trial intervention as follows: 2 mg/kg Sibeprenlimab: 38 subjects 4 mg/kg Sibeprenlimab: 41 subjects 8 mg/kg Sibeprenlimab: 38 subjects Placebo: 38 subjects Overall, the participants were predominantly Asian (115 of 155 participants [74.2%]). Of the participants enrolled in the study, 88 of 155 participants (56.8%) were male and 67 of 155 participants (43.2%) were female. The mean age overall was 40.7 years, and the mean age ranged from 18 to 73 years. The mean BMI overall was 27.56 kg/m2 and the mean BMI ranged from 16.3 to 48.3 kg/m2. Fifteen participants were enrolled in Japan (12.3 %); the other regional parameter was 'Rest of World' which enrolled 136 (87.7%) participants. Almost all participants were on ACEI or ARB therapy with 37 (97.4%), 40 (97.6%), 37 (97.4%) and 38 (100%) for the 2, 4, 8 mg/kg and placebo groups respectively at baseline. Use of SGLT2i at baseline was much lower with a range of 1 to 3 participants (2.6% to 4.9%) use at baseline. Baseline 24-hour uPCR geometric mean was 1.46, 1.53, 1.44 1.68 for the 2, 4, 8 mg/kg and placebo groups, respectively. The number of participants with a baseline uPCR <= 2 g/g was 27, 27, 27 and 25 across the 2, 4, 8 mg/kg and placebo groups respectively; baseline uPCR >2 g/g was 10, 13, 8, 11 participants in the 2, 4, 8 mg/kg and placebo groups, respectively. Baseline median eGFR (mL/min/1.73m2) for the groups was 58.0, 64.0, 56.0 and 68.5 for the 2, 4, 8 mg/kg and placebo groups, respectively.

The VIS649-201 study was a placebo-controlled, randomized study which assigned participants to the 2 mg/kg, 4 mg/kg, 8 mg/kg and placebo groups in a 1:1:1:1 scheme. A total of 323 participants were screened for this trial and 155 participants were enrolled. Of the 155 participants enrolled and started the study and 146 completed the study. For the VIS649 2 mg/kg group, 38 participants started the study and 35 completed. Reasons for withdrawal were adverse event (1 participant) and withdrawal by subject for 2 participants. In the VIS649 4 mg/kg group, 41 participants started the study and 39 participants completed it. Reasons for withdrawal were protocol violation (1 participant) and withdrawal by subject (1 participant). In the VIS649 8 mg/kg group, 38 participants started the study and 37 participants completed. One participant did not complete (withdrawal by subject). In the placebo group, 38 participants started the study and 35 participants completed it. Reasons for discontinuation in placebo were physician decision (1 participant) and withdrawal by subject (2 participants). Of the 155 participants enrolled and randomized 146 participants (94.2%) completed the planned treatment, 9 participants (5.8%) discontinued treatment early, and 7 participants (4.5%) discontinued the trial early.

The monthly IV administration of 2, 4, and 8 mg/kg sibeprenlimab to participants with IgAN resulted in no significant or known safety concerns. Overall, 119 of 155 participants (76.8%) reported at least 1 TEAE during the trial. the incidence of TEAEs was similar across the sibeprenlimab dose groups (73.7% [2 mg/kg], 80.5% [4 mg/kg], and 81.6% [8 mg/kg] and the placebo group (71.1%). Serious adverse events were reported for 7 of 155 participants (4.5%) during this trial, including the death of 1 (placebo) of the 155 participants (0.6%) None of these events were considered by the investigator to be treatment related. The most commonly reported TEAE was COVID-19 (51 of 155 participants [32.9%]); however, a total of 56 of 155 participants (36.1%) had COVID infection (including events of COVID-19, Coronavirus infection, Coronavirus test positive, and SARS-COV-2 test positive) reported as a TEAE during the trial. The total number of participants with COVID infection was higher in the placebo group (17 of 38 participants [44.7%] compared with the pooled sibeprenlimab treatment group (39 of 117 participants [33.3%]). Treatment-emergent AEs considered by the investigator to be related to the trial intervention were reported for 23 of 155 participants (14.8%). The incidence of treatment-related TEAEs was also similar across the sibeprenlimab dose groups (18.4% [2 mg/kg], 17.1% [4 mg/kg], and 10.5% [8 mg/kg]) and the placebo group (13.2%). The most commonly reported treatment-related TEAE was headache (3 of 155 participants [1.9%]) Other safety parameters Treatment-emergent AEs related to abnormal clinical laboratory test results which were considered by the investigator to be related to the trial intervention included blood, creatinine increased reported for 1 participant (placebo); blood triglycerides increased reported for 1 participant (4 mg/kg sibeprenlimab); hypertriglyceridaemia and hyperglycaemia reported for 1 participant (8 mg/kg sibeprenlimab); and eosinophil count increased reported for 1 participant (4 mg/kg sibeprenlimab). Treatment-emergent AEs related to vital sign assessments which were considered by the investigator to be related to the trial intervention included postprocedural hypotension reported for 1 participant (placebo).

1. uPCR at Month 12 After 12 months of treatment, there was a statistically significant linear treatment effect for the primary endpoint of change from baseline in 24-hour uPCR (p-value = 0.0004). The geometric mean ratio reduction (SE) for 24-hour uPCR from baseline was 56.66% for pooled sibeprenlimab and 20.20% for placebo. By treatment, the geometric mean ratio reduction (SE) for 24-hour uPCR from baseline was 47.18%, 58.77%, and 62.02% in the sibeprenlimab 2, 4, and 8 mg/kg treatment groups, respectively, demonstrating a dose dependent effect of sibeprenlimab on proteinuria. Compared with placebo, the reductions in 24-hour uPCR were statistically significant across all dose levels with p-values of 0.0477, 0.0013, and 0.0004 for sibeprenlimab 2, 4, 8 mg/kg, respectively. A similar trend for reduction in proteinuria was observed for spot uPCR measurements. 2. uPCR at Months 9 and 16 After 9 months of treatment, the geometric mean ratio reduction (SE) for 24-hour uPCR from baseline was 57.38% for pooled sibeprenlimab and 15.65% for placebo. By treatment, the geometric mean ratio reduction (SE) for 24hour uPCR from baseline was 50.53%, 57.41%, and 62.90%, in the sibeprenlimab 2, 4, and 8 mg/kg groups, respectively. The reductions in uPCR seen at Month 12 were maintained through Month 16 in the sibeprenlimab 4 and 8 mg/kg treatment groups, but began returning towards baseline in the 2 mg/kg treatment group by Month 16. 3. Urine Protein Excretion After 12 months of treatment, the reduction of ratio change (95% CI) from baseline for urine protein excretion was 58.25% (49.2 and 65.7) for pooled sibeprenlimab and 18.75% (-11.6, 40.9) for placebo. By treatment, the reduction of ratio change (95% CI) from baseline for 24 hour uPCR was 49.47% (30.6, 63.2), 57.80% (43.0, 68.8), and 65.49% (53.1, 74.6) in the sibeprenlimab 2, 4, and 8 mg/kg groups, respectively, demonstrating a dose dependent effect of sibeprenlimab on urine protein excretion. The reductions in urine protein excretion seen at Month 12 were maintained through Month 16 in the sibeprenlimab 4 and 8 mg/kg treatment groups and began returning towards baseline in the 2 mg/kg treatment group by Month 16. 4. eGFR Changes from baseline (LSM [SE]) at the end of the 12 month treatment period were -2.74 (1.8), +0.22 (1.7), and -1.54 (1.8) mL/min/1.73 m2, in the 2, 4, and 8 mg/kg sibeprenlimab groups respectively compared with a -7.35 (1.8) mL/min/1.73 m2 decline in the placebo group. The LSMD (95% CI) relative to placebo in eGFR from baseline to Month 12 was +4.61 (-0.3,9.5) mL/min/1.73 m2 in the 2 mg/kg sibeprenlimab treatment group, +7.57 (2.8, 12.3) mL/min/1.73 m2 in the 4 mg/kg sibeprenlimab treatment group (p = 0.0020), and +5.81 (0.9, 10.7) mL/min/1.73 m2 in the 8 mg/kg sibeprenlimab treatment group (p = 0.0195). 5. Clinical Remission Proteinuria remission was defined as a reduction in 24-hour urine protein excretion to < 300 mg/day for at least 3 consecutive months or uPCR < 0.2 g/g for at least 3 consecutive months. The percentage of participants with proteinuria remission was 10.5% (Month 9), 7.9% (Month 12), and 7.9% (Month 16) for the 2 mg/kg treatment group; 12.2% (Month 9), 12.2% (Month 12), and 17.1% (Month 16) for the 4 mg/kg treatment group; 18.4% (Month 9), 26.3% (Month 12), and 23.7% (Month 16) for the 8 mg/kg treatment group; and 2.6% (Months 9, 12, and 16) for the placebo group. The percentage of participants with sustained proteinuria remission at Months 12 and 16 was 2.6% for the 2 mg/kg treatment group, 9.8% (Month 12) and 12.2% (Month 16) for the 4 mg/kg treatment group, and 13.2% (Month 12) and 23.7% (Month 16) for the 8 mg/kg treatment group. No participants met the criteria for sustained proteinuria remission at Months 12 and 16 in the placebo group.

In 117 IgAN patients, a monthly IV administration of sibeprenlimab (2, 4, or 8 mg/kg): - Reduced 24-hour uPCR by 47% to 62% at Month 12 in comparison to 20% in the placebo group. - Stabilized eGFR through Month 12 in the 4 and 8 mg/kg treatment groups and slowed eGFR decline in the 2 mg/kg treatment group relative to the placebo group. - Was well tolerated and resulted in so significant or known safety concerns.

Nov. 02, 2023

https://pubmed.ncbi.nlm.nih.gov/37916620/

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2041210130

Nishioka Tsuyoshi

Fortrea Japan K.K.

Harumi Triton Square Office Tower Y 8F, 1-8-11 Harumi, Chuo-ku, Tokyo

Tsuyoshi.Nishioka@fortrea.com

Nishioka Tsuyoshi

Fortrea Japan K.K.

Harumi Triton Square Office Tower Y 8F, 1-8-11 Harumi, Chuo-ku, Tokyo

+81-80-2334-6812

Tsuyoshi.Nishioka@fortrea.com

Complete

Jan. 19, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Participant is a male or female >= 18 years of age at the time of signing the informed consent.
2. Participant has biopsy-confirmed IgAN.
3. Participant has medical records showing they have been on stable and maximally tolerated doses of either ACEI or ARB, as per local SOC and applicable guidelines, for at least 3 months preceding screening. Participants should optimally be on at least 50% of the maximum recommended dose of these agents; however, if a participant is on their maximally tolerated dose (and this is < 50% of the maximum recommended dose) and has been on this dose for at least 3 months, they may be enrolled. Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in the study if their overall management of IgAN, including BP control, is as per local SOC and applicable guidelines.
4. Participant has screening uPCR >= 0.75 g/g measured from a 24-hour urine (or an intended 24 hour urine sample) or 24-hour urine protein >= 1.0 g/d, as measured from 24 hour urine collection (or an intended 24 hour urine sample).
- The proteinuria should be assessed when the participant is considered to be in a steady state with no recent heavy exercise, fever, or other potential issues that could impact the result. Re-testing may be allowed if it is determined that the participant was not in steady state after consultation with the medical monitor.
5. Participant has eGFR >= 45 mL/min/1.73 m2, calculated using the CKD-EPI formula.
- Retesting may be allowed if it is determined that the participant was not in steady state after consultation with the medical monitor.
- Participants with eGFR >= 30 mL/min/1.73 m2 and < 45 mL/min/1.73 m2 may also undergo screening, if they have undergone a kidney biopsy within 12 months of the date of initial screening and do not have >= 50% tubulo-interstitial fibrosis (T2 if using MEST-C score) or crescents in > 25% of glomeruli (C2 if using MEST-C score).The eGFR should be measured when the participant is considered to be in a steady state without recent changes in volume status, medications that could impact the result (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides, co-trimoxazole), or changes in dietary protein intake.
6. Participants serum Ig values must meet the following criteria:
- IgG: >= 700 mg/dL
- IgM: >= 37 mg/dL
- IgA: >= 70 mg/dL
7. Female participants of childbearing potential must have a negative serum pregnancy test prior to the first dose.
8. Participant is willing to adhere to contraceptive requirements.
9. Participant or a legally authorized representative is able to understand the purpose and risks of the study and is willing to give voluntary written informed consent as described.

1. Participant has secondary forms of IgAN as defined by the treating physician (eg, Henoch Schonlein purpura (IgA vasculitis), infection-associated IgAN, or IgAN associated with hepatic cirrhosis).
2. Participant has co-existing CKD, other than IgAN.
3. Participant has evidence of additional pathological findings in the kidney biopsy (eg, diabetic kidney disease, membranous nephropathy, or lupus nephritis). However, hypertensive vascular changes are acceptable.
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 from the Oxford IgAN classification schema. If MEST-scoring was not performed, the presence of > 50% tubulo interstitial fibrosis or crescents in > 25% of glomeruli is exclusionary.
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour urine protein > 3.5 g with concurrent hypoalbuminemia (serum albumin < 2.5 g/dL), hyperlipidemia (total cholesterol > 350 mg/dL), and edema. Participants with isolated nephrotic range proteinuria (>3.5 g/d) will be eligible.
6. Participant has received a solid organ transplant, including kidney.
7. Participant has received bone marrow or hematologic stem cell transplantation.
8. Participant is currently receiving systemic immunosuppression (excluding topical, ophthalmic, per rectum, or inhaled corticosteroids).
9. Participant has received treatment with systemic corticosteroid therapy (excluding topical, ophthalmic, per rectum, or inhaled corticosteroids) within 16 weeks of initial screening.
10. Participant has received treatment with a systemic immunosuppressive agent (e.g., mycophenolate mofetil, azathioprine, calcineurin inhibitors, cyclophosphamide/cytotoxic agents) within 16 weeks of initial screening.
11. Participant has any chronic infectious disease (eg, chronic urinary tract infection; chronic sinusitis; bronchiectasis; active pulmonary or systemic tuberculosis; chronic viral hepatitis, such as hepatitis C or hepatitis B; or human immunodeficiency virus infection). See Section 4.1 Study Design for further details.
12. Participant has acute infectious disease at the time of screening. Participants may be rescreened following resolution of acute infection (such as urinary tract infection or respiratory tract infection), provided there is no evidence of an immunosuppressive condition that predisposed the participant to this infection.
13. Participant has Type 1 diabetes.
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin A1c value > 8%.
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg diastolic), Systolic and diastolic BP should be assessed while the participant is seated or supine for at least 5 minutes in a quiet room without distractions. BP should be measured with a completely automated device. At least 3 readings should be taken and average values from these 3 readings should be calculated.
16. Participant has a history of chronic autoimmune neurodegenerative disorder such as multiple sclerosis.
17. Participant has a known allergy or intolerance to any component of the study intervention.
18. Participant is breastfeeding.
19. Participant has poorly compensated or controlled ischemic heart disease or cardiomyopathy, as judged by the Investigator.
20. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has required systemic steroid therapy during the prior year. If COPD is present, severity must not exceed Global Initiative for Chronic Obstructive Lung Disease 1 (mild), defined as a forced 1-second expiratory volume (FEV1) > 80% of predicted.
21. Participant has known cirrhosis or liver dysfunction, defined as presence of coagulopathy, platelet count < 100,000/uL or alanine aminotransferase > 3x upper limit of normal.
22. Participant has active malignancy or is receiving chemotherapy for malignancy, except for nonmelanoma skin cancers and cervical carcinoma in situ. Participants with prior malignancy who have been documented to be cancer-free for >= 5 years may be enrolled.
23. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is acceptable (if greater than 6 months prior to screening).
24. Participant enrolled in another investigational drug or device study within 3 months prior to initial screening.
25. Participant with a pre-existing illness other than those listed above that, in the opinion of the Investigator, would place the participant at increased risk through participation in this study.
26. Participant is unable to comply with study protocol procedures and/or study visit schedules.
27. Participant with known or suspected alcohol or drug abuse that would compromise their safety or study participation, in the opinion of the Investigator.

Both

Immunoglobulin A(IgA) Nephropathy

VIS649 or placebo will be administered as a single, monthly IV infusion for 12 monthly doses.

Safety:
- AEs graded by severity, clinical laboratory tests, vital sign measurements, and physical examinations
Efficacy:
- Change from baseline in uPCR (measured on natural log scale from 24-hour urine collection or the intended 24-hour urine collection) at Month 12 (ie, approximately 30 days after the 12th dose is administered)

+81-562-93-2873

June. 17, 2020

The United States/Singapore/United Kingdom/Canada/India/Malaysia/Hong Kong/Australia/Philippines/Spain/South Korea/Thailand/Taiwan/Sri Lanka