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A Double Blind, Randomized, Placebo-Controlled, Multicenter Phase IIa, Clinical Trial to Assess Efficacy and Safety of the Human Anti-CD38 Antibody Felzartamab in IgA Nephropathy

Randomized, placebo-controlled, multi-center, double-blind, proof of concept phase IIa and dose evaluation trial of Felzartamab in IgAN. (IGNAZ )

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The study was to enroll participants aged 18 to 80 years (inclusive; 18 to 70 years for Czech Republic) with biopsy-confirmed diagnosis of IgA Nephropathy (IgAN) within the past 8 years prior to signature of the ICF and with a proteinuria level of 1.0 g/d or above (0.5 g/d or above for Japanese Cohort [Part II] only) at screening. Enrolled participants were to have the treatment with an ACEi and/or ARB at maximum doses or maximally tolerated doses for >=3 months prior to date of informed consent and adequate BP (systolic/diastolic) control of less than 125/75 mmHg. Participants were excluded if they had secondary forms of IgAN, rapidly progressive variant of IgAN, minimal change variant of IgAN, or any other medical condition as per the investigator.

The number of eligible patients projected before the study initiation was 44 patients for Part I and up to 8 Japanese patients for Part II. A total of 97 participants were screened, of whom 48 (49.5%) participants were randomly assigned to receive the study drugs, 46 (47.4%) participants completed the treatment phase, and 48 (49.5%) patients completed the follow-up phase. In Part I of the study, a total of 48 participants were randomly assigned to 1 of 4 treatment groups (12 to placebo, 12 to the dosing arm M1, 11 to M2, and 13 to M3). Of the 48 randomized participants, 40 (83.3%) participants completed the treatment phase, and 8 (16.7%) participants discontinued the treatment phase; the major reason for discontinuation was AEs (10.4%). In Part II of the study, a total of 6 participants were randomly assigned to receive 9 doses of felzartamab. All 6 (100%) patients completed the treatment phase and follow-up phase.

Overall, 39 (72.2%) participants reported treatment-emergent adverse events (TEAEs). Majority of participants reported mild TEAEs (38.9%) or moderate TEAEs (29.6%). 24 (44.4%) participants reported AEs related to study drug, 7 (13.0%) participants reported TEAEs leading to dose interruption, 6 (11.1%) participants reported TEAEs leading to study drug discontinuation, 1 (1.9%) participant reported Grade 1, and 7 (13.0%) participants reported Grade 3 treatment-emergent Adverse Events of Special Interest (AESIs), and 2 (3.7%) participants reported treatment-emergent serious adverse events (SAEs). No death was reported during the study. The incidence of TEAEs reported during the study was 6 (50.0%) in the placebo group, 10 (83.3%) in M1 arm, 9 (81.8%) in M2 arm, 11 (84.6%) in M3 arm in Part I, and 3 (50.0%) in Part II. Overall, 36 (66.7%) participants reported post-treatment adverse events (PTAEs). Majority of participants reported mild PTAEs 27 (50.0%) or moderate PTAEs 8 (14.8%). None of the participants reported post-treatment AESIs and 1 (1.9%) participant reported post-treatment SAEs. No post-treatment death was reported. The incidence of PTAEs reported during the study was 8 (66.7%) in the placebo group, 9 (75.0%) in M1 arm, 6 (54.5%) in M2 arm, 8 (61.5%) in M3 arm in Part I, and 5 (83.3%) in Part II. The number of RETEAE were 6 (50.0%) in the placebo group, 10 (83.3%) in M1 arm, 9 (81.8%) in M2 arm, 12 (92.3%) in M3 arm of Part I, and 5 (83.3%) in Part II. The number of on-study AEs were 10 (83.3%) in the placebo group, 11 (91.7%) in M1 arm, 9 (81.8%) in M2 arm, 12 (92.3%) in M3 arm of Part I, and 6 (100.0%) in Part II. The most commonly reported (>5% of participants in total group) TEAEs by PT included COVID-19, nasopharyngitis, upper respiratory tract infection, diarrhoea, fatigue, IRR, headache, dizziness, and hematuria. Most of the TEAEs were Grade 1 to 2. Number of participants reporting Grade 3 or higher AEs were 2 (16.7) in the placebo group, 3 (25.0%) in M1 arm, 3 (27.3%) in M2 arm, and 3 (23.1%) in M3 arm of Part I. None of the participant had Grade 4 or Grade 5 TEAEs. Most commonly reported (>=2 participants in total group) Grade 3 AEs were: IRR, drug hypersensitivity, and neutropenia. Out of 24 participants, number of participants with any AE assessed by the investigator to be related to study drug are 3 (25.0%) in the placebo, 6 (50.0%) in M1, 6 (54.5%) in M2, 7 (53.8%) in M3 in Part I and 2 (33.3%) in Part II. Grade >=3 adverse events related to study drug are IRR, neutropenia, drug hypersensitivity, and lipase increased. No death was reported during the study. Overall, 2 participants (1 each from M1 and M2) reported 2 treatment-emergent SAEs. In M2 arm, 1 participant reported Grade 3 IRR which was considered related to the study drug and 1 participant from M1 arm reported Grade 3 tendon rupture which was considered not related to the study drug. Both the events were considered resolved. One participant from the placebo group reported post-treatment Grade 3 SAE of dedifferentiated liposarcoma which resolved and was considered not related to the study drug. Out of 7 (13%) participants, number of participants with any TEAE leading to drug interruption are 1 (8.3%) in M1, 2 (18.2%) in M2, 3 (23.1%) in M3 in Part I and 1 (16.7%) Part II. None of the participants in the placebo had TEAE leading to drug interruption. The TEAEs by PT included COVID-19, upper respiratory tract infection, and cellulitis. Out of 6 (11.1%) participants, number of participants with any TEAE leading to drug withdrawal are 1 (8.3%) in M1, 3 (27.3%) in M2, 2 (15.4%) in M3 in Part I and none in Part II. None of the participants in the placebo and Part II had TEAE leading to drug withdrawal. The TEAEs by PT included IRR, drug hypersensitivity, and anxiety. Out of 8 (14.8%) participants, number of participants with treatment-emergent AESI are 2 (16.7%) in M1, 3 (27.3%) in M2, 3 (23.1%) in M3 in Part I. The treatment-emergent AESI by PT included IRR, neutropenia, cytokine release syndrome, and drug hypersensitivity. None of the participants in the placebo and Part II had treatment-emergent AESI. Overall, 18 (33.3%) participants reported AE related to COVID-19. The number of participants with AE related to COVID-19 are 3 (25.0%) in the placebo group, 4 (33.3%) in M1, 3 (27.3%) in M2, 6 (46.2%) in M3 in Part I and 2 (33.3%) in Part II. The AE related to COVID-19 by PT included COVID-19, SARS-CoV-2 test positive, and myalgia. There were no apparent clinically significant treatment-related trends and no clinically relevant changes were seen in hematology, central serum biochemistry parameters, and urinalysis. However, a total of 3 (5.6%) participants were positive for hepatitis B core antibody (2 [16.7] in the placebo group and 1 [7.7%] in the M3 arm). No abnormalities of potential clinically relevant were reported for any physical examination parameter except for one participant in Part II. The values of vital signs and ECG parameters were high and/or abnormal but not clinically significant in few participants. One participant from Part I M3 arm had abnormal clinically significant diastolic blood pressure on Day 366. All participants had a normal ECG interpretation through Month 24 in Part I and Month 12 in Part II except for 2 participants from placebo group.

Primary Endpoint: relative change in UPCR from baseline to 9 months At Month 9 in Part I, UPCR decreased from baseline in a dose-dependent manner. Percent change from baseline in geometric mean (SD) was -16.5 (19.41) in M1 arm, -30.6 (21.72) in M2 arm, -38.5 (18.60) in M3 arm, and -24.7 (19.43) in placebo arm. Between-groups geometric LS mean differences (95% CI) versus placebo were 1.11 (0.67, 1.84) in M1 arm, 0.92 (0.54, 1.57) in M2 arm, and 0.82 (0.49, 1.35) in M3 arm. At Month 9, the percent decrease from baseline in geometric mean UPCR was -48.8 (26.49) for the open-label Part II cohort. The geometric LS mean ratio (95% CI) at Month 9 over baseline (relative to placebo) was 0.67 (0.37, 1.22). Secondary Endpoint: relative change in UPCR from baseline to 3, 6, 12, 18 and 24 months The UPCR value showed a decrease from baseline starting as early as Month 3. The relative decrease from baseline in UPCR was more pronounced in the M2 and M3 arms than the M1 arm at all timepoints up to Month 12. The geometric LS mean ratio (95% CI) of UPCR decrease over baseline (relative to placebo) in the M1, M2, and M3 arms, respectively at Month 3 was 1.13 (0.79, 1.62), 0.79 (0.53, 1.19), and 0.79 (0.54, 1.15); at Month 6 was 0.81 (0.47, 1.38), 0.64 (0.36, 1.13), and 0.64 (0.37, 1.11); and at Month 24 was 1.37 (0.59, 3.17), 1.12 (0.46, 2.69), and 0.83 (0.37, 1.88). In Part II, in the Japanese Cohort, the UPCR showed similar trend of decrease from baseline from Month 3 to Month 12. The geometric LS mean ratios (95% CI) of UPCR over baseline (relative to placebo) at Month 3, Month 6, and Month 12 were 0.80 (0.52, 1.23), 0.67 (0.36, 1.24), and 0.48 (0.26, 0.87), respectively. Secondary Endpoint: Complete Response at 3, 6, 9, 12, 18, and 24 months. Complete response (CR) was defined as the reduction of proteinuria to less than 0.3 g/g UPCR, serum albumin within the reference range of the central laboratory and stable eGFR (at least 80% of value at baseline visit). At Month 3, the CR (observed) was seen in 1 (11.1%) participant in the M3 arm and in no participants in other study groups. Throughout the study, CR was observed in the M3 arm at all visits, with 4 (40.0%) participants showing complete response at Month 24 (observed values). In the other study groups, CR was seen in 1 (9.1%) participant in the M1 arm at Month 6 and 1 (10.0%) participant in the placebo group at Month 24. Secondary Endpoint: Response Response was defined as the reduction of proteinuria to below 0.6 g/g (UPCR) and stable eGFR (at least 80% of value at baseline visit), but not CR. Response (observed) was first seen at Month 3, in 1 (8.3%), 1 (9.1%), and 4 (44.4%) participants in the placebo, M1, and M3 arms, and none of the participants in the M2 arm. Throughout the study, responders were consistently noted in the M3 arm, and the response rate was also higher than the other study groups. At Month 6, response was seen in the M1 and M3 arms (1 [9.1%] and 5 [55.6%] participants, respectively); at Month 12, response was seen in the placebo, M2, and M3 arms (1 [9.1%], 2 [22.2%], and 3 [27.3%] participants, respectively); and at Month 24, response was seen in M1, M2, and M3 arms (1 [11.1%], 1 [12.5%], and 2 [20.0%] participants, respectively). Secondary Endpoint: Albumin-Creatinine Ratio The baseline ACRs were comparable in all study groups and decreased from baseline starting as early as Month 3. The percent change from baseline within the groups and subsequently the decrease over baseline relative to placebo in ACR was more in the M2 and M3 arms than the M1 arm at all timepoints up to Month 24. The geometric LS mean ratio (95% CI) of ACR decrease over baseline (relative to placebo) in the M1, M2, and M3 arms, respectively at Month 3 was 1.06 (0.74, 1.51), 0.79 (0.52, 1.19), and 0.73 (0.50, 1.07); at Month 6 was 0.76 (0.44, 1.33), 0.65 (0.36, 1.18), and 0.60 (0.34, 1.07); and at Month 24 was 1.39 (0.54, 3.61), 1.20 (0.44, 3.28), and 0.85 (0.34, 2.17). In Part II of the study, in the Japanese Cohort, the ACR showed a decrease from baseline starting at Month 3 and maintained through Month 12. The mean (SD) percent change from baseline in ACR at Month 3, Month 6, and Month 12 were -23.84 (23.435), -29.79 (34.772), and -43.73 (34.108), respectively. Secondary Endpoint: Time to response was defined as date of 1st observation of response minus date of randomization +1 day. Throughout the study, a total of 8 (16.7%) participants had complete response, of which 6 participants belonged to the M3 arm (complete response rate: 46.2%). A total of 15 (31.3%) participants had any response (response or complete response), of which 8 participants belonged to the M3 arm (response rate: 61.5%). The median time to achieve first response in the M3 arm was 176 days. Overall, the median duration of response was 192 days (95% CI: 85.0 to 451.0 days). Secondary Endpoint: Estimated glomerular filtration rate While the placebo and M1 arms consistently showed a decrease in the eGFR from baseline throughout the study, the M2 and M3 arms showed no change to small increase in the eGFR values from baseline to Month 6. Summary statistics of Month-6 change from baseline in mean (SE) in the placebo, M1, M2, and M3 arms were -8.2 (3.42), -2.2 (3.54), 2.6 (4.34), and -1.3 (3.56), respectively. After Month 6, the eGFR values started decreasing in the M2 and M3 arms also, such that at Month 24, the mean (SE) change from baseline in the placebo, M1, M2, and M3 arms were -10.1 (4.28), -7.3 (4.36), -5.1 (4.74), and -7.1 (4.05), respectively. At Month 24, there were total 4 participants in the felzartamab groups who had a decrease in eGFR of >=30% from baseline throughout the study (1 [10%] each in M1 and M3 arms and 2 [25%] in M2 arm). Secondary Endpoint: Other Efficacy Endpoint Results The proportion of participants with progressive disease was numerically higher in the placebo group than the felzartamab groups. At Month 6, 6 (60.0%) participants in the placebo group had progressive disease as compared with 1 (9.1%), 2 (28.6%), and 2 (22.2%) participants in the M1, M2, and M3 arms. At Month 24, 7 (70.0%), 3 (33.3%), 4 (50.0%), and 6 (60.0%)participants in the placebo, M1, M2, and M3 arms had progressive disease. At baseline, majority of the participants had normal urine (19 [40.4%] participants) or abnormal, not clinically significant hematuria (22 [46.8%] participants) and the proportions were similar across all study groups. A total of 6 (12.8%) participants had abnormal, clinically significant hematuria at baseline (1 [8.3%], 1 [8.3%], 2 [20.0%], and 2 [15.4%] participants in the placebo, M1, M2, and M3 arms, respectively). At Month 6, 4 [10.0%] participants had abnormal, clinically significant hematuria (1 [9.1%], 1 [9.1%], 2 [25.0%], and zero participants in the placebo, M1, M2, and M3 arms, respectively). At Month 24, only 2 (5.6%) participants had abnormal, clinically significant hematuria: 1 (10.0%) participant in the M1 arm and the other (14.3%) in the M2 arm. In Part II of the study, in the Japanese Cohort, only 1 of 6 (16.7%) participants had abnormal clinically significant hematuria at baseline. At Month 6, 2 (33.3%) participants had abnormal clinically significant hematuria but none at Month 24.

In Part I, 12 participants were exposed to placebo and 36 participants were exposed to felzartamab. In Part II, 6 participants were exposed to felzartamab. UPCR levels were reduced at Month 9 and throughout in all felzartamab-treated groups. Felzartamab also reduced ACR and stabilized eGFR in IgAN patients. Felzartamab had a favorable safety profile and was well tolerated across different dose levels.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210119

Shinnosuke Mamiya

PPDSNBL K.K

St Luke's Tover 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo

shinnosuke.mamiya@ppd.com

Shinnosuke Mamiya

PPDSNBL K.K

St Luke's Tover 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo

+81-6-4560-6778

shinnosuke.mamiya@ppd.com

Complete

Sept. 13, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

-Patients >=18 to =<80 years (at date of signing the informed consent form [ICF]), but at least of legal age in the given country
-Biopsy confirmed diagnosis of IgAN within the past 8 years prior to signature of the ICF
-Proteinuria at screening visit >=1.0 g/d
-Treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) at maximum doses or maximally tolerated doses for >= 3 months prior to date of informed consent and adequate blood pressure (BP) control
-A female of childbearing potential (FCBP), is only eligible to participate if she is not pregnant, not breast feeding, and agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of IMP

-Hemoglobin < 90 g/L
-Thrombocytopenia: Platelets < 100.0 x 10^9/L.
-Neutropenia: Neutrophils < 1.5 x 10^9/L.
-Leukopenia: Leukocytes < 3.0 x 10^9/L
-Diabetes mellitus type 1
-Aspartate aminotransferase or alanine aminotransferase >1.5 x ULN, alkaline phosphatase >3.0 x ULN

Both

IgA Nephropathy

In the double-blind part of the trial, the IgA Nephropathy patients will be randomized to receive one of 3 different dosing schedules of MOR202 (dosing arms M1, M2 or M3) or placebo as 1:1:1:1, and be administered for 6 months. The absolute dose to be administered intravenously (i.v.) will be determined according to body weight of the patient. The patients in open label part of the trial will receive MOR202 according to M3 schedule.

Relative change in UPCR in 24h urine at 9 months compared to the reference proteinuria value in the Felzartamab dose groups vs. placebo.

+81-942-31-7200

July. 20, 2021

Germany/Belgium/USA/Australia/South Korea/Serbia/Spain/Malaysia/Georgia/Czech Republic/Canada/Philippines/Taiwan/United Kingdom/Ukraine/Bulgaria