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A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLINDED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PEGCETACOPLAN IN PATIENTS WITH C3 GLOMERULOPATHY OR IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (A PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PEGCETACOPLAN IN PATIENTS WITH C3 GLOMERULOPATHY OR IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS)

APL2-C3G-310

63

Overall, Study APL2-C3G-310 was generally representative of a real-world C3G or primary IC-MPGN population. Patient demographics and disease characteristics at baseline were generally similar and balanced between the treatment groups. The overall mean (SD) age at screening was 26.0 (15.86) years, with a mean age of 28.2 (17.08) years and 23.6 (14.26) years in the pegcetacoplan group and placebo group, respectively. The age difference was not considered to be meaningful as data demonstrated similar results between adolescents and adults. Overall, 54 participants (43.5%) were male, and 70 participants (56.5%) were female. Most participants were White (91 participants [73.4%]) and identified as Not Hispanic or Latino (88 participants [71.0%]). The mean weight, height, body mass index, systolic blood pressure, and diastolic blood pressure at baseline were balanced between the pegcetacoplan and placebo groups. Of the 124 participants overall, 51 (81.0%) in the pegcetacoplan group, and 45 (73.8%) in the placebo group had C3G underlying disease based on screening biopsy. Twelve (19.0%) participants in the pegcetacoplan group and 16 (26.2%) in the placebo group had IC-MPGN underlying disease based on screening biopsy. Medical history characteristics were balanced. Indication per disease-specific medical history form was C3G for 48 (76.2%) participants in the pegcetacoplan group and 48 (78.7%) participants in the placebo group. For IC-MPGN, it was 15 (23.8%) participants in the pegcetacoplan group and 13 (21.3%) participants in the placebo group. Collection of medical history data showed that participants in the placebo group had more genetic risk factors for C3G/IC-MPGN (16.4%) than participants in the pegcetacoplan group (6.3%). Because genetic testing was not a requirement for this study, this numerical difference may result from the fact that not all participants had the genetic test. Randomized Controlled Period: Pegcetacoplan: Overall Number of Baseline Participants 63. All adult subjects (regardless of weight) and adolescent subjects with body weight >=50 kg received pegcetacoplan 1080 mg SC infusion twice weekly for 26 weeks in RCP. Adolescent subjects with body weight 35 to <50 kg received pegcetacoplan 648 mg for the first SC infusion and 810 mg SC infusion thereafter twice weekly for 26 weeks in RCP. Adolescent subjects with body weight 30 to <35 kg received pegcetacoplan 540 mg for the first 2 SC infusions and 648 mg SC infusion thereafter twice weekly for 26 weeks in RCP. Randomized Controlled Period: Placebo: Overall Number of Baseline Participants 61. All adult subjects (regardless of weight) and adolescent subjects (with body weight: 30 to <35 kg, 35 to <50 kg, and >=50 kg) received placebo matching with pegcetacoplan SC infusion twice weekly for 26 weeks in RCP. Total: Total number of all reporting groups 124.

Recruitment Details: This Phase 3 randomized, placebo-controlled, double-blinded study was conducted in subjects with complement 3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) at 122 sites. Pre-assignment Details: This study consisted of a screening period (10 weeks), 26-week randomized controlled period (RCP), followed by a 26-week open-label period (OLP) and follow-up period (8 weeks). Subjects were randomized to receive pegcetacoplan or placebo in a ratio of 1:1 in RCP. A total of 124 subjects were enrolled in this study. Please see attachment in section 2-1 for detail.

Safety data from the overall study demonstrate that pegcetacoplan is safe and well tolerated with long-term treatment. The safety profile observed was generally consistent with that observed during the RCP. The safety profile was similar in participants who switched from placebo to pegcetacoplan in the placebo-to-pegcetacoplan group during the OLP. No new safety signals for pegcetacoplan were identified. During the overall study, the most commonly reported TEAEs were pyrexia (16.7%), headache (14.2%), diarrhea and nasopharyngitis (11.7% each), and vomiting (10.0%). Participants reported TEAEs during the overall study that were mild (36.7%) or moderate (39.2%) in severity. Rejection episodes due to TEAEs were reported for 1 (1.6%) posttransplant participant in the pegcetacoplan-to-pegcetacoplan group. No TEAEs led to graft loss. In total, 49 (40.8%) participants had a treatment-related TEAE and 36 (30.0%) participants had an infusion-related TEAE during the overall study. The most common treatment-related TEAEs were injection site pruritus and pruritus (5 [4.2%] each).The most common infusion-related TEAE was injection site swelling (6 [5.0%]). No deaths occurred during the OLP. One participant in the pegcetacoplan group died during the RCP due to respiratory failure secondary to COVID-19 pneumonia, which was considered by the investigator to be unrelated to study drug. In total, 14 (11.7%) participants had a serious adverse event (SAE) during the overall study. The most common SAEs were acute kidney injury (3 [2.5%]) (one of which also had an SAE of acute kidney injury during the RCP) and dehydration and pyrexia (2 [1.7%] each). No other specific SAE (Preferred Term) was experienced by more than 1 participant during the overall study. During RCP, 1 participant had an SAE of pyrexia that was considered by the investigator to be related to study drug. One participant had an SAE (herpes zoster meningoencephalitis) during the OLP that was considered by the investigator to be possibly related to pegcetacoplan; however, this event was not considered by the sponsor to be related to pegcetacoplan. During the overall study, 6 (5.0%) participants had an AE leading to treatment discontinuation, 18 (15.0%) participants had an AE leading to dose interruption, and 4 (3.3%) participants had an AE leading to study discontinuation. In total, 36 (30.0%) participants had an infusion site reaction during the overall study. The incidence of protocol-defined AEs of special interest during the OLP was low: 1 (0.8%) participant had thrombocytopenia, 3 (2.5%) participants had a severe infection, 12 (10.2%) participants had a hypersensitivity event, and 3 (2.5%) participants had a severe acute kidney injury. Laboratory findings were consistent with those expected in participants with C3G or primary IC-MPGN, and changes in these parameters were consistent with the efficacy findings that pegcetacoplan improves kidney function. No significant trends or correlations in ECG parameters or vital signs were observed.

Overall, efficacy results from the study demonstrated that the consistent and robust treatment effects of pegcetacoplan in patients with C3G or primary IC-MPGN were sustained throughout 52 weeks of treatment. The benefit of pegcetacoplan treatment was also evident and replicated in participants who switched from placebo to pegcetacoplan in the placebo-to-pegcetacoplan group during the OLP. Specifically, treatment with pegcetacoplan during the overall study resulted in: - Robust reduction in proteinuria as measured by FMU uPCR at week 52 compared to baseline (67.2% reduction in the pegcetacoplan-to-pegcetacoplan group; 51.3% reduction in the placebo-to-pegcetacoplan group). - A rapid reduction in uPCR (FMU) in both treatment groups as early as the first time point measured after participants commenced pegcetacoplan treatment. - A large proportion of participants had a 50% or more reduction in uPCR at week 52 compared with baseline (50.79% in the pegcetacoplan-to-pegcetacoplan group; 40.98% in the placebo-to-pegcetacoplan group). - Stabilization of eGFR after participants received treatment with pegcetacoplan which continued throughout the duration of the study. Additionally, both treatment arms experienced a meaningful increase in the proportion of participants who achieved proteinuria <1 g per day which further increased in the pegcetacoplan-to-pegcetacoplan group through week 48 and was comparable in the placebo-to-pegcetacoplan group after starting pegcetacoplan treatment. Efficacy results are further supported by the improvements seen in the patient-reported outcomes, in which the majority of participants in both treatment groups reported an improvement at week 52 as a result of pegcetacoplan treatment (Patient Global Impression of Change: 68.9% and 75.0% reported very much improved, much improved, or minimally improved). The benefits of treatment with pegcetacoplan were also reflected across multiple additional exploratory efficacy measures at week 52.

This study demonstrated that pegcetacoplan has a positive benefit-risk profile in the treatment of C3G and primary IC-MPGN. The treatment effect of Pegcetacoplan demonstrated a durable response in the pegcetacoplan-to-pegcetacoplan group for the 52-week overall study and the replicability of reduction in proteinuria in the placebo-to-pegcetacoplan group after switching to study drug in the OLP. Results from the placebo-to-pegcetacoplan group provide further support for the efficacy of pegcetacoplan treatmen

Yes

Requests for access to the deidentified data will be reviewed by Apellis External Research Committee.

https://jrct.mhlw.go.jp/latest-detail/jRCT2041230022

Mizuno Masashi

Nagoya University Hospital

65 Tsurumai-cho, Showa-ku, Nagoya City

mmizu@med.nagoya-u.ac.jp

Shinoki Yoshi

Worldwide Clinical Trials Japan K.K.

Shinagawa Intercity, Tower A, Level 28, 2-15-1, Konan, Minato-ku, Tokyo 108-6028

+81-3-6717-4360

yoshi.shinoki@worldwide.com

Complete

Oct. 03, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1.Aged at least 18 years; where approved, adolescents (aged 12-17 years) weighing at least 30 kg may also be enrolled.
2.A diagnosis of primary C3G or IC-MPGN (with or without previous renal transplant).
3.Evidence of active renal disease, based on one or more of the following:
a.In adults or adolescents with a baseline renal biopsy (either one collected during screening or a historic biopsy collected within 28 weeks prior to randomization), at least 2 C3c staining on the baseline renal biopsy.
b.In adolescents not providing a baseline renal biopsy, at least one of the following:
Plasma sC5b-9 level above the upper limit of normal during screening
Serum C3 below the LLN during screening
Presence of an active urine sediment during screening, as evidenced by hematuria with at least 5 red blood cells per high-power field and/or red blood cell casts on routine local or central microscopic analysis of urine
Presence of C3 nephritic factor within 6 months of screening, based on central laboratory results or medical history
4.No more than 50% global glomerulosclerosis or interstitial fibrosis on the baseline biopsy for adult participants or adolescent participants providing a baseline biopsy.
5.At least 1 g/day of proteinuria on a screening 24-hour urine collection and a uPCR of at least 1000 mg/g in at least 2 first-morning spot urine samples collected during screening.

1. Previous exposure to pegcetacoplan.
2. Evidence of improving renal disease in the 8 weeks prior to screening or during the screening period according to available data; improving renal disease is defined as more than 30% increase in eGFR or more than 50% decrease in proteinuria.
3. From a renal transplant participant, evidence of rejection that requires treatment in the baseline renal biopsy collected during screening.
4. C3G/IC-MPGN secondary to another condition (eg, infection, malignancy, monoclonal gammopathy, a systemic autoimmune disease such as systemic lupus erythematosus, chronic antibody-mediated rejection, or a medication), in the opinion of the investigator.
5. Current or prior diagnosis of HIV, hepatitis B, or hepatitis C infection or positive serology during screening that is indicative of infection with any of these viruses.
6. Body weight greater than 100 kg at screening.
7. Hypersensitivity to pegcetacoplan or to any of the excipients.
8. History of meningococcal disease.
9. Malignancy, except for the following:
a. Cured basal or squamous cell skin cancer
b. Curatively treated in situ disease
c. Malignancy-free and off treatment for more than 5 years
10. Severe infection (eg, requiring IV antibiotic therapy) within 14 days prior to the first dose of pegcetacoplan.
11. An absolute neutrophil count less than 1000 cells/mm3 at screening.

Both

C3 GLOMERULOPATHY OR IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

All participants will receive SC infusions of pegcetacoplan or matching volumes of placebo twice weekly. All adult participants (regardless of weight), and adolescent participants who weigh at least 50 kg, will receive 20 mL SC infusions. Adolescent participants who weigh at least 35 kg but less than 50 kg will receive a reduced infusion volume (12 mL for the first infusion and 15 mL for each infusion thereafter). Adolescent participants who weigh at least 30 kg but less than 35 kg will receive a further reduced infusion volume (10 mL for the first 2 infusions and 12 mL twice weekly thereafter). Participant weight will be assessed at each visit; if an adolescent participants weight has changed, the dose and infusion volume should be adjusted accordingly.

C3 GLOMERULOPATHY

The log-transformed ratio of uPCR at week 26 compared to baseline

The proportion of participants who meet the criteria for achieving a composite renal endpoint (a stable or improved eGFR compared to the baseline visit (less than 15% reduction in eGFR), and a more than 50% reduction in uPCR compared to the baseline visit.)
The proportion of participants with a reduction of at least 50% from baseline in uPCR
Change from baseline in eGFR
For participants with evaluable renal biopsies, the change from baseline in the activity score of the C3G histologic index score
The proportion of participants with evaluable renal biopsies showing decreases in C3c staining on renal biopsy from baseline

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