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A PHASE 2, 24-WEEK, ADAPTIVE, OPEN LABEL, SEQUENTIAL COHORT TRIAL TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06730512 FOLLOWING MULTIPLE DOSES IN ADULT SUBJECTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) (PODO)

A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (FSGS) (PODO)

47

Of the 47 participants, most were white (76.6%); gender distribution was overall balanced (male: 53.2%, female: 46.8%); more than half of participants (55.3%) were aged 18 to <45 years old. The median (range) age in Cohort 1 (47.0 [21, 59] years old) was numerically higher than that in Cohort 2 (39.0 [21, 75] years old). The median (range) body mass index (BMI) of the 47 participants at Baseline was 27.770 (11.69-44.60) kg/m2. The average (standard deviation [SD]) duration of disease (years) in Cohort 1 (3.72 [4.04]) was less than that in Cohort 2 (5.72 [7.60]); the average (SD) baseline urine protein to creatinine ratio (UPCR) (g/g) based on 24-hour urine collection in Cohort 1 (5.42 [4.11]) was lower than that in Cohort 2 (6.03 [3.51]), so was the average (SD) baseline estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) (63.12 [18.86] in Cohort 1 and 69.25 [24.83] in Cohort 2).

All 47 participants received at least 1 dose of their assigned study intervention: 10 participants (1 in Cohort 1 and 9 in Cohort 2) discontinued the study intervention; a total of 24 participants (18 in Cohort 1 and 6 in Cohort 2) completed 12-week Investigational Treatment Period; and a total of 13 participants (4 in Cohort 1 and 9 in Cohort 2) completed 24-week Investigational Treatment Period. Two participants (both in Cohort 1) did not receive the planned 1000 mg dose and instead received 1080 mg at 3 visits, which were recorded as important protocol deviations and medication errors. Additionally, 5 participants (1 in Cohort 1 and 4 in Cohort 2) had study intervention interruption due to adverse events (AEs), and in 4/5 participants the interruption was due to treatment-emergent AEs (TEAEs).

A total of 124 all-causality and 24 treatment-related TEAEs were reported in 37 (78.7%) and 15 (31.9%) participants, respectively. The majority of the TEAEs were mild or moderate in severity. Serious AEs (SAEs) and severe TEAEs were reported in 4 (8.5%) and 3 (6.4%) participants, respectively, and none of these were treatment-related. There was 1 participant (in Cohort 1) who discontinued the study intervention due to non-treatment-related TEAE. No participant in Cohort 2 discontinued the study intervention due to TEAE. A total of 4 participants (1 in Cohort 1 and 3 in Cohort 2) underwent dose reduction or treatment interruption due to TEAEs, and for 1 of them the TEAEs were treatment-related. Incidence of all-causality TEAEs was higher in Cohort 1 compared to Cohort 2 (87.0% vs 70.8%). Incidences of SAEs (8.7% vs 8.3%), treatment-related TEAEs (30.4% vs 33.3%), and severe TEAEs (4.3% vs 8.3%) were similar between the 2 cohorts. The most frequently reported TEAEs in the study (in >=5% of participant in total) included fatigue and headache (10.6% each), coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positive, and diarrhoea (8.5% each), and vomiting and acute kidney injury (6.4% each). The TEAEs reported in >=2 participants in Cohort 1 included fatigue in 3 participants, and diarrhoea, vomiting, pyrexia, viral infection, SARS-CoV-2 test positive, dehydration, headache, insomnia, acute kidney injury, and cough (each in 2 participants); those in Cohort 2 included COVID-19 and headache (each in 3 participants), and diarrhoea, fatigue, oedema, nasopharyngitis, urinary tract infection, infusion related reaction, SARS-CoV-2 test positive, flank pain, muscle spasms, and dizziness (each in 2 participants). Treatment-related TEAEs reported in >=2 participants in Cohort 1 included fatigue and headache (each in 2 participants); those in Cohort 2 included fatigue, infusion related reaction, and headache (each in 2 participants), all others were reported in single participants. Clinical Laboratory Evaluation, Electrocardiogram (ECG), and Vital Signs There were no clinically important trends in lab values. There were no notable changes from baseline in ECG parameters, or vital signs.

Primary Efficacy Endpoint: Percent Change From Baseline (%CFB) in UPCR to Week 13 - 24-hour Urine Collection Primary Analyses Based on 24-hour urine collection, the least squares mean (LS mean) %CFB in UPCR at Week 13 was -12.283% (90% confidence interval [CI]: -26.096%, 4.112%) and -0.045% (90% CI: -9.528%, 10.432%) in Cohort 1 and Cohort 2, respectively. The posterior probability of being at least 95% confident that the UPCR reduction >0% at Week 13 was 89.74% and 50.30% in Cohort 1 and Cohort 2, respectively. The posterior probability of being at least 50% confident that the UPCR reduction >35% at Week 13 was<1% in both cohorts. Secondary Efficacy Endpoints %CFB in UPCR to Weeks 5 and 9 - 24-hour Urine Collection and First Morning Void (FMV) For the secondary endpoint "%CFB in UPCR to Weeks 2, 5, and 9", the number of participants who had Week 2 visit was too small to successfully run the statistical model, and therefore LS mean %CFB results were not provided at Week 2 for the endpoint. Based on 24-hour urine collection, the LS mean %CFB in UPCR: * at Week 5 was 6.250% (90% CI: -7.035%, 21.433%) and -3.788% (90% CI: -11.344%, 4.411%) in Cohort 1 and Cohort 2, respectively; and * at Week 9 was -11.335% (90% CI: -20.746%, -0.807%) and -2.354% (90% CI: -11.069%, 7.215%) in Cohort 1 and Cohort 2, respectively. Based on FMV, the LS mean %CFB in UPCR: * at Week 5 was 8.509% (90% CI: -3.471%, 21.976%) and 0.917% (90% CI: -10.167%, 13.369%) in Cohort 1 and Cohort 2, respectively; and * at Week 9 was 6.803% (90% CI: -8.049%, 24.054%) and 0.423% (90% CI: -9.177%, 11.036%) in Cohort 1 and Cohort 2, respectively. %CFB in eGFR to Weeks 3, 5, 9, and 13 From Week 3 through Week 13, the LS mean %CFB in eGFR: * at Week 3 was 5.657% (90% CI: -0.722%, 12.446%) and -0.180% (90% CI: -4.179%, 3.987%) in Cohort 1 and Cohort 2, respectively; * at Week 5 was 2.174% (90% CI: -3.012%, 7.637%) and -2.038% (90% CI: -8.008%, 4.319%) in Cohort 1 and Cohort 2, respectively; * at Week 9 was -1.536% (90% CI: -15.575%, 14.838%) and -5.017% (90% CI: -11.596%, 2.052%) in Cohort 1 and Cohort 2, respectively; and * at Week 13 was 2.892% (90% CI: -6.096%, 12.740%) and -12.217% (90% CI: -18.831%, -5.063%) in Cohort 1 and Cohort 2, respectively. Pharmacokinetic Results: Following multiple intravenous (IV) infusions of PF-06730512 at doses of 300 mg every 2 weeks (Q2W) and 1000 mg Q2W in adult participants with focal segmental glomerulosclerosis (FSGS), maximum serum concentration during the dosing interval (Cmax) was observed shortly after the end of the 1-hour infusion (median time for Cmax [Tmax] range of approximately 1.1 to 1.2 hours). Serum PF-06730512 Day 71 Cmax and area under the concentration-time profile from time zero to time tau, the dosing interval, where tau = 336 hours for Q2W dosing (AUCtau increased approximately proportionally from 300 mg Q2W to 1000 mg Q2W. At steady state (Days 71 and 155), geometric mean clearance for IV dosing (CL) was 0.043 L/h and 0.029 L/h and geometric mean volume of distribution at steady state for IV dosing (Vss) was 6.5 L and 5.4 L for 300 mg and 1000 mg doses, respectively. Mean terminal half-life (t1/2) was 224 hours and 252 hours for 300 mg and 1000 mg doses, respectively. Participant variability in PF-06730512 exposure based on geometric percent coefficient of variation (CV%) for AUCtau and Cmax ranged between 31% to 41% on Day 1 and 70% to 134% on Day 71. On Day 155, variability was low for the 1000 mg dose group (geometric CV% for AUCtau and Cmax was 15% and 21%, respectively), while for the 300 mg dose group variability was high with geometric CV% for AUCtau and Cmax at 226% and 361%, respectively. In participants with baseline UPCR >=3 g/g (nephrotic group), median trough serum concentrations were generally 30-60% of that in participants in the non-nephrotic group (baseline UPCR <3 g/g), in both the 1000 mg and 300 mg IV Q2W dose cohorts. Immunogenicity Results: Of the 47 participants evaluated for anti-drug antibody (ADA) and neutralizing antibody (NAb), the overall incidence of positive ADA during the study treatment was 2.1%, and the overall incidence of positive NAb was 0%. The positive ADA, which was detected in only 1 participant in Cohort 1, was treatment-induced and transient in duration.

PF-06730512 was in general safe and tolerable, with no clinically significant safety signals being identified. The study failed to meet the primary efficacy endpoint of percent reduction from baseline in UPCR at Week 13 based on 24-hour urine collection at both tested doses of PF-06730512 1000 mg and 300 mg IV Q2W.

Mar. 15, 2024

Yes

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

https://jrct.mhlw.go.jp/latest-detail/jRCT2021200032

Kawai Norisuke

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Complete

May. 17, 2021

Interventional

non-randomized controlled trial

double blind

uncontrolled control

single assignment

treatment purpose

Inclusion Criteria:
1.Adults age 18 years and older who have a confirmed diagnosis of FSGS.
2.Estimated glomerular filtration rate (eGFR) greater than or equal to 45 ml/min/1.73 m2. If eGFR is 30 - 45 ml/min/1.73 m2, a recent biopsy (within 12 months prior to Screening) must demonstrate < 50% tubulointerstitial fibrosis.
3.Urine protein:creatinine ratio (UPCR) greater than 1.5 g/g at screening.
4.Treated with at least one but not more than 3 classes of immunosuppressants either alone or in combination, or has a contraindication to use of an immunosuppressant or is intolerant to an immunosuppressant per investigator judgment

1. Diagnosis of collapsing FSGS.
2. Advanced chronic changes on renal biopsy as evidenced by greater than 50% tubulointerstitial fibrosis.
3. Organ transplant.
4. History of malignancy, with the exception of basal or squamous cell carcinoma that has been treated and fully resolved for a minimum of 5 years.
5. Body mass index (BMI) greater than 45 kg/m2.
6. Subjects with a history of prior treatment with or use of interferon, lithium, pamidronate, mTOR inhibitors (eg, sirolimus), testosterone/anabolic steroids, anthracycline (eg, doxorubicin), heroin.

Both

Focal Segmental Glomerulosclerosis (FSGS)

Drug: PF-06730512
Subjects in cohort 1 will receive Dose 1 Intravenous infusion (IV). Subjects in cohort 2 will receive Dose 2 IV.

Percentage Change From Baseline in Urinary Protein to Creatinine Ratio (UPCR) Based on 24-hour Urine Collection at Week 13 [Time Frame: Baseline, Week 13]

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Time Frame: From Day 1 of treatment up to 9 weeks after last dose of study treatment (up to Week 33)]
2. Number of Participants With Abnormalities in Laboratory Test Parameters [Time Frame: From Day 1 of treatment up to Week 33]
3. Change From Baseline in Body Weight [Time Frame: Baseline, Change at Weeks 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 and 33]
4. Change From Baseline in Blood Pressure [Time Frame: Baseline, Change at Weeks 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 and 33]
5. Change From Baseline in Pulse Rate [Time Frame: Baseline, Change at Weeks 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 and 33]
6. Change From Baseline in Body Temperature [Time Frame: Baseline, Change at Weeks 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 and 33]
7. Number of Participants With Abnormalities in Electrocardiogram (ECG) [Time Frame: Weeks 3, 7, 11, 13, 17, 21, 25 and 33]
8. Percentage Change From Baseline in Urinary Protein to Creatinine Ratio (UPCR) at Weeks 2, 5, 9 and 13 [Time Frame: Baseline, Weeks 2, 5, 9 and 13]
9. Percentage Change From Baseline in Estimated Glomerular Filtration Rate (eGFR ) at Weeks 3, 5, 9 and 13 [Time Frame: Baseline, Weeks 3, 5, 9 and 13]
10. Serum PF-06730512 Concentration Versus Time Summary [Time Frame: For 12-Week treatment(WT): pre-dose on Days 1, 8, 15, 29, 43, 57, 71, follow-up(Fup)visit on Days 85, 99, 113, 141, For 24-WT: pre-dose on Days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, Fup visit on Days 169, 183, 197, 225; 1 hour post-dose on Days 1, 71, 155(only applicable for 24-WT)]
11. Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibody(NAb) [Time Frame: From Day 1 of treatment up to Week 33]

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Aug. 04, 2020

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