Open Label Extension Study of 1 mg/kg Pegunigalsidase Alfa Every 2 Weeks in Patients With Fabry Disease

Chiesi Farmaceutici S.p.A.97 enrolled

Overview

The objective of CLI-06657AA1-04 (formerly PB-102-F60) was to evaluate the long-term safety, tolerability, and efficacy parameters of 1 mg/kg pegunigalsidase alfa administered intravenously every other week in adult Fabry patients who had successfully completed studies PB-102-F20, PB-102-F30, or at least 48 months in study PB-102-F03.

This was an open-label study. Participants were enrolled to receive 1 mg/kg pegunigalsidase alfa as intravenous infusions every 2 weeks (±3 days). The duration of treatment was until pegunigalsidase alfa was commercially available to the participant, or at the discretion of the Sponsor. Efficacy and safety analyses were summarized using descriptive statistics for continuous variables and counts and percentages for categorical variables. Data from the parent studies were also included in the analyses.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Fabry Disease

Interventions

pegunigalsidase alfaDRUG

Recombinant human alpha galactosidase A

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Completion of study PB-102-F20, study PB-102-F30, or at least 48 months in study PB-102-F03. 2. The participant signed informed consent. 3. Female participants and male participants whose co-partners were of child-bearing potential agreed to use a medically acceptable method of contraception. These included combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) supplemented with a barrier method (preferably male condom), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) supplemented with a barrier method (preferably male condom), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence. Contraception had to be used for 2 weeks after treatment termination. Exclusion Criteria: Presence of any medical, emotional, behavioral, or psychological condition that, in the judgment of the Investigator, would interfere with patient compliance with the requirements of the study.

Locations (30)

Outcomes

Primary Outcomes

Number of Participants With Treatment-related Adverse Events

No primary or secondary endpoints were specified for this trial. Evaluation of safety was a main objective. A treatment-emergent adverse event (TEAE) was defined as any adverse event (AE) occurring after the start of study treatment and within the time of residual drug effect (20 days after last administration of study treatment) or a pre-treatment AE or medical condition that worsened in severity after the start of study treatment and within the time of residual drug effect. Each TEAE was classified for severity based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and for causality in the categories unrelated, unlikely, possible, probable and definitely. Treatment-related AEs were TEAEs with causality assessed as possible, probable or definitely related to study treatment. TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version (v)19.0. Related TEAEs reported in ≥2 percent of participants by Preferred Term are reported.

Time frame: From first ever infusion of pegunigalsidase alfa, which could have been in the parent study (PB-102-F01/F20/F30) or this extension study, CLI-06657AA1-04, until 90 days after the final dose visit for each participant. Mean individual exposure: 5.5 years

Secondary Outcomes

Change From Baseline to the Last Observation for the eGFR

The eGFR, calculated based on serum creatinine values, according to the Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) formula (2009).

Time frame: From baseline (assessment before first exposure to study drug, which could have been in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Annualized eGFR Slope

The annualized eGFR slope was added in the statistical analysis plan. Individual eGFR slopes were derived for each participant using a linear regression model and summarized descriptively.

Time frame: From first ever infusion of pegunigalsidase alfa (which could have been in the parent study, PB-102-F01/F20/F30, or this extension study, CLI-06657AA1-04), until the end of the extension study; mean individual exposure: 5.5 years

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

UAB Medicine

Birmingham, Alabama, United States

Phoenix Children's Hospital

Phoenix, Arizona, United States

University of California San Diego

La Jolla, California, United States

University of California Irvine Center

Orange, California, United States

University of Florida

Gainesville, Florida, United States

Emory University School of Medicine

Atlanta, Georgia, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

Infusion Associates

Grand Rapids, Michigan, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

...and 20 more locations

Shift From Baseline to the Last Scheduled Visit in UPCR Category

The UPCR was assessed by spot urine test. Participants were categorized according to UPCR at baseline and subsequent visits.

Time frame: Shift from baseline (assessment before first exposure to study drug which could be in the parent study PB-102-F01/F02/F30 or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change From Baseline to the Last Observation in Plasma Lyso-Gb3 and Globotriaosylceramide (Gb3) Concentrations

Plasma concentrations of Lyso-Gb3 and Gb3 (biomarkers for Fabry disease) were assessed at baseline and subsequent time points and change from baseline was assessed.

Time frame: Change from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04 ) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change From Baseline to the Last Observation for Pain Severity Items of the Brief Pain Inventory (BPI)

The short form Brief Pain Inventory (BPI) consists of 4 pain severity items (pain at its worst in the last 24 hours, pain at its least in the last 24 hours, pain on average and current pain) and 7 pain interference items (general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life) assessed over a 24-hour recall period. Each item is rated on a scale from 0 (no pain/interference) to 10 (worst pain imaginable/complete interference). Participants report percentage of pain relief by analgesics over the past 24 hours as well. Assessment of pain (by the BPI) was performed at baseline and subsequent time points.

Time frame: Change from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change From Baseline to the Last Observation in Overall Score for the Mainz Severity Score Index (MSSI)

The MSSI represents patients with Fabry disease. Overall scores of \<20, ≥20 and ≤40 and \>40 indicate that patients are mildly, moderately or severely affected, respectively. An increase in the score indicates increased severity of the disease. Symptom assessment by the MSSI was performed at baseline and at subsequent time points. The ranges for the MSSI general, neurological, cardiovascular and renal dysfunction domain scores are 0 to 18, 0 to 20, 0 to 20 and 0 to 18 respectively. The overall score considered for the study is the sum of the domain scores - min 0 max 76

Time frame: Change from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change in Use of Pain Medication During Treatment

At baseline, participants were categorized by the number of pain medications used (0, 1 and 2+ pain medications). Shifts from baseline to 72 months in the number of participants using pain medications (categorized by number of pain medications used) are presented.

Time frame: Shift from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to 72 months, in number of participants using pain medications (categorized by 0, 1 and 2+ pain medications)

Change From Baseline to the Last Observation in the EuroQoL Visual Analog Scale (EQ VAS) Score

Quality of life was assessed by administering the EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire at baseline and subsequent time points. The assessment includes the EuroQoL-5 Dimensions (EQ-5D) descriptive system and the EQ VAS. For the EQ VAS, participants rated their current health on a vertical VAS which has endpoints labelled 'the best health you can imagine' (score of 100) and 'the worst health you can imagine' (score of 0). An increase in score indicates improvement.

Time frame: Change from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change From Baseline to the Last Observation in Left Ventricular Mass Index

Cardiac assessment was performed by cardiac magnetic resonance imaging (MRI) at baseline and subsequent time points and various parameters including the left ventricular mass index (LVMI) (g/m\^2) with and without hypertrophy were assessed.

Time frame: Change from baseline (assessment before first exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or CLI-06657AA1-04) to last observation (last non-missing assessment; Mean(SD) exposure: 5.5 (1.96) years; range:1.3;10.6 years)

Change in Infusion Premedication Use From Baseline to 12 Months

Infusion premedication use was not collected in studies PB-102-F01/F02/F03. Changes in use of infusion premedication were analyzed in a pooled sample of participants enrolled from studies PB-102-F20 and PB-102-F30. Participants were categorized at baseline by number of infusion premedications used (0, 1, 2 and 3 or more) and shifts from baseline to 12 months in the number of participants using infusion premedications, categorized by number of infusion premedications used, are presented.

Time frame: Baseline (assessment before fist exposure to study drug, which could be in the parent study, PB-102-F01/F20/F30, or this extension study, CLI-06657AA1-04) to 12 months

Change in Infusion Premedication Use From Baseline to 24 Months

Infusion premedication use was not collected in studies PB-102-F01/F02/F03. Changes in use of infusion premedication were analyzed in a pooled sample of participants enrolled from studies PB-102-F20 and PB-102-F30. Participants were categorized at baseline by number of infusion premedications used (0, 1, 2 and 3 or more) and shifts from baseline to 24 months in the number of participants using infusion premedications, categorized by number of infusion premedications used, are presented.

Time frame: Baseline (assessment before first exposure to study drug, which could have been in the parent study, PB-102-F01/F20/F30 or this extension study, CLI-06657AA1-04) to 24 months

Change in Infusion Premedication Use From Baseline to 48 Months

Infusion premedication use was not collected in studies PB-102-F01/F02/F03. Changes in use of infusion premedication were analyzed in a pooled sample of participants enrolled from studies PB-102-F20 and PB-102-F30. Participants were categorized at baseline by number of infusion premedications used (0, 1, 2 and 3 or more) and shifts from baseline to 48 months in the number of participants using infusion premedications, categorized by number of infusion premedications used, are presented.

Time frame: Baseline (assessment before first exposure to study drug, which could have been in the parent study, PB-102-F01/F20/F30 or this extension study, CLI-06657AA1-04) to 48 months

Change in Infusion Premedication Use From Baseline to 72 Months

Infusion premedication use was not collected in studies PB-102-F01/F02/F03. Changes in use of infusion premedication were analyzed in a pooled sample of participants enrolled from studies PB-102-F20 and PB-102-F30. Participants were categorized at baseline by number of infusion premedications used (0, 1, 2 and 3 or more) and shifts from baseline to 72 months in the number of participants using infusion premedications, categorized by number of infusion premedications used, are presented.

Time frame: Baseline (assessment before first exposure to study drug, which could have been in the parent study, PB-102-F01/F20/F30 or this extension study, CLI-06657AA1-04) to 72 months

Number of Participants Who Had ADA at Any Post-baseline Visit

The ADA status was assessed as per the schedule of assessments based on sequential evaluation. The participant was considered ADA-positive if IgG screening was presumptive positive and subsequent IgG immunodepletion was positive.

Time frame: From first ever infusion of pegunigalsidase alfa (which could have been in the parent study, PB-102-F01/F20/F30, or in this extension study, CLI-06657AA1-04), until the end of the study. Mean individual exposure was 5.5 years.

Number of Participants With Treatment-emergent ADA Who Had Titer-boosted or Treatment-induced ADA

The ADA status at a visit was decided based on a sequential evaluation as per the schedule of assessments. If the IgG screening was negative, the participant was ADA-negative at that visit. If the IgG screening was presumptive positive, an IgG immunodepletion test was performed and the participant was considered ADA-positive or -negative at the visit based on whether the test was positive or negative. Baseline was the last assessment before the first infusion of pegunigalsidase alfa. Participants were considered to be treatment-emergent ADA-positive if they had titer-boosted or treatment-induced ADA. The ADA were titer-boosted if participants were ADA-positive at baseline and ADA titer had increased by at least 4-fold from baseline during treatment. The ADA were treatment-induced if participants were ADA-negative at baseline and ADA-positive in at least one timepoint post-first infusion.

Infusion-related Reactions (IRRs) Occurring During the Infusion or Within 2 Hours After Its Completion (IRR-2H) in More Than One Participant Overall by MedDRA Preferred Term (PT)

An IRR was defined as a reaction to the infusion of pharmacological and/or biological substances; symptoms could appear within minutes to 2 hours following the end of the infusion and could include pruritus, flushing, swelling, dyspnea, bronchospasm and hypotension. IRRs could be evaluated up to 24 hours from occurrence. Two time frames were considered for IRR analysis: IRR-2H and IRRs occurring during the infusion or within 24 hours after its completion (IRR-24H). All IRR-2H were also classified as IRR-24H. The IRR-2H reported for more than one participant overall by MedDRA PT are presented.

Infusion-related Reactions Occurring During the Infusion or Within 24H After Its Completion (IRR-24H) in More Than One Participant Overall by MedDRA PT

An IRR was defined as a reaction to the infusion of pharmacological and/or biological substances; symptoms could appear within minutes to 2 hours following the end of the infusion and could include pruritus, flushing, swelling, dyspnea, bronchospasm and hypotension. IRRs could be evaluated up to 24 hours from occurrence. Two time frames were considered for IRR analysis: IRR-2H and IRR-24H. All IRR-2H were also classified as IRR-24H. IRR-24H reported for more than one participant overall by MedDRA PT are presented.