scholarly journals Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials

2020 ◽  
Author(s):  
Kai-Uwe Eckardt ◽  
Rajiv Agarwal ◽  
Youssef Mk Farag ◽  
Alan G Jardine ◽  
Zeeshan Khawaja ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Open Label ◽  
Adverse Cardiovascular Event ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Endogenous Erythropoietin ◽  
Study Results ◽  
Long Term Treatment ◽  
Baseline Characteristics

Abstract Background Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0–23), maintenance (Weeks 24–52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24–36). Results A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

scholarly journals MO001ROXADUSTAT FOR THE TREATMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS: A PHASE 3, RANDOMISED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jonathan Barratt ◽  
Branislav Andrić ◽  
Avtandil Tataradze ◽  
Michael Schömig ◽  
Michael Reusch ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Study Drug ◽  
Controlled Study ◽  
Open Label ◽  
Phase 3 ◽  
Study Results ◽  
Iv Iron ◽  
Change In Mean ◽  
To Receive

Abstract Background and Aims Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia in patients (pts) with chronic kidney disease (CKD). Efficacy and safety of roxadustat compared with darbepoetin alfa (DA) for the treatment of anaemia in CKD pts not on dialysis (NDD) was assessed in a randomised, open-label, active-controlled phase 3 study. Results from a protocol-specified interim analysis, performed after pts had either completed ≥36 weeks of treatment or had withdrawn from the study, are presented here. Method This study (CL-0610) enrolled pts with NDD CKD stages 3-5 and anaemia (haemoglobin [Hb] ≤10.5 g/dL) and randomised them to receive roxadustat or DA. Following prescribed initial doses (weight-based), dose adjustments were permitted, with the goal of correcting and maintaining Hb. The primary endpoint was Hb response, defined as Hb ≥11.0 g/dL and an Hb increase from baseline (BL) of ≥1.0 g/dL in pts with BL Hb >8.0 g/dL, or an increase of ≥2.0 g/dL in pts with BL Hb ≤8.0 g/dL, during the first 24 weeks of treatment without rescue therapy. Key secondary endpoints included change in serum lipids, time to first IV iron use, change in mean arterial pressure (MAP), and occurrence of hypertension. Noninferiority of roxadustat to DA was declared if the lower bound of the two-sided 95% confidence interval (CI; roxadustat – DA) for change in Hb was >-0.15. Adverse events (AEs) were assessed across the study and are presented as events/100 patient exposure years (PEY) unless otherwise specified. The full analysis set (FAS) included pts who received ≥1 dose of study drug and had ≥1 post-dose Hb assessment. The per protocol set (PPS) included FAS pts who did not meet exclusion criteria. The safety analysis set (SAF) included pts who received ≥1 dose of study drug. Results As of 15 June 2018, 616 pts were randomised to receive roxadustat (n=323) or DA (n=293); of these 616 pts, 395 pts (roxadustat, n=194; DA, n=201) were still receiving treatment and 89 pts had completed ≥2 years of treatment (roxadustat, n=55; DA, n=34). In the PPS, 89.5% (n=256) of roxadustat pts responded in the first 24 weeks compared with 78.0% (n=213) of DA pts, for a difference of 11.51% (95% CI: 5.66%, 17.36%), thereby establishing roxadustat’s noninferiority to DA. Noninferiority of roxadustat to DA was also demonstrated for MAP and time to occurrence of hypertension. In the FAS, superiority of roxadustat to DA was demonstrated for low-density lipoprotein (LDL) and time to first IV iron use. (Table) In the SAF, overall incidence of AEs was comparable between roxadustat and DA (85.8% and 84.6%, respectively). Conclusion This analysis demonstrates that roxadustat was noninferior to DA in correction of Hb levels during the first 24 weeks of treatment in pts with NDD CKD stages 3-5 and anaemia. Safety profiles were comparable between groups. Final analysis of this study’s data will be presented at the congress.

scholarly journals Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial

2020 ◽  
Vol 36 (1) ◽  
pp. 111-120 ◽  
Author(s):  
Sunil Bhandari ◽  
Philip A Kalra ◽  
Mario Berkowitz ◽  
Diogo Belo ◽  
Lars L Thomsen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Single Dose ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Iron Sucrose ◽  
Hypersensitivity Reactions ◽  
Open Label ◽  
Pronounced Increase ◽  
Safety And Efficacy ◽  
Significant Difference

Abstract Background The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. Methods In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). Results A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: –0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. Conclusions Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.

MO034A SUBGROUP ANALYSIS OF FEMALE PATIENTS IN A PHASE 3 OPEN-LABEL STUDY TO ASSESS THE SAFETY AND EFFICACY OF PEGUNIGALSIDASE ALFA IN PATIENTS WITH FABRY DISEASE PREVIOUSLY TREATED WITH AGALSIDASE ALFA

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Derralynn Hughes ◽  
Gabriela Dostalova ◽  
Kathy Nicholls ◽  
Michael West ◽  
Camilla Tã¸ndel ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Fabry Disease ◽  
Subgroup Analysis ◽  
Open Label ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Agalsidase Alfa ◽  
Previously Treated ◽  
Egfr Slope

Abstract Background and Aims Females with Fabry disease (FD) often develop symptoms and disease complications later in life than males. However, they can experience significant health declines, including renal function impairment. Pegunigalsidase alfa is a novel PEGylated alpha-galactosidase A enzyme in development for the treatment of patients with FD with potential pharmacokinetic benefits. We previously reported that males with FD showed improvements in several parameters including median (minimum, maximum) estimated glomerular filtration rate (eGFR) slope from -4.6 (-20.5, 4.8) to -1.1 (-18.6, 14.2) mL/min/1.73m2/year after treatment with pegunigalsidase alfa.(Tondel et al. ASN 2020. PO0562. www.asn.scientificposters.com) Here we report a subgroup analysis of the safety and efficacy of pegunigalsidase alfa treatment in females with FD. Method BRIDGE (PB-102-F30; NCT03018730) is a phase 3, open-label, switch-over study designed to assess the safety and efficacy of pegunigalsidase alfa in adults with FD previously treated with agalsidase alfa for at least 2 years. Patients received intravenous pegunigalsidase alfa at 1 mg/kg every other week for 12 months. Results Twenty-two patients were enrolled in the study; of the 20 patients who completed 12 months of study treatment, 7 were female. Females had a mean age of 46.7 years (range: 26–59 years), and had the following median (minimum, maximum) baseline measurements: residual enzymatic activity in leucocytes of 23.7% (16, 46) of the normal laboratory mean; plasma lyso-Gb3 of 12.9 (7.4, 23.2) nmol/L; eGFR of 87.7 (55.3, 109.2) mL/min/1.73m2; and an annualized eGFR slope of −3.7 (-11.2, 1.5) mL/min/1.73m2/year. After 12 months of pegunigalsidase alfa treatment, the annualized eGFR slope was 1.4 (-6.3, 4.1) mL/min/1.73m2/year, indicating an improvement from baseline of 5.9 mL/min/1.73m2/year. In addition, plasma lyso-Gb3 had a reduction of 23.3% (-45.7, -17.3). Although all females had baseline mean residual enzyme activity > 5% and were previously treated with agalsidase alfa, only 2 had stable kidney disease (eGFR slope ≥ -3 mL/min/1.73m2/year), while 2 had moderately progressing kidney disease (eGFR slope between ≥-5 and < -3 mL/min/1.73m2/year), and 3 had fast progressing kidney disease (eGFR slope < -5 mL/min/1.73 m²/year).( Wanner et al. 2018 Mol Genet Metab 124:189-203) After treatment all but 1 patient experienced categorical improvement or remained stable; this patient had a decline of < 3 mL/min/1.73m2/year and remained in the fast progressing disease category. Mean left ventricular mass index in females increased from 66.9 g/m2 at baseline to 74.1 g/m2 at month 12, but remained within normal ranges(47–77 g/m2).(Kawel-Boehm et al. 2015 J Cardiovasc Magn Reson 17:29) All females had at least 1 treatment-emergent adverse event (TEAE), and all TEAEs were mild or moderate. The most common TEAEs reported in female were nasopharyngitis (n=2), oropharyngeal pain (n=2), and headache (n=2). None of these TEAEs were considered related to treatment. However, 2 females had injection site reactions and 2 developed transient, non-neutralizing anti-drug antibodies to pegunigalsidase alfa treatment. Conclusion The current study included females with symptoms of Fabry disease comparable to the disease presentation of males enrolled in this study. At baseline most females had eGFR decline characterizing progressive or rapidly progressive kidney disease. Most females showed improvements in disease status following 12 months of pegunigalsidase alfa treatment, as previously reported for males enrolled in this study. This long-term, controlled study suggests a potential benefit and a favorable safety profile for pegunigalsidase alfa on renal function in females with FD previously treated with agalsidase alfa. While this subgroup analysis should be interpreted with caution due to the small number of patients, these findings may provide valuable insight for future studies.

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