Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience

Zimran, Ari; Altarescu, Gheona; Philips, Mici; Attias, Denise; Jmoudiak, Marina; Deeb, Maher; Wang, Nan; Bhirangi, Kiran; Cohn, Gabriel; Elstein, Deborah

doi:10.1182/blood-2010-02-268649

Cited by 122 publications

(105 citation statements)

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“…Collectively, these studies demonstrated that velaglucerase alfa was generally well tolerated among both treatment‐naïve and switch patients including children, adults, pregnant patients, and geriatric patients 2, 3, 4, 5, 6. There were few drug‐related serious adverse events (AEs) and the vast majority of AEs were classified by the investigators as infusion related and considered to be mild to moderate and transient in nature.…”

Section: Introductionmentioning

confidence: 95%

“…One case of anaphylactoid reaction was reported (<1%) 5. Overall, <1% of patients developed anti‐drug antibodies following exposure to velaglucerase alfa and no patients developed IgE antibodies 2, 3, 4, 5, 6.…”

Section: Introductionmentioning

confidence: 97%

“…Velaglucerase alfa is manufactured in a human cell line, HT‐1080, using gene activation technology® 1, 2. Following targeted recombination with a constitutively active promoter, the human wild type GBA gene is expressed.…”

Section: Introductionmentioning

confidence: 99%

“…This trial was a 9‐month, single‐arm, single‐center study undertaken to evaluate the safety and clinical activity of velaglucerase alfa among adults with GD1. Twelve patients were enrolled and received velaglucerase alfa intravenously at a dose of 60 U/kg body weight every other week (EOW) 2. Ten patients completed the phase I/II trial and were eligible to participate in a phase I/II extension study (TKT025EXT).…”

Section: Introductionmentioning

confidence: 99%

“…Ten patients completed the phase I/II trial and were eligible to participate in a phase I/II extension study (TKT025EXT). The extension study had many unique attributes, one being a step‐wise dose reduction at 15 to 18 months to 30 U/kg body weight EOW for patients who met two of the four goals for hematology and viscera 2.…”

Section: Introductionmentioning

confidence: 99%

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Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

et al. 2015

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Velaglucerase alfa is a human β‐glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7‐year experience of the now‐completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9‐month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug‐related adverse event or required premedication. No patient developed anti‐drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and −42% (−53%, −31%) and −78% (−94%, −62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near‐normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters. Am. J. Hematol. 90:577–583, 2015. © 2015 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

et al. 2015

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Use of Ambroxol as Therapy for Gaucher Disease

et al. 2023

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ImportanceAmbroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.ObjectivesTo assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment.Design, Setting, and ParticipantsPatients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022.InterventionAn escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d).Main Outcomes and MeasuresPatients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment.ResultsA total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P &lt; .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, −2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], −5.16 [5.44] MN; 95% CI, −10.19 to −0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], −0.39 [0.42] MN; 95% CI, −0.75 to −0.04; P = .03). Biomarker median percentage changes from baseline were −43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = −3.413; P = .001) and −34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = −2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, −5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = −2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = −2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events.Conclusions and RelevanceIn this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.

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Gaucher Disease

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Zimran

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Lysosomal Storage Disorders

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Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience

Cited by 122 publications

References 10 publications

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

Use of Ambroxol as Therapy for Gaucher Disease

Gaucher Disease

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