Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes

a randomised, placebo-controlled clinical trial

Joseph Proietto, Jaret Malloy, Dongliang Zhuang, Mark Arya, Neale D. Cohen, Ferdinandus J. de Looze, Christopher Gilfillan, Paul Griffin, Stephen Hall, Thomas Nathow, Geoffrey S. Oldfield, David N. O’Neal, Adam Roberts, Bronwyn G.A. Stuckey, Dennis Yue, Kristin Taylor, Dennis Kim

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Aims/hypothesis: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53–97 mmol/mol [7–11%] and fasting glucose <15.6 mmol/l). Methods: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. Conclusions/interpretation: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. Trial registration:: ClinicalTrials.gov NCT02324491 Funding:: The study was funded by Zafgen, Inc.

Original languageEnglish
Pages (from-to)1918-1922
Number of pages5
JournalDiabetologia
Volume61
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Anti-obesity medication
  • Glucose-lowering medication
  • Glycaemic control
  • MetAP2

Cite this

Proietto, Joseph ; Malloy, Jaret ; Zhuang, Dongliang ; Arya, Mark ; Cohen, Neale D. ; de Looze, Ferdinandus J. ; Gilfillan, Christopher ; Griffin, Paul ; Hall, Stephen ; Nathow, Thomas ; Oldfield, Geoffrey S. ; O’Neal, David N. ; Roberts, Adam ; Stuckey, Bronwyn G.A. ; Yue, Dennis ; Taylor, Kristin ; Kim, Dennis. / Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes : a randomised, placebo-controlled clinical trial. In: Diabetologia. 2018 ; Vol. 61, No. 9. pp. 1918-1922.
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title = "Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial",
abstract = "Aims/hypothesis: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53–97 mmol/mol [7–11{\%}] and fasting glucose <15.6 mmol/l). Methods: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2{\%} with placebo (n = 22) vs −13.5 ± 1.1{\%} and −12.7 ± 1.3{\%} with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3{\%}]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2{\%}) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2{\%}) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3{\%}) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. Conclusions/interpretation: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. Trial registration:: ClinicalTrials.gov NCT02324491 Funding:: The study was funded by Zafgen, Inc.",
keywords = "Anti-obesity medication, Glucose-lowering medication, Glycaemic control, MetAP2",
author = "Joseph Proietto and Jaret Malloy and Dongliang Zhuang and Mark Arya and Cohen, {Neale D.} and {de Looze}, {Ferdinandus J.} and Christopher Gilfillan and Paul Griffin and Stephen Hall and Thomas Nathow and Oldfield, {Geoffrey S.} and O’Neal, {David N.} and Adam Roberts and Stuckey, {Bronwyn G.A.} and Dennis Yue and Kristin Taylor and Dennis Kim",
year = "2018",
month = "9",
day = "1",
doi = "10.1007/s00125-018-4677-0",
language = "English",
volume = "61",
pages = "1918--1922",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer-Verlag London Ltd.",
number = "9",

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Proietto, J, Malloy, J, Zhuang, D, Arya, M, Cohen, ND, de Looze, FJ, Gilfillan, C, Griffin, P, Hall, S, Nathow, T, Oldfield, GS, O’Neal, DN, Roberts, A, Stuckey, BGA, Yue, D, Taylor, K & Kim, D 2018, 'Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial', Diabetologia, vol. 61, no. 9, pp. 1918-1922. https://doi.org/10.1007/s00125-018-4677-0

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes : a randomised, placebo-controlled clinical trial. / Proietto, Joseph; Malloy, Jaret; Zhuang, Dongliang; Arya, Mark; Cohen, Neale D.; de Looze, Ferdinandus J.; Gilfillan, Christopher; Griffin, Paul; Hall, Stephen; Nathow, Thomas; Oldfield, Geoffrey S.; O’Neal, David N.; Roberts, Adam; Stuckey, Bronwyn G.A.; Yue, Dennis; Taylor, Kristin; Kim, Dennis.

In: Diabetologia, Vol. 61, No. 9, 01.09.2018, p. 1918-1922.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes

T2 - a randomised, placebo-controlled clinical trial

AU - Proietto, Joseph

AU - Malloy, Jaret

AU - Zhuang, Dongliang

AU - Arya, Mark

AU - Cohen, Neale D.

AU - de Looze, Ferdinandus J.

AU - Gilfillan, Christopher

AU - Griffin, Paul

AU - Hall, Stephen

AU - Nathow, Thomas

AU - Oldfield, Geoffrey S.

AU - O’Neal, David N.

AU - Roberts, Adam

AU - Stuckey, Bronwyn G.A.

AU - Yue, Dennis

AU - Taylor, Kristin

AU - Kim, Dennis

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Aims/hypothesis: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53–97 mmol/mol [7–11%] and fasting glucose <15.6 mmol/l). Methods: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. Conclusions/interpretation: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. Trial registration:: ClinicalTrials.gov NCT02324491 Funding:: The study was funded by Zafgen, Inc.

AB - Aims/hypothesis: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53–97 mmol/mol [7–11%] and fasting glucose <15.6 mmol/l). Methods: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. Conclusions/interpretation: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. Trial registration:: ClinicalTrials.gov NCT02324491 Funding:: The study was funded by Zafgen, Inc.

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