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Glembatumumab vedotin Product Analysis
Ref Code: DMKC0159162 Publication Date: 15/04/2016 Author: David Dahan glembatumumab vedotin Product Analysis DMKC0159162 | Published on 15/04/2016
Reference: DMKC0159162 First published: 15/04/2016
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Datamonitor Healthcare 2 Pharma intelligence | glembatumumab vedotin Product Analysis DMKC0159162 | Published on 15/04/2016
TABLE OF CONTENTS
4 PRODUCT PROFILES 4 glembatumumab vedotin : Breast cancer: triple-negative
LIST OF FIGURES
9 Figure 1: Glembatumumab vedotin for triple-negative breast cancer – SWOT analysis 9 Figure 2: Datamonitor Healthcare's drug assessment summary of glembatumumab vedotin for triple-negative breast cancer 10 Figure 3: Datamonitor Healthcare's drug assessment summary of glembatumumab vedotin for triple-negative breast cancer
LIST OF TABLES
4 Table 1: Glembatumumab vedotin drug profile 5 Table 2: Glembatumumab vedotin Phase IIb trial in triple-negative breast cancer 7 Table 3: Glembatumumab vedotin Phase IIb data in triple-negative breast cancer
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PRODUCT PROFILES
glembatumumab vedotin : Breast cancer: triple-negative
PRODUCT PROFILE
Analyst Outlook Glembatumumab vedotin (Celldex) is positioned to be the first antibody–drug conjugate approved for triple-negative breast cancer (TNBC). It is currently in a Phase II registration trial where it is being assessed as a first-, second-, or third-line treatment in metastatic TNBC patients overexpressing the transmembrane glycoprotein non-metastatic B (GPNMB). As an antibody–drug conjugate, glembatumumab vedotin could have a better safety profile than the chemotherapeutics currently being used in metastatic TNBC. Glembatumumab vedotin will be restricted to the subpopulation of TNBC patients that overexpress the GPNMB target; however, it is not yet clear how big this patient group will be.
Drug Overview Glembatumumab vedotin is an antibody–drug conjugate that targets cancer cells expressing GPNMB. This fully human monoclonal antibody is linked to monomethyl auristatin E (MMAE), a potent, peptide-derived antimitotic drug which targets microtubules and which is too toxic to be used as a monotherapy. Glembatumumab vedotin uses a valine-citrulline enzyme cleavable linker that is stable in the bloodstream. Once the drug is internalized into the cell, MMAE is released and induces apoptosis.
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Table 1: Glembatumumab vedotin drug profile
Molecule glembatumumab vedotin
Phase of development Phase IIb
Mechanism of action Tubulin inhibitor
Originator Celldex
Marketing company Celldex
Targeted indication Metastatic GPNMB-overexpressing TNBC
Formulation Intravenous infusion
Pricing strategy $9,800 per month (based on Kadcyla)
Dosing frequency Administered on day 1 of each 21-day cycle
Estimated approval date Q3 2017 (US, 5EU), Q3 2020 (Japan)
Alternative names CDX-011, CR011-vcMMAE, CR-011-vcMMAE, CR011, glemba
5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); TNBC = triple-negative breast cancer; GPNMP = glycoprotein non- metastatic B
Source: Datamonitor Healthcare; Biomedtracker; Medtrack; Pharmaprojects; ClinicalTrials.gov
DEVELOPMENT OVERVIEW Glembatumumab vedotin is an antibody–drug conjugate developed by Celldex. It is currently being investigated in METRIC, a Phase IIb trial for patients with metastatic GPNMB-overexpressing TNBC (ClinicalTrials.gov identifier: NCT01997333). In May 2010, the US Food and Drug Administration granted fast track designation to glembatumumab vedotin for the treatment of advanced refractory/resistant GPNMB-expressing breast cancer.
The table below summarizes the design of the Phase IIb registration study.
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Table 2: Glembatumumab vedotin Phase IIb trial in triple-negative breast cancer
Trial Sample size Target patients Study design Treatment arms Primary Start endpoints date/primary completion date
METRIC 300 Metastatic I, R, ES, PA, OL, T Arm 1: PFS December GPNMB- glembatumumab 2013/September
(NCT01997333) overexpressing vedotin IV infusion 2016 TNBC on day 1 of each
(Phase IIb) 21-day cycle
Arm 2: capecitabine on days 1–14 of each 21-day cycle
ES = efficacy/safety; GPNMB = glycoprotein non-metastatic B; I = interventional; IV = intravenous; OL = open-label; PA = parallel- assignment; PFS = progression-free survival; R = randomized; T = treatment; TNBC = triple-negative breast cancer
Source: Biomedtracker; ClinicalTrials.gov
An overview of early-phase data for glembatumumab vedotin in TNBC is summarized in the table below.
Datamonitor Healthcare 6 6 Pharma intelligence | © Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed glembatumumab vedotin Product Analysis DMKC0159162 | Published on 15/04/2016
Table 3: Glembatumumab vedotin Phase IIb data in triple-negative breast cancer
Phase Sample size Target patients Dosing tested and duration Results Reference
EMERGE 124 GPNMB-expressing, advanced, Arm 1: glembatumumab vedotin All patients: Yardley et al., 2015 heavily pretreated breast cancer (1.88mg/kg) administered as an
(Phase IIb) intravenous infusion on Day 1 of Arm 1: ORR = 6% each 21-day cycle Arm 2: ORR = 7%; Arm 2: IC single-agent chemotherapy High GPNMB expression patients:
Arm 1 (n = 23):
ORR = 30%
PFS = 2.8 months
OS = 10.0 months
Arm 2 (n = 11):
ORR = 9%
PFS = 1.5 months
OS = 5.7 months;
TNBC & high GPNMB expression
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Table 3: Glembatumumab vedotin Phase IIb data in triple-negative breast cancer
Phase Sample size Target patients Dosing tested and duration Results Reference
Arm 1 (n = 10):
ORR = 40%
PFS = 3.5 months
OS = 10.0 months
Arm 2 (n=6):
ORR = 0%
PFS = 1.5 months
OS = 5.5 months
GPNMB = glycoprotein non-metastatic B; IC = investigator’s choice; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; TNBC = triple-negative breast cancer
Source: see above
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SWOT ANALYSIS
Figure 1: Glembatumumab vedotin for triple-negative breast cancer – SWOT analysis
Source: Datamonitor Healthcare
CLINICAL AND COMMERCIAL ATTRACTIVENESS The figure below depicts Datamonitor Healthcare’s drug assessment summary for glembatumumab vedotin in TNBC.
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Figure 2: Datamonitor Healthcare's drug assessment summary of glembatumumab vedotin for triple-negative breast cancer
Source: Datamonitor Healthcare
The figure below provides a breakdown of how Datamonitor Healthcare scored glembatumumab vedotin’s clinical and commercial attractiveness. The weighting given to each attribute is also shown. Abraxane (albumin-bound paclitaxel; Celgene/Taiho) was used as the comparator drug.
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Figure 3: Datamonitor Healthcare's drug assessment summary of glembatumumab vedotin for triple-negative breast cancer
Source: Datamonitor Healthcare
Glembatumumab vedotin is positioned to be the first antibody–drug conjugate approved for TNBC Glembatumumab vedotin is positioned to be the first antibody–drug conjugate approved for TNBC. It is currently in a Phase II registration trial where it is being assessed as a first-, second-, or third-line treatment in metastatic TNBC patients expressing GPNMB. The Phase IIb EMERGE study showed an impressive doubling in overall survival in TNBC patients with high GPNMB expression (5.5 months for investigator’s choice chemotherapy versus 10.0 months with glembatumumab vedotin: n=6 and n=10, respectively). These patients were heavily pretreated with 2–7 lines of prior chemotherapy. Glembatumumab vedotin was found to be well tolerated in this patient group, and the most common treatment-related adverse events were nausea, rash, fatigue, neuropathy, alopecia, and neutropenia. As an antibody–drug conjugate, glembatumumab vedotin is likely to have a better safety profile than the chemotherapeutics currently being used in metastatic TNBC.
Glembatumumab vedotin will target a subpopulation of TNBC patients Glembatumumab will be used as a targeted therapy for the treatment of TNBC but it is uncertain how big its target population will be. In the Phase IIb EMERGE study, 99% of TNBC patients that were assessed met the enrollment criteria of GPNMB expression in ≥5% of cells. However, optimal results were seen in a subpopulation of TNBC patients that had expression of GPNMB in >25% of malignant epithelial cells. It is not yet clear what percentage of TNBC patients fall in this high GPNMB expression group. The registration trial is enrolling TNBC patients that overexpress GPNMB, which is
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likely to correspond to the higher 25% threshold.
Combination with Gleevec could allow glembatumumab vedotin to access a larger population of TNBC patients Preclinical data has shown that the tyrosine kinase inhibitor Gleevec (imatinib; Novartis) increased GPNMB expression by western blot in both melanoma and glioblastoma cell lines (Qian et al., 2008). It is therefore feasible that a combination therapy of glembatumumab vedotin and Gleevec could increase the target population for this therapy in TNBC by boosting the number of malignant cells expressing GPNMB. However, no trial looking at this combination has been announced to date.
Bibliography Qian X, Mills E, Torgov M, LaRochelle WJ, Jeffers M (2008) Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate. Molecular Oncology, 2(1), 81–93
Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, et al. (2015) EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB–Expressing Breast Cancer. Journal of Clinical Oncology, 33(14), 1609–19
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