(cid:5)(cid:6)(cid:7)(cid:8)
`
`(cid:9)(cid:10)(cid:10)(cid:11)(cid:12)(cid:3)(cid:13)(cid:14)(cid:15)(cid:16)(cid:4)(cid:17)(cid:18)(cid:19)(cid:16)(cid:3)(cid:20)(cid:21)(cid:22)(cid:23)(cid:24)(cid:25)(cid:26)(cid:3)(cid:13)(cid:14)(cid:15)(cid:16)(cid:4)(cid:17)(cid:18)(cid:27)(cid:17)(cid:3)(cid:20)(cid:28)(cid:24)(cid:29)(cid:23)(cid:24)(cid:30)(cid:26)(cid:3)(cid:31)(cid:32)(cid:33)(cid:22)(cid:24)(cid:34)(cid:29)(cid:3)(cid:35)(cid:32)(cid:5)(cid:30)(cid:36)(cid:34)(cid:37)(cid:30)(cid:12)(cid:3)(cid:35)(cid:25)(cid:25)(cid:36)(cid:12)(cid:38)(cid:38)(cid:39)(cid:39)(cid:39)(cid:40)(cid:25)(cid:34)(cid:24)(cid:41)(cid:42)(cid:32)(cid:24)(cid:29)(cid:23)(cid:24)(cid:30)(cid:40)(cid:43)(cid:32)(cid:5)(cid:38)(cid:29)(cid:32)(cid:23)(cid:38)(cid:44)(cid:5)(cid:34)(cid:7)(cid:16)(cid:17)
`
`(cid:6)(cid:24)(cid:25)(cid:23)(cid:7)(cid:32)(cid:41)(cid:45)(cid:4)(cid:7)(cid:34)(cid:8)(cid:30)(cid:41)(cid:3)(cid:25)(cid:35)(cid:30)(cid:22)(cid:34)(cid:36)(cid:30)(cid:33)(cid:25)(cid:23)(cid:43)(cid:8)(cid:3)(cid:25)(cid:32)(cid:3)(cid:39)(cid:34)(cid:25)(cid:43)(cid:35)(cid:3)(cid:23)(cid:24)(cid:3)(cid:16)(cid:17)(cid:13)(cid:13)
`
`(cid:31)(cid:34)(cid:24)(cid:23)(cid:43)(cid:30)(cid:3)(cid:46)(cid:40)(cid:3)(cid:47)(cid:30)(cid:23)(cid:43)(cid:35)(cid:30)(cid:22)(cid:25)
`
`(cid:48)(cid:32)(cid:3)(cid:43)(cid:23)(cid:25)(cid:30)(cid:3)(cid:25)(cid:35)(cid:23)(cid:8)(cid:3)(cid:34)(cid:22)(cid:25)(cid:23)(cid:43)(cid:29)(cid:30)(cid:12)(cid:3)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)(cid:10)(cid:3)(cid:11)(cid:12)(cid:3)(cid:13)(cid:10)(cid:8)(cid:9)(cid:14)(cid:10)(cid:15)(cid:16)(cid:3)(cid:17)(cid:18)(cid:19)(cid:20)(cid:20)(cid:21)(cid:3)(cid:22)(cid:7)(cid:16)(cid:8)(cid:23)(cid:24)(cid:25)(cid:26)(cid:4)(cid:23)(cid:6)(cid:27)(cid:10)(cid:25)(cid:3)(cid:16)(cid:14)(cid:10)(cid:15)(cid:6)(cid:28)(cid:10)(cid:29)(cid:16)(cid:8)(cid:9)(cid:27)(cid:3)(cid:16)(cid:24)(cid:3)(cid:30)(cid:6)(cid:16)(cid:9)(cid:14)(cid:3)(cid:8)(cid:7)(cid:3)(cid:18)(cid:19)(cid:20)(cid:20)(cid:3)(cid:31)
`(cid:32)(cid:22)(cid:23)(cid:27)(cid:31)(cid:3)(cid:33)(cid:34)(cid:20)(cid:31)(cid:3)(cid:35)(cid:36)(cid:4)(cid:37)(cid:37)(cid:31)(cid:3)(cid:38)(cid:39)(cid:40)(cid:34)(cid:3)(cid:20)(cid:19)(cid:12)(cid:41)(cid:20)(cid:36)(cid:20)(cid:42)(cid:32)(cid:6)(cid:23)(cid:27)(cid:12)(cid:33)(cid:12)(cid:20)(cid:12)(cid:20)(cid:33)(cid:43)(cid:37)(cid:44)
`
`(cid:48)(cid:32)(cid:3)(cid:29)(cid:23)(cid:24)(cid:44)(cid:3)(cid:25)(cid:32)(cid:3)(cid:25)(cid:35)(cid:23)(cid:8)(cid:3)(cid:34)(cid:22)(cid:25)(cid:23)(cid:43)(cid:29)(cid:30)(cid:12)(cid:3) (cid:5)(cid:6)(cid:6)(cid:7)(cid:8)(cid:9)(cid:10)(cid:10)(cid:11)(cid:12)(cid:13)(cid:14)(cid:12)(cid:15)(cid:16)(cid:10)(cid:17)(cid:18)(cid:14)(cid:19)(cid:17)(cid:20)(cid:17)(cid:10)(cid:21)(cid:22)(cid:23)(cid:8)(cid:14)(cid:24)(cid:14)(cid:17)(cid:14)(cid:17)(cid:24)(cid:25)(cid:26)(cid:27)
`
`(cid:28)(cid:12)(cid:7)(cid:29)(cid:15)(cid:13)(cid:16)(cid:5)(cid:6)(cid:3)(cid:30)(cid:3)(cid:31)(cid:18)(cid:17)(cid:17)(cid:3)(cid:32)(cid:22)(cid:33)(cid:11)(cid:34)(cid:8)(cid:3)(cid:35)(cid:13)(cid:12)(cid:8)(cid:36)(cid:13)(cid:34)(cid:33)(cid:36)(cid:34)
`
`(cid:37)(cid:38)(cid:23)(cid:39)(cid:13)(cid:8)(cid:5)(cid:34)(cid:11)(cid:3)(cid:12)(cid:33)(cid:39)(cid:13)(cid:33)(cid:34)(cid:9)(cid:3)(cid:18)(cid:17)(cid:3)(cid:40)(cid:22)(cid:33)(cid:3)(cid:31)(cid:18)(cid:17)(cid:17)(cid:14)
`
`(cid:41)(cid:38)(cid:23)(cid:21)(cid:13)(cid:6)(cid:3)(cid:29)(cid:12)(cid:38)(cid:15)(cid:3)(cid:22)(cid:15)(cid:6)(cid:13)(cid:36)(cid:39)(cid:34)(cid:3)(cid:6)(cid:12)(cid:3)(cid:6)(cid:5)(cid:13)(cid:8)(cid:3)(cid:42)(cid:12)(cid:38)(cid:15)(cid:33)(cid:22)(cid:39)(cid:3)
`
`(cid:43)(cid:15)(cid:6)(cid:13)(cid:36)(cid:39)(cid:34)(cid:3)(cid:44)(cid:13)(cid:34)(cid:45)(cid:8)(cid:9)(cid:3)(cid:46)(cid:27)(cid:25)
`
`(cid:47)(cid:13)(cid:34)(cid:45)(cid:3)(cid:15)(cid:34)(cid:39)(cid:22)(cid:6)(cid:34)(cid:11)(cid:3)(cid:22)(cid:15)(cid:6)(cid:13)(cid:36)(cid:39)(cid:34)(cid:8)(cid:3)
`
`(cid:28)(cid:13)(cid:6)(cid:13)(cid:33)(cid:16)(cid:3)(cid:22)(cid:15)(cid:6)(cid:13)(cid:36)(cid:39)(cid:34)(cid:8)(cid:9)(cid:3)(cid:17)(cid:27)(cid:18)(cid:3)(cid:47)(cid:13)(cid:34)(cid:45)(cid:3)(cid:36)(cid:13)(cid:6)(cid:13)(cid:33)(cid:16)(cid:3)(cid:22)(cid:15)(cid:6)(cid:13)(cid:36)(cid:39)(cid:34)(cid:8)(cid:3)
`
`(cid:48)(cid:38)(cid:39)(cid:39)(cid:3)(cid:49)(cid:34)(cid:15)(cid:21)(cid:8)(cid:3)(cid:50)(cid:3)(cid:28)(cid:12)(cid:33)(cid:11)(cid:13)(cid:6)(cid:13)(cid:12)(cid:33)(cid:8)(cid:3)(cid:12)(cid:51)(cid:3)(cid:22)(cid:36)(cid:36)(cid:34)(cid:8)(cid:8)(cid:3)(cid:22)(cid:33)(cid:11)(cid:3)(cid:38)(cid:8)(cid:34)(cid:3)(cid:36)(cid:22)(cid:33)(cid:3)(cid:23)(cid:34)(cid:3)(cid:51)(cid:12)(cid:38)(cid:33)(cid:11)(cid:3)(cid:22)(cid:6)
`(cid:5)(cid:6)(cid:6)(cid:7)(cid:9)(cid:10)(cid:10)(cid:45)(cid:45)(cid:45)(cid:14)(cid:6)(cid:22)(cid:33)(cid:11)(cid:51)(cid:12)(cid:33)(cid:39)(cid:13)(cid:33)(cid:34)(cid:14)(cid:36)(cid:12)(cid:21)(cid:10)(cid:22)(cid:36)(cid:6)(cid:13)(cid:12)(cid:33)(cid:10)(cid:42)(cid:12)(cid:38)(cid:15)(cid:33)(cid:22)(cid:39)(cid:52)(cid:33)(cid:51)(cid:12)(cid:15)(cid:21)(cid:22)(cid:6)(cid:13)(cid:12)(cid:33)(cid:53)(cid:42)(cid:12)(cid:38)(cid:15)(cid:33)(cid:22)(cid:39)(cid:28)(cid:12)(cid:11)(cid:34)(cid:54)(cid:55)(cid:21)(cid:22)(cid:23)(cid:31)(cid:18)
`
`Apotex Exhibit 1020
`Page 1 of 25
`
`

`

` EDITOR’S CORNER
`mAbs 3:1, 76-99; January/February 2011; © 2011 Landes Bioscience
`
`Antibody-based therapeutics to watch in 2011
`
`Janice M. Reichert
`
`Tufts Center for the Study of Drug Development; Boston, MA USA
`
`This overview of 25 monoclonal antibody (mAb) and five Fc fusion protein therapeutics provides brief descriptions
`of the candidates, recently published clinical study results and on-going Phase 3 studies. In alphanumeric order, the
`2011 therapeutic antibodies to watch list comprises AIN-457, bapineuzumab, brentuximab vedotin, briakinumab,
`dalotuzumab, epratuzumab, farletuzumab, girentuximab (WX-G250), naptumomab estafenatox, necitumumab,
`obinutuzumab, otelixizumab, pagibaximab, pertuzumab, ramucirumab, REGN88, reslizumab, solanezumab, T1h,
`teplizumab, trastuzumab emtansine, tremelimumab, vedolizumab, zalutumumab and zanolimumab. In alphanumeric
`order, the 2011 Fc fusion protein therapeutics to watch list comprises aflibercept, AMG-386, atacicept, Factor VIII-Fc
`and Factor IX-Fc. Commercially-sponsored mAb and Fc fusion therapeutics that have progressed only as far as Phase
`2/3 or 3 were included. Candidates undergoing regulatory review or products that have been approved may also be
`in Phase 3 studies, but these were excluded. Due to the large body of primary literature about the candidates, only
`selected references are given and results from recent publications and articles that were relevant to Phase 3 studies are
`emphasized. Current as of September 2010, the information presented here will serve as a baseline against which future
`progress in the development of antibody-based therapeutics can be measured.
`
`Introduction
`
`The pharmaceutical and biotechnology
`industry is currently investing substan-
`tial resources in the development of anti-
`body-based therapeutic products. Novel
`monoclonal antibodies (mAbs) have been
`entering clinical study at a rate of over 40
`per year since 2007 and new products are
`being approved at a steady pace.1 Hundreds
`of mAbs, as well as novel Fc fusion proteins
`that are composed of binding peptides or
`proteins fused to the Fc domain of immu-
`noglobulin G, are undergoing clinical
`study as potential treatments for disease.
`By the end of 2010, a total of 30 of these
`candidates (25 mAb and five Fc fusion
`protein) were in Phase 2/3 or Phase 3
`clinical studies sponsored by commercial
`firms, and these are included on the 2011
`antibody-based therapeutics to watch list.
`A total of 26 mAbs in commercially-
`sponsored Phase 2/3 or Phase 3 clinical
`studies were included on the 2010 anti-
`bodies to watch list.2 In alphanumeric
`order by mAb name, these candidates
`were: 131-I mAb 81C6, bapineuzumab,
`belimumab,
`briakinumab,
`dalotu-
`zumab,
`epratuzumab,
`farletuzumab,
`figitumumab, galiximab, girentuximab
`
`inotuzumab ozogamicin,
`(WX-G250),
`ipilimumab, mepolizumab, naptumomab
`estafenatox, ocrelizumab, otelixizumab,
`pagibaximab, pertuzumab, ramucirumab,
`reslizumab,
`solanezumab,
`tanezumab,
`teplizumab,
`trastuzumab
`emtansine,
`vedolizumab and zalutumumab.
`Nine of the 26 mAbs on the 2010 list
`were not included in the 2011 version for
`various reasons. Two mAbs (belimumab
`and ipilimumab) advanced to regulatory
`review, all studies of two mAbs (galix-
`imab and 131-I mAb 81C6) were sus-
`pended or terminated and development
`of five (figitumumab, inotuzumab ozo-
`gamicin, mepolizumab, ocrelizumab and
`tanezumab) reverted to Phase 2 studies.
`New to the 2011 list are eight mAbs that
`entered a first Phase 3 clinical study or re-
`entered a Phase 3 study since September
`2009. In alphanumeric order by mAb
`name, these are: AIN-457, brentuximab
`vedotin, necitumumab, obinutuzumab,
`REGN88, T1h, tremelimumab and zano-
`limumab. Two (trelimumab and zano-
`limumab) were previously in Phase 3
`studies that were terminated prior to
`2009, and so were not on the “antibodies
`to watch in 2010” list. As a consequence
`of these changes to the 2010 list, there
`
`are 25 “antibodies to watch” in 2011.
`The complete list of the 25 mAbs in alpha-
`numeric order by target appears in Tables
`1, 3 and 5.
`Information about mAbs that are in
`regulatory review or approved for mar-
`keting by the United States Food and
`Drug Administration (US FDA) are listed
`in Tables 2, 4 and 6 for comparison.
`Two mAbs, catumaxomab and nimotu-
`zumab, that are approved for marketing
`outside of the US should also be noted.
`Catumaxomab
`(Removab®; Fresenius
`Biotech GmbH, Trion Pharma) is a
`mouse/rat-derived, bispecific mAb that
`targets the epithelial cell adhesion mol-
`ecule (EpCAM) on tumor cells and CD3
`on T cells.3 The product was approved
`for marketing in the European Union in
`April 2009 for treatment of patients with
`malignant ascites. Catumaxomab is in an
`on-going Phase 3 study [NCT00822809]
`as a treatment of malignant ascites due to
`epithelial cancer.
`Nimotuzumab
`(BIOMAb-EGFR,
`Thera-CIM; Biocon, YM Biosciences,
`Oncosciences)
`is a humanized IgG1
`mAb that targets the epithelial growth
`factor receptor (EGFR).4 The product is
`approved for marketing in a number of
`
`*Correspondence to: Janice M. Reichert; Email: janice.reichert@tufts.edu
`Submitted: 10/11/10; Accepted: 10/11/10
`DOI: 10.4161/mabs.3.1.13895
`
`76
`
`mAbs
`
`Volume 3 Issue 1
`
`
`
`
`Apotex Exhibit 1020
`Page 2 of 25
`
`

`

` EDITOR’S CORNER
`
`Table 1. Monoclonal antibodies in Phase 3 studies as treatments for cancer indications
`
`Sponsoring company
`
`International
` non-proprietary name
`
`Target and type
`
`Indication of Phase 3 study
`
`EDITOR’S CORNER
`
`FDA designations
`for Phase 3 study
`indication
`
`Active Biotech Research
`
`Naptumomab estafenatox
`
`5T4; Fab conj. to staph.
`enterotoxin A
`
`Wilex AG
`
`Girentuximab
`
`Carbonic anhydrase ix; IgG1
`
`TenX Biopharma/Genmab
`Glycart/Genentech/Biogen
`Idec
`
`Zanolimumab
`
`Obinutuzumab
`
`Seattle Genetics
`
`Brentuximab vedotin
`
`Pfizer
`Genmab
`ImClone
`Morphotek
`
`Genentech
`
`Tremelimumab
`Zalutumumab
`Necitumumab
`Farletuzumab
`
`CD4; IgG1
`
`CD20; IgG1
`
`CD30; IgG1; conjugated to
`monomethyl auristatin E
`CTLA-4; IgG2
`EGFR; IgG1
`EGFR; IgG1
`Folate receptor α; IgG1
`
`Metastatic melanoma
`Head and neck cancer
`Non-small cell lung cancer
`Ovarian cancer
`Locally advanced or metastatic
`breast cancer
`Metastatic breast cancer
`Metastatic colorectal cancer
`Metastatic gastric or
` gastroesophageal junction
`adenocarcinoma; breast can-
`cer; hepatocellular carcinoma
`Information current as of September 1, 2010. CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated antigen; EGFR, epidermal growth
`factor receptor; Fab, antigen-binding fragment; FDA, US Food and Drug Administration; FT, fast track designation; HER2, human epidermal growth
`factor receptor; IGF-1R, insulin-like growth factor-1 receptor; O, orphan drug designation; VEGFR2, vascular endothelial cell growth factor receptor 2.
`International non-proprietary naming convention: -umab, human; -zumab, humanized; -ximab, chimeric; -momab, murine.
`
`Advanced renal cell carcinoma
`
`Non-metastatic renal cell
` carcinoma
`Cutaneous T-cell lymphoma
`
`Chronic lymphocytic leukemia
`
`O
`
`FT, O
`
`Hodgkin lymphoma
`
`FT, O
`
`FT
`
`O
`
`Trastuzumab emtansine
`
`HER2; IgG1 conj. to DM1
`
`Genentech
`Merck, Pierre Fabre
`
`Pertuzumab
`Dalotuzumab
`
`HER2; IgG1
`IGF-1R; IgG1
`
`Imclone Systems/Eli Lilly
`
`Ramucirumab
`
`VEGFR2; IgG1
`
`Trade name
`
`Target and type
`
`FDA approval year
`
`Table 2. Monoclonal antibodies in FDA review or approved as treatments for cancer indications
`International
`Indication under review or
` non-proprietary name
`first approved
`Ofatumumab
`Chronic lymphocytic leukemia
`Tositumomab-I131
`Non-Hodgkin lymphoma
`Ibritumomab tiuxetan
`Non-Hodgkin lymphoma
`Rituximab
`Non-Hodgkin’s lymphoma
`Gemtuzumab ozogamicin
`Acute myeloid leukemia
`Alemtuzumab
`Chronic myeloid leukemia
`
`Arzerra
`Bexxar
`Zevalin
`Rituxan
`Mylotarg
`Campath-1H
`
`CD20; human IgG1
`CD20; murine IgG2a
`CD20; murine IgG1
`CD20; chimeric IgG1
`CD33; humanized IgG4
`CD52; humanized IgG1
`
`2009
`2003
`2002
`1997
`2000#
`2001
`Pending (PDUFA action
`date Dec. 25, 2010)
`2006
`Colorectal cancer
`EGFR; human IgG2
`Vectibix
`Panitumumab
`2004
`Colorectal cancer
`EGFR; chimeric IgG1
`Erbitux
`Cetuximab
`1998
`Breast cancer
`HER2; humanized IgG1
`Herceptin
`Trastuzumab
`2004
`Colorectal cancer
`VEGF; humanized IgG1
`Avastin
`Bevacizumab
`Information current as of September 1, 2010. #Voluntarily withdrawn from US market. CD, cluster of differentiation; EGFR, epidermal growth factor
`receptor; CTLA, cytotoxic T-lymphocyte-associated antigen; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor;
`PDUFA, Prescription Drug User Fee Act; VEGF, vascular endothelial growth factor. International non-proprietary naming convention: -umab, human;
`-zumab, humanized; -ximab, chimeric; -momab, murine.
`
`Ipilimumab
`
`Pending
`
`CTLA-4; human IgG1
`
`Advanced melanoma
`
`www.landesbioscience.com
`
`mAbs
`
`77
`
`
`
`
`Apotex Exhibit 1020
`Page 3 of 25
`
`

`

`Table 3. Monoclonal antibodies in Phase 3 studies as treatments for immunological indications
`
`Sponsoring company
`
`International
` non-proprietary name
`
`Target and type
`
`Indication of Phase 3 study
`
`FDA designations
`for Phase 3 study
`indication
`
`Millennium/Takeda
`
`Tolerx
`Macrogenics/Eli Lilly
`Biocon/CIMAB SA
`Immunomedics/UCB
`Cephalon
`
`Vedolizumab
`
`Otelixizumab
`Teplizumab*
`T1h
`Epratuzumab
`Reslizumab
`
`α4 β7 integrin; IgG1
`
`CD3; IgG1
`CD3; IgG1
`CD6; humanized IgG1
`CD22; IgG1
`IL-5; IgG4
`
`O
`O
`
`FT
`O
`
`Moderate-to-severe Crohn disease;
`ulcerative colitis
`Type 1 diabetes mellitus
`Type 1 diabetes mellitus
`Psoriasis
`Systemic lupus erythematosus
`Eosinophilic esophagitis
`Ankylosing spondylitis, rheumatoid
`arthritis
`Plaque psoriasis
`IL-12/23; IgG1
`Briakinumab**
`Abbott
`Uveitis
`IL-17A; human IgG1
`AIN-457
`Novartis
`Information current as of September 1, 2010. CD, cluster of differentiation; FDA, US Food and Drug Administration; FT, fast track designation; IL,
`interleukin; O, orphan drug designation. International non-proprietary naming convention: -umab, human; -zumab, humanized. *Note added in proof:
`In a press release issued in October 2010, Lilly announced that the primary endpoint in the PROTÉGÉ study (NCT00385697) had not been met and
`enrollment and dosing in the PROTÉGÉ and PROTÉGÉ Encore (NCT00920582) studies were suspended. **Note added in proof: In a press release issued
`in October 2010, Abbott announced that marketing applications for briakinumab were filed in the US and Europe during the third quarter of 2010.
`
`Regeneron
`
`REGN88
`
`IL-6R; human IgG1
`
`Table 4. Monoclonal antibodies in FDA review or approved as treatments for immunological indications
`International
`Indication under consideration or first
` non-proprietary name
`approved
`
`Target and type
`
`Trade name
`
`Belimumab
`
`Pending
`
`Eculizumab
`Muromonab-CD3
`Basiliximab
`Daclizumab
`Efalizumab
`Tocilizumab
`Ustekinumab
`Canakinumab
`Omalizumab
`Natalizumab
`
`Soliris
`Orthoclone Okt3
`Simulect
`Zenapax
`Raptiva
`Actemra
`Stelara
`Ilaris
`Xolair
`Tysabri
`
`B-lymphocyte stimulator;
`human IgG1
`C5; humanized IgG2/4
`CD3; murine IgG2a
`IL2R; chimeric IgG1
`IL2R; humanized IgG1
`CD11a; humanized IgG1
`IL6R; humanized IgG1
`IL12/23; human IgG1
`IL1β; human IgG1
`IgE; humanized IgG1
`α4 integrin; humanized IgG4
`
`Golimumab
`
`Simponi
`
`TNF; human IgG1
`
`Systemic lupus erythematosus
`
`Paroxysmal nocturnal hemoglobinuria
`Reversal of kidney transplant rejection
`Prevention of kidney transplant rejection
`Prevention of kidney transplant rejection
`Psoriasis
`Rheumatoid arthritis
`Plaque psoriasis
`Muckle-Wells syndrome
`Asthma
`Multiple sclerosis
`Rheumatoid and psoriatic arthritis,
` ankylosing spondylitis
`
`FDA approval year
`
`Pending (PDUFA action
`date Dec. 9, 2010)
`2007
`1986#
`1998
`1997#
`2003#
`2010
`2009
`2009
`2003
`2004
`
`2009
`
`Certolizumab pegol
`
`Cimzia
`
`TNF; humanized Fab,
` pegylated
`2002
`Rheumatoid arthritis
`TNF; human IgG1
`Humira
`Adalimumab
`1998
`Crohn disease
`TNF; chimeric IgG1
`Remicade
`Infliximab
`Information current as of September 1, 2010. #Voluntarily withdrawn from US market. C5, complement 5; CD, cluster of differentiation; FDA, US Food
`and Drug Administration; IL, interleukin; PDUFA, Prescription Drug User Fee Act; TNF, tumor necrosis factor. International non-proprietary naming
`convention: -umab, human; -zumab, humanized; -ximab, chimeric; -momab, murine.
`
`Crohn disease
`
`2008
`
`countries, e.g., India, Cuba, Argentina,
`Columbia, Ivory Coast, Gabon, Ukraine,
`Peru and Sri Lanka as a treatment for
`patients with squamous cell carcinoma
`of the head and neck; Cuba, Argentina,
`Philippines and Ukraine as a treat-
`ment for glioma in pediatric and adult
`patients and China for patients with
`
`nasopharyngeal cancer. Nimotu-zumab
`is in commercially-sponsored, ongoing
`Phase 3 studies in patients with glioblas-
`toma multiforma (NCT00753246) and
`patients with advanced nasopharyngeal
`cancer (NCT01074021).
`With six products in FDA review or
`approved and five candidates in Phase 3
`
`studies, Fc fusion protein therapeutics are
`a growing class of antibody-based mol-
`ecules that have been included on the
`2011 watch list. In alphanumeric order,
`the 2011 Fc fusion protein therapeu-
`tics to watch list comprises aflibercept,
`AMG-386, atacicept, Factor VIII-Fc and
`Factor IX-Fc (Table 7). For comparison,
`
`78
`
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`
`Volume 3 Issue 1
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`Table 5. Monoclonal antibodies in Phase 3 studies as treatments for non-traditional indications
`
`Sponsoring company
`
`International
` non-proprietary name
`
`Target and type
`
`Indication of Phase 3 study
`
`FDA designations
`for Phase 3 study
`indication
`
`Biosynexus
`
`Pagibaximab
`
`Lipoteichoic acid; IgG1
`
`Prevention of staphylococcal sepsis in
`very low birth weight neonates
`Alzheimer disease
`Amyloid beta; IgG1
`Solanezumab
`Lilly
`FT
`Alzheimer disease
`Amyloid beta; IgG1
`Bapineuzumab
`Pfizer, Janssen
`Information current as of September 1, 2010. FDA, US Food and Drug Administration; FT, fast track designation; O, orphan drug designation. Interna-
`tional non-proprietary naming convention: -zumab, humanized; -ximab, chimeric.
`
`O
`
`Trade name
`
`Target and type
`
`Table 6. Monoclonal antibodies in FDA review or approved as treatments for non-traditional indications
`Indication under consideration or first
`International
`approved
` non-proprietary name
`B. anthrasis PA; human IgG1
`Pending
`Pending
`Raxibacumab
`Anthrax infection
`1994
`GPIIb/IIIa; chimeric IgG1 Fab
`Reopro
`Abciximab
`Prevention of blood clots in angioplasty
`2010
`RANK-L; human IgG2
`Prolia
`Denosumab
`Bone loss
`Pending
`RSV; humanized IgG1
`Pending
`Motavizumab
`Prevention of respiratory syncytial virus infection
`1998
`RSV; humanized IgG1
`Synagis
`Palivizumab
`Prevention of respiratory syncytial virus infection
`2006
`VEGF; humanized IgG1 Fab
`Lucentis
`Ranibizumab
`Macular degeneration
`Information current as of September 1, 2010. FDA, US Food and Drug Administration; GP; glycoprotein; PA, protective antigen; RANK-L, receptor acti-
`vator of NFκb ligand; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelial cell growth factor.
`
`FDA approval year
`
`Table 7. Fc fusion protein therapeutics in Phase 3 studies for any indication
`International
` non-proprietary
`or code name
`
`Sponsoring
` company
`
`Description
`
`Regeneron/Sanofi-
`aventis/Bayer
`
`Aflibercept
`
`Extracellular domains of VEGFR1 and
`VEGFR2 fused to Fc of human IgG1
`
`Amgen
`
`AMG 386
`
`ZymoGenetics/
`Merck Serono
`
`Atacicept
`
`Angiopoietin-1 and -2 binding peptide
`fused to Fc of human IgG1
`
`Extracellular domain of transmembrane
`activator and calcium-modulating ligand
`interactor fused with Fc of human Ig
`
`FDA designa-
`tions for Phase 3
`study indication
`
`FT (for
`symptomatic
`malignant
`ascites)
`
`Indications of Phase 3 study
`
`Ovarian cancer with symptomatic
`malignant ascites, prostate, small cell
`lung, colorectal and pancreatic can-
`cers*; wet age-related macular degen-
`eration; central retinal vein occlusion
`Epithelial ovarian, primary peritoneal
`or fallopian tube cancers*
`
`Systemic lupus erythematosus
`
`Biogen Idec/Swedish
`Orphan Biovitrum
`
`Biogen Idec/Swedish
`Orphan Biovitrum
`
`Factor VIII-Fc
`
`Factor VIII fused to Fc of human IgG1
`
`Severe hemophilia A
`
`Factor IX-Fc
`
`Factor IX fused to Fc of human IgG1
`
`Hemophilia B-associated hemorrhagic
`events
`
`O
`
`Data current as of September 2010. *Five separate Phase 3 studies, with one in each indication. **Single Phase 3 study [NCT01204749] in which patients
`may have any of these indications; listed on clinicaltrials.gov as not yet open for participation as of September 2010. FDA, United States Food and Drug
`Administration; FT, fast track; O, orphan drug; VEGFR, vascular endothelial growth factor receptor.
`
`information about Fc fusion proteins
`that are in regulatory review or approved
`for marketing by the FDA are listed
`in Table 8.
`Commercially-sponsored mAb and
`Fc fusion protein therapeutics that have
`progressed only to Phase 2/3 or Phase 3
`were included. Candidates undergoing
`
`regulatory review or products already on
`the market may also be in Phase 3 studies,
`but these were excluded. MAbs in devel-
`opment sponsored solely by academic,
`government and non-profit organizations
`were also excluded. Due to the large body
`of primary literature about the 30 candi-
`dates on the 2011 watch list, only selected
`
`references are given, and results from
`recent publications and articles that were
`relevant to Phase 3 studies are empha-
`sized. Current as of September 2010, the
`information presented here will serve as a
`baseline against which future progress in
`the development of antibody-based thera-
`peutics can be measured.
`
`www.landesbioscience.com
`
`mAbs
`
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`Table 8. Fc fusion protein therapeutics approved in the US as treatments for any indication
`International
` non-proprietary name
`
`Trade name
`
`Description
`
`Indication under review or first approved
`
`Year of first
`FDA approval
`
`Pending
`
`2005
`
`2008
`
`2003
`
`1998
`
`2008
`
`Belatacept
`
`Pending
`
`Extracellular domain of CTLA-4 fused to
`Fc of a human IgG1
`
`Prophylaxis of organ rejection and preser-
`vation of a functioning allograft in adult
`patients receiving renal transplants
`
`Abatacept
`
`Orencia
`
`Extracellular domain of CTLA-4 fused to
`Fc of a human IgG1
`
`Moderate-to-severely active rheumatoid
`arthritis
`
`Rilonacept
`
`Arcalyst
`
`Extracellular domain of interleukin-1
`receptor fused to Fc of human IgG1
`
`Cryopyrin-associated periodic syndromes
`
`Alefacept
`
`Amevive
`
`Extracellular domain of LFA-3 fused to Fc
`of a human IgG1
`
`Treatment of adults with moderate-to-
`severe plaque psoriasis
`
`Etanercept
`
`Romiplostim
`
`Enbrel
`
`NPlate
`
`Data current as of September 2010.
`
`Extracellular domain of tumor necrosis
`factor receptor fused to Fc of human IgG1
`
`Moderate-to-severely active rheumatoid
`arthritis
`
`Thrombopoietin-binding peptide fused to
`Fc of human IgG1
`
`Thrombocytopenia in chronic immune
`thrombocytopenic purpura patients
`
`Eight New mAbs
`in Phase 3 Clinical Studies
`
`Of the eight mAbs that entered (or re-
`entered) Phase 3 clinical studies recently,
`five (zanolimumab, obinutuzumab, bren-
`tuximab vedotin, tremelimumab, neci-
`tumumab) are potential treatments for
`cancer indications (Table 1) and three
`(T1h, REGN88, AIN-457) are being
`studied as treatments for immunological
`disorders (Table 3). Four of these mAbs
`target antigens that are unique compared
`to those targeted by mAb products already
`on the market or in regulatory review.
`The antigens are: CD4 (target of zanoli-
`mumab), CD30 (target of brentuximab
`vedotin), CD6 (target of T1h) and inter-
`leukin (IL)-17A (target of AIN-457).
`Zanolimumab
`(HuMax-CD4,
`MDX-CD4; TenX Biopharma)
`is a
`human IgG1 mAb that targets CD4 on
`the surface of T cells. The mAb has been
`shown to inhibit or deplete T cells through
`a variety of mechanisms such as alteration
`of T-cell receptor signal transduction,
`Fc-dependent CD4 receptor down-mod-
`ulation and antibody dependent cellular
`cytotoxicity (ADCC).5 Zanolimumab has
`been evaluated as a treatment for a variety
`of diseases characterized by T-cell disor-
`ders, including rheumatoid arthritis, pso-
`riasis and lymphoma. The current focus of
`Phase 3 clinical development is on cuta-
`neous T-cell lymphomas (CTCLs), which
`are rare lymphomas presenting primarily
`in the skin and include mycosis fungoides
`
`and Sézary syndrome.6 Zanolimumab
`was designated a Fast Track candidate as
`a treatment for CTCL patients who have
`failed current therapy and an Orphan
`drug specifically for treatment of mycosis
`fungoides by the FDA.
`Zanolimumab was assessed in two
`Phase 2 studies as a treatment for early
`(Hx-CD4-007; NCT00071071) and late
`(Hx-CD4-008; NCT00071084)
`stage
`CTCL.7 Initiated in 2003, both of these
`multicenter Phase 2 studies were non-ran-
`domized, uncontrolled (i.e., no placebo
`arm was included), open label and single
`group assignment. Prior to enrollment,
`patients in both studies had been previ-
`ously treated with at least one treatment
`regimen and had failed or relapsed. For
`both studies, patients were administered
`intravenous (iv) doses of zanolimumab over
`15 min on a weekly basis. Seventeen infu-
`sions were given over 16 weeks, with a
`follow up visit four weeks later. Response
`rates, duration of responses, relief of
`symptoms and the safety profile of the
`mAb were evaluated in the 38 mycosis
`fungoides patients and nine Sézary syn-
`drome patients who enrolled in the two
`studies. The studies were designed as
`single arm evaluations of 280 mg doses of
`zanolimumab, but data review indicated
`that T-cell depletion might be inadequate.
`Additional study arms with doses of 560
`mg for mycosis fungoides patients and
`980 mg for Sézary syndrome patients were
`then added.
`
`The Hx-CD4-007 (NCT00071071)
`study included 25 early stage (IB-IIA)
`mycosis fungoides patients, 11 and 14 of
`which were administered 280 and 560 mg
`doses of zanolimumab,
`respectively.7
`The Hx-CD4-008
`(NCT00071084)
`study included a total of 22 patients
`dosed as follows: nine late stage (IIB-
`IVB) mycosis fungoides and four Sézary
`syndrome patients received 280 mg
`doses of zanolimumab and four late
`stage (IIB-IVB) mycosis fungoides and
`five Sézary syndrome patients received
`980 mg doses of zanolimumab.7 An objec-
`tive response, based on composite assess-
`ment of the index lesion disease severity
`score, was obtained by 13 mycosis fungoi-
`des patients (3 of 20 at 280 mg dose level,
`7 of 14 at 560 mg dose level and 3 of 4 at
`980 mg dose level). One of four and one
`of five Sézary syndrome patients who were
`administered 280 mg or 980 mg doses of
`zanolimumab, respectively, obtained an
`objective response. The response rate of
`56% in the high dose group was obtained
`with a median response of 81 weeks.
`Increased titers of anti-drug antibodies
`were observed in only one patient. Adverse
`events (AEs) included inflammatory skin
`reactions and infections; nine infections
`were deemed drug-related although no
`dose relation was apparent.
`A Phase 3
`study
`(Hx-CD4-110;
`NCT00127881) of zanolimumab as a
`treatment for mycosis fungoides started
`by Genmab in 2005 was discontinued in
`2008 due to slow enrollment and a need
`
`80
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`by the company to reserve resources at
`that time. TenX Biopharma acquired the
`mAb in 2010 and re-initiated enrollment
`in the study, which is designed as non-ran-
`domized, open label, dose escalation, fol-
`lowed by open label and single arm. Adult
`patients (18 years or older) with mycosis
`fungoides (Stage IB-IVB) or Sézary syn-
`drome who are refractory or intolerant to
`bexarotene and one other standard ther-
`apy will receive 12 weekly infusions. The
`primary outcome measure is efficacy as
`measured by physician’s global assessment
`(PGA); the estimated date for final data
`collection for the PGA is February 2011.
`Obinutuzumab (RO5072759, GA101;
`Genentech/Roche), a glyco-engineered
`anti-CD20 IgG1 mAb, is undergoing
`evaluation in combination with other
`drugs in two Phase 3 studies as a treat-
`ment for non-Hodgkin lymphoma (NHL)
`and chronic lymphocytic leukemia (CLL).
`Obinutuzumab differs from the marketed
`anti-CD20 ofatumumab and rituximab
`in its mechanisms of action. The mAb is
`a Type II antibody and so has a distinct
`effector function profile that includes
`reduced binding to C1q and lower levels
`of CDC but potent induction of cell death
`through caspase-independent apoptosis.8
`Enhanced activity was correlated with a
`modified elbow hinge residue (valine at
`Kabat position 11 instead of leucine).9
`Obinutuzumab also contains a glyco-
`engineered Fc region, with bisected, com-
`plex, non-fucosylated oligosaccharides
`attached to asparagines 297, that allows
`the mAb to bind with increased affinity
`to FcγRIII.9
`Obinutuzumab is being evaluated as a
`monotherapy in an on-going open-label,
`dose-escalating Phase 1/2 study with a
`randomized Phase 2 part (NCT00517530)
`of patients with CD20+ malignant disease.
`The study was initiated in September
`2007 and results for the first 12 patients
`were
`reported
`in December 2008.10
`Obinutuzumab was administered by iv
`infusion at a flat dose on days 1, 8 and 22
`and subsequently every three weeks for a
`total of nine infusions. The dose was esca-
`lated according to a 3 + 3 design; doses
`ranging from 50–800 mg were adminis-
`tered to patients who had follicular NHL
`(nine patients), diffuse large B-cell lym-
`phoma (one patient), CLL (one patient)
`
`or Waldenstrom macroglobulinemia (one
`patient). No dose-limiting toxicity was
`observed. The most common AEs were
`infusion-related
`reactions;
`six minor
`infections were observed. The pharmaco-
`kinetics of the mAb showed a dose-depen-
`dent increase in exposure, but significant
`inter- and intra-patient variability was
`noted. At the time of the report, 7 of 12
`patients had responded to treatment by
`day 85. The objective response rate (ORR)
`was 58%, with complete response in three
`patients (25%) and partial response in
`four patients (33%).10
`Obinutuzumab in combination with
`chlorambucil is undergoing evaluation in
`a Phase 3 study (NCT01010061) of adult
`(18 years and older) patients with previ-
`ously untreated CLL. The open label,
`randomized study will have three arms:
`(1) 1 g doses of obinutuzumab iv admin-
`istered on days 1, 8 and 15 in cycle 1 and
`on day 1 of cycles 2–6 in combination
`with 0.5 mg/kg chlorambucil adminis-
`tered orally on day 1 and 15 of each cycle;
`(2) 375 mg/m2 rituximab iv administered
`on day 1 in cycle 1 and 500 mg/m2 on
`day 1 of cycles 2–6 in combination with
`chlorambucil administered as in arm 1;
`(3) chlorambucil only administered as in
`arm 1. The primary outcome measure is
`progression-free survival as assessed every
`two weeks while patients are on study
`treatment, 28 days after last dose and at
`intervals for at least 5 years of follow-up.
`Secondary outcome measures
`include
`response rates, duration of response and
`disease-free survival in patients with com-
`plete response, overall survival, molecu-
`lar remission, minimal residual disease,
`safety profile, pharmacokinetics of obinu-
`tuzumab and patient reported outcomes.
`The estimated enrollment is 786 patients
`and the estimated study completion date
`is February 2022.
`A second Phase 3 study (NCT-
`01059630; GADOLIN) is investigating
`the efficacy and safety of obinutuzumab in
`combination with bendamustine in adult
`patients with rituximab-refractory, indo-
`lent NHL. This open label, randomized
`study will compare results for the com-
`bination of drugs with those obse