MABS 2016, VOL. 8, NO. 2, 197–204 http://dx.doi.org/10.1080/19420862.2015.1125583
PERSPECTIVE
Antibodies to watch in 2016 Janice M. Reichert Managing Director, Reichert Biotechnology Consulting LLC, Framingham, MA, 01701
ABSTRACT
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (PraluentÒ ), evolocumab (RepathaÒ ), daratumumab (DarzalexÒ ), dinutuximab (UnituxinÒ ), idarucizumab (PraxbindÒ ), mepolizumab (NucalaÒ )) granted first approvals as of mid-November. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016. Commercial late-stage antibody therapeutics development exceeded expectations by increasing from 39 candidates in Phase 3 studies as of late 2014 to 53 as of late 2015. Of the 53 candidates, transitions to regulatory review by the end of 2016 are projected for 8 (atezolizumab, benralizumab, bimagrumab, durvalumab, inotuzumab ozogamicin, lebrikizumab, ocrelizumab, tremelimumab). Other "antibodies to watch" include 15 candidates (bavituximab, bococizumab, dupilumab, fasinumab, fulranumab, gevokizumab, guselkumab, ibalizumab, LY2951742, onartuzumab, REGN2222, roledumab, romosozumab, sirukumab, Xilonix) undergoing evaluation in Phase 3 studies that have estimated primary completion dates in 2016. As evidenced by the antibody therapeutics discussed in this perspective, the biopharmaceutical industry has a highly active late-stage clinical pipeline that may deliver numerous new products to the global market in the near future. See Note added in proof for updates through December 31, 2015.
ARTICLE HISTORY
Received 24 November 2015 Accepted 24 November 2015 KEYWORDS
Antibody therapeutics; clinical studies; drug development; European Medicines Agency; Food and Drug Administration
Abbreviations: ALL, acute lymphoblastic leukemia; CD, cluster of differentiation; EGFR, epidermal growth factor
receptor; EMA, European Medicines Agency; EU, European Union; FDA, US Food and Drug Administration; HIV, human immunodeficiency virus; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; NSCLC, non–small cell lung cancer; PCSK9, proprotein convertase subtilisin kexin type 9; PD-L1, programmed cell death ligand 1; RSV, respiratory syncytial virus; SLAM, signaling lymphocyte activation molecule; sIBM, sporadic inclusion body myositis; US, United States
In terms of the number of drugs in late-stage clinical development, monoclonal antibody (mAb) therapeutics development by the biopharmaceutical industry in 2015 has far exceeded expectations. As of mid-November 2015, 53 novel antibody therapeutics were in Phase 3 studies, which is a 36% and 104% increase compared to the number in Phase 3 studies in late 2014 and 2009, respectively.1,2 For the long-term, the prospects appear bright for the continued transition of molecules into Phase 3 from early-stage clinical studies, based on the fact that ~210 novel antibody therapeutics are in each of the 2 early phases of clinical development. Now totaling over 470 molcules, the commercial clinical pipeline of antibody therapeutics is thus quite robust. The recent increase in late-stage clinical development has led to an increase in the number of antibody therapeutics that enter regulatory review and receive marketing approvals. Based on information available as of mid-November 2015, the annual number of first approvals of antibody therapeutics is expected to be in the range of 5–8 in 2014, 2015 and 2016. If expectations are met, this outcome would be unprecedented because a year in which the number of first approvals is high (4–6 approvals)
CONTACT Janice M. Reichert © 2016 Taylor & Francis Group, LLC
[email protected]
has historically been followed by 4 or more years when the number is low (0–3 approvals).3 As of mid-November, 6 novel antibody therapeutics (alirocumab (PraluentÒ ), evolocumab (RepathaÒ ), idarucizumab (PraxbindÒ ), dinutuximab (UnituxinÒ ), mepolizumab (NucalaÒ ), daratumumab (DarzalexÒ )) were granted first marketing approvals during 2015; the approvals were granted in either the European Union (EU) or the US (Table 1; see Note added in proof for updates through December 31, 2015.). Secukinumab, which targets interleukin (IL)-17a, also received marketing approvals for treatment of psoriasis in these regions in 2015, but the product was first approved in Japan in late 2014. Both alirocumab and evolocumab target proprotein convertase subtilisin kexin type 9 (PCSK9) and inhibit its function, which ultimately leads to a reduction in levels of low-density lipoprotein cholesterol. Idarucizumab targets dabigatran and reverses the effects of this anticoagulant agent. The anti-GD2 antibody dinutuximab was approved for pediatric neuroblastoma. Mepolizumab, which targets IL-5, was approved in the US for use with other asthma medicines for the maintenance treatment of asthma in patients who are age 12 y and older. Anti-CD38 daratumumab was granted accelerated approval in the US to treat
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Table 1. Novel antibody therapeutics first approved in 2015 in the EU or US. INN
Brand name
Daratumumab Mepolizumab Alirocumab Evolocumab Dinutuximab Idarucizumab Secukinumab
Darzalex Nucala Praluent Repatha Unituxin Praxbind Cosentyx
Target; Molecular format
Indication
CD38; Human IgG1 IL-5; Humanized IgG1 PCSK9; Human IgG1 PCSK9; Human IgG2 GD2; Chimeric IgG1 Dabigatran; Humanized Fab IL-17a; Human IgG1
Multiple myeloma Severe eosinophilic asthma High cholesterol High cholesterol Neuroblastoma Reversal of dabigatran-induced anticoagulation Psoriasis
Status in EU
Status in US
In review Approved Approved Approved Approved Approved Approved
Approved Approved Approved Approved Approved Approved Approved
Note: Secukinumab was approved in Japan in December 2014. Abbreviations: EU, European Union; GD, glycolipid disialoganglioside; IL, interleukin; INN, international non-proprietary name; PCSK9, proprotein convertase subtilisin kexin type 9; US, United States.
patients with multiple myeloma who have received at least 3 prior treatments. Daratumumab is the first mAb approved for treating this disease. A marketing application for daratumumab for multiple myeloma was submitted to the European Medicines Agency (EMA) in September 2015. The focus of this perspective is on the late-stage clinical development and approval of antibody therapeutics in the pipelines of biopharmaceutical companies. In the following sections, regulatory actions and marketing application submissions for antibody therapeutics that may occur in late 2015 or during 2016, as well as relevant Phase 3 studies with estimated primary completion dates in this period, are discussed. Due to the copious literature on the antibodies, references are limited to clinical study results published in 2015.
Regulatory actions: Projections for December 2015 through 2016 Regulatory actions are expected either in December 2015 or in 2016 for at least 7 antibody therapeutics (Table 2; see Note added in proof for updates through December 31, 2015.). Marketing applications for necitumumab, which targets epidermal growth factor receptor, were submitted to regulatory authorities in 2014. Data from the Phase 3 SQUIRE study of necitumumab were reviewed in July 2015 by the US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee. The majority of the panel members agreed that the benefits of adding necitumumab to gemcitabine and cisplatin for patients with squamous non–small cell lung cancer (NSCLC) outweighed the risks. The FDA is expected to make a decision on the marketing application for necitumumab by the end of 2015.
Elotuzumab is undergoing regulatory review as a treatment for multiple myeloma. Marketing applications for elotuzumab were validated for review by EMA and the FDA in July and September 2015, respectively. EMA granted the marketing authorization application submitted to them an accelerated assessment, and the FDA gave priority review designation to the biologics license application (BLA) submitted to them. Elotuzumab, which was granted breakthrough therapy designation by FDA, is a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody for the treatment of multiple myeloma as combination therapy in patients who have received one or more prior therapies. Recently published results from the Phase 3 ELOQUENT-2 study (NCT01239797) indicated that patients with relapsed or refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone had a significant relative reduction in the risk of disease progression or death.4 Brodalumab and ixekizumab, which are antibody therapeutics that interfere with the biological activity of the proinflammatory cytokine IL-17A, are undergoing regulatory review as treatments for psoriasis. Brodalumab targets the IL-17 receptor while ixekizumab targets the IL-17A ligand. An application for marketing approval of brodalumab was submitted to Japan’s Ministry of Health, Labor and Welfare in July 2015. Brodalumab was developed for plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. In the Phase 3 AMAGINE-2 and AMAGINE-3 studies (NCT01708603 and NCT01708629, respectively), treatment with brodalumab resulted in significant clinical improvements in patients with moderate to severe psoriasis.5 In 2 Phase 3 studies of ixekizumab (UNCOVER-2 and UNCOVER-3, NCT01597245 and NCT01646177,
Table 2. Antibody therapeutics in first regulatory review in the EU or US. INN
Brand name
Necitumumab Elotuzumab Brodalumab Ixekizumab Reslizumab Begelomab Obiltoxaximab
(Pending) Empliciti (Pending) (Pending) (Pending) BEGEDINA Anthim
Target; Molecular format
Indication
EGFR; Human IgG1 SLAMF7; Humanized IgG1 IL-17R; Human IgG2 IL-17a; Humanized IgG4 IL-5; Humanized IgG4 CD26; Murine IgG2b Protective antigen of B. anthracis exotoxin; Chimeric IgG1
Non-small cell lung cancer Multiple myeloma Psoriasis Psoriasis Asthma Graft-vs-host disease Prevention of inhalational anthrax
Location of review EU, US EU, US EU EU EU, US EU US
Abbreviations: CD, cluster of differentiation; EGFR, epidermal growth factor receptor; EU, European Union; IL, interleukin; INN, international non-proprietary name; SLAM, signaling lymphocyte activation molecule; US, United States.
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respectively), participants were randomly assigned to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks or every 4 weeks after a 160 mg starting dose. Both ixekizumab dose regimens were shown to have greater efficacy than placebo and etanercept over 12 weeks in these studies.6 As of June 2015, ixekizumab was undergoing evaluation at EMA. Reslizumab targets IL-5, a cytokine involved in the maturation, recruitment, and activation of eosinophils, which mediate diseases such as asthma. Results from 2 Phase 3 studies (NCT01287039, NCT01285323) support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroidbased therapy.7 As of June 2015, a BLA for reslizumab had been accepted by the FDA for standard review. FDA’s Pulmonary-Allergy Drugs Advisory Committee is scheduled to discuss the BLA for reslizumab in December 2015, and a regulatory action is expected in March 2016. A marketing application for reslizumab as a treatment for inadequately controlled asthma in adult patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen, was submitted to EMA in July 2015, and EMA’s opinion on reslizumab is anticipated in the second half of 2016. Begelomab, which targets CD26 on CD4+ T lymphocytes, is undergoing evaluation by EMA as an orphan medicinal product for treatment of steroid resistant acute graft-versus-host disease in adult patients who underwent allogeneic haematopoietic progenitor cell transplantation and received a standard immunosuppressive regimen. A prospective Phase 2/3 study (NCT02411084) to compare begelomab vs. conventional treatment for treating steroid-resistant acute graft-versus host disease is due to start recruiting patients in January 2016. Obiltoxaximab was developed for the treatment and prevention of inhalational anthrax. The chimeric antibody was granted Fast Track and orphan drug designations by the FDA; a BLA was submitted in March 2015. Efficacy data
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was derived from animal models of inhalational anthrax and safety data from healthy human volunteers receiving the proposed human therapeutic dose of obiltoxaximab administered either intravenously or intramuscularly. The product is intended to serve as an anthrax biowarfare countermeasure.
Marketing application submissions: Projections for late 2015 through 2016 Two antibodies, bezlotoxumab and sarilumab, may transition into regulatory review by the end of 2015, with an additional 8 following during 2016. Bezlotoxumab, which targets Clostridium difficile enterotoxin B, is being developed for the prevention of recurrent Clostridium difficile infection. The primary efficacy endpoint, reduction in C. difficile recurrence through week 12 compared to placebo when used in conjunction with standard of care antibiotics for the treatment of C. difficile, was met in the Phase 3 MODIFY I and MODIFY II studies (NCT01241552 and NCT01513239, respectively) of bezlotoxumab. Submission of marketing applications to regulatory agencies in the EU, US and Canada is planned by the end of 2015. Sarilumab targets the IL-6 receptor, thereby blocking IL-6 from binding to the receptor and interrupting cytokine-mediated inflammatory signaling. In the Phase 3 MOBILITY study (NCT01061736), significant improvements in symptomatic, functional, and radiographic outcomes were observed in rheumatoid arthritis patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX.8 Nine additional Phase 3 studies of sarilumab for rheumatoid arthritis are either completed or active and not recruiting patients. Submission of a marketing application to the FDA is planned by the end of 2015. Four antibody therapeutics (atezolizumab, durvalumab, tremelimumab, inotuzumab ozogamicin) now in Phase 3 studies for cancer (Table 3) may transition to a first regulatory
Table 3. Antibody therapeutics in Phase 2/3 or Phase 3 clinical studies of cancer indications. Primary sponsoring company
INN or code name
Pfizer Viventia Bio MacroGenics Merrimack Pharmaceuticals
Inotuzumab ozogamicin Oportuzumab monatox Margetuximab MM-302
Molecular format
Target
Most advanced phase Phase 3 indication(s)
CD22 EpCAM HER2 HER2
Phase 3 Phase 3 Phase 3 Phase 2/3
Acute lymphoblastic leukemia Bladder cancer Breast cancer Breast cancer
TG Therapeutics XBiotech, Inc. AstraZeneca/ MedImmune Daiichi Sankyo Genentech Peregrine Pharmaceuticals Recombio SL EMD Serono Genentech
Humanized IgG4 ADC Humanized scFv immunotoxin Chimeric IgG1 scFv-targeted liposome containing doxorubicin Ublituximab Chimeric IgG1 Xilonix Human IgG1 Moxetumomab pasudotox Murine IgG1 dsFv immunotoxin Patritumab Human IgG1 Onartuzumab Humanized IgG1 Fab-Fc Bavituximab Chimeric IgG1 Racotumomab Murine IgG1 Avelumab Human IgG1 Atezolizumab Humanized IgG1
CD20 IL-1 a CD22 HER3 cMet Phosphatidylserine GM3 PD-L1 PD-L1
Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3
AstraZeneca/ MedImmune AstraZeneca/ MedImmune Immunomedics, Inc. Gilead Sciences
Durvalumab (MEDI-4736) Tremelimumab Clivatuzumab tetraxetan GS-5745
PD-L1 CTLA4 MUC5AC MMP9
Phase 3 Phase 3 Phase 3 Phase 3
Chronic lymphocyticleukemia Colorectal cancer Hairy cell leukemia NSCLC NSCLC NSCLC NSCLC NSCLC NSCLC, bladder cancer, renal cell carcinoma, breast cancer NSCLC, head and neck cancer NSCLC, head and neck cancer Pancreatic cancer Gastric cancer or gastroesophageal junction adenocarcinoma
Human IgG1 Human IgG2 Humanized IgG1 Humanized IgG4
Data available as of November 16, 2015. Abbreviations: ADC, antibody-drug conjugate; CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated protein; EpCAM, epithelial cellular adhesion molecule; GM, monosialodihexosylganglioside; HER, human epidermal growth factor receptor; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; MM, matrix metallopeptidase; MUC, mucin; NSCLC, non-small cell lung cancer; PD, programmed death.
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Table 4. Antibody therapeutics in Phase 2/3 or Phase 3 clinical studies of non-cancer indications. Primary sponsoring company
INN or code name
Ablynx
Caplacizumab
Pfizer ProthenaTherapeutics Ltd. LFB Group Janssen Research and Development, LLC Merck Sharp andDohme Corp Janssen Research and Development, LLC Chugai Pharmaceuticals/ Roche AstraZeneca/MedImmune Genentech AstraZeneca/MedImmune RegeneronPharmaceuticals AstraZeneca/MedImmune
Molecular format
Target
Most advanced phase
Phase 3 indication(s)
von Willebrand factor
Phase 3
Acquired thromboticthrombocytopenicpurpura
Bococizumab NEOD001 Roledumab Guselkumab
Humanized nanobody Humanized IgG2 Humanized IgG1 Human IgG1 Human IgG1
PCSK9 Amyloid Rhesus D IL-23 p19 subunit
Phase 3 Phase 3 Phase 2/3 Phase 3
High cholesterol Primary systemicamyloidosis Rh disease Psoriasis
Tildrakizumab Sirukumab
Humanized IgG1 Human IgG1
IL-23 p19 subunit IL-6
Phase 3 Phase 3
Psoriasis Rheumatoid arthritis, giant cell arteritis
Emicizumab
Factor IXa, Factor X
Phase 3
Hemophilia A
Benralizumab Lebrikizumab Tralokinumab Dupilumab Inebilizumab
Humanized bispecific IgG4 Humanized IgG1 Humanized IgG4 Human IgG4 Human IgG4 Humanized IgG1
IL-5 receptor IL-13 IL-13 IL-4 receptor a CD19
Phase 3 Phase 3 Phase 3 Phase 3 Phase 2/3
Chugai Pharmaceuticals/ Roche Xoma AstraZeneca/ MedImmune
SA237
Humanized IgG2
IL-6 receptor
Phase 3
Gevokizumab Anifrolumab
Humanized IgG2 Human IgG1
Phase 3 Phase 3
UCB, Inc. Genentech
Epratuzumab Etrolizumab
Humanized IgG1 Humanized IgG1
Phase 3 Phase 3
Systemic lupus erythematosus Ulcerative colitis, Crohn’s disease
Genentech Novartis Pharmaceuticals Corp. TaiMed Biologics Inc. CytoDyn Regeneron Ultragenyx Pharmaceutical; Kyowa Hakko Kirin Co. Biogen Eli Lilly & Company Hoffmann-La Roche Eli Lilly & Company Alder Biopharma. Amgen Pfizer; Eli Lilly & Company
Ocrelizumab Bimagrumab
Humanized IgG1 Human IgG1
Phase 3 Phase 2/3
Multiple sclerosis Sporadic inclusion body myositis
Ibalizumab PRO-140, PA14 REGN2222 KRN23
Humanized IgG4 Humanized IgG4 Human IgG1 Human IgG1
Phase 3 Phase 2/3 Phase 3 Phase 3
HIV infection HIV infection RSV infection prevention X-linked hypophosphatemia
Aducanumab Solanezumab Gantenerumab LY2951742 ALD403 AMG 334 Tanezumab
Human IgG1 Humanized IgG1 Human IgG1 Humanized IgG4 Humanized IgG1 Human IgG2 Humanized IgG2
IL-1 b IF a, b, omega receptor 1 CD22 Alpha4-beta7/ alphaE-beta7 integrin receptor CD20 Activin A receptor type IIB CD4 CCR5 RSV F protein Fibroblast growth factor 23 Amyloid b Amyloid b Amyloid b CGRP CGRP CGRP receptor Nerve growth factor
Asthma, chronic obstructive pulmonary disease Asthma Asthma Atopic dermatitis, asthma Neuromyelitis optica and neuromyelitis optica spectrum disorders Neuromyelitis optica and neuromyelitis optica spectrum disorders Pyodermagangrenosum Systemic lupus erythematosus
Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3
Fasinumab Fulranumab
Human IgG4 Human IgG2
Nerve growth factor Nerve growth factor
Phase 2/3 Phase 3
Alzheimer disease Alzheimer disease Alzheimer disease Chronic or episodic cluster headache Episodic migraine prevention Migraine prevention Chronic low back pain, cancer pain due to bone metastasis Pain due to osteoarthritis of knee or hip Pain due to osteoarthritis of knee or hip
Lampalizumab Brolucizumab
Humanized IgG1 Fab Humanized scFv
Complement factor D VEGF-A
Phase 3 Phase 3
Geographic atrophy Neovascular age-related maculardegeneration
Romosozumab
Humanized IgG2
Sclerostin
Phase 3
Osteoporosis
Regeneron Pharmaceuticals Janssen Research and Development, LLC Genentech Novartis Pharmaceuticals Corp. UCB, Amgen
Abbreviations: CD, cluster of differentiation; CGRP, Calcitonin gene-related peptide; Fab, antigen-binding fragment; HIV, human immunodeficiency virus; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; PCSK9, proprotein convertase subtilisin kexin type 9; RSV, respiratory syncytial virus; scFv, single-chain variable fragment; VEGF, vascular endothelial growth factor.
review in 2016. Both atezolizumab and durvalumab target programmed cell death ligand 1 (PD-L1) expressed on tumor cells and tumor-infiltrating immune cells, thereby preventing it from binding to PD-1 and B7.1 on the surface of T cells. By interfering with an immune checkpoint, these mAbs may enable the activation of T cells. As of November 2015, atezolizumab is being evaluated in at least 10 Phase 3 studies (6 in NSCLC, 2 in bladder cancer, 1 in breast cancer, 1 in renal cell carcinoma). Of these studies, only the OAK study (NCT02008227), a Phase 3 study of atezolizumab compared to docetaxel in patients with locally advanced or metastatic NSCLC who failed platinum therapy, is active but not recruiting participants. Atezolizumab, which was engineered so that it
does not induce either antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity, has received 2 breakthrough therapy designations from the FDA: 1) for the treatment of patients whose NSCLC expresses PD-L1 and whose disease worsened during or after standard treatments, and 2) for patients whose metastatic bladder cancer expresses PD-L1. Submission of a marketing application for atezolizumab is planned in 2016. Durvalumab is being studied alone and in combination with another immune checkpoint inhibitor, tremelimumab, which targets cytotoxic T-lymphocyte-associated protein 4 (also known as CD152). As of November 2015, Phase 3 studies evaluating durvalumab or the combination of durvalumab and
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tremelimumab in NSCLC, including the PACIFIC (NCT02125461), ATLANTIC (NCT02087423), ARCTIC (NCT02352948), MYSTIC (NCT02453282) and NEPTUNE (NCT02542293) trials, and in squamous cell carcinoma of the head and neck were recruiting patients. Three additional Phase 3 studies were not yet recruiting patients. In April 2015, tremelimumab was granted US orphan drug designation for the treatment of malignant mesothelioma. Submission of marketing applications for durvalumab and tremelimumab may occur by the end of 2016. Inotuzumab ozogamicin, an antibody-drug conjugate that targets CD22, is being evaluated in the Phase 3 INO-VATE ALL trial, which compares inotuzumab ozogamicin to standard of care chemotherapy in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). Topline results from the trial announced in April 2015 indicated that one of the 2 primary endpoints, complete hematologic remission rate, was met. As of November 2015, data on the second endpoint, overall survival, had not yet been released. Inotuzumab ozogamicin received FDA’s breakthrough therapy designation for ALL in October 2015. Submission of a marketing application for inotuzumab ozogamicin may occur by the end of 2016. Four antibody therapeutics (bimagrumab, ocrelizumab, benralizumab, lebrikizumab) that are now in Phase 3 studies for diseases other than cancer (Table 4) may transition to first regulatory review by the end of 2016. Bimagrumab targets activin A receptor type IIB and is undergoing evaluation in Phase 3 studies of patients with sporadic inclusion body myositis (sIBM), a rare and potentially life-threatening muscle-wasting condition. FDA granted breakthrough therapy designation to bimagrumab for sIBM in August 2013. The Phase 3 RESILIENT study (NCT01925209) is evaluating the efficacy, safety and tolerability of bimagrumab at 52 weeks on the physical function, muscle strength and mobility of sIBM patients. The estimated primary completion date of the study is December 2015; positive results may allow the submission of a marketing application by the end of 2016. The anti-CD20 antibody therapeutic ocrelizumab showed superiority to interferon b-1a in 2 identical Phase 3 studies (OPERA I and OPERA II, NCT01247324 and NCT01412333, respectively) in patients with relapsing multiple sclerosis (MS). Ocrelizumab also significantly reduced the risk of progression of clinical disability sustained for at least 12 weeks by 24 percent compared with placebo in patients with primary progressive MS in the Phase 3 ORATORIO study (NCT01194570). Marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS will be pursued, and data from the ocrelizumab OPERA I and OPERA II studies and from the ORATORIO study may be submitted to the FDA in early 2016. Benralizumab and lebrikizumab are in Phase 3 studies of patients with asthma. Benralizumab targets IL-5 receptor a chain expressed on eosinophils and basophils, and induces apoptosis via ADCC. This antibody therapeutic is undergoing evaluation in 7 Phase 3 studies of patients with asthma, as well as 2 Phase 3 studies of patients with moderate to very severe chronic obstructive pulmonary disease. Phase 3 study results for benralizumab in severe asthma are expected in 2016; regulatory submissions may occur later that year. Lebrikizumab targets IL13
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and, as of November 2015, it is undergoing evaluation in 4 Phase 3 studies of asthma patients. The estimated primary completion date of the Phase 3 NCT02104674 study evaluating the efficacy and safety of lebrikizumab in adult patients with mild to moderate asthma is January 2016; positive results may allow the submission of a marketing application by the end of 2016.
Phase 3 studies with completion dates in late 2015 or in 2016: Cancer indications Of the 17 antibody therapeutics being evaluated in Phase 3 clinical studies of patients with cancer (Table 3), 3 (bavituximab, Xilonix, onartuzumab) are in studies that have estimated primary completion dates in late 2015 or in 2016. The anti-phosphatidyserine antibody bavituximab plus docetaxel is being compared to docetaxel alone in patients with previously treated stage IIIb/IV non-squamous NSCLC in the Phase 3 SUNRISE study (NCT01999673). The estimated primary completion date for the study is December 2016. Bavituximab has been granted Fast Track designation by the FDA for the potential treatment of second-line NSCLC. The IL-1 a-targeted antibody Xilonix, also known as MABp1, is undergoing evaluation in 2 Phase 3 studies (NCT02138422 and NCT01767857) in patients with colorectal cancer. A variety of mechanisms of action for the antibody have been proposed, including interruption of signals that drive angiogenesis and invasiveness, blockade of tumor microenvironment infiltration by leukocytes that suppress antitumor immunity, and correction of metabolic dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central nervous system. The Phase 3 study NCT02138422 will assess how effectively Xilonix slows tumor growth, and whether it improves symptoms of muscle loss, fatigue, appetite loss, and pain in patients with colorectal cancer compared with placebo. The estimated completion date for the study is December 2015. The aim of the Phase 3 XCITE study (NCT01767857) is to determine if Xilonix can prolong the life of colorectal carcinoma patients who are refractory to standard therapy. The XCITE study’s estimated primary completion date is December 2016. Onartuzumab, which has a Fab-Fc format, targets the receptor tyrosine kinase cMet. The safety and efficacy of onartuzumab in combination with erlotinib as second- or third-line treatment is being compared to erlotinib alone in patients with incurable Met-positive NSCLC in the Phase 3 NCT02031744 study. This study’s estimated primary completion date is December 2016. The Phase 3 METLung study (NCT01456325) of the onartuzumab / erlotinib combination in NSCLC patients who had received standard chemotherapy for advanced/metastatic disease did not confirm efficacy results observed in a Phase 2 study.
Phase 3 studies with completion dates in 2016: Non-cancer indications Most (36/53; 68%) of novel antibody therapeutics currently in Phase 3 clinical studies are for non-cancer indications (Table 4). Phase 3 studies of 12 of these antibodies have estimated
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primary completion dates in late 2015 or in 2016: 4 (gevokizumab, dupilumab, sirukumab, guselkumab) are for immunemediated disorders, 2 (fasinumab, fulranumab) are for pain, 2 are for infectious diseases (REGN2222, ibalizumab), and 4 (bococizumab, LY2951742, roledumab, romosozumab) are for other disorders. The efficacy and safety of anti-IL-1 b gevokizumab in treating active ulcers of pyoderma gangrenosum are being evaluated in 2 Phase 3 studies (NCT02315417, NCT02326740). Pyoderma gangrenosum is a rare inflammatory skin condition that leads to formation of deep, painful ulcers. In 2014, FDA granted gevokizumab an orphan drug designation for this disease. Dupilumab, which targets the IL-4 receptor, is being evaluated as monotherapy in adults with moderate to severe atopic dermatitis in 4 Phase 3 clinical studies with estimated primary completion dates in the late 2015 to 2016 period: SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), SOLO-Continue (NCT02395133) and NCT02260986. The estimated primary completion date for SOLO 1, SOLO 2 and NCT02260986 is November 2015, and the estimated primary completion date for SOLO-Continue is July 2016. The mAb received breakthrough therapy designation from the FDA for use in patients with moderate to severe atopic dermatitis who are insufficiently responsive to or cannot use topical prescription treatments. Dupilumab is also in Phase 3 studies of patients with asthma, but the earliest estimated primary completion date for any of these studies is August 2017. Anti-IL-6 sirukumab has been or is being evaluated as a treatment for rheumatoid arthritis in 5 Phase 3 studies; 3 of these studies have estimated primary completion dates in late 2015 or in 2016. The objective of the Phase 3 NCT02019472 study, which has estimated primary completion and study completion dates in October 2015 and August 2016, respectively, is to investigate the efficacy of sirukumab monotherapy compared with adalimumab monotherapy in biologic na€ıve patients with active rheumatoid arthritis who are intolerant to methotrexate, who are considered inappropriate for treatment with methotrexate or who are inadequate responders to methotrexate. The Phase 3 SIRROUND-T study (NCT01606761), which has estimated primary completion and study completion dates in December 2015 and April 2016, respectively, is assessing the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis in patients with active rheumatoid arthritis who are unresponsive or intolerant to treatment with anti-tumor necrosis factor agents. The Phase 3 SIRROUND-D study (NCT01604343) is assessing the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis and inhibition of radiographic progression in patients with active RA who are unresponsive to treatment with disease-modifying anti-rheumatic drugs; this study’s estimated primary completion date is July 2016. Guselkumab, which targets the IL-23 p19 subunit, is being evaluated as a treatment for psoriasis in 3 Phase 3 studies with estimated primary completion dates in late 2015 or in 2016. Results of the 52-week, Phase 2 X-PLORE study (NCT01483599) in which guselkumab was compared with
adalimumab in patients with moderate to severe plaque psoriasis suggested that guselkumab may be an effective therapy for plaque psoriasis.9 The Phase 3 NCT02207231 study is an active comparator-controlled study evaluating the efficacy and safety of guselkumab in the treatment of patients with moderate to severe plaque-type psoriasis. The active comparator is adalimumab, and the estimated primary completion and study completion dates are October 2015 and June 2016, respectively. The efficacy and safety of guselkumab is being compared with that of adalimumab for the treatment of patients with moderate to severe plaque-type psoriasis with randomized withdrawal and retreatment in the Phase 3 VOYAGE 2 (NCT02207244) study, which has estimated primary completion and study completion dates in May 2016. The Phase 3 NAVIGATE study (NCT02203032), which has an estimated primary completion date in August 2016, is evaluating guselkumab’s efficacy and efficacy in patients with moderate to severe plaque-type psoriasis and an inadequate response to ustekinumab. Two mAb therapeutics that target nerve growth factor, fasinumab (REGN475) and fulranumab, are being evaluated in Phase 2/3 or Phase 3 studies with estimated primary completion dates in 2016. The effectiveness of fasinumab is being compared to placebo in patients with pain due to osteoarthritis of the knee or hip and a history of inadequate joint pain relief or intolerance to current analgesic therapy in the Phase 3 NCT02447276 study, which has an estimated primary completion date in March 2016. A total of 4 Phase 3 studies (NCT02289716, NCT02336698, NCT02336685, NCT02301234) of fulranumab as a treatment for pain due to osteoarthritis of the knee or hip have estimated primary completion dates in November 2016. Fulranumab is being assessed as monotherapy in the NCT02289716 and NCT02336698 studies, and as adjunctive therapy in the NCT02336685 and NCT02301234 studies. Two mAbs, REGN2222 and ibalizumab, are being studied for either the prevention or treatment of infectious diseases. The efficacy and safety of REGN2222, which targets the respiratory syncytial virus (RSV) F protein, for the prevention of medically attended RSV infection in preterm infants is being evaluated in the Phase 3 NCT02325791 study. In Part A of the study, the pharmacokinetics in pre-term infants will be determined to enable the selection of dosing regimens for Part B, which is designed to evaluate the efficacy, safety, and serum concentration of REGN2222, and the immunogenicity of intramuscular administration of REGN2222 in preterm infants for whom palivizumab is not recommended. The estimated primary completion date of the study is July 2016. Ibalizumab targets CD4, which is the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits viral entry. NCT02475629 is a Phase 3 study of ibalizumab plus an optimized background regimen in treatment-experienced patients infected with multi-drug resistant HIV-1. In this study, patients are administered a loading dose of 2000 mg intravenous ibalizumab on Day 7, followed by 800 mg intravenous ibalizumab once every 2 weeks, plus an optimized background regimen beginning on Day 14. The primary outcome measures are Day 14 viral
MABS
load reduction and proportion of patients achieving a >/D 0.5 log10 decrease from Day 7/baseline viral load. The estimated primary completion date of the study is October 2016. Ibalizumab was granted breakthrough therapy and orphan drug designations by the FDA. Bococizumab, LY2951742, roledumab and romosozumab complete the group of non-cancer antibodies to watch in 2016. Bococizumab, which targets PCSK9, is undergoing evaluation in 8 Phase 3 studies listed on clinicaltrials.gov as recruiting or active, not recruiting patients, as of midNovember 2015. Six Phase 3 studies of patients with hyperlipidemia have estimated primary completion dates in late 2015 or during 2016. In chronological order of the estimated primary completion dates, these are the SPIRE-SI (NCT02135029), SPIRE-AI (NCT02458287), SPIRE-FH (NCT01968980), SPIRE-HR (NCT01968954), SPIRE-LDL (NCT01968967), and SPIRE-LL (NCT02100514) studies, which have estimated primary completion dates of November 2015, February 2016, April 2016, April 2016, July 2016 and July 2016, respectively. Results of a Phase 2 clinical study indicated that bococizumab significantly reduced LDLC, and regimens of 150 mg every 14 d and 300 mg every 28 d were the most efficacious.10 The efficacy and safety of 150 mg bococizumab administered every 14 d is being evaluated in the Phase 3 studies. LY2951742, which targets calcitonin gene-related peptide, is undergoing evaluation in 2 Phase 3 studies. The efficacy and safety of LY2951742 in patients with episodic cluster headaches is being evaluated in the Phase 3 NCT02397473 study. Patients with chronic cluster headache are being recruited for the Phase 3 NCT02438826 study. The primary outcome measure for both studies is the mean change from baseline in the number of weekly cluster headache attacks; the estimated primary completion dates for the 2 studies are May and August 2016, respectively. Roledumab targets the human RhD antigen on RhD-positive circulating red blood cells. The mAb is being evaluated for the prevention of hemolytic disease of the fetus or newborn, which can occur when maternal anti-RhD antibodies are produced and pass through the placenta during pregnancy. Because it is manufactured in the rat cell line YB2/0, roledumab has low fucose content, and thus high ADCC activity. The Phase 2/3 NCT02287896 study is assessing: 1) the pharmacokinetic profile of roledumab in RhD-negative pregnant women carrying an RhD-positive fetus, 2) the safety of roledumab in RhD-negative pregnant women and in RhD-positive fetus and newborns, 3) the efficacy of 300 mg roledumab administered intramuscularly and intravenously to prevent RhD alloimmunization in RhD-negative pregnant women carrying an RhD-positive fetus, and 4) the immunogenicity of roledumab. The estimated primary completion date of the study is December 2016. Romosozumab targets sclerostin, an osteocyte-derived inhibitor of osteoblast activity, and thereby increases bone formation. The efficacy and safety of romosozumab are being evaluated in 2 Phase 3 studies with estimated primary completion dates in 2016. The Phase 3 BRIDGE (NCT02186171) and FRAME (NCT01575834) studies are comparing the effects of romosozumab with placebo in men and
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postmenopausal women with osteoporosis, respectively. The estimated primary completion dates of the 2 studies are June and December 2016, respectively.
Outlook for 2016 and beyond As evidenced by the antibody therapeutics discussed here, the biopharmaceutical industry has a highly active late-stage pipeline that may deliver numerous products to the global market in the near future. A total of 53 antibody therapeutics currently in Phase 3 studies were included here, but more are due to enter Phase 3 studies very soon. For example, Phase 3 studies of BI51655066, a human IgG1 mAb that targets the IL-23 p19 subunit,11 are in preparation. Continuing the tradition established in 2009,2 mAbs will track the progress of antibody therapeutics in clinical development and regulatory review during 2016, and updated information will be reported in the next installment of the "Antibodies to watch" series.
Note on updates This note was added in proof to update readers on transitions that occurred between mid-November 2015, when this paper was written, and December 31, 2015. Updates regarding the novel antibody therapeutics first approved in 2015 in the EU or US A total of 9 antibody therapeutics were first approved in 2015 in the EU or US: all 7 antibodies listed in Table 1; elotuzumab (EmplicitiÒ ), an anti-SLAMF7 humanized IgG1, first approved in the US on November 30, 2015 as a treatment for multiple myeloma; and necitumumab (PortrazzaÒ ), an anti-EGFR human IgG1 first approved in the US on November 24, 2015 for non-small cell lung cancer. Updates regarding antibody therapeutics in first regulatory review in the EU or US A total of 7 antibody therapeutics were in a first regulatory review in the EU or US as of the end of 2015: 5 antibody therapeutics listed in Table 2 (brodalumab, ixekizumab, reslizumab, begelomab, obiltoxaximab); sarilumab, an anti-IL6 receptor human IgG1 evaluated in Phase 3 studies as a treatment for rheumatoid arthritis; and bezlotoxumab, an antiClostridium difficile enterotoxin B human IgG1 evaluated in Phase 3 studies for the prevention of Clostridium difficile infection recurrence.
Disclaimer This article discusses information collected from the public domain. Reichert Biotechnology Consulting LLC makes no representation or warranties with respect to the accuracy, completeness, or timeliness of the information contained herein, and specifically disclaims any implied warranties of fitness for a particular purpose.
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Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References 1. Reichert JM. Antibodies to watch in 2015. MAbs 2015; 7:1-8; PMID:25484055; http://dx.doi.org/10.4161/19420862.2015.988944. 2. Reichert JM. Antibodies to watch in 2010. MAbs 2010; 2:84-100; PMID:20065640; http://dx.doi.org/10.4161/mabs.2.1.10677. 3. Reichert JM. Marketed therapeutic antibodies compendium. MAbs 2012; 4:413-5; PMID:22531442; http://dx.doi.org/10.4161/ mabs.19931. 4. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, et al. ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373:621-31; PMID:26035255; http://dx.doi.org/10.1056/NEJMoa1505654. 5. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, Papp K, Spelman L, Toth D, Kerdel F, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 2015; 373:1318-28; PMID:26422722; http://dx.doi.org/ 10.1056/NEJMoa1503824. 6. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, Cameron GS, Erickson J, Zhang L, Secrest RJ, et al. UNCOVER-2 and UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; 386:541-51; PMID:26072109; http://dx.doi.org/10.1016/ S0140-6736(15)60125-8.
7. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O’Brien C, Korn S. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3:355-366; PMID:25736990; http://dx.doi.org/10.1016/S22132600(15)00042-9. 8. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and Inadequate response to methotrexate: Results of a Phase III study. Arthritis Rheumatol 2015; 67:1424-37; PMID:25733246; http://dx.doi.org/10.1002/art.39093. 9. Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, Shen YK, Szapary P, Randazzo B, Reich K. A Phase 2 trial of guselkumab vs. adalimumab for plaque psoriasis. N Engl J Med 2015; 373:136-144; PMID:26154787; http://dx.doi.org/10.1056/ NEJMoa1501646. 10. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, Sweeney K, Kaila N, Vincent J, Bays H. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol 2015; 115:1212-21; PMID:25784512; http://dx.doi.org/10.1016/j.amjcard. 2015.02.006. 11. Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, Lalovic B, Aslanyan S, Wang EE, Hall D, Solinger A, Padula S, Scholl P. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2015; 136:116-124; PMID:25769911; http://dx.doi.org/10.1016/j.jaci.2015.01.018.
PERSPECTIVE
Antibodies to watch in 2016 Janice M. Reichert Managing Director, Reichert Biotechnology Consulting LLC, Framingham, MA, 01701
ABSTRACT
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (PraluentÒ ), evolocumab (RepathaÒ ), daratumumab (DarzalexÒ ), dinutuximab (UnituxinÒ ), idarucizumab (PraxbindÒ ), mepolizumab (NucalaÒ )) granted first approvals as of mid-November. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016. Commercial late-stage antibody therapeutics development exceeded expectations by increasing from 39 candidates in Phase 3 studies as of late 2014 to 53 as of late 2015. Of the 53 candidates, transitions to regulatory review by the end of 2016 are projected for 8 (atezolizumab, benralizumab, bimagrumab, durvalumab, inotuzumab ozogamicin, lebrikizumab, ocrelizumab, tremelimumab). Other "antibodies to watch" include 15 candidates (bavituximab, bococizumab, dupilumab, fasinumab, fulranumab, gevokizumab, guselkumab, ibalizumab, LY2951742, onartuzumab, REGN2222, roledumab, romosozumab, sirukumab, Xilonix) undergoing evaluation in Phase 3 studies that have estimated primary completion dates in 2016. As evidenced by the antibody therapeutics discussed in this perspective, the biopharmaceutical industry has a highly active late-stage clinical pipeline that may deliver numerous new products to the global market in the near future. See Note added in proof for updates through December 31, 2015.
ARTICLE HISTORY
Received 24 November 2015 Accepted 24 November 2015 KEYWORDS
Antibody therapeutics; clinical studies; drug development; European Medicines Agency; Food and Drug Administration
Abbreviations: ALL, acute lymphoblastic leukemia; CD, cluster of differentiation; EGFR, epidermal growth factor
receptor; EMA, European Medicines Agency; EU, European Union; FDA, US Food and Drug Administration; HIV, human immunodeficiency virus; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; NSCLC, non–small cell lung cancer; PCSK9, proprotein convertase subtilisin kexin type 9; PD-L1, programmed cell death ligand 1; RSV, respiratory syncytial virus; SLAM, signaling lymphocyte activation molecule; sIBM, sporadic inclusion body myositis; US, United States
In terms of the number of drugs in late-stage clinical development, monoclonal antibody (mAb) therapeutics development by the biopharmaceutical industry in 2015 has far exceeded expectations. As of mid-November 2015, 53 novel antibody therapeutics were in Phase 3 studies, which is a 36% and 104% increase compared to the number in Phase 3 studies in late 2014 and 2009, respectively.1,2 For the long-term, the prospects appear bright for the continued transition of molecules into Phase 3 from early-stage clinical studies, based on the fact that ~210 novel antibody therapeutics are in each of the 2 early phases of clinical development. Now totaling over 470 molcules, the commercial clinical pipeline of antibody therapeutics is thus quite robust. The recent increase in late-stage clinical development has led to an increase in the number of antibody therapeutics that enter regulatory review and receive marketing approvals. Based on information available as of mid-November 2015, the annual number of first approvals of antibody therapeutics is expected to be in the range of 5–8 in 2014, 2015 and 2016. If expectations are met, this outcome would be unprecedented because a year in which the number of first approvals is high (4–6 approvals)
CONTACT Janice M. Reichert © 2016 Taylor & Francis Group, LLC
[email protected]
has historically been followed by 4 or more years when the number is low (0–3 approvals).3 As of mid-November, 6 novel antibody therapeutics (alirocumab (PraluentÒ ), evolocumab (RepathaÒ ), idarucizumab (PraxbindÒ ), dinutuximab (UnituxinÒ ), mepolizumab (NucalaÒ ), daratumumab (DarzalexÒ )) were granted first marketing approvals during 2015; the approvals were granted in either the European Union (EU) or the US (Table 1; see Note added in proof for updates through December 31, 2015.). Secukinumab, which targets interleukin (IL)-17a, also received marketing approvals for treatment of psoriasis in these regions in 2015, but the product was first approved in Japan in late 2014. Both alirocumab and evolocumab target proprotein convertase subtilisin kexin type 9 (PCSK9) and inhibit its function, which ultimately leads to a reduction in levels of low-density lipoprotein cholesterol. Idarucizumab targets dabigatran and reverses the effects of this anticoagulant agent. The anti-GD2 antibody dinutuximab was approved for pediatric neuroblastoma. Mepolizumab, which targets IL-5, was approved in the US for use with other asthma medicines for the maintenance treatment of asthma in patients who are age 12 y and older. Anti-CD38 daratumumab was granted accelerated approval in the US to treat
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Table 1. Novel antibody therapeutics first approved in 2015 in the EU or US. INN
Brand name
Daratumumab Mepolizumab Alirocumab Evolocumab Dinutuximab Idarucizumab Secukinumab
Darzalex Nucala Praluent Repatha Unituxin Praxbind Cosentyx
Target; Molecular format
Indication
CD38; Human IgG1 IL-5; Humanized IgG1 PCSK9; Human IgG1 PCSK9; Human IgG2 GD2; Chimeric IgG1 Dabigatran; Humanized Fab IL-17a; Human IgG1
Multiple myeloma Severe eosinophilic asthma High cholesterol High cholesterol Neuroblastoma Reversal of dabigatran-induced anticoagulation Psoriasis
Status in EU
Status in US
In review Approved Approved Approved Approved Approved Approved
Approved Approved Approved Approved Approved Approved Approved
Note: Secukinumab was approved in Japan in December 2014. Abbreviations: EU, European Union; GD, glycolipid disialoganglioside; IL, interleukin; INN, international non-proprietary name; PCSK9, proprotein convertase subtilisin kexin type 9; US, United States.
patients with multiple myeloma who have received at least 3 prior treatments. Daratumumab is the first mAb approved for treating this disease. A marketing application for daratumumab for multiple myeloma was submitted to the European Medicines Agency (EMA) in September 2015. The focus of this perspective is on the late-stage clinical development and approval of antibody therapeutics in the pipelines of biopharmaceutical companies. In the following sections, regulatory actions and marketing application submissions for antibody therapeutics that may occur in late 2015 or during 2016, as well as relevant Phase 3 studies with estimated primary completion dates in this period, are discussed. Due to the copious literature on the antibodies, references are limited to clinical study results published in 2015.
Regulatory actions: Projections for December 2015 through 2016 Regulatory actions are expected either in December 2015 or in 2016 for at least 7 antibody therapeutics (Table 2; see Note added in proof for updates through December 31, 2015.). Marketing applications for necitumumab, which targets epidermal growth factor receptor, were submitted to regulatory authorities in 2014. Data from the Phase 3 SQUIRE study of necitumumab were reviewed in July 2015 by the US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee. The majority of the panel members agreed that the benefits of adding necitumumab to gemcitabine and cisplatin for patients with squamous non–small cell lung cancer (NSCLC) outweighed the risks. The FDA is expected to make a decision on the marketing application for necitumumab by the end of 2015.
Elotuzumab is undergoing regulatory review as a treatment for multiple myeloma. Marketing applications for elotuzumab were validated for review by EMA and the FDA in July and September 2015, respectively. EMA granted the marketing authorization application submitted to them an accelerated assessment, and the FDA gave priority review designation to the biologics license application (BLA) submitted to them. Elotuzumab, which was granted breakthrough therapy designation by FDA, is a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody for the treatment of multiple myeloma as combination therapy in patients who have received one or more prior therapies. Recently published results from the Phase 3 ELOQUENT-2 study (NCT01239797) indicated that patients with relapsed or refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone had a significant relative reduction in the risk of disease progression or death.4 Brodalumab and ixekizumab, which are antibody therapeutics that interfere with the biological activity of the proinflammatory cytokine IL-17A, are undergoing regulatory review as treatments for psoriasis. Brodalumab targets the IL-17 receptor while ixekizumab targets the IL-17A ligand. An application for marketing approval of brodalumab was submitted to Japan’s Ministry of Health, Labor and Welfare in July 2015. Brodalumab was developed for plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. In the Phase 3 AMAGINE-2 and AMAGINE-3 studies (NCT01708603 and NCT01708629, respectively), treatment with brodalumab resulted in significant clinical improvements in patients with moderate to severe psoriasis.5 In 2 Phase 3 studies of ixekizumab (UNCOVER-2 and UNCOVER-3, NCT01597245 and NCT01646177,
Table 2. Antibody therapeutics in first regulatory review in the EU or US. INN
Brand name
Necitumumab Elotuzumab Brodalumab Ixekizumab Reslizumab Begelomab Obiltoxaximab
(Pending) Empliciti (Pending) (Pending) (Pending) BEGEDINA Anthim
Target; Molecular format
Indication
EGFR; Human IgG1 SLAMF7; Humanized IgG1 IL-17R; Human IgG2 IL-17a; Humanized IgG4 IL-5; Humanized IgG4 CD26; Murine IgG2b Protective antigen of B. anthracis exotoxin; Chimeric IgG1
Non-small cell lung cancer Multiple myeloma Psoriasis Psoriasis Asthma Graft-vs-host disease Prevention of inhalational anthrax
Location of review EU, US EU, US EU EU EU, US EU US
Abbreviations: CD, cluster of differentiation; EGFR, epidermal growth factor receptor; EU, European Union; IL, interleukin; INN, international non-proprietary name; SLAM, signaling lymphocyte activation molecule; US, United States.
MABS
respectively), participants were randomly assigned to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks or every 4 weeks after a 160 mg starting dose. Both ixekizumab dose regimens were shown to have greater efficacy than placebo and etanercept over 12 weeks in these studies.6 As of June 2015, ixekizumab was undergoing evaluation at EMA. Reslizumab targets IL-5, a cytokine involved in the maturation, recruitment, and activation of eosinophils, which mediate diseases such as asthma. Results from 2 Phase 3 studies (NCT01287039, NCT01285323) support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroidbased therapy.7 As of June 2015, a BLA for reslizumab had been accepted by the FDA for standard review. FDA’s Pulmonary-Allergy Drugs Advisory Committee is scheduled to discuss the BLA for reslizumab in December 2015, and a regulatory action is expected in March 2016. A marketing application for reslizumab as a treatment for inadequately controlled asthma in adult patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen, was submitted to EMA in July 2015, and EMA’s opinion on reslizumab is anticipated in the second half of 2016. Begelomab, which targets CD26 on CD4+ T lymphocytes, is undergoing evaluation by EMA as an orphan medicinal product for treatment of steroid resistant acute graft-versus-host disease in adult patients who underwent allogeneic haematopoietic progenitor cell transplantation and received a standard immunosuppressive regimen. A prospective Phase 2/3 study (NCT02411084) to compare begelomab vs. conventional treatment for treating steroid-resistant acute graft-versus host disease is due to start recruiting patients in January 2016. Obiltoxaximab was developed for the treatment and prevention of inhalational anthrax. The chimeric antibody was granted Fast Track and orphan drug designations by the FDA; a BLA was submitted in March 2015. Efficacy data
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was derived from animal models of inhalational anthrax and safety data from healthy human volunteers receiving the proposed human therapeutic dose of obiltoxaximab administered either intravenously or intramuscularly. The product is intended to serve as an anthrax biowarfare countermeasure.
Marketing application submissions: Projections for late 2015 through 2016 Two antibodies, bezlotoxumab and sarilumab, may transition into regulatory review by the end of 2015, with an additional 8 following during 2016. Bezlotoxumab, which targets Clostridium difficile enterotoxin B, is being developed for the prevention of recurrent Clostridium difficile infection. The primary efficacy endpoint, reduction in C. difficile recurrence through week 12 compared to placebo when used in conjunction with standard of care antibiotics for the treatment of C. difficile, was met in the Phase 3 MODIFY I and MODIFY II studies (NCT01241552 and NCT01513239, respectively) of bezlotoxumab. Submission of marketing applications to regulatory agencies in the EU, US and Canada is planned by the end of 2015. Sarilumab targets the IL-6 receptor, thereby blocking IL-6 from binding to the receptor and interrupting cytokine-mediated inflammatory signaling. In the Phase 3 MOBILITY study (NCT01061736), significant improvements in symptomatic, functional, and radiographic outcomes were observed in rheumatoid arthritis patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX.8 Nine additional Phase 3 studies of sarilumab for rheumatoid arthritis are either completed or active and not recruiting patients. Submission of a marketing application to the FDA is planned by the end of 2015. Four antibody therapeutics (atezolizumab, durvalumab, tremelimumab, inotuzumab ozogamicin) now in Phase 3 studies for cancer (Table 3) may transition to a first regulatory
Table 3. Antibody therapeutics in Phase 2/3 or Phase 3 clinical studies of cancer indications. Primary sponsoring company
INN or code name
Pfizer Viventia Bio MacroGenics Merrimack Pharmaceuticals
Inotuzumab ozogamicin Oportuzumab monatox Margetuximab MM-302
Molecular format
Target
Most advanced phase Phase 3 indication(s)
CD22 EpCAM HER2 HER2
Phase 3 Phase 3 Phase 3 Phase 2/3
Acute lymphoblastic leukemia Bladder cancer Breast cancer Breast cancer
TG Therapeutics XBiotech, Inc. AstraZeneca/ MedImmune Daiichi Sankyo Genentech Peregrine Pharmaceuticals Recombio SL EMD Serono Genentech
Humanized IgG4 ADC Humanized scFv immunotoxin Chimeric IgG1 scFv-targeted liposome containing doxorubicin Ublituximab Chimeric IgG1 Xilonix Human IgG1 Moxetumomab pasudotox Murine IgG1 dsFv immunotoxin Patritumab Human IgG1 Onartuzumab Humanized IgG1 Fab-Fc Bavituximab Chimeric IgG1 Racotumomab Murine IgG1 Avelumab Human IgG1 Atezolizumab Humanized IgG1
CD20 IL-1 a CD22 HER3 cMet Phosphatidylserine GM3 PD-L1 PD-L1
Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3
AstraZeneca/ MedImmune AstraZeneca/ MedImmune Immunomedics, Inc. Gilead Sciences
Durvalumab (MEDI-4736) Tremelimumab Clivatuzumab tetraxetan GS-5745
PD-L1 CTLA4 MUC5AC MMP9
Phase 3 Phase 3 Phase 3 Phase 3
Chronic lymphocyticleukemia Colorectal cancer Hairy cell leukemia NSCLC NSCLC NSCLC NSCLC NSCLC NSCLC, bladder cancer, renal cell carcinoma, breast cancer NSCLC, head and neck cancer NSCLC, head and neck cancer Pancreatic cancer Gastric cancer or gastroesophageal junction adenocarcinoma
Human IgG1 Human IgG2 Humanized IgG1 Humanized IgG4
Data available as of November 16, 2015. Abbreviations: ADC, antibody-drug conjugate; CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated protein; EpCAM, epithelial cellular adhesion molecule; GM, monosialodihexosylganglioside; HER, human epidermal growth factor receptor; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; MM, matrix metallopeptidase; MUC, mucin; NSCLC, non-small cell lung cancer; PD, programmed death.
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Table 4. Antibody therapeutics in Phase 2/3 or Phase 3 clinical studies of non-cancer indications. Primary sponsoring company
INN or code name
Ablynx
Caplacizumab
Pfizer ProthenaTherapeutics Ltd. LFB Group Janssen Research and Development, LLC Merck Sharp andDohme Corp Janssen Research and Development, LLC Chugai Pharmaceuticals/ Roche AstraZeneca/MedImmune Genentech AstraZeneca/MedImmune RegeneronPharmaceuticals AstraZeneca/MedImmune
Molecular format
Target
Most advanced phase
Phase 3 indication(s)
von Willebrand factor
Phase 3
Acquired thromboticthrombocytopenicpurpura
Bococizumab NEOD001 Roledumab Guselkumab
Humanized nanobody Humanized IgG2 Humanized IgG1 Human IgG1 Human IgG1
PCSK9 Amyloid Rhesus D IL-23 p19 subunit
Phase 3 Phase 3 Phase 2/3 Phase 3
High cholesterol Primary systemicamyloidosis Rh disease Psoriasis
Tildrakizumab Sirukumab
Humanized IgG1 Human IgG1
IL-23 p19 subunit IL-6
Phase 3 Phase 3
Psoriasis Rheumatoid arthritis, giant cell arteritis
Emicizumab
Factor IXa, Factor X
Phase 3
Hemophilia A
Benralizumab Lebrikizumab Tralokinumab Dupilumab Inebilizumab
Humanized bispecific IgG4 Humanized IgG1 Humanized IgG4 Human IgG4 Human IgG4 Humanized IgG1
IL-5 receptor IL-13 IL-13 IL-4 receptor a CD19
Phase 3 Phase 3 Phase 3 Phase 3 Phase 2/3
Chugai Pharmaceuticals/ Roche Xoma AstraZeneca/ MedImmune
SA237
Humanized IgG2
IL-6 receptor
Phase 3
Gevokizumab Anifrolumab
Humanized IgG2 Human IgG1
Phase 3 Phase 3
UCB, Inc. Genentech
Epratuzumab Etrolizumab
Humanized IgG1 Humanized IgG1
Phase 3 Phase 3
Systemic lupus erythematosus Ulcerative colitis, Crohn’s disease
Genentech Novartis Pharmaceuticals Corp. TaiMed Biologics Inc. CytoDyn Regeneron Ultragenyx Pharmaceutical; Kyowa Hakko Kirin Co. Biogen Eli Lilly & Company Hoffmann-La Roche Eli Lilly & Company Alder Biopharma. Amgen Pfizer; Eli Lilly & Company
Ocrelizumab Bimagrumab
Humanized IgG1 Human IgG1
Phase 3 Phase 2/3
Multiple sclerosis Sporadic inclusion body myositis
Ibalizumab PRO-140, PA14 REGN2222 KRN23
Humanized IgG4 Humanized IgG4 Human IgG1 Human IgG1
Phase 3 Phase 2/3 Phase 3 Phase 3
HIV infection HIV infection RSV infection prevention X-linked hypophosphatemia
Aducanumab Solanezumab Gantenerumab LY2951742 ALD403 AMG 334 Tanezumab
Human IgG1 Humanized IgG1 Human IgG1 Humanized IgG4 Humanized IgG1 Human IgG2 Humanized IgG2
IL-1 b IF a, b, omega receptor 1 CD22 Alpha4-beta7/ alphaE-beta7 integrin receptor CD20 Activin A receptor type IIB CD4 CCR5 RSV F protein Fibroblast growth factor 23 Amyloid b Amyloid b Amyloid b CGRP CGRP CGRP receptor Nerve growth factor
Asthma, chronic obstructive pulmonary disease Asthma Asthma Atopic dermatitis, asthma Neuromyelitis optica and neuromyelitis optica spectrum disorders Neuromyelitis optica and neuromyelitis optica spectrum disorders Pyodermagangrenosum Systemic lupus erythematosus
Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3 Phase 3
Fasinumab Fulranumab
Human IgG4 Human IgG2
Nerve growth factor Nerve growth factor
Phase 2/3 Phase 3
Alzheimer disease Alzheimer disease Alzheimer disease Chronic or episodic cluster headache Episodic migraine prevention Migraine prevention Chronic low back pain, cancer pain due to bone metastasis Pain due to osteoarthritis of knee or hip Pain due to osteoarthritis of knee or hip
Lampalizumab Brolucizumab
Humanized IgG1 Fab Humanized scFv
Complement factor D VEGF-A
Phase 3 Phase 3
Geographic atrophy Neovascular age-related maculardegeneration
Romosozumab
Humanized IgG2
Sclerostin
Phase 3
Osteoporosis
Regeneron Pharmaceuticals Janssen Research and Development, LLC Genentech Novartis Pharmaceuticals Corp. UCB, Amgen
Abbreviations: CD, cluster of differentiation; CGRP, Calcitonin gene-related peptide; Fab, antigen-binding fragment; HIV, human immunodeficiency virus; Ig, immunoglobulin; IL, interleukin; INN, international non-proprietary name; PCSK9, proprotein convertase subtilisin kexin type 9; RSV, respiratory syncytial virus; scFv, single-chain variable fragment; VEGF, vascular endothelial growth factor.
review in 2016. Both atezolizumab and durvalumab target programmed cell death ligand 1 (PD-L1) expressed on tumor cells and tumor-infiltrating immune cells, thereby preventing it from binding to PD-1 and B7.1 on the surface of T cells. By interfering with an immune checkpoint, these mAbs may enable the activation of T cells. As of November 2015, atezolizumab is being evaluated in at least 10 Phase 3 studies (6 in NSCLC, 2 in bladder cancer, 1 in breast cancer, 1 in renal cell carcinoma). Of these studies, only the OAK study (NCT02008227), a Phase 3 study of atezolizumab compared to docetaxel in patients with locally advanced or metastatic NSCLC who failed platinum therapy, is active but not recruiting participants. Atezolizumab, which was engineered so that it
does not induce either antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity, has received 2 breakthrough therapy designations from the FDA: 1) for the treatment of patients whose NSCLC expresses PD-L1 and whose disease worsened during or after standard treatments, and 2) for patients whose metastatic bladder cancer expresses PD-L1. Submission of a marketing application for atezolizumab is planned in 2016. Durvalumab is being studied alone and in combination with another immune checkpoint inhibitor, tremelimumab, which targets cytotoxic T-lymphocyte-associated protein 4 (also known as CD152). As of November 2015, Phase 3 studies evaluating durvalumab or the combination of durvalumab and
MABS
tremelimumab in NSCLC, including the PACIFIC (NCT02125461), ATLANTIC (NCT02087423), ARCTIC (NCT02352948), MYSTIC (NCT02453282) and NEPTUNE (NCT02542293) trials, and in squamous cell carcinoma of the head and neck were recruiting patients. Three additional Phase 3 studies were not yet recruiting patients. In April 2015, tremelimumab was granted US orphan drug designation for the treatment of malignant mesothelioma. Submission of marketing applications for durvalumab and tremelimumab may occur by the end of 2016. Inotuzumab ozogamicin, an antibody-drug conjugate that targets CD22, is being evaluated in the Phase 3 INO-VATE ALL trial, which compares inotuzumab ozogamicin to standard of care chemotherapy in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). Topline results from the trial announced in April 2015 indicated that one of the 2 primary endpoints, complete hematologic remission rate, was met. As of November 2015, data on the second endpoint, overall survival, had not yet been released. Inotuzumab ozogamicin received FDA’s breakthrough therapy designation for ALL in October 2015. Submission of a marketing application for inotuzumab ozogamicin may occur by the end of 2016. Four antibody therapeutics (bimagrumab, ocrelizumab, benralizumab, lebrikizumab) that are now in Phase 3 studies for diseases other than cancer (Table 4) may transition to first regulatory review by the end of 2016. Bimagrumab targets activin A receptor type IIB and is undergoing evaluation in Phase 3 studies of patients with sporadic inclusion body myositis (sIBM), a rare and potentially life-threatening muscle-wasting condition. FDA granted breakthrough therapy designation to bimagrumab for sIBM in August 2013. The Phase 3 RESILIENT study (NCT01925209) is evaluating the efficacy, safety and tolerability of bimagrumab at 52 weeks on the physical function, muscle strength and mobility of sIBM patients. The estimated primary completion date of the study is December 2015; positive results may allow the submission of a marketing application by the end of 2016. The anti-CD20 antibody therapeutic ocrelizumab showed superiority to interferon b-1a in 2 identical Phase 3 studies (OPERA I and OPERA II, NCT01247324 and NCT01412333, respectively) in patients with relapsing multiple sclerosis (MS). Ocrelizumab also significantly reduced the risk of progression of clinical disability sustained for at least 12 weeks by 24 percent compared with placebo in patients with primary progressive MS in the Phase 3 ORATORIO study (NCT01194570). Marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS will be pursued, and data from the ocrelizumab OPERA I and OPERA II studies and from the ORATORIO study may be submitted to the FDA in early 2016. Benralizumab and lebrikizumab are in Phase 3 studies of patients with asthma. Benralizumab targets IL-5 receptor a chain expressed on eosinophils and basophils, and induces apoptosis via ADCC. This antibody therapeutic is undergoing evaluation in 7 Phase 3 studies of patients with asthma, as well as 2 Phase 3 studies of patients with moderate to very severe chronic obstructive pulmonary disease. Phase 3 study results for benralizumab in severe asthma are expected in 2016; regulatory submissions may occur later that year. Lebrikizumab targets IL13
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and, as of November 2015, it is undergoing evaluation in 4 Phase 3 studies of asthma patients. The estimated primary completion date of the Phase 3 NCT02104674 study evaluating the efficacy and safety of lebrikizumab in adult patients with mild to moderate asthma is January 2016; positive results may allow the submission of a marketing application by the end of 2016.
Phase 3 studies with completion dates in late 2015 or in 2016: Cancer indications Of the 17 antibody therapeutics being evaluated in Phase 3 clinical studies of patients with cancer (Table 3), 3 (bavituximab, Xilonix, onartuzumab) are in studies that have estimated primary completion dates in late 2015 or in 2016. The anti-phosphatidyserine antibody bavituximab plus docetaxel is being compared to docetaxel alone in patients with previously treated stage IIIb/IV non-squamous NSCLC in the Phase 3 SUNRISE study (NCT01999673). The estimated primary completion date for the study is December 2016. Bavituximab has been granted Fast Track designation by the FDA for the potential treatment of second-line NSCLC. The IL-1 a-targeted antibody Xilonix, also known as MABp1, is undergoing evaluation in 2 Phase 3 studies (NCT02138422 and NCT01767857) in patients with colorectal cancer. A variety of mechanisms of action for the antibody have been proposed, including interruption of signals that drive angiogenesis and invasiveness, blockade of tumor microenvironment infiltration by leukocytes that suppress antitumor immunity, and correction of metabolic dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central nervous system. The Phase 3 study NCT02138422 will assess how effectively Xilonix slows tumor growth, and whether it improves symptoms of muscle loss, fatigue, appetite loss, and pain in patients with colorectal cancer compared with placebo. The estimated completion date for the study is December 2015. The aim of the Phase 3 XCITE study (NCT01767857) is to determine if Xilonix can prolong the life of colorectal carcinoma patients who are refractory to standard therapy. The XCITE study’s estimated primary completion date is December 2016. Onartuzumab, which has a Fab-Fc format, targets the receptor tyrosine kinase cMet. The safety and efficacy of onartuzumab in combination with erlotinib as second- or third-line treatment is being compared to erlotinib alone in patients with incurable Met-positive NSCLC in the Phase 3 NCT02031744 study. This study’s estimated primary completion date is December 2016. The Phase 3 METLung study (NCT01456325) of the onartuzumab / erlotinib combination in NSCLC patients who had received standard chemotherapy for advanced/metastatic disease did not confirm efficacy results observed in a Phase 2 study.
Phase 3 studies with completion dates in 2016: Non-cancer indications Most (36/53; 68%) of novel antibody therapeutics currently in Phase 3 clinical studies are for non-cancer indications (Table 4). Phase 3 studies of 12 of these antibodies have estimated
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primary completion dates in late 2015 or in 2016: 4 (gevokizumab, dupilumab, sirukumab, guselkumab) are for immunemediated disorders, 2 (fasinumab, fulranumab) are for pain, 2 are for infectious diseases (REGN2222, ibalizumab), and 4 (bococizumab, LY2951742, roledumab, romosozumab) are for other disorders. The efficacy and safety of anti-IL-1 b gevokizumab in treating active ulcers of pyoderma gangrenosum are being evaluated in 2 Phase 3 studies (NCT02315417, NCT02326740). Pyoderma gangrenosum is a rare inflammatory skin condition that leads to formation of deep, painful ulcers. In 2014, FDA granted gevokizumab an orphan drug designation for this disease. Dupilumab, which targets the IL-4 receptor, is being evaluated as monotherapy in adults with moderate to severe atopic dermatitis in 4 Phase 3 clinical studies with estimated primary completion dates in the late 2015 to 2016 period: SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), SOLO-Continue (NCT02395133) and NCT02260986. The estimated primary completion date for SOLO 1, SOLO 2 and NCT02260986 is November 2015, and the estimated primary completion date for SOLO-Continue is July 2016. The mAb received breakthrough therapy designation from the FDA for use in patients with moderate to severe atopic dermatitis who are insufficiently responsive to or cannot use topical prescription treatments. Dupilumab is also in Phase 3 studies of patients with asthma, but the earliest estimated primary completion date for any of these studies is August 2017. Anti-IL-6 sirukumab has been or is being evaluated as a treatment for rheumatoid arthritis in 5 Phase 3 studies; 3 of these studies have estimated primary completion dates in late 2015 or in 2016. The objective of the Phase 3 NCT02019472 study, which has estimated primary completion and study completion dates in October 2015 and August 2016, respectively, is to investigate the efficacy of sirukumab monotherapy compared with adalimumab monotherapy in biologic na€ıve patients with active rheumatoid arthritis who are intolerant to methotrexate, who are considered inappropriate for treatment with methotrexate or who are inadequate responders to methotrexate. The Phase 3 SIRROUND-T study (NCT01606761), which has estimated primary completion and study completion dates in December 2015 and April 2016, respectively, is assessing the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis in patients with active rheumatoid arthritis who are unresponsive or intolerant to treatment with anti-tumor necrosis factor agents. The Phase 3 SIRROUND-D study (NCT01604343) is assessing the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis and inhibition of radiographic progression in patients with active RA who are unresponsive to treatment with disease-modifying anti-rheumatic drugs; this study’s estimated primary completion date is July 2016. Guselkumab, which targets the IL-23 p19 subunit, is being evaluated as a treatment for psoriasis in 3 Phase 3 studies with estimated primary completion dates in late 2015 or in 2016. Results of the 52-week, Phase 2 X-PLORE study (NCT01483599) in which guselkumab was compared with
adalimumab in patients with moderate to severe plaque psoriasis suggested that guselkumab may be an effective therapy for plaque psoriasis.9 The Phase 3 NCT02207231 study is an active comparator-controlled study evaluating the efficacy and safety of guselkumab in the treatment of patients with moderate to severe plaque-type psoriasis. The active comparator is adalimumab, and the estimated primary completion and study completion dates are October 2015 and June 2016, respectively. The efficacy and safety of guselkumab is being compared with that of adalimumab for the treatment of patients with moderate to severe plaque-type psoriasis with randomized withdrawal and retreatment in the Phase 3 VOYAGE 2 (NCT02207244) study, which has estimated primary completion and study completion dates in May 2016. The Phase 3 NAVIGATE study (NCT02203032), which has an estimated primary completion date in August 2016, is evaluating guselkumab’s efficacy and efficacy in patients with moderate to severe plaque-type psoriasis and an inadequate response to ustekinumab. Two mAb therapeutics that target nerve growth factor, fasinumab (REGN475) and fulranumab, are being evaluated in Phase 2/3 or Phase 3 studies with estimated primary completion dates in 2016. The effectiveness of fasinumab is being compared to placebo in patients with pain due to osteoarthritis of the knee or hip and a history of inadequate joint pain relief or intolerance to current analgesic therapy in the Phase 3 NCT02447276 study, which has an estimated primary completion date in March 2016. A total of 4 Phase 3 studies (NCT02289716, NCT02336698, NCT02336685, NCT02301234) of fulranumab as a treatment for pain due to osteoarthritis of the knee or hip have estimated primary completion dates in November 2016. Fulranumab is being assessed as monotherapy in the NCT02289716 and NCT02336698 studies, and as adjunctive therapy in the NCT02336685 and NCT02301234 studies. Two mAbs, REGN2222 and ibalizumab, are being studied for either the prevention or treatment of infectious diseases. The efficacy and safety of REGN2222, which targets the respiratory syncytial virus (RSV) F protein, for the prevention of medically attended RSV infection in preterm infants is being evaluated in the Phase 3 NCT02325791 study. In Part A of the study, the pharmacokinetics in pre-term infants will be determined to enable the selection of dosing regimens for Part B, which is designed to evaluate the efficacy, safety, and serum concentration of REGN2222, and the immunogenicity of intramuscular administration of REGN2222 in preterm infants for whom palivizumab is not recommended. The estimated primary completion date of the study is July 2016. Ibalizumab targets CD4, which is the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits viral entry. NCT02475629 is a Phase 3 study of ibalizumab plus an optimized background regimen in treatment-experienced patients infected with multi-drug resistant HIV-1. In this study, patients are administered a loading dose of 2000 mg intravenous ibalizumab on Day 7, followed by 800 mg intravenous ibalizumab once every 2 weeks, plus an optimized background regimen beginning on Day 14. The primary outcome measures are Day 14 viral
MABS
load reduction and proportion of patients achieving a >/D 0.5 log10 decrease from Day 7/baseline viral load. The estimated primary completion date of the study is October 2016. Ibalizumab was granted breakthrough therapy and orphan drug designations by the FDA. Bococizumab, LY2951742, roledumab and romosozumab complete the group of non-cancer antibodies to watch in 2016. Bococizumab, which targets PCSK9, is undergoing evaluation in 8 Phase 3 studies listed on clinicaltrials.gov as recruiting or active, not recruiting patients, as of midNovember 2015. Six Phase 3 studies of patients with hyperlipidemia have estimated primary completion dates in late 2015 or during 2016. In chronological order of the estimated primary completion dates, these are the SPIRE-SI (NCT02135029), SPIRE-AI (NCT02458287), SPIRE-FH (NCT01968980), SPIRE-HR (NCT01968954), SPIRE-LDL (NCT01968967), and SPIRE-LL (NCT02100514) studies, which have estimated primary completion dates of November 2015, February 2016, April 2016, April 2016, July 2016 and July 2016, respectively. Results of a Phase 2 clinical study indicated that bococizumab significantly reduced LDLC, and regimens of 150 mg every 14 d and 300 mg every 28 d were the most efficacious.10 The efficacy and safety of 150 mg bococizumab administered every 14 d is being evaluated in the Phase 3 studies. LY2951742, which targets calcitonin gene-related peptide, is undergoing evaluation in 2 Phase 3 studies. The efficacy and safety of LY2951742 in patients with episodic cluster headaches is being evaluated in the Phase 3 NCT02397473 study. Patients with chronic cluster headache are being recruited for the Phase 3 NCT02438826 study. The primary outcome measure for both studies is the mean change from baseline in the number of weekly cluster headache attacks; the estimated primary completion dates for the 2 studies are May and August 2016, respectively. Roledumab targets the human RhD antigen on RhD-positive circulating red blood cells. The mAb is being evaluated for the prevention of hemolytic disease of the fetus or newborn, which can occur when maternal anti-RhD antibodies are produced and pass through the placenta during pregnancy. Because it is manufactured in the rat cell line YB2/0, roledumab has low fucose content, and thus high ADCC activity. The Phase 2/3 NCT02287896 study is assessing: 1) the pharmacokinetic profile of roledumab in RhD-negative pregnant women carrying an RhD-positive fetus, 2) the safety of roledumab in RhD-negative pregnant women and in RhD-positive fetus and newborns, 3) the efficacy of 300 mg roledumab administered intramuscularly and intravenously to prevent RhD alloimmunization in RhD-negative pregnant women carrying an RhD-positive fetus, and 4) the immunogenicity of roledumab. The estimated primary completion date of the study is December 2016. Romosozumab targets sclerostin, an osteocyte-derived inhibitor of osteoblast activity, and thereby increases bone formation. The efficacy and safety of romosozumab are being evaluated in 2 Phase 3 studies with estimated primary completion dates in 2016. The Phase 3 BRIDGE (NCT02186171) and FRAME (NCT01575834) studies are comparing the effects of romosozumab with placebo in men and
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postmenopausal women with osteoporosis, respectively. The estimated primary completion dates of the 2 studies are June and December 2016, respectively.
Outlook for 2016 and beyond As evidenced by the antibody therapeutics discussed here, the biopharmaceutical industry has a highly active late-stage pipeline that may deliver numerous products to the global market in the near future. A total of 53 antibody therapeutics currently in Phase 3 studies were included here, but more are due to enter Phase 3 studies very soon. For example, Phase 3 studies of BI51655066, a human IgG1 mAb that targets the IL-23 p19 subunit,11 are in preparation. Continuing the tradition established in 2009,2 mAbs will track the progress of antibody therapeutics in clinical development and regulatory review during 2016, and updated information will be reported in the next installment of the "Antibodies to watch" series.
Note on updates This note was added in proof to update readers on transitions that occurred between mid-November 2015, when this paper was written, and December 31, 2015. Updates regarding the novel antibody therapeutics first approved in 2015 in the EU or US A total of 9 antibody therapeutics were first approved in 2015 in the EU or US: all 7 antibodies listed in Table 1; elotuzumab (EmplicitiÒ ), an anti-SLAMF7 humanized IgG1, first approved in the US on November 30, 2015 as a treatment for multiple myeloma; and necitumumab (PortrazzaÒ ), an anti-EGFR human IgG1 first approved in the US on November 24, 2015 for non-small cell lung cancer. Updates regarding antibody therapeutics in first regulatory review in the EU or US A total of 7 antibody therapeutics were in a first regulatory review in the EU or US as of the end of 2015: 5 antibody therapeutics listed in Table 2 (brodalumab, ixekizumab, reslizumab, begelomab, obiltoxaximab); sarilumab, an anti-IL6 receptor human IgG1 evaluated in Phase 3 studies as a treatment for rheumatoid arthritis; and bezlotoxumab, an antiClostridium difficile enterotoxin B human IgG1 evaluated in Phase 3 studies for the prevention of Clostridium difficile infection recurrence.
Disclaimer This article discusses information collected from the public domain. Reichert Biotechnology Consulting LLC makes no representation or warranties with respect to the accuracy, completeness, or timeliness of the information contained herein, and specifically disclaims any implied warranties of fitness for a particular purpose.
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Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
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