Antibodies to watch in 2016(2016抗体发展)

Full Terms & Conditions of access and use can be found at /action/journalInformation?journalCode=kmab20Download by: [Radcliffe Infirmary]Date:21 January 2016, At: 23:54mAbsISSN: 1942-0862 (Print) 1942-0870 (Online) Journal homepage: /loi/kmab20Antibodies to watch in 2016Janice M. Reichert PhDTo cite this article: Janice M. Reichert PhD (2015): Antibodies to watch in 2016, mAbs, DOI:10.1080/19420862.2015.1125583To link to this article:/10.1080/19420862.2015.1125583Accepted author version posted online: 14Dec 2015.Submit your article to this journalArticle views: 482View related articlesView Crossmark dataACCEPTED MANUSCRIPT1 Perspective“Perspective” article for publication in mAbs issue 8.2Antibodies to watch in 2016Janice M. ReichertJanice M. Reichert, PhD Managing Director, Reichert Biotechnology Consulting LLC, Framingham MA 01701 janice@ Received: 24 November 2015 Revised: N/A Accepted: 24 November 2015D o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT2 AbstractThe number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) 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 10 (atezolizumab, benralizumab, bezlotoxumab, bimagrumab, durvalumab, inotuzumab ozogamicin, lebrikizumab, ocrelizumab, sarilumab, 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 thisperspective, 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.Keywords: antibody therapeutics, drug development, clinical studies, Food and Drug Administration, European Medicines AgencyD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT3 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.D o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT4 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 molecules, 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 5-7 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) has historically been followed by 4 or more years when the number is low (0-3 approvals).3As of mid-November, 6 novel antibody therapeutics (alirocumab (Praluent®), evolocumab (Repatha®), idarucizumab (Praxbind®), dinutuximab (Unituxin®), mepolizumab (Nucala®), daratumumab (Darzalex®)) were granted first marketing approvals during 2015; the approvals were granted in either the European Union (EU) or the US (Table 1). 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. BothD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT5 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 years and older. Anti-CD38 daratumumab was granted accelerated approval in the US to treat patients with multiple myeloma who have received at least three 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 2016Regulatory actions are expected either in December 2015 or in 2016 for at least 7 antibody therapeutics (Table 2). Marketing applications for necitumumab, which targets epidermal growth factor receptor, were submitted to regulatory authorities in 2014. Data fromD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT6 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 diseaseprogression or death. 4Brodalumab and ixekizumab, which are antibody therapeutics that interfere with the biological activity of the pro-inflammatory 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 plaqueD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT7 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 two Phase 3 studies of ixekizumab (UNCOVER-2 and UNCOVER-3, NCT01597245 and NCT01646177, 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 two 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 corticosteroid-based 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. Amarketing 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-hostD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT8 disease in adult patients who underwent allogeneic hematopoietic progenitor cell transplantation and received a standard immunosuppressive regimen. A prospective Phase 2/3 study (NCT02411084) to compare begelomab versus 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 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 Of the 53 novel antibody therapeutics in Phase 3 clinical studies as of mid-November 2015 (Tables 3 and 4), 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, reductionin 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 PhaseD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016ACCEPTED MANUSCRIPT 9 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 may transition to a first regulatory 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 two breakthrough therapydesignations 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.D o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016Durvalumab 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 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 two 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 may transition to first regulatory review by the end of 2016. Bimagrumab targets activin A receptor type IIB and is undergoing evaluationD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016in 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 beta-1a in two 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 α 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 and, as of November 2015, it is undergoing evaluation in 4 Phase 3 studies of asthmaD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016patients. 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 indicationsOf 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 alpha-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 tumormicroenvironment 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 toD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016determine 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 primary completion dates in late 2015 or in 2016: 4 (gevokizumab, dupilumab, sirukumab, guselkumab) are for immune-mediated 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 beta 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.D o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016Dupilumab, 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; three 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 naïve patients with active rheumatoid arthritis who are intolerant tomethotrexate, 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 3D o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016SIRROUND-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 three 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 3NAVIGATE 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 inD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016patients 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 four 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 estimatedprimary 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 two weeks, plus an optimized background regimenD o w n l o a d e d b y [R a d c l i f f e I n f i r m a r y ] a t 23:54 21 J a n u a r y 2016。