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Update on antibody therapeutics in late-stage clinical studies

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Five monoclonal antibody (mAb) therapeutics have recently transitioned into late-stage clinical studies. Three (utomilumab, isatuximab, SHR-1210) are being evaluated as treatments for cancer, and the effects of two (crizanlizumab, olokizumab) are being studied in patients with other disorders.  Utomilumab (PF-05082566) is a human IgG2 antibody agonist that targets the extracellular domain of 4-1BB (CD137), which is a co-stimulatory receptor expressed on activated T cells. In preclinical studies, Fisher et al (1) demonstrated that utomilumab can activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a xenograft tumor model. Utomilumab is included in a multi-center, international, randomized, open label, 2-component (Phase 1b followed by Phase 3), parallel-arm study (Javelin DLBCL; NCT02951156) of avelumab in combination with various agents for the treatment of relapsed/refractory diffuse large B-cell lymphoma. The study includes a total of 5 arms (A: avelumab/utomilumab/rituximab; B: avelumab/utomilumab/azacitidine; C: avelumab/rituximab/bendamustine; D: selected regimen from Phase 1b component, which may be the agents investigated in study arms A or B or C; E: investigator’s choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). Progression-free survival is the primary outcome measure of the Phase 3 component of the study, which has an estimated primary completion date of February 2021.

Isatuximab (SAR650984), a humanized anti-CD38 IgG1 mAb, is undergoing evaluation in a Phase 3 randomized, open-label, multicenter study (ICARIA-MM; NCT02990338) comparing the mAb in combination with pomalidomide and low-dose dexamethasone vs. pomalidomide and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. Jiang et al (2) demonstrated that isatuximab utilizes multiple mechanisms of action in mediating multiple myeloma cell cytotoxicity, and that pomalidomide augments this cytotoxicity. Progression-free survival is the primary outcome measure of the Phase 3 study, which has an estimated primary completion date of May 2018.

SHR-1210 is a humanized IgG4 antibody targeting programmed death-1. A randomized controlled multi-center Phase 2/3 study (NCT02989922) to evaluate SHR-1210 in patients with advanced hepatocellular carcinoma who failed or intolerable to prior systemic treatment is currently recruiting patients. The study will assess whether SHR-1210 treatment improves objective response rate and overall survival compared with the standard of care. The estimated primary completion date of the study is December 2018.

Crizanlizumab (SEG101, SelG1) is a humanized IgG2 P-selectin (CD62) inhibitor undergoing evaluation for prevention or reduction of the occurrence of pain crises in patients with sickle cell disease. Results from the Phase 2 SUSTAIN study (NCT01895361) showed that crizanlizumab administered at 5.0 mg/kg intravenously 14 times over a period of 52 weeks reduced the median annual rate of sickle cell-related pain crises by 45.3% compared to placebo (1.63 vs 2.98, p=0.010) (3). The median time to the first crisis was significantly longer in patients who received crizanlizumab compared with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). Crizanlizumab is listed as in Phase 3, with a planned filing date of 2020, in the Novartis Annual Report 2016.

Olokizumab, an anti-interleukin-6 humanized IgG4 mAb (4), is undergoing evaluation in three Phase 3 studies evaluating two doses of olokizumab (64 mg subcutaneous every 2 or 4 weeks) in patients with rheumatoid arthritis (RA). The primary outcome measures are the ACR20 response at Week 14. The Phase 3 NCT02760368 study (CREDO 1) will determine how safe and effective olokizumab is compared to placebo in RA patients who are already receiving, but not fully responding to, treatment with methotrexate. The study’s estimated primary completion date is May 2018. In study NCT02760407 (CREDO 2), the effectiveness and safety of olokizumab is being compared to placebo and adalimumab in RA patients who are taking methotrexate but have active disease. The study’s estimated primary completion date is January 2019. In study NCT02760433 (CREDO 3), the effects of olokizumab are being compared to placebo in patients with RA who are already receiving, but not fully responding to treatment with a tumor necrosis factor inhibitor (CREDO 3). The study’s estimated primary completion date is February 2019. Olokizumab, formerly known as CDP-6038, is under development by R-Pharm under a worldwide exclusive license from UCB Pharma S.A.

The Antibody Society maintains comprehensive tables that list mAbs in late-stage clinical studies (i.e., pivotal Phase 2, Phase 2/3 or Phase 3) for cancer and non-cancer indications. These tables are updated versions of Tables 3 and 4 in the article ‘Antibodies to watch in 2017’.  The tables will be updated with new information about antibody therapeutics that enter late-stage studies as the information is made available during the year. Information in bold was added during 2017. Antibody therapeutics that transition from late-stage studies to regulatory review are listed with the ‘Approved antibodies’ in the Members Only section of The Antibody Society’s website.

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1.       Fisher TS, et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother. 2012; 61(10):1721-33.

2.       Jiang H, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016; 30(2):399-408.

3.       Ataga KI, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017; 376(5):429-439.

4.       Shaw S, et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs. 2014; 6(3):774-82.

FDA approves brodalumab

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On February 15, 2017, the US Food and Drug Administration approved brodalumab (Siliq; Valent Pharmaceuticals International, Inc.) to treat adults with moderate-to-severe plaque psoriasis. Brodalumab, an IgG2 monoclonal antibody targeting the interleukin (IL)-17 receptor, inhibits the biological activity of IL-17A, IL-17F and other IL-17s. Labeling for brodalumab includes a Black Box Warning for the risks of suicidal thoughts or behavior. The product was approved with a Risk Evaluation and Mitigation Strategy (REMS) that includes prescriber and pharmacy certifications and informed consent by patients.

Brodalumab was granted its first marketing approval from the Ministry of Health, Labour and Welfare in Japan on July 4, 2016 for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and psoriatic erythroderma. The product’s brand name in Japan is Lumicef®. A marketing authorization application for brodalumab in psoriasis is undergoing evaluation by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of February 16, 2017, marketing applications for a total of 12 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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First approval for sarilumab

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On January 12, 2017, Health Canada approved sarilumab (Kevzara) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more biologic or non-biologic disease-modifying anti-rheumatic drugs. This is the first approval in any country for sarilumab, which is a human IgG1 that binds to soluble and membrane-bound forms of the interleukin-6 receptor. Marketing applications for sarilumab were submitted to the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Ministry of Health, Labour and Welfare in Japan. The marketing applications for sarilumab are based on results from Phase 3 trials in the SARIL-RA clinical development program, which includes ~ 2,900 adults with moderately to severely active RA who had an inadequate response or intolerance to previous treatment regimens. FDA issued a complete response letter in October 2016; resubmission of the application to FDA is expected in the first quarter of 2017, and an action by FDA is expected in the second quarter of 2017. An opinion regarding the marketing application submitted to EMA is expected in 2017.

The annual number of first approvals for new antibody therapeutics is expected to reach a record in 2017.  Sarilumab’s approval is the first of at least 12 first approvals for new antibody therapeutics expected in 2017. The Antibody Society will post reports on the progress of mAb therapeutics during 2017, with an emphasis on first marketing application submissions and approvals in the European Union, United States and Japan. The Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. Please log in to access the table, located in the Members Only section.

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Free virtual issue featuring articles on neonatal Fc receptor is online now

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In a special issue of mAbs, Guest Editor Zita Schneider, D.V.M., Ph.D., Texas A&M Health Science Center, has compiled 12 articles describing recent results obtained about the neonatal Fc receptor, FcRn. All articles can be freely downloaded for a limited time. As a regulator of immunoglobulin G (IgG) and albumin homeostasis and a modulator of immune functions, this receptor has been attracting the interest of the scientific community and has become an unavoidable factor for consideration in the development of IgG- and albumin-based diagnostic and therapeutic reagents.

Burvenich et al. identified important amino acids playing a role in FcRn-IgG interaction, whereas Hironiwa et al. showed efficient antigen drop-off and IgG recycling utilizing calcium-dependent antigen-antibody binding. Ying and colleagues provided a tool to increase the transcytosis and half-life of engineered antibody domains through an FcRn-binding motif, whereas Meyer et al. utilized the albumin-binding characteristics of FcRn to generate IgA molecules with elongated half-life. Adams et al. used an anti-albumin Fv domain to extend the half-life of an Fab fragment, and Davé et al. used this domain to generate an Fab-dsFv bispecific antibody format.

FcRn can also serve as a screening tool for antibody selection as demonstrated by Souders et al. who developed a novel FcRn-binding biolayer interferometry assay, while Fan and colleagues used online peptide immune-affinity chromatography coupled with high resolution mass spectrometry to determine human FcRn expression levels in transgenic (Tg) mice and Avery et al. characterized these human FcRn Tg mice with respect to mAb pharmacokinetics (PK) prediction. Unverdorben et al. provided details of the PK of various Fc fusions compared to IgG molecules, Kelly et al. proved that FcRn-independent antigen-independent nonspecific interactions can also play a role in antibody PK, and Datta-Mannan et al. investigated several properties of mAbs in order to optimize PK parameters.

These articles provide valuable details to explore the possibilities offered by utilizing the functions of FcRn.

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Increased clinical pipeline of Antibody Drug Conjugates in 2016

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The antibody-drug conjugate (ADC) clinical pipeline has continued to grow in 2016. Last month two ADCs entered the clinic: Genmab’s MMAE-conjugated HuMax-AXL-ADC is now in Phase 1/2 development for five different types of solid tumors (ovary, cervix, endometrium, lung and thyroid). Additionally, a PBD-conjugated ADC for multiple myeloma (SGN-CD352A), was added to Seattle Genetics’ clinical pipeline.

In total, 32 clinical trials involving ADCs were initiated in 2016 and a significant progression of the pipeline into Phase 2 and 3 clinical trial was observed that year. During last year, 14 novel ADCs entered Phase 1, now totaling 37 Phase 1 ADCs. Three ADCs initiated Phase 1/2 development in 2016, increasing the total number of ADCs in this stage to 8. Four ADCs (AGS-16C3F, Anetumab Ravtansine, SAR566658, Rova-T) progressed towards Phase 2 (11 ADCs are now in Phase 2) and two drugs (IMGN853, SGN-CD33A) entered Phase 3 trials, doubling the number of ADCs in this clinical phase.

This year, a market approval could become a reality for inotuzumab ozogamicin. Currently, a marketing authorization application for acute lymphocytic leukemia (ALL) is being reviewed by EMA. Another possible approval is the re-approval for Mylotarg using a different dosing regimen.