The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016.
As of mid-December 2017, 10 antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab, cemiplimab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018.
Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 13 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 13 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 5 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab, isatuximab).
Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in the ‘Antibodies to watch in 2018’ article, which is now available on the mAbs website. A PDF of this open-access article is available here.
Emicizumab granted FDA approval
Emicizumab (Hemlibra, emicizumab-kxwh, ACE910, RO5534262), a bispecific IgG4 mAb targeting Factors IXa and X, was approved by the FDA on November 16, 2017. The drug, which is administered once a week, was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed Factor VIII inhibitors. The biologics license application was granted Priority Review and a Breakthrough Therapy designation. Hemlibra was also granted an orphan drug designation by the FDA.
Marketing applications for emicizumab are under review in the European Union and Japan; the European Medicines Agency is reviewing the marketing authorization application under accelerated assessment. Emicizumab was granted an orphan drug designation in Japan for the prevention and reduction of bleeding episodes in patients with congenital factor VIII deficiency with inhibitors. The drug was created by Chugai Pharmaceutical Co., Ltd. and co-developed by Chugai, Roche and Genentech.
The marketing applications for emicizumab include results from the Phase 3 HAVEN 1 (NCT02622321) study and interim analysis of the HAVEN 2 (NCT02795767) study. In the HAVEN 1 study, adult and adolescent patients (12 or older) who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point of the study was the difference in bleeding rates between Group A and Group B. Emicizumab was administered subcutaneously at a dose of 3 milligrams per kilogram per week (mg/kg/week) for 4 weeks followed by 1.5 mg/kg/week up to the end of the study. The annualized bleeding rate in Group A was reduced by 87% compared to Group B (2.9 events vs 23.3 events, P<0.001). [1] The HAVEN 2 study is evaluating the efficacy, safety, and pharmacokinetics of subcutaneous administration of emicizumab in hemophilia A pediatric patients with inhibitors.
1. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818. doi: 10.1056/NEJMoa1703068.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 16, 2017, a total of 10 mAbs have been granted first approvals in either the US or EU in 2017, and marketing applications for a total of 9 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.
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Benralizumab granted FDA approval
On November 14, 2017, AstraZeneca announced that benralizumab (Fasenra), an afucosylated IgG1 mab targeting the alpha subunit of IL-5R found on eosinophils, received a US Food and Drug Administration approval for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. The European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion on November 10, 2017, recommending the marketing authorization of benralizumab as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting b-agonists. The European Commission’s decision regarding marketing authorization in the EU is pending. Marketing applications for benralizumab are undergoing review in Japan and other countries. The mAb was in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Hakko Kirin Co., Ltd. by MedImmune.
The safety and efficacy of benralizumab as a treatment for asthma were evaluated in the WINDWARD program, which included six Phase 3 trials, SIROCCO, CALIMA, ZONDA, BISE, BORA and GREGALE. The randomized, double-blinded, parallel-group, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) trials evaluated the efficacy and safety of a regular, subcutaneous administration of a fixed 30 mg dose of benralizumab for up to 56 weeks in exacerbation-prone adult and adolescent patients 12 years of age and older. Study results were published in 2016. [1, 2] In the 28-week randomized ZONDA study (NCT02075255), the effects of 30 mg benralizumab administered subcutaneously either every 4 weeks or every 8 weeks (with the first three doses administered every 4 weeks) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The study’s primary outcome measure, percentage reduction in final oral steroid dose compared with baseline while maintaining asthma control, was met. The median final oral glucocorticoid doses from baseline were reduced by 75% in patients who received either dose of benralizumab, compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). [3]
- Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkström V, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; pii: S0140-6736(16)31324-1. doi: 10.1016/S0140-6736(16)31324-1.
- FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; pii: S0140-6736(16)31322-8. doi: 10.1016/S0140-6736(16)31322-8.
- Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. doi: 10.1056/NEJMoa1703501.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 15, 2017, a total of 9 mAbs have been granted first approvals in either the US or EU in 2017, and marketing applications for a total of 10 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.
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Mogamulizumab enters EU regulatory review
Mogamulizumab (KW-0761, Poteligeo®), is an IgG1 afucosylated humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4) expressed on tumor cells of patients with cutaneous T-cell leukemia lymphoma (CTCL), including mycosis fungoides and Sézary syndrome. Afucosylation enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the mAb. Mogamulizumab was initially approved in Japan in March 2012 for the treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL), and then granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and CTCL in March 2014, and with chemotherapy-naive CCR4-positive ATL in December 2014.
In October 2017, Kyowa Hakko Kirin announced that a marketing authorization application (MAA) for mogamulizumab, for the treatment of CTCL in adults who have received at least one prior systemic therapy, is under review at the European Medicines Agency. The MAA includes data from the randomized, open-label, multi-center Phase 3 MAVORIC study (NCT01728805), which evaluated the effects of mogamulizumab versus vorinostat (Zolinza®) in patients with refractory cutaneous T cell lymphoma who failed previous treatment. The study included 372 patients who were randomized to receive either mogamulizumab (1.0 mg/kg weekly x 4 in cycle 1, then every other week until progression) or vorinostat (400 mg orally daily). The primary outcome measure of the study was progression-free survival (PFS), with the target being a 50% improvement over the reference median PFS for vorinostat (median PFS of 254 days for the mogamulizumab arm versus 169 days for the vorinostat arm). In April 2017, Kyowa Hakko Kirin announced top-line results from the MAVORIC study indicating the primary endpoint of PFS had been met. In August 2017, mogamulizumab received breakthrough therapy designation in the US for mycosis fungoides and Sézary syndrome based on results from the MAVORIC study.
The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 10, 2017, marketing applications for a total of 11 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.
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Post-translational Modification in Antibody Function
The Antibody Society is pleased to invite you to attend its annual Meeting, Antibody Engineering & Therapeutics, which will be held December 12-15, 2017, in San Diego, CA. We will be celebrating the 10th anniversary of the Society at the Society’s Special Session on Thursday December 14, 2017. In this session summary, Dennis R. Burton (The Scripps Research Institute) and Paul W.H.I. Parren (Leiden University Medical Center) discuss what you will learn in their session on post-translational modification in antibody function.
The critical importance of sequence variation in antibodies is well recognized. Sequence diversity in antibody variable domains is essential for specific antigen recognition while linkage to different constant domains leads to distinct Fc-mediated effector activities. Post-translational modifications (PTMs) of these domains provide an additional immune mechanism by which the binding and activity of antibodies can be modulated. PTMs vary from chain additions, such as N- and O-linked glycosylation, glycation, cysteinylation and sulfation; chain trimming, such as C-terminal lysine clipping; amino acid modifications such as cyclization (into a N-terminal pyroglutamic acid), deamidation, oxidation, isomerization and carbamylation; to disulfide scrambling of hinge region interchain disulfide bonds. Each antibody can therefore give rise to a myriad of distinct antibody molecules with large activity and potency differences. Although post-translational modifications of antibodies have been observed and studied for decades, we only now start to understand the full impact of this incredible microheterogeneity. PTMs have moved from being viewed as a mere nuisance to antibody manufacturing that requires controlling to a potential handle to modify and improve specific antibody functions.
In this session, we will hear about current state-of-the-art in PTM detection and novel insights into the role and modulation of PTMs in our immune system as well as the way in which we can exploit PTMs to make better (therapeutic) antibodies. The first and the second (after the break) part of our session will be initiated with lectures by renowned experts in their fields. Professor Albert Heck (Utrecht University) is a world-expert on the structural analysis of proteins by mass spectrometry. He received the Frank H. Field and Joe L. Franklin Award for outstanding achievement in mass spectrometry from the American Chemical Society and in 2017 he was received the NWO Spinoza Prize, which is the highest award in Dutch Science. Prof Heck will discuss how innovative and advanced mass spectrometry methods can be used to map antibody heterogeneity due to PTMs. Leendert Trouw (Leiden University Medical Center) will discuss the role of two amino acid modifications (citrullination and carbamylation) in the autoimmune disease rheumatoid arthritis (RA). On the one hand, the presence of antibodies against citrullinated or carbamylated proteins represents a prognostic marker for the disease. How antibodies recognize diverse antigens carrying these modifications is therefore an important area of study. Carbamylation of antibodies furthermore may also have functional consequences for antibody effector functions which will be highlighted. Professor Gerhard Krönke (University of Erlangen) will discuss how the PTM profile and inflammatory activity of autoantibodies in RA is regulated by TH17 helper T cells. His work gives us a novel insight into a mechanism by which the cellular immune system regulates the activity of antibodies and how its derailment may lead to the initiation of (autoimmune) disease.
After the break, Taia Wang (Stanford University School of Medicine) will discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors, which are influenced by the Fc’s amino acid sequence and the complex, biantennary Fc-associated N-linked glycan, in the context of infectious, autoimmune, and neoplastic disorders. Yingda Xu (Adimab) will bring us back to the importance of PTMS in manufacturing and control of therapeutic antibody production. He will show novel data on the identification of chemically labile sites in antibodies and how this information may be used in therapeutic antibody lead selection. Finally, Raiees Andrabi (The Scripps Research Institute) will discuss how sulfation of residues in the antibody binding site is critical for certain broadly neutralizing anti-HIV-1 antibodies targeting the envelope glycoprotein.
We hope that this session will convey the current interest and high excitement in antibody PTMs and will serve to promote further research into the importance and impact of PTM microheterogeneity for polyclonal antibody responses as well as for monoclonal antibody therapeutics.
Interested in attending the meeting? Learn more from this PDF, which includes all session summaries written by the chairpersons.
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