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First approval for fremanezumab-vfrm

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On September 14, 2018, the U.S. Food and Drug Administration (FDA) approved fremanezumab-vfrm (Ajovy) for the preventive treatment of migraine in adults. The drug may be administered as either 225 mg monthly, or 675 mg quarterly, subcutaneous doses. Fremanezumab-vfrm is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), thereby blocking the binding of the ligand to its receptor. The monoclonal antibody erenumab-aooe (Aimovig), which was approved by the FDA in May 2018 for the preventive treatment of migraine in adults, targets CGRP receptor, rather than the ligand. Marketing applications for galcanezumab, another monoclonal antibody that targets CGRP, are undergoing review by FDA and the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. As of September 14, a total of 9 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 7 that have not yet been approved in either the EU or US are undergoing review in these regions. Please log in to access the table in either PDF or Excel formats, located in the Members Only section.

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First approval for caplacizumab

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On September 3, 2018 Sanofi announced that the European Commission granted a marketing approval for caplacizumab (Cablivi), a bivalent single-domain Nanobody targeting von Willebrand factor, as a treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP). During episodes of this rare, life-threatening blood clotting disorder, microclots can form, leading to low platelet counts, ischemia and organ dysfunction in aTTP patients. Caplacizumab was granted Fast Track designation in the US and orphan drug designations in the US and EU for the treatment of aTTP. The biologics license application (BLA) for caplacizumab is undergoing a priority review at the US Food and Drug Administration (FDA). A first action by FDA is expected by February 6, 2019. Caplacizumab was developed by Ablynx, a Sanofi company.

The approval of caplacizumab in the European Union was based in part on the Phase 3 HERCULES study (NCT02553317), a placebo-controlled, randomized study to evaluate the efficacy and safety of caplacizumab in more rapidly restoring normal platelet counts as a measure of the prevention of further microvascular thrombosis. Positive results from this study were announced in October 2017. The HERCULES study recruited 145 patients with an acute episode of aTTP who were randomized 1:1 to receive either caplacizumab or placebo in addition to standard-of-care treatment, which was daily plasma exchange (PEX) and immunosuppression. Patients were administered a single IV bolus of 10 mg caplacizumab or placebo followed by daily SC dose of 10 mg caplacizumab or placebo until 30 days after the last daily PEX. Depending on the response, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. The primary endpoint (time to platelet count response) and several secondary endpoints of HERCULES study were met. In particular, there was a statistically significant reduction in time to platelet count response, with, at any given time, patients treated with caplacizumab 50% more likely to achieve platelet count response;  a 74% relative reduction in the percentage of patients with aTTP-related death, a recurrence of aTTP, or at least one major thromboembolic event during the study drug treatment period; and a 67% relative reduction in the percentage of patients with aTTP recurrence during the overall study period. A 3-year Phase 3 follow-up study (NCT02878603) of patients who completed the HERCULES study is in progress.

The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. As of Sep 3, a total of 7 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 9 that have not yet been approved in either the EU or US are undergoing review in these regions. Please log in to access the table in either PDF or Excel formats, located in the Members Only section.

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First approval for tildrakizumab-asmn

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On March 20, 2018, the US Food and Drug Administration (FDA) approved tildrakizumab-asmn (Ilumya) for treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Tildrakizumab, a humanized IgG1 kappa monoclonal antibody, targets IL-23p19 and blocks the interaction of IL-23 with its receptor, thereby inhibiting release of pro-inflammatory cytokines and chemokines.

FDA approval was supported by results from two Phase 3 trials (reSURFACE 1 and 2) in which patients were randomized to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo (2:2:1; reSURFACE 1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2; reSURFACE 2). In these trials, the tildrakizumab 200 mg and 100 mg doses were well tolerated and found to be efficacious compared with placebo and etanercept in the treatment of patients with moderate-to-severe chronic plaque psoriasis. The results of both studies were published in The Lancet in July 2017.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. As of March 23, a total of 3 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 8 that have not yet been approved in either the EU or US are undergoing review in these regions. Please log in to access the table, located in the Members Only section.

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Post-translational Modification in Antibody Function

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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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First approvals for ocrelizumab and dupilumab

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On March 28, 2017, the US Food and Drug Administration (FDA) granted first approvals for two monoclonal antibody (mAb) therapeutics, ocrelizumab (OCREVUS) and dupilumab (Dupixent®). Ocrelizumab is indicated for relapsing multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS), while dupilumab is a treatment for adults with moderate-to-severe eczema (atopic dermatitis).

Ocrelizumab (OCREVUS), a humanized IgG1 mAb targeting CD20, is the first drug approved by the FDA for PPMS. Ocrelizumab was granted FDA’s Breakthrough Therapy and Fast Track designations, and its application received priority review. A marketing application for ocrelizumab for the treatment of relapsing multiple sclerosis and primary progressive multiple sclerosis (MS) is being reviewed by the European Medicines Agency. The marketing applications are based on positive results from three Phase 3 studies, OPERA I (NCT01247324), OPERA II (NCT01412333), and ORATORIO (NCT01194570). Identical in their study design, OPERA I and OPERA II evaluated the efficacy and safety of 600 mg ocrelizumab intravenously (IV) administered every six months compared with 44 mg interferon beta-1a (Rebif®) subcutaneously administered 3 times per week in 1,656 people with relapsing forms of MS. Compared with Rebif®, ocrelizumab showed superior efficacy in reducing annualized relapse rates and disability progression sustained for at least three and for at least six months. The ORATORIO study evaluated the efficacy and safety of 600 mg ocrelizumab administered by IV infusion every six months compared with placebo in 732 people with primary progressive MS. Compared to patients who received placebo, patients who received ocrelizumab in this study showed significant reductions in disability progression sustained for at least three and for at least six months, as well as in other measures of progressive disease.

Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, was granted Breakthrough Therapy designation for moderate-to-severe atopic dermatitis, and the biologics license application was granted a priority review by FDA. The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adults with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). A marketing application for dupilumab is being reviewed 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 March 28, 2017, marketing applications for a total of 10 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.

Please log in to access the table, located in the Members Only section.

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Membership is free for students and employees of the Society’s corporate sponsors.