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US approval for mogamulizumab

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On August 8, 2018, the U.S. Food and Drug Administration (FDA) approved Poteligeo (mogamulizumab-kpkc) for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. The diseases are subtypes of cutaneous T-cell lymphoma (CTCL), which is a rare and difficult-to-treat type of non-Hodgkin lymphoma. The FDA had previously granted mogamulizumab Breakthrough Therapy and Orphan Drug designations, and the biologics license application for mogamulizumab received a priority review.

FDA’s approval was based on an open-label, multi-center, randomized Phase 3 clinical trial (NCT01728805) of 372 patients with relapsed MF or SS who received either mogamulizumab or vorinostat. Study sites were located in the US, Europe, Japan and Australia. Median progression-free survival was 7.6 months for patients administered mogamulizumab compared to 3.1 month for patients taking vorinostat in this clinical trial.

Developed by Kyowa Kirin, mogamulizumab is a humanized glyco-engineered monoclonal antibody that binds to CC chemokine receptor type 4 on cancer cells. Mogamulizumab was produced using Kyowa Hakko Kirin’s proprietary POTELLIGENT® platform, which produces antibodies with low / no fucose content. Such antibodies have increased affinity to FcγRIIIa (CD16), and enhanced antibody-dependent cell-mediated cytotoxicity activity. Mogamulizumab’s first approval, in 2012, was granted by the Japanese Ministry of Health, Labour and Welfare for treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. As of Aug 8, a total of 5 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 11 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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Most read from mAbs

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The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these brief summaries based on the abstracts of the most read papers published in recent issues. All the articles are open access; PDFs can be downloaded by following the links below.

Issue 10.5 (July 2018)

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. In this new review, Pereira et al. discuss the relevance of antibody core fucosylation to antibody-dependent cell-mediated cytotoxicity, and different strategies to produce afucosylated antibodies, and provide an update of afucosylated antibody drugs currently undergoing clinical trials, as well as those that have been approved.

A long non-coding SINEUP RNA boosts semi-stable production of fully human monoclonal antibodies in HEK293E cells. Sasso et al. report the results of their study of SINEUP technology applied to semi-stable production of monoclonal antibodies in HEK293E cells. SINEUP RNAs are long non-coding transcripts, possessing the ability to enhance translation of selected mRNAs. The authors propose SINEUP technology as a valuable tool to enhance semi-stable antibody production in human cell lines.

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC. Figueroa et al. present a practical approach that uses limited pharmacokinetic (PK) and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. Their findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. In this report, Betts et al. used population-pharmacokinetic (popPK) modeling to determine a single set of ‘typical’ popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Issue 10.4 (May/June 2018)

When monoclonal antibodies are not monospecific: Hybridomas frequently express additional functional variable regions. Bradbury et al. discuss results of their study, which analyzed 185 random hybridomas, in a large multicenter dataset, to determine the genetic diversity in antibody heavy chain and light chain genes found within individual hybridomas. Of the hybridomas evaluated, 126 (68.1%) contained no additional productive chains, while the remaining 59 (31.9%) contained one or more additional productive heavy or light chains. The expression of additional chains degraded properties of the antibodies, including specificity, binding signal and/or signal-to-noise ratio, as determined by enzyme-linked immunosorbent assay and immunohistochemistry. Their findings, reflecting the current state of hybridomas used in research, reiterate the importance of using sequence-defined recombinant antibodies for research or diagnostic use.

Evaluation of analytical similarity between trastuzumab biosimilar CT-P6 and reference product using statistical analyses. In this report, Lee et al. evaluated analytical similarity of CT-P6, a biosimilar product of trastuzumab, with the reference products (EU-Herceptin® or US-Herceptin®) following risk-based statistical approaches recommended in a recent US Food and Drug Administration guideline for the risk-based statistical approaches recommended by the US Food and Drug Administration. Various quality attributes of trastuzumab were first ranked based on the clinical impact of each attribute and subsequently adjusted to one of three tiers (Tier 1, Tier 2 and Tier 3) considering the characteristics of the assay, the level of attribute present and the feasibility of statistical analysis. Analytical similarity assessment analyzed by the three tiers clearly demonstrated that CT-P6 exhibits highly similar structural and physicochemical properties, as well as functional activities, compared with the reference products.

Analytical and functional similarity of Amgen biosimilar ABP 215 to bevacizumab. Seo et al. report the results of their analytical similarity assessment, which was designed to assess the structural and functional similarity of ABP 215 and bevacizumab sourced from both the United States (US) and the European Union (EU). Similarity assessment was also made between the US- and EU-sourced bevacizumab to assess the similarity between the two products. More than 20 batches of bevacizumab (US) and bevacizumab (EU), and 13 batches of ABP 215 representing unique drug substance lots were assessed for similarity. The large dataset allows meaningful comparisons and garners confidence in the overall conclusion for the analytical similarity assessment of ABP 215 to both US- and EU-sourced bevacizumab. The structural and purity attributes, and biological properties of ABP 215 are demonstrated to be highly similar to those of bevacizumab.

 

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First approval for erenumab

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On May 17, 2018, the U.S. Food and Drug Administration approved erenumab-aooe (Aimovig) for the preventive treatment of migraine in adults. Erenumab is a human monoclonal antibody that targets calcitonin gene-related peptide (CGRP) receptor, thereby blocking the activity of CGRP, which is involved in migraine attacks. The treatment is given by once-monthly subcutaneous injections.

The approval was based on data from three clinical trials that compared erenuman-aooe to placebo. Over 2000 participants were included in the studies. In the first study (STRIVE, NCT02456740), which included 955 participants with a history of episodic migraine, patients administered erenumab-aooe experienced, on average, one to two fewer monthly migraine days than those on placebo over a 6 month period. In the second study (ARISE, NCT02483585), which included 577 patients with a history of episodic migraine, patients administered erenumab-aooe experienced, on average, one fewer migraine day per month than those on placebo over a 3 month period. The third study, which evaluated 667 patients with a history of chronic migraine, patients treated with erenumab-aooe experienced, on average, 2.5 fewer monthly migraine days than those receiving placebo over a three month period.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. As of May 17, a total of 4 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 10 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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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.

Not a member? Please join! Membership is free for students and employees of the Society’s corporate sponsors.

First approval for ibalizumab-uiyk

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On March 6, 2018, the US Food and Drug Administration (FDA) approved ibalizumab-uiyk (Trogarzo) for adult patients infected with human immunodeficiency virus (HIV) who were previously treated with multiple HIV medications and whose HIV infections are resistant currently available therapies. Ibalizumab-uiyk, a humanized IgG4 monoclonal antibody, is a CD4 domain 2-directed post-attachment HIV-1 inhibitor. The marketing application was granted Breakthrough Therapy, Fast Track and Priority Review designations, and ibalizumab was granted an orphan drug designation by FDA. Theratechnologies Inc. and TaiMed Biologics, Inc. have an agreement to market and distribute Trogarzo in the US and Canada.

The product is administered intravenously (IV) as a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks after dilution in 250 mL of 0.9% sodium chloride. The safety and efficacy of ibalizumab-uiyk were evaluated in the Phase 3 TMB-301 study (NCT02475629), which was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected patients with multidrug resistant HIV-1. At Week 25, viral load <50 was achieved in 43% of patients, while 55% and 48% of patients had a ≥ 1 log10 reduction in viral load and a ≥ 2 log10 reduction in viral load, respectively. The most common adverse reactions reported in at least 5% of subjects were diarrhea, dizziness, nausea, and rash. In total, 292 patients with HIV-1 infection were exposed to ibalizumab-uiyk IV infusion during clinical studies. Additional prescribing information for the drug can be found here.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 7, 2018, a total of 2 mAbs have been granted first approvals in either the US or EU in 2018, 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. Please log in to access the table, located in the Members Only section.

Not a member? Please join! Membership is free for students and employees of the Society’s corporate sponsors.