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Uptick in biosimilar antibody products approved by FDA

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The US Food and Drug Administration (FDA) began approving biosimilar products in 2015. According to FDA’s definition, a biosimilar is highly similar to, and has no clinically meaningful differences in safety, purity, and potency from, an existing FDA-approved reference product. The availability of these products can help patients by increasing the number of medication options at potentially lower costs.

 

During March 2015 to July 2019, FDA approved a total of 16 antibody therapeutics that are biosimilars of 5 reference products:

  • Trastuzumab (5 biosimilars)
  • Adalimumab (4 biosimilars)
  • Infliximab (3 biosimilars)
  • Bevacizumab (2 biosimilars)
  • Rituximab (2 biosimilars)

Notably, the rate of FDA approvals has increased in 2019. The numbers of  biosimilar antibody therapeutics approved by FDA were 0, 2, 5, and 3 for the years 2015-2018, while a total of 6 were approved in the first 7 months of 2019. The products approved in 2019 are:

Patients may soon also have access to ranibizumab and denosumab biosimilar antibody products.

  • Formycon and Bioeq IP AG recently announced that an FDA submission for FYB201, a biosimilar candidate for Lucentis®* (ranibizumab), is expected for the beginning of the fourth quarter of 2019. The submission to the European Medicines Agency (EMA) is scheduled for the first quarter of 2020. If the submissions progress as planned, marketing authorization approvals in the US and the EU are expected in 2021.
  • SB11, a proposed ranibizumab biosimilar to Lucentis is undergoing evaluation in a Phase 3 study (NCT03150589) of patients with neovascular age-related macular degeneration. Sponsored by Samsung Bioepis Co., Ltd., the study is active, but no longer recruiting patients. The estimated completion date of the study is in November 2019.
  • Sandoz recently announced the first patient was enrolled an integrated Phase 1/3 clinical study (NCT03974100) that will compare the pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity of GP2411 (proposed biosimilar denosumab) and Prolia® (EU-authorized) in postmenopausal women with osteoporosis. The estimated primary completion date of the study is in December 2021.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Located in the ‘Web Resources’ section of our website, the list is updated regularly and can be downloaded in Excel format. Information about antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

Four new antibody therapeutics enter regulatory review

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Marketing applications for four antibody therapeutics (crizanlizumab, enfortumab vedotin, teprotumumab, isatuximab) were recently submitted to the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

On July 16, 2019, Novartis announced the FDA accepted the company’s Biologics License Application (BLA) and has granted Priority Review for crizanlizumab (SEG101). Novartis submitted the application for crizanlizumab for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). The FDA submission is supported by results from the Phase 2 SUSTAIN study, which showed that crizanlizumab (5 mg/kg) reduced the median annual rate of VOCs leading to health care visits by 45.3% compared with placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea. Clinically significant reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype or hydroxyurea use. A marketing authorization application for crizanlizumab is undergoing evaluation by EMA.

  • Crizanlizumab, humanized IgG2 targeting P-selectin, was granted Breakthrough Therapy designation in December 2018

On July 16, 2019, Seattle Genetics, Inc. and Astellas Pharma Inc. announced submission of a BLA for accelerated approval to the FDA for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The submission is based on results from the first cohort of patients in the EV-201 pivotal Phase 2 clinical trial that were presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO) in June.

  • Enfortumab vedotin is a human IgG1 antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers.

On July 10, 2019, Horizon Therapeutics plc announced that it has submitted a BLA to FDA for teprotumumab for the treatment of active thyroid eye disease. Teprotumumab has Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA. Horizon requested priority review for the application, which, if granted, could result in a six-month review process. The FDA has a 60-day filing review period to determine whether the BLA is complete and acceptable for filing.

  • Teprotumumab is a human IgG1 antibody that targets insulin-like growth factor 1 receptor.

On July 10, 2019, Sanofi announced that the FDA has accepted for review the BLA for isatuximab (SAR650984) for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). The target action date for the FDA decision is April 30, 2020. Isatuximab received orphan designation for relapsed/refractory multiple myeloma from both the FDA and the EMA, and in the second quarter of 2019 the EMA accepted a marketing authorization application for evaluation.

  • Isatuximab is a novel IgG1 antibody that binds selectively to a specific epitope on CD38.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Located in the ‘Web Resources’ section of our website, the list is updated regularly and can be downloaded in Excel format. Information about antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

Anti-IL17 netakimab registered in Russia

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On May 7, 2019, BIOCAD announced the registration of netakimab (Efleira®, BCD-085) in Russia for the treatment of moderate to severe plaque psoriasis. Netakimab is a humanized IgG1 monoclonal antibody (mAb) in which the VH domain is replaced by a Lama glama VHH domain possessing a long complementarity-determining region (CDR-H3).  The mAb targets interleukin (IL)-17, a pro-inflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. The registration is the first for an innovative mAb developed in Russia.

The efficacy and safety of Efleira® in psoriasis patients was confirmed in the Phase 3 BCD-085-7/PLANETA study (NCT03390101), which was conducted in 22 certified study sites in Russia and 2 study sites in the Republic of Belarus. After 12 weeks of the treatment, 83.3% of patients who received netakimab once a month after induction for the first 3 weeks achieved a 75% improvement in Psoriasis Area and Severity Index. The total duration of therapy and follow-up in this study is 3 years.

BIOCAD, which is based in Moscow, is planning to start a pivotal clinical trial of netakimab in psoriasis in Europe later in 2019.

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Most read from mAbs, April 2019

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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 summaries based on the abstracts of the most read papers published in a recent issue. All the articles are open access; PDFs can be freely downloaded by following the links below.

Issue 11.3 (April 2019)

CH2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering

Yageta et al examined the small-angle X-ray scattering (SAXS) profile of the glycosylated Fc region (gFc) and aglycosylated Fc region (aFc) in solution to determine if removal of the N-linked glycan alters the CH2 domain orientation in the Fc region. For both gFc and aFc, the best-fitted SAXS profiles corresponded to ones calculated based on the crystal structure of gFc that formed a “semi-closed” CH2 domain orientation. Collectively, the data indicated that the removal of the N-linked glycan only negligibly affected the CH2 domain orientation in solution. Their findings will guide the development of methodology for the production of highly refined functional Fc variants.

Charge variants characterization and release assay development for co-formulated antibodies as a combination therapy

Characterization of co-formulated biologics can be challenging due to the high degree of similarity in the physicochemical properties of co-formulated proteins, especially at different concentrations of individual components. In this new report, Cao et al present the results of a deamidation study of one monoclonal antibody component (mAb-B) in co-formulated combination antibodies (referred to as COMBO) that contain various ratios of mAb-A and mAb-B. A single deamidation site in the complementarity-determining region of mAb-B was identified as a critical quality attribute (CQA) due to its impact on biological activity. A conventional charge-based method of monitoring mAb-B deamidation presented specificity and robustness challenges, especially when mAb-B was a minor component in the COMBO, making it unsuitable for lot release and stability testing. The authors developed and qualified a new, quality-control-friendly, single quadrupole Dalton mass detector (QDa)–based method to monitor site-specific deamidation. Their approach can be also used as a multi-attribute method for monitoring other quality attributes in COMBO. This analytical paradigm is applicable to the identification of CQAs in combination therapeutic molecules, and to the subsequent development of a highly specific, highly sensitive, and sufficiently robust method for routine monitoring CQAs for lot release test and during stability studies.

Capture and display of antibodies secreted by hybridoma cells enables fluorescent on-cell screening

Puligedda et. al describe a system in which hybridomas specifically capture and display the mAbs they secrete. Using On-Cell mAb Screening (OCMS™), monoclonal antibodies (mAbs) displayed on the cell surface can be rapidly assayed for expression level and binding specificity using fluorescent antigens with high-content (image-based) methods or flow cytometry. OCMS™ demonstrated specific mAb binding to poliovirus and rabies virus by forming a cell surface IgG “cap”, as a universal assay for anti-viral mAbs. The authors produced and characterized OCMS™-enabled hybridomas secreting mAbs that neutralize poliovirus and used fluorescence microscopy to identify and clone a human mAb specific for the human N-methyl-D-aspartate receptor. They also used OCMS™ to assess expression and antigen binding of a recombinant mAb produced in 293T cells.

Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®

As discussed by Xu et al, development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China’s Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efficacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.

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First approval for risankizumab

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AbbVie has announced that SKYRIZI (risankizumab) was granted its first approval. The Japanese Ministry of Health, Labour and Welfare approved risankizumab for the treatment of plaque psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis in adult patients who have an inadequate response to conventional therapies. AbbVie is leading the development and commercialization of SKYRIZI, which is included in a collaboration with Boehringer Ingelheim.

Risankizumab is a humanized IgG1 monoclonal antibody that targets IL-23. The approval in Japan is based on efficacy and safety data from Phase 2 and Phase 3 clinical trials, sustaIMM, ultIMMa-1 and IMMspire, evaluating SKYRIZI in Japanese patients with plaque psoriasis, generalized pustular psoriasis and erythrodermic psoriasis, as well as a global Phase 2 study in patients with active psoriatic arthritis.

Marketing applications were submitted for risankizumab in both the EU and US, and regulatory decisions are anticipated in the first half of 2019. The European Medicines Agency’s Committee for Medicinal Products for Human Use has announced that it adopted a positive opinion for SKYRIZI for treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy.

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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Please log in to access the table, which is located in the Members Only section and can be downloaded in Excel format. Information about other antibody therapeutics that may be approved or enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.