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Mogamulizumab enters EU regulatory review

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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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Antibody therapeutics for immune-mediated disorders

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Antibody impressionPatients’ choice in antibody therapeutics for common immune-mediated disorders such as psoriasis and rheumatoid arthritis (RA) is set to substantially increase in 2017. As of December 1, 2016, marketing applications for 10 antibody therapeutics are being evaluated by either the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for possible first approvals in the US or EU, respectively. Of these, five (brodalumab, dupilumab, sirukumab, sarilumab, and guselkumab) are being considered as treatments for immune-mediated disorders.

Brodalumab (LUMICEF®) is a human anti-IL-17 receptor A mAb that inhibits biological activity of IL-17A, IL-17F and other IL-17s. The product was granted a 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 FDA’s action date for the biologics license application (BLA) is February 16, 2017. A marketing authorization application for brodalumab in psoriasis is undergoing evaluation by EMA. Guselkumab, an IgG1 mAb that targets the IL-23 p19 subunit, is undergoing review by FDA and EMA as a treatment for plaque psoriasis. Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, is undergoing review by FDA for atopic dermatitis. The mAb has Breakthrough Therapy designation for this indication, and the BLA was granted a priority review. FDA’s action date for the application is March 29, 2017. Sirukumab is a human anti-IL-6 mAb being evaluated by EMA, FDA and the Ministry of Health, Labour and Welfare for the treatment of adult patients with moderately to severely active RA. Sarilumab, a human IgG1 targeting IL-6R, is undergoing review by EMA, FDA and the Ministry of Health, Labour and Welfare in Japan for the treatment of adult patients with moderately to severely active RA. The BLA submitted to FDA has undergone a first review; deficiencies identified were detailed in a complete response letter.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the US or EU. Please log in to access the table, located in the Members Only section.

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

First approval for olaratumab, a new antibody therapeutic for sarcoma

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Antibody impressionOlaratumab (Lartruvo®) was granted an accelerated approval for treatment, with doxorubicin, of adults with soft tissue sarcoma by the US Food and Drug Administration on October 19, 2016. This new monoclonal antibody (mAb) therapeutic targets platelet-derived growth factor receptor-α. The approval was granted in part based on results of a clinical study that compared administration of doxorubicin alone with the combination of olaratumab with doxorubicin. In this study, median overall survival was 14.7 vs. 26.5 months for patients who received doxorubicin alone vs. those who received the combination of drugs. Olaratuzumab’s application was granted numerous FDA designations intended to facilitate the development of new drugs, especially those for serious or life-threatening diseases, including Fast Track and Breakthrough Therapy designations, and priority review. The product also received orphan drug designations in both the US and European Union (EU). On September 15, 2016, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for olaratumab for the treatment of advanced soft tissue sarcoma. A decision by the European Commission is pending.

Olaratumab is the 5th new antibody therapeutic to be granted a first approval in 2016. Of the applications for 9 new mAb therapeutics currently undergoing regulatory review in the US or EU (i.e., mAbs not previously approved for any indication in these regions), 4 have FDA action dates known to occur in late October-December 2016. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the US or EU. Please log in to access the table, located in the Members Only section.

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Antibody-based biosimilar products approved in the EU or US

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Antibody impressionThe number of antibody-based biosimilar therapeutics approved in the European Union or United States is poised to grow substantially in 2016 and 2017. The originator products that target tumor necrosis factor (TNF) have been of particular interest to the biosimilar industry due to the expiration of key patents and the large global markets for the products. In 2013, the three top-selling originator anti-TNF products were infliximab (Remicade®), etanercept (Enbrel®) and adalimumab (Humira®), which combined had global sales of nearly $18 billion that year. The first biosimilar anti-TNF products approved in either the EU or US were Inflectra® and Remsima®, both of which are versions of infliximab.  Inflectra® and Remsima® were approved in the EU in September 2013 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

While no antibody-based biosimilar products were approved in either the EU or US in 2014 or 2015, two products have been approved in each of these regions so far in 2016, and more may be approved soon. In the EU, the biosimilar etanercept BENEPALI® was approved in January 2016 for moderate to severe rheumatoid arthritis, psoriatic arthritis, severe ankylosing spondylitis, severe non-radiographic axial spondyloarthritis, and plaque psoriasis, and the biosimilar infliximab Flixabi® was approved in May 2016 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. In the US, Inflectra® was approved in April 2016 for the treatment of moderately to moderately to severely active rheumatoid arthritis, severely active Crohn’s disease, moderately to severely active ulcerative colitis, active ankylosing spondylitis, active psoriatic arthritis, chronic severe plaque psoriasis, and the biosimilar etanercept Erelzi® was approved in August 2016 for moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, active psoriatic arthritis, active ankylosing spondylitis, and chronic moderate to severe plaque psoriasis. A biosimilar adalimumab (ABP-501) may be approved soon, as the Food and Drug Administration’s (FDA) Arthritis Advisory Committee voted unanimously to support approval of it in July 2016. The product was recommended for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis in patients aged 4 years and older, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, and plaque psoriasis.

Although the FDA does not release comprehensive lists of products in review, the European Medicines Agency (EMA) does provide limited information on applications for centralized marketing authorization under evaluation. As of August 3, 2016, a total of 6 applications for biosimilar adalimumab (3 applications), etanercept (1 application), and the anti-CD20 rituximab (2 applications) were under evaluation. In late August, EMA also accepted for review a marketing authorization application for a proposed biosimilar trastuzumab, which is used to treat certain HER2-positive breast and gastric cancers. Thus, there may soon be as many as 11 biosimilar antibody-based therapeutics on the market in the EU, and many of these could also gain approval in the US.

Two antibodies in first regulatory review

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Antibody impressionFirst marketing applications were recently submitted for two novel antibody therapeutics, ocrelizumab and inotuzumab ozogamicin, intended as treatments for multiple sclerosis (MS) and CD22-positive acute lymphoblastic leukemia (ALL), respectively. Applications for ocrelizumab (OCREVUS), a humanized IgG1 antibody that targets CD20, as a treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) are undergoing regulatory review by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). No products are currently approved for both forms of MS. A priority review designation has been granted by FDA, and a first action on ocrelizumab’s biologics license application (BLA) is thus expected by December 28, 2016. The marketing applications are based on positive results from two identical Phase 3 studies (OPERA I and OPERA II) in people with RMS and the Phase 3 ORATORIO study in people with PPMS. All primary and key secondary endpoints were met in these three studies.

The antibody-drug conjugate inotuzumab ozogamicin targets CD22, an antigen found on the surface of cancer cells in most ALL patients. Results of a Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL were recently published in the New England Journal of Medicine. Improvements over chemotherapy on a number of measures, including complete hematologic remission and progression-free survival, were observed in this study. A marketing application for inotuzumab ozogamicin is undergoing review by the EMA; a BLA submission is likely. Inotuzumab ozogamicin received Breakthrough Therapy designation for ALL from FDA, and priority review of applications is a benefit of the designation, which suggests that an approval by FDA is thus possible by the end of 2016.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review (currently 8 mAbs) in the European Union and United States. The antibody target, format and year of first approval are included. Please log in to access the table, located in the Members Only section.

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