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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’.

Marketing application submitted for brolucizumab, an anti-VEGF-A antibody for macular degeneration

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The European Medicines Agency’s March 2019 summary of applications for new human medicines under evaluation by the Committee for Medicinal Products for Human Use indicates that an application for brolucizumab as a ophthalmological is undergoing review.

Brolucizumab, a humanized scFv that targets all isoforms of vascular endothelial growth factor-A, has been evaluated in clinical studies as a treatment for neovascular age-related macular degeneration (nAMD). In October 2018, Novartis released 96-week results from the Phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) studies that reaffirmed positive 48-week findings. The two studies included more than 1,800 patients in comparing the efficacy and safety of intravitreal injections of 6 mg brolucizumab or 3 mg brolucizumab (HAWK study only) versus 2 mg aflibercept in patients with nAMD. The primary efficacy endpoint of the studies, non-inferiority to aflibercept (EYLEA®) in mean change in best-corrected visual acuity (BCVA) at week 48, was met. The 96-week results indicate patients administered brolucizumab maintained robust visual gains, with mean change in BCVA of 5.9 letters for brolucizumab 6 mg versus 5.3 letters for aflibercept in the HAWK study, and 6.1 letters versus 6.6 letters, respectively, in the HARRIER study. Superior reductions in retinal fluid and central subfield thickness (CST) demonstrated at 48 weeks were reaffirmed at 96 weeks. The percentage of patients with nAMD that had intra-retinal fluid and/or sub-retinal fluid was 24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (p=0.0001) and 24% vs. 39%, respectively, in the HARRIER study (P<0.0001). Absolute reductions in CST from baseline were -175 µm for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (p=0.0057) and -198 µm versus -155 µm, respectively, in the HARRIER study (P<0.0001).

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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 enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

“Antibodies to watch in 2019”

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The latest “Antibodies to watch” article is now freely accessible at mAbs! 

For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, the scope of the data presented was expanded to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. The data indicate that: 1) antibody therapeutics are entering clinical study, and being approved, in record numbers; 2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and 3) Phase 1 to approval success rates are favorable, ranging from 17–25%, depending on the therapeutic area (cancer vs. non-cancer).

As of November 2018, a record number of antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United States (US). Also as of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) were in regulatory review in China. In addition, the data show that 3 product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019. Notably, approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab, spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018 and in 2019, and are thus ‘antibodies to watch’. The Antibody Society looks forward to documenting progress made with these and other ‘antibodies to watch’ in the next installment of this article series.

Update: Data in “Antibodies to watch in 2019” is as of November 2018. As noted in the post below, risankizumab was approved by FDA on December 21, 2018, bringing the total number of antibody therapeutics approved in the EU or US during 2018 to 13.

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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Antibodies new to the market, and exiting

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On February 23, 2018, Kyowa Hakko Kirin Co. Ltd and its partner Ultragenyx Pharmaceutical Inc. announced that a conditional marketing authorization had been granted in the European Union (EU) for burosumab (Crysvita) as a treatment for X-linked hypophosphatemia in children 1 year of age and older, and adolescents with growing skeletons. Burosumab is a human IgG1 monoclonal antibody that binds to and inhibits the activity of fibroblast growth factor 23, thereby reducing loss of phosphate from the kidney and other metabolic abnormalities, and ameliorating bone changes that are a hallmark of the disease. The marketing approval in the EU is the first for burosumab. A biologics license application is undergoing review by the US Food and Drug Administration (FDA), and an action on the application is expected by April 17, 2018.

On February 27, 2018, Roche announced that emicizumab (Hemlibra®) had been approved in the EU for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Emicizumab, a bispecific IgG4 mAb targeting Factors IXa and X that originated at Chugai Pharmaceutical Co. Ltd., was approved by the FDA on November 16, 2017.

On March 2, 2018, Biogen and AbbVie announced the voluntary worldwide withdrawal of marketing authorizations for ZINBRYTA® (daclizumab) for relapsing multiple sclerosis (MS). The withdrawal coincides with an urgent review by the European Medicines Agency (EMA) of inflammatory brain disorder in 8 patients, and follows a 2017 review by EMA of reports of liver injury. Due to the risk of serious liver damage, EMA limited use of Zinbryta to MS patients who had tried at least two other disease modifying treatments and could not be treated with any other such treatments. ZINBRYTA® had been marketed in the EU, US, Switzerland, Canada and Australia.

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