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Crizanlizumab-tmca (Adakveo) approved by FDA

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On November 15, 2019, the U.S. Food and Drug Administration approved crizanlizumab-tmca (Adakveo) as a treatment to reduce the frequency of vaso-occlusive crisis (VOC), which occurs when blood circulation is obstructed by sickled red blood cells, for patients age 16 years and older. Crizanlizumab is a humanized antibody directed against P-selectin, which contributes to the pathogenesis of sickle cell disease, including vaso-occlusive events and hemolytic anemia. Crizanlizumab was granted Orphan Drug designation in the US and European Union for the treatment of VOC in patients with sickle cell disease, as well as FDA’s Breakthrough Therapy designation for prevention of VOCs in patients of all genotypes with sickle cell disease. A marketing application for crizanlizumab is undergoing review by the European Medicines Agency.

FDA’s approval was based on Phase 2 results from the SUSTAIN study (NCT01895361), which demonstrated that crizanlizumab provided significant benefit over placebo, such as:  1) the percentage of crizanlizumab-treated patients (5 mg/kg) who did not experience any vaso-occlusive crisis (VOC) was higher compared to those treated with placebo (36% vs 17%, P=0.010); 2) 45% reduction in the median annual rate of VOCs leading to health care visits in patients with or without hydroxyurea therapy compared to placebo (1.63 vs 2.98, P=0.010); 3) 42% reduction in median annual rate of days hospitalized versus placebo (4.00 vs 6.87 P=0.45), and 4) A three-fold longer median time to first VOC vs placebo (4.07 vs 1.38 months, P< 0.001). [1, 2]

1. Novartis. FDA accepts file and accelerates review of Novartis sickle cell disease medicine crizanlizumab (SEG101). July 16, 2019 press release.

2. Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, Knight-Madden JM, Bruederle A, Shi M, Zhu Z, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. Am J Hematol. Am J Hematol. 2019 Jan;94(1):55-61. doi: 10.1002/ajh.25308.

Interested in more information about US- or EU- approved antibody therapeutics? The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US in the Web Resources section of our website. 

FDA approves brolucizumab-dbll (BEOVU®)

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On October 7, 2019, the US Food and Drug Administration (FDA) approved brolucizumab-dbll (BEOVU®) for the treatment of neovascular age-related macular degeneration (nAMD). Brolucizumab is a humanized antibody single-chain variable fragment that binds to the 3 major isoforms of human vascular endothelial growth factor (VEGF), thereby interfering with their interaction with receptors VEGFR-1 and VEGFR-2 and suppressing endothelial cell proliferation, neovascularization and vascular permeability. BEOVU is administered by intravitreal injection, and the recommended dose is 6 mg monthly for the first three doses, followed by one dose of 6 mg every 8-12 weeks. A marketing application for brolucizumab is undergoing review by EMA.

FDA’s approval was based on data from two Phase 3 studies, HAWK (NCT02307682) and HARRIER (NCT02434328), comparing the efficacy and safety of intravitreal injections of brolucizumab versus aflibercept in nAMD. Brolucizumab met the primary efficacy endpoint of non-inferiority to aflibercept (EYLEA®) in mean change in best-corrected visual acuity (BCVA) at week 48 in both trials, with a mean change in BCVA of 6.6 letters for brolucizumab 6 mg versus 6.8 letters for aflibercept in HAWK trial and 6.9 letters versus 7.6 letters, respectively, in the HARRIER study. Additionally, at week 48, brolucizumab was superior to aflibercept in secondary endpoints considered key parameters of the disease, such as central subfield retinal thickness and retinal fluid (intraretinal fluid and/or subretinal fluid). Results at 96 weeks reaffirmed the superiority of brolucizumab 6 mg in reduction of retinal fluid, and patients who received this dose continued to demonstrate reductions in central subfield thickness.

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The Antibody Society maintains a comprehensive table of approved monoclonal antibody 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.

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’.

Antibodies to watch and more

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The Antibody Society’s presentation, “Antibodies to watch and more: Early and late-stage clinical development trends” was given on June 26, 2019, as part of KNect365’s Digital Week.

In this presentation, Dr. Janice Reichert, Executive Director of the Society, provided an update to the Antibodies to Watch in 2019 paper, which was published in mAbs in February. She gave a brief summary of antibody therapeutics approved January to June this year in either the US or EU, and antibodies in regulatory review and those that might enter regulatory review soon. Dr. Reichert also discussed trends for nearly 160 antibodies that entered clinical study from January 2018 to mid-June 2019, including use of different antibody formats and mechanisms of action, and she provided specifics regarding the popular and less trendy targets.

Click here to download the presentation and learn which antibodies are the ones to watch in 2019 and 2020!

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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.

New antibody-drug conjugate approved in the US

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On June 10, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in combination with the chemotherapy bendamustine and a rituximab product (BR), to treat adult patients with diffuse large B-cell lymphoma (DLBCL) that has progressed or returned after at least two prior therapies. Polivy is composed of a humanized anti-CD79b IgG1 antibody conjugated to the antimitotic agent monomethyl auristatin E (MMAE). The antibody’s target is highly expressed on B cells of patients with lymphoma. The biologics license application for Polivy was granted FDA’s Breakthrough Therapy and priority review designations. The drug also has European Medicines Agency (EMA)’s PRIME designation, and US and EU Orphan Drug designations for DLBCL. EMA is reviewing a marketing authorization application for Polivy.

The drug’s efficacy was evaluated in a study of 80 patients with relapsed or refractory DLBCL who were randomized to receive Polivy with BR or BR alone. Efficacy was based on complete response rate and duration of response (DOR), defined as the time the disease stays in remission. At the end of treatment, the complete response rate was 40% with Polivy plus BR compared to 18% with BR alone. Of the 25 patients who achieved a partial or complete response to Polivy plus BR, 16 (64%) had a DOR of at least six months and 12 (48%) had a DOR of at least 12 months.

Like this post but not a member? Please join!

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 other antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.