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First approval for teprotumumab-trbw (Tepezza)

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On January 21, 2020, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, which is associated with an outward bulging of the eye that can cause eye pain, double vision, light sensitivity or difficulty closing the eye. Teprotumumab, a human IgG1 antibody targeting insulin growth factor 1 receptor, was granted Fast Track, Breakthrough Therapy and Orphan Drug designations by the FDA. Positive data from both Phase 2 (NCT01868997) and Phase 3 (OPTIC, NCT03298867) studies were reported by Horizon Pharma. In the randomized, placebo-controlled OPTIC study, teprotumumab met the study’s primary endpoint, which was a responder rate of ≥ 2 mm reduction of proptosis (bulging) in the study eye (without deterioration in the fellow eye) at Week 24. Data from the OPTIC study showed that 82.9% of patients receiving teprotumumab were proptosis responders compared to 9.5% of patients receiving placebo at Week 24 (p<0.001). All secondary endpoints in the study were also met.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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“Antibodies to Watch in 2020” is now online!

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This 2020 installment of the annual ‘Antibodies to Watch’ series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*.  At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry’s clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future.

*Note on key updates through December 20, 2019: 1) the US Food and Drug Administration granted accelerated approval to [fam-]trastuzumab deruxtecan (Enhertu) on December 20, 2019; 2) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 7; 3) the European Commission approved romosozumab on December 9, 2019; 4) the European Medicines Agency issued a positive opinion for brolucizumab; 5) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 6) GlaxoSmithKline submitted a BLA for belantamab mafodotin; 7) Macrogenics submitted a BLA for margetuximab; and 8) the status of the Phase 3 study (NCT04128696) of GSK3359609 in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting.

Good and bad news for antibody-drug conjugates

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On August 23, 2019 GlaxoSmithKline announced positive headline results from the pivotal DREAMM-2 study of the antibody-drug conjugate belantamab mafodotin (GSK2857916) for multiple myeloma. The two-arm study met its primary objective and demonstrated a clinically meaningful overall response rate with belantamab mafodotin in the patient population. The safety and tolerability profile was consistent with that observed in DREAMM-1, the first time in human study of belantamab mafodotin. Data from the DREAMM-2 study will be the basis for regulatory filings starting later this year.

•             Belantamab mafodotin is a humanized anti-B-cell maturation antigen monoclonal antibody that is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin-F.

On August 29, 2019 AbbVie announced that MERU (NCT03033511), a Phase 3 trial evaluating the antibody-drug conjugate rovalpituzumab tesirine (Rova-T) as a first-line maintenance therapy for advanced small-cell lung cancer, demonstrated no survival benefit at a pre-planned interim analysis for patients receiving Rova-T as compared with placebo. The overall safety profile was generally consistent with that observed in previous studies. The MERU trial is being closed, and the Rova-T research and development program has been terminated. AbbVie will move forward prioritizing other development programs within its oncology pipeline.

•             Rovalpituzumab tesirine is an antibody-drug conjugate composed of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine dimer toxin with a drug-to-antibody ratio of 2. The antibody component targets cancer-stem cell-associated delta-like protein 3.

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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’.

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’.