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The Antibody Society

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FDA approves isatuximab-irfc for multiple myeloma

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On March 2, 2020, the U.S. Food and Drug Administration (FDA) approved Sarclisa (isatuximab-irfc), in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. FDA granted isatuximab Orphan Drug designation for multiple myeloma. Developed by Sanofi, isatuximab (SAR650984) is a chimeric IgG1 antibody directed against CD38 expressed on malignant plasma cells. The antibody acts through a combination of mechanisms, which may depend on the expression level of the target.

The approval was based on the results of the Phase 3 ICARIA-MM study (NCT02990338) demonstrating a statistically significant improvement in progression-free survival (PFS). This study included 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Patients who received Sarclisa in combination with pomalidomide and low-dose dexamethasone showed improvement in PFS, with a 40% reduction in the risk of disease progression or death compared to patients who received pomalidomide and dexamethasone. These patients also had an overall response rate of 60.4%. Patients who only received pomalidomide and low-dose dexamethasone had an overall response rate of 35.3%.

The European Medicines Agency is currently evaluating a marketing authorization application for isatuximab for the treatment of relapsed/refractory multiple myeloma.

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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FDA approves eptinezumab-jjmr for preventative treatment of migraine

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H. Lundbeck A/S has announced that Vyepti™ (eptinezumab-jjmr) was approved by the U.S. Food and Drug Administration for the preventive treatment of migraine in adults and will be available in April 2020. The recommended dosage is 100 mg as an intravenous infusion over approximately 30 minutes every 3 months; some patients may benefit from a dosage of 300 mg. Lundbeck expects to submit eptinezumab for approval to regulatory authorities in the European Union during 2020, followed by submissions for approval in other regions. Development of eptinezumab was initiated by Alder BioPharmaceuticals, Inc., which was acquired by Lundbeck in October 2019.

Eptinezumab-jjmr is a humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand. It is produced in Pichia pastoris yeast cells by recombinant DNA technology. The safety of VYEPTI was evaluated in over 2000 patients with migraine who received at least one dose of the drug. The approval was supported by positive results from the PROMISE 1 (NCT02559895) and PROMISE 2 (NCT02974153) Phase 3 clinical trials, which investigated eptinezumab for episodic and chronic migraine prevention, respectively. In PROMISE-1, a total of 665 patients were randomized to receive placebo (N=222), 100 mg Vyepti (N=221), or 300 mg Vyepti (N=222) every 3 months for 12 months. Mean migraine frequency at baseline was approximately 8.6 migraine days per month and was similar across treatment groups; mean change from baseline in monthly migraine days (MMD) with Vyepti compared with placebo months 1-3 was -3.9 days for 100 mg (p=0.018), -4.3 days for 300 mg (p<0.001), and -3.2 days for placebo. In PROMISE-2, a total of 1,072 patients were randomized to receive placebo (N=366), 100 mg Vyepti (N=356) or 300 mg Vyepti (N=350) every 3 months for 6 months. Mean migraine frequency at baseline was approximately 16.1 migraine days per month and was similar across treatment groups. Mean change from baseline in MMD compared with placebo months 1-3 was -7.7 days for 100 mg (p<0.001), -8.2 days for 300 mg (p<0.001), and -5.6 days for placebo

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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Two new antibody therapeutics enter regulatory review

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Biologics license applications (BLA) for tanezumab and dostarlimab have been submitted by Pfizer and GlaxoSmithKline, respectively.

Tanezumab is a humanized IgG2 antibody that selectively targets nerve growth factor. It has a novel mechanism compared to opioids and other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), and, in studies to date, tanezumab has not demonstrated a risk of addiction, misuse or dependence. FDA granted Fast Track designation for tanezumab for the treatment of osteoarthritis pain and chronic lower back pain. During a Q4 earnings conference call on January 28, 2020, Pfizer announced that it completed a marketing application submission for tanezumab in December 2019. This submission was done in close collaboration with the FDA, and it includes the 2.5 mg dose in moderate-to-severe osteoarthritis patients. A decision on the application may occur by the end of 2020. The submission was confirmed by development partner Eli Lilly. Tanezumab is also being evaluated in Phase 3 study of patients with cancer pain due to bone metastasis who are taking background opioid therapy.

Dostarlimab (TSR-042) is a humanized IgG4 antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. Dostarlimab is being developed by Tesaro (a division of GlaxoSmithKline) for the treatment of solid tumors, including endometrial cancer that could be classified as microsatellite stable (MSS/75%) or microsatellite instability-high (MSI-H/25%). GlaxoSmithKline’s BLA is for dostarlimab as second-line treatment of recurrent endometrial cancer. Tesaro is also evaluating dostarlimab as a treatment for ovarian cancer in the Phase 3 FIRST study (NCT03602859). This study will compare platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of Stage III or IV non-mucinous epithelial ovarian cancer.

Tanezumab and dostarlimab are now queued for a possible first approval in 2020 along with 13 other antibody therapeutics:

  1. Isatuximab, a humanized IgG1 targeting CD38 for multiple myeloma
  2. Inebilizumab, a humanized IgG1 targeting CD19 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  3. Eptinezumab, a humanized IgG1 targeting CGRP for migraine prevention
  4. Leronlimab, a humanized IgG4 targeting CCR5 for HIV infection
  5. Sacituzumab govitecan, a humanized IgG1 antibody-drug conjugate targeting TROP-2 for  triple-negative breast cancer
  6. Satralizumab, a humanized IgG2 targeting IL-6R for neuromyelitis optica spectrum disorder
  7. Narsoplimab, a human IgG4 targeting MASP-2 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  8. Tafasitamab, a humanized IgG1 CD19 for diffuse large B-cell lymphoma
  9. REGNEB3, mixture of 3 human IgG1 targeting the Ebola virus for Ebola virus infection
  10. Naxitamab, a humanized IgG1 targeting GD2 for high-risk neuroblastoma and refractory osteomedullary disease
  11. Oportuzumab monatox, a humanized scFv immunotoxin targeting EpCAM for bladder cancer
  12. Belantamab mafodotin, a humanized IgG1 ADC targeting B-cell maturation antigen for multiple myeloma
  13. Margetuximab, a chimeric IgG1  targeting HER2 for HER2+ metastatic breast cancer

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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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.