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EUA issued for anti-SARS-CoV-2 sotrovimab

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On March 27, 2021, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for sotrovimab (VIR-7831; GSK4182136) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death. The EUA was issued to GlaxoSmithKline.

Sotrovimab, a human anti-SARS-CoV2 antibody, is being evaluated in a Phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result. The EUA is based on an interim analysis of results for 583  patients in the study, 291 and 292  of whom received sotrovimab or placebo, respectively, within five days of onset of COVID-19 symptoms. The primary endpoint was progression of COVID-19 (defined as hospitalization for greater than 24 hours for acute management of any illness or death from any cause) through day 29. Hospitalization or death occurred in 21 (7%) patients who received placebo compared to 3 (1%) patients treated with sotrovimab.

Sotrovimab is administered as a 500 milligram single dose given intravenously over 30 minutes by health care providers.

Prior to the authorization of sotrovimab, FDA issued EUAs for the treatment of mild-to-moderate COVID-19 for two combinations of anti-SARS-CoV-2 monoclonal antibodies. The combination of casirivimab and imdevimab was authorized in November 2020 and the combination of bamlanivimab and etesevimab was authorized in February 2021. In addition, Celltrion’s anti-SARS-CoV-2 antibody regdanvimab (CT-P59; Regkirona) received authorization in South Korea in February 2021.

More than 20 additional anti-SARS-CoV-2 monoclonal antibodies are undergoing evaluation in clinical studies. Of these, 7 monotherapies or combinations are in late-stage clinical studies, including ADG20 (Adagio Therapeutics) and AZD7442 (AstraZeneca). The Antibody Society will continue to track these investigational antibodies and report progress in the future.

Amivantamab granted FDA approval for non-small cell lung cancer

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On May 21, 2021, U.S. Food and Drug Administration approved Rybrevant (amivantamab-vmjw) as the first treatment for adult patients with non-small cell lung cancer (NSCLC) whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Rybrevant received Priority Review and Breakthrough Therapy designation for this indication.

Amivantamab (JNJ-61186372; Janssen Pharmaceutical Companies of Johnson & Johnson) is a human, low-fucose IgG1-based bispecific antibody targeting EGFR and mesenchymal epithelial transition factor (MET) that was created using Genmab’s DuoBody technology. Amivantamab has been shown to function through multiple mechanisms of action in preclinical models of NSCLC with EGFR exon 20 insertion driver mutations, which cause tumor cells to be insensitive to EGFR tyrosine kinase inhibitors.

The efficacy of amivantamab was evaluated in a study of 81 patients with non-small cell lung cancer and EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. In the trial population in which all patients received the drug, the overall response rate was 40% and the median duration of response was 11.1 months, with 63% of patients having a duration of response of 6 months or more.

FDA’s review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For review of amivantamab, the FDA collaborated with the Brazilian Health Regulatory Agency and United Kingdom’s Medicines and Healthcare products Regulatory Agency.

Need help keeping up to date on US and EU approvals?

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.

Loncastuximab tesirine granted first approval by FDA for large B-cell lymphoma

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On April 23, 2021, the  US Food and Drug Administration (FDA) granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA) for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. This marketing application was granted priority review and orphan drug designation by FDA. The review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Loncastuximab tesirine (ADCT-042) is an antibody-drug conjugate composed of an anti-CD19 humanized IgG1k antibody conjugated via a linker to pyrrolobenzodiazepine-dimer toxin that induces the killing of CD19-expressing malignant B cells.

The BLA submission was supported by data from the open-label, single-arm Phase 2 LOTIS 2 study (NCT03589469), which evaluated the safety and efficacy of loncastuximab tesirine for the treatment of patients with relapsed or refractory DLBCL following ≥2 lines of prior systemic therapy. A total of 145 patients received loncastuximab tesirine as an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg for 2 cycles, then 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria. The primary outcome measure is the overall response rate (ORR). Positive initial data from LOTIS 2 were presented during the virtual 25th Annual Congress of the European Hematology Association. The ORR was 48.3% (70/145 patients), the complete response rate was 24.1% (35/145 patients), and the median duration of response was 10.25 months. The toxicity profile was manageable and no new safety concerns were identified.

Need help keeping up to date on US and EU approvals?

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.

Dostarlimab approved by FDA for endometrial cancer

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On April 22, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Jemperli (dostarlimab) for treating patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are deficient in their ability to repair DNA inside the cell, as determined by an FDA-approved test. FDA granted dostarlimab Priority Review and Breakthrough Therapy designations for this indication. Dostarlimab (TS-042, GSK4057190A) is an anti-PD-1 humanized IgG4k antibody generated by Anaptysbio under partnership with Tesaro, which was acquired by GlaxoSmithKline in 2019.

Interim analyses of data for patients with mismatch repair (MMR)-deficient endometrial cancer with recurrent or advanced disease that progressed on a platinum doublet regimen enrolled in the Phase 1 GARNET study (NCT02715284) were reported at the European Society for Medical Oncology (ESMO) Virtual Congress in September 2020. Patients received 500 mg of dostarlimab every 3 weeks for the first 4 cycles, then 1,000 mg every 6 weeks until disease progression or discontinuation. The primary endpoints included confirmed objective response rate (ORR) and duration of response (DOR). The ORR was 44.7% in patients with deficient mismatch repair (dMMR) disease and 13.4% in those with MMR-proficient (MMRp) disease. In the dMMR cohort (n = 103), 11 complete responses, and 35 partial responses were observed. Thirteen patients achieved stable disease, while 39 patients experienced disease progression. In the MMRp cohort (n = 142), 3 patients had complete responses, 16 had partial responses, 31 achieved stable disease, and 77 patients experienced progressive disease. At the time of data cutoff, with a median follow up of 11.2 months, the median DOR had not been reached.

Dostarlimab is also being evaluated as a treatment for various types of cancer in early-stage clinical studies, as well as two Phase 3 studies, RUBY and FIRST. The RUBY study (NCT03981796) is evaluating dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in patients with recurrent or primary advanced endometrial cancer. The primary outcome measure is the progression-free survival (PFS) assessed by an investigator, and the primary completion date is July 2021. The FIRST study (NCT03602859) is a comparison of 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. The primary outcome measure is the PFS and the primary completion date is January 2023.

Need help keeping up to date on US and EU approvals?

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.

Defying the “inevitable” development of type 1 diabetes

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Post written by Raquel Barroso Ferro, University of Aberdeen

Regular exogenous insulin injections, monitoring food and activity levels, increased risk of developing heart and kidney disease. These are some of the many challenges faced by people with type 1 diabetes (T1D), an autoimmune disease where the body’s own immune cells destroy its insulin-producing beta cells. This chronic condition affects over 540,000 children worldwide according to a leading UK charity, and is the second most common childhood disease in the US after asthma (1). Current estimates place a global increase in incidence of 2-5% every year (2), highlighting the increasing number of individuals having to physically, emotionally, and financially bear this burden and the need to develop therapeutics that can prevent, cure or improve the management of this condition.

Development of drugs that can delay the onset of T1D is ongoing. One such drug is teplizumab (hOKT3 γ1(Ala-Ala)), a humanized anti-CD3 monoclonal antibody that has been engineered to have reduced Fc receptor binding. Teplizumab works by modulating T cells, which are immune cells believed to be key players in the destruction of beta cells (3). Maintaining the remaining activity of the beta cells and enabling self-blood glucose control without the need for exogenous influence is critical to controlling the disease.

Results of a Phase 2 study (TrialNet TN10, NCT01030861) of teplizumab reported in 2019 were very promising (4). This randomized, blinded trial investigated if a single two-week course of treatment with teplizumab could delay or prevent the onset of T1D in high-risk individuals that were without a clinical diagnosis of T1D. The researchers observed that over the course of approximately 7 years (July 2011 to November 2018) teplizumab was able to delay the onset of T1D. Furthermore, this trial provided additional evidence of the importance of the T-cell mediated response for the onset of T1D, suggesting the value of using immunomodulation to affect disease development.

Sims et al. (5) extended the follow-up of participants in the original study, and have now reported that the effects persisted in the initial participants who received teplizumab. The median time to onset of T1D was more than double in participants who received teplizumab compared to those who received the placebo (~5 vs 2 years, respectively). Moreover, they observed improvements in beta cell function and, in some, a partial reversal in the decline of insulin secretion. Despite using a small cohort (total study enrolment = 76 participants) and a single 14-day course of drug, the results of this study form the foundation for exciting work in the future to actively prevent the onset of this lifelong condition whose prevalence only seems to be increasing.

A biologics license application for teplizumab for the delay or prevention of clinical T1D in at-risk individuals is undergoing priority review by the U.S. Food and Drug Administration, and their first action on the application is expected by July 2, 2021. The European Medicines Agency is evaluating a marketing authorization application for teplizumab.

References
1.       Menke et al. (2013). The prevalence of type 1 diabetes in the United States. Epidemiology 2013;24:773-774.
2.       Moobaseri et al. (2020).  Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020; 10(2): 98–115. DOI: 10.34172/hpp.2020.18.
3.       Gaglia J, Kissler S. Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707.
4.       Herold et al. (2019). An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019; 381:603-613. DOI:  10.1056/NEJMoa1902226.
5.       Sims et al. (2021).  Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science Translational Medicine. 13 (583); eabc8980. DOI: 10.1126/scitranslmed.abc8980.