FDA Pipeline: Breakthrough Designations in CML and for Cachexia, EUA for COVID-19

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Recently, the U.S. Food and Drug Administration (FDA) issued a Breakthrough Therapy designation to asciminib for chronic myeloid leukemia (CML); a Breakthrough Device designation to an assay designed to help select patients with cachexia for treatment with an investigational therapeutic; and an Emergency Use Authorization for a combination of monoclonal antibodies for the treatment of COVID-19.

Breakthrough Therapy Designations for Asciminib in Chronic Myeloid Leukemia

Asciminib—a novel investigational treatment specifically targeting the ABL myristoyl pocket (STAMP)—has been granted Breakthrough Therapy designation for the treatment of adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase previously treated with two or more tyrosine kinase inhibitors. Asciminib was also granted Breakthrough Therapy designation for the treatment of adult patients with Philadelphia chromosome–positive CML in chronic phase harboring a T315I mutation.

These FDA designations were based on the pivotal phase III ASCEMBL trial, where asciminib was compared with bosutinib in patients Philadelphia chromosome–positive CML in chronic phase previously treated with two or more tyrosine kinase inhibitors, as well as a phase I trial that included patients with Philadelphia chromosome–positive CML, some of them with a T315I mutation.

ASCEMBL is the first head-to-head clinical trial in CML using a second-generation tyrosine kinase inhibitor as a comparator. As a phase III multicenter, open-label, randomized study, ASCEMBL was designed to evaluate superiority in major molecular response rate at 24 weeks of the oral investigational treatment asciminib (ABL001) vs bosutinib in patients with Philadelphia chromosome–positive CML in chronic phase previously treated with two or more tyrosine kinase inhibitors. Patients with failure or intolerance to the most recently administered tyrosine kinase inhibitors were included in the trial.

Data from ASCEMBL was presented at the 2020 American Society of Hematology Annual Meeting and Exposition (Abstract LBA4).

Breakthrough Device Designation for GDF-15 Assay to Identify Patients Suitable for Cachexia Treatment

The FDA granted Breakthrough Device designation to the Elecsys GDF-15 assay as a companion diagnostic in cancer treatment. This in vitro diagnostic immunoassay is intended for measurement of growth differentiation factor-15 (GDF-15) in cachectic patients aged 18 and older with solid tumors for treatment with the investigational drug PF-06946860.

Cachexia is a metabolic disorder and comorbidity that occurs with several chronic diseases including cancer, heart failure, chronic obstructive pulmonary disease, and chronic kidney disease. It impacts more than 30 million people globally. Cachexia manifests as marked involuntary body weight loss, muscle atrophy, and reduced appetite, progressing to significant functional impairment and increased risk of death.

Cachexia is a highly prevalent complication of cancer, affecting between 50% to 80% of all patients with cancer. This range depends on the tumor type, the patient response to tumor progression, and on individual body type. Elevated GDF-15 is associated with cachexia in patients with cancer.
Elecsys GDF-15 is a quantitative serologic, two-incubation step electrochemiluminescence immunoassay (ECLIA) using the sandwich test format for the detection of GDF-15 in human serum. The ECLIA is intended for use on cobas e immunoassay analyzers. GDF-15 has CE approval in several intended uses in cardiology including risk prediction of major bleeding events of atrial fibrillation patients, and risk stratification of patients with acute coronary syndrome or chronic heart failure.

FDA Issues EUA for Monoclonal Antibodies in the Treatment of COVID-19

On February 9, the FDA issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (aged 12 years or older weighing at least 40 kg [about 88 lb]) who test positive for SARS-CoV-2 and who are at high risk for progression to severe COVID-19. The authorized use includes treatment for those aged 65 or older or who have certain chronic medical conditions.

In a clinical trial of patients with COVID-19 at high risk for disease progression, a single intravenous infusion of bamlanivimab and etesevimab administered together significantly reduced COVID-19–related hospitalization and death during 29 days of follow-up compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continue to be evaluated.

Bamlanivimab and etesevimab are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. Treatment with bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. Bamlanivimab and etesevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells. Bamlanivimab and etesevimab bind to different but overlapping sites on the spike protein of the virus.

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that bamlanivimab and etesevimab administered together may be effective in treating certain patients with mild or moderate COVID-19. When used to treat COVID-19 for the authorized population, the known and potential benefits of these antibodies outweigh the known and potential risks. There are no adequate, approved, and available alternative treatments to bamlanivimab and etesevimab administered together for the authorized population.

The data supporting this EUA for bamlanivimab and etesevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 1,035 nonhospitalized adults with mild to moderate COVID-19 symptoms who were at high risk for progressing to severe COVID-19. Of these patients, 518 received a single infusion of bamlanivimab at 2,800 mg and etesevimab at 2,800 mg together; 517 received placebo. The primary endpoint was COVID-19 related hospitalizations or death due to any cause during 29 days of follow-up.  Hospitalization or death occurred in 36 (7%) patients who received placebo compared to 11 (2%) patients treated with the combination therapy, a 70% reduction. All 10 deaths (2%) deaths occurred in the placebo group.

The authorized dosage of 700 mg of bamlanivimab and 1,400 mg of etesevimab administered together is based on analyses of available preclinical, clinical, and virologic data, as well as pharmacokinetic and pharmacodynamic modeling, which, in totality, support that the authorized dosage is expected to have a similar clinical and virologic effect to 2,800 mg of bamlanivimab and 2,800 mg of etesevimab administered together.

On November 9, 2020, the FDA issued an EUA for a single infusion of 700 mg of bamlanivimab for the treatment of mild to moderate COVID-19 in adult and certain pediatric patients. While bamlanivimab and etesevimab administered together resulted in a lower risk of resistant viruses developing during treatment compared with bamlanivimab administered alone, both treatments are expected to benefit patients at high risk of disease progression. At present, both 700 mg of bamlanivimab alone as well as 700 mg of bamlanivimab and 1,400 mg of etesevimab administered together will be available under an EUA.  

Under the EUA, fact sheets that provide important information about using bamlanivimab and etesevimab administered together in treating COVID-19 as authorized must be made available to health-care providers as well as patients and caregivers. These fact sheets include dosing instructions, potential side effects, and drug interactions. Serious and unexpected adverse events including hypersensitivity, anaphylaxis, and infusion-related reactions have been observed with bamlanivimab with and without coadministration of etesevimab. In addition, clinical worsening following bamlanivimab administration has been reported, although it is not known if these events were related to bamlanivimab use or were due to progression of COVID-19. Possible side effects of bamlanivimab and etesevimab administered together include nausea, dizziness, pruritus, and rash.

The EUA was issued to Eli Lilly and Co.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.