The U.S. Food and Drug Administration (FDA) has rejected sacituzumab govitecan also known as IMMU-132, a novel, investigational, antibody-drug conjugate or ADC consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized monoclonal antibody targeting trophoblastic antigen-2 (Trop2), which is expressed in approximately 80% to 90% of breast cancers.
Triple-negative breast cancer
The investigational drug is designed for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease.
About 15% of all diagnosed breast cancers is triple-negative breast cancer and, according to the American Cancer Society, the an annual incidence of the disease in the United States alone is estimated to be about 40,000 patients, with 20,000 diagnosed with metastatic TNBC, in the United States alone.
Triple-negative breast cancer does not express estrogen, progesterone or the HER2 receptor. As a result, the disease is insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapies like trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies such as tamoxifen or the aromatase inhibitors.
“We believe in sacituzumab govitecan’s potential to be a viable treatment option for these patients,” said Michael Pehl, President and Chief Executive Officer of Immunomedics.
This believe was, in part, based on a Breakthrough Therapy Designation the company received in February 2016 and results from various clinical trials investigating the activity of sacituzumab govitecan in patients with advanced cancers. One of the trials, presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), showed that sacituzumab govitecan, as a single agent demonstrated, had significant clinical activity in heavily pre-treated patients with HR-positive, HER-2-negative metastatic breast cancer and has a predictable and manageable safety profile.
However, regardless of the results of clinical results, on february 17, 2019 Immunimedics confirmed that it has received a Complete Response Letter from the FDA for the Biologics License Application in which the FDA rejected the drugs.
Although the FDA did not raise concerns about the safety or efficacy of sacituzumab govitecan, the disappointing outcome follows serious manufacturing problems identified in the FDA inspection between August 6 and 14, 2018.
“The issues related to approvability in the Complete Response Letter were exclusively focused on Chemistry, Manufacturing and Control matters and no new clinical or preclinical data need to be generated,” Pehl noted.
This investigation revealed that Immunomedics’s quality control unit at the company’s Morris Plains, New Jersey, drug substance manufacturing facility didn’t have the authority to investigate a February 2018 data integrity breach, which didn’t trigger a deviation. This breach included manipulated bioburden samples, misrepresentation of an integrity test procedure in the batch record, and backdating of batch records, such as dates of analytical results.
According to the FDA, Immunomedics did not give an assurance that samples and batch records from commercial batches it manufactured before the data integrity breach were not impacted by it, and the agency was unable to conduct a proper assessment.
As a result of the problems, the FDA cited Immunomedics for multiple violations. However, according to statements to investors in December 2018 made by the company, the identified problems for which the company has been penalized have been addressed and are now (completely) resolved.
“We are going to request a meeting with the FDA as soon as possible to gain a full understanding of the Agency’s requirements and timelines for approval and we will work closely with the FDA,” Pehl said.
“The goal [is to bring] this important medicine to patients as soon as possible,” he concluded.