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U.S. Food and Drug Administration Rejects Sacituzumab Govitecan

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.

In an edition of The Onco’Zine Brief on PRX (Public Radio Exchange), recorded during the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, June 1 – 5, 2018, Peter Hofland and Sonia Portillo spoke with Michael Pehl, President and Chief Executive Officer of Immunomedics about advancements in the development of targeted anti-cancer drugs such as antibody-drug conjugates. Developing successful antibody-drug conjugates has remained a challenge for several decades. And to date only 4 different antibody-drug conjugates have been approved for the treatment of various forms of cancer. Hofland and Portillo ask Pehl how antibody-drug conjugate can be used for the treatment of advanced or metastatic triple negative breast cancer, a form of breast cancer that occurs in about 10% – 20% of all cases of breast cancer. Hofland and Portillo also spoke with Pehl about Immunomedics submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for a new antibody-body drug conjugate for the treatment of patients with advanced or metastatic triple negative breast cancer who previously received at least two prior therapies for metastatic disease [Click here to listen to the program].
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.

Viable treatment
“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.

Next steps
“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.

Last Editorial Review: January 18, 2019

Featured Image: Pink ribbon for the breast cancer awareness. Courtesy: © Fotolia. Used with permission.

Copyright © 2010 – 2019 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


CPhI Worldwide 2015, Antibody-drug Conjugates and Market Progression

Ahead of CPhI Worldwide 2015, CPhI expert panelist, Vivek Sharma, CEO of Pharma Solutions at Piramal, analyses the challenges in developing and manufacturing of Antibody-drug Conjugates (ADCs) and how the market has progressed over the past few years.

Major challenges faced by companies looking to enter the ADCs market are the availability of technologies, which are few as yet, and the complex supply chain to manage while going for the clinics. Many a time a sponsor ends up working with 4 different CMOs before the clinical supplies are available for dosing – one each for antibody, cytotoxic molecules, the ADC conjugate & the Fill/Finish. Add to it the availability of quality CMOs in the space and this becomes a major stumbling block for the ADC player.

Most high potent facilities are not suitably designed to produce biologics (i.e. environmental standards, particularly microbiological controls may be inadequate) and, similarly, most biologics facilities don’t have high potent capabilities – so it is rare to find a recognized, credible manufacturer that operates in both fields.

Hugely under resourced
As such, despite the increase in development targets for ADCs, the global contract manufacturing sector still remains hugely under resourced, with only a couple of players having the experience & necessary regulatory approvals to commercialize these products.

Piramal is one of the longest established ADC producers (beginning in 2004) and the main challenge when they transitioned was moving from the high potent field to biologics and combining the two practices for successful conjugation. For many CMOs entering this space now, the real issue is building a facility with high containment in mind. Furthermore, having the desired skillsets to work efficiently with ADCs is crucial, as each new ADC requires specialist adoption and a track record of prior experience is understandably what all pharma companies are searching for in a partner.

ADC manufacturing involves a complex supply chain and it is a major concern for pharma clients, as they seek to de-risk the process as much as possible. So, our view is that you will see pharma consolidating a majority of their projects with a few specialized players.

Linker chemistry improvements
Looking at the industry as a whole, over the past few years, we have definitely seen improvement over the aggregation of proteins. In the past, first generation drug linkers would produce 20-30% aggregation of proteins, which is a big problem as it gives a low yield. However, through linker chemistry improvements this has now dropped to 1-2% of aggregation, which is a giant step forward. The next stage is a consolidation amongst specialists.

Supply chain
The complexity of the supply chain and market demand for looking at projects more in their entirety, from production of mAb all the way through to fill/finish; the more parts of these that can be aligned, the easier it is for all parties. There is definitely a distinct benefit for the client, particularly if the different supply chain areas are across the same company – with shared project management, established point of contacts, and using the same quality and release systems.

Some of the industry’s most active producers of antibody-drug conjugates – Almac, Calalent, Lonza and Piramal – will be in attendance at CPhI Worldwide 2015.

Last Editorial Review: October 2, 2015

Feature Image: IFEMA – Feria de Madrid, Madrid, Spain. Feature image Courtesy: © IFEMA – Feria de Madrid, Madrid, Spain. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. CC BY-SA 3.0

Copyright © 2015 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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