Despite their initial promise, so far the group of drugs called antibody-drug conjugates have not transformed cancer medicine. Sacituzumab govitecan is one of the more exciting developmental agents in this group of therapies. This agent features prominently in one of the first Highlights covered from 3 Things in Biotech You Should Learn Today. So I thought we should learn a little more about it!
This page was last updated on June 20.
Developer of sacituzumab govitecan
Immunomedics is the main developer of sacituzumab govitecan. There are currently no major partners for this drug. Back in January 2018, the company licensed royalty rights to Royalty Pharma. This provided Immunomedics with cash needed to advance the product to market. It did not entail any sort of commitment from Royalty Pharma to develop the drug.
Immunomedics did have a partnership with Seattle Genetics. However, legal action caused the deal to sink due to an Immunomedics shareholder disputing the licensing arrangement.
Mechanism of action of sacituzumab govitecan
Antibody-drug conjugates are drugs that combine the highly specific targeting potential of an antibody with a highly toxic payload. So we have two pieces for sacituzumab govitecan:
- An antibody targeting TROP-2, a cell surface marker expressed on various solid tumors
- SN-38, the active metabolite of the chemotherapy irinotecan
Here is a mockup of how the drug works.
Step 1: The antibody portion of the drug binds to TROP-2 molecules on the surface of the cell. The antibody interaction makes this an incredibly specific targeting for the SN-38 payload.
Next, whenever an antibody binds to the cell surface, there is a chance that the cell will use a process called “endocytosis” to move the proteins inside. This helps the cell sort out unusual molecules so it can send them to lysosomes where they’ll be degraded. Importantly, the mechanism of action makes use of this degradation process.
Once absorbed into the cell, the antibody is broken up into bits by the protein-degrading machinery of the cell. This is a normal process to prevent unusual proteins from building up and causing damage to the cell. However, in this case, degradation of the antibody deploys the SN-38.
Once released in the cell, SN-38 disrupts proper DNA replication, leading to double-strand breaks that overwhelm the cancer cell. This damage leads to controlled cell death, also called apoptosis.
Overall, this method of targeting has two major benefits. First, we can generally avoid highly toxic side effects by delivering lethal agents right to the tumor cells expressing the marker we want to target. Second, when the cell dies, it will release some of its contents into the surrounding area. This increases the chance of hitting other cancer cells nearby, potentially killing off even those cancer cells that don’t have the TROP-2 marker.
Diseases of interest
Triple-negative breast cancer
The biggest indication that IMMU is looking to tackle with this agent is triple-negative breast cancer. This is a molecular subgroup lacking in three key features:
- High estrogen receptor expression
- Elevated progesterone receptor expression
- High HER2 expression
Basically, triple-negative breast cancer is the absence of three receptors that would normally tell the doctor the best path forward for management. In the case of estrogen/progesterone receptor-positive breast cancer, you can give the patient anti-hormone therapy. This is often good enough to control the disease for years. The same goes for HER2-positive breast cancer, where you can give patients anti-HER2 molecules like trastuzumab (Herceptin) or pertuzumab (Perjeta).
These therapies are good enough to cover upwards of 80 to 85% of patients with breast cancer. If they lack the markers, however, there are very few good options. You had chemotherapy yes, and now we have PARP inihibitors like olaparib for women with BRCA mutations. Still, the pack of therapies is not huge, and researchers have been looking for a long time for something that can help.
Enter sacituzumab govitecan. This agent demonstrated strong response rates in heavily pretreated disease. This was shown in a phase 2 study at he 2017 San Antonio Breast Cancer Symposium. Patients achieved a 34% overall response rate with sacituzumab govitecan. Now, the ongoing ASCENT study is testing the antibody-drug conjugate in comparison with chemotherapy for patients who have had no prior therapy.
It’s no surprise that the FDA granted this drug Breakthrough Therapy designation, which may greatly speed along the development of the agent. Accelerated approval is even a possibility, given the strength of the phase 2 findings.
Hormone receptor-positive breast cancer
At ASCO 2018, we also saw that sacituzumab govitecan could also provide disease control for patients with estrogen/progesterone receptor-positive breast cancer. Here is the waterfall plot, which shows the individual tumor responses. Each patient is one bar on this graph:
This translates into an overall response rate of 31%, which is impressive considering the typical patient in this study had 5 prior lines of therapy, including 2 prior lines of chemotherapy! So this suggests that IMMU could be onto a serious treatment option for late-line, hormone-positive breast cancer, as well.
The next most advanced indication for sacituzumab govitecan is urothelial cancer, which is a form of cancer occurring anywhere in the urinary system, including the bladder. Last time we heard from the company in this line was ESMO 2017, where IMMU showed off some impressive response and clinical benefit rates, including in patients who have relapsed on prior chemotherapy and immune checkpoint inhibitors.
For those keeping score at home, that basically exhausts all options!
Response rates ranged from 34% to 39% in these patients, and in the overall population, progression-free survival was an encouraging 7.2 months, with 15.5 months overall survival. While it’s still early to tell, it is clear that sacituzumab govitecan has some very interesting legs in bladder cancer.
Key headlines relating to sacituzumab govitecan
Commentary: This is important news because it sets up another future direction for both Clovis and Immunomedics.
Commentary: This is another direction Immunomedics might be able to take the franchise in next. Although ER-positive breast cancer currently has a rapidly expanding arsenal of tools at its disposal, later-line therapy remains an unmet need. So this should be considered an early guiding light for potential investors.
Commentary: No surprise, given the favorable results the company saw in phase 2.
Commentary: This is a huge piece of the puzzle for IMMU. As of this writing, there is no word yet on whether the FDA has accepted the application, but I expect this will come any day now (as of June 20).
So what can we do with this information? For my sake, I would follow the same principles in trading that I outline in the No BS Plan, which you can learn more about here! Thank you very much for reading.
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