Context Therapeutics’ lead candidate ONA-XR prevents interaction between progesterone and its receptor, downregulates cancer stem cell mobilization and blocks immune evasion.
A lot of companies are developing therapies targeting women’s cancers – breast, ovarian and endometrial – but none of them are curative beyond, perhaps, early-stage diagnoses. Even if the tumor is removed, it recurs in 5-10% of patients. One of the reasons is that tumors become non-responsive to estrogen-based approaches over time.
Context Therapeutics is addressing that gap by targeting progesterone receptors. Its pipeline, therefore, targets those receptors specifically for hormone-driven female cancers.
“Estrogen and progesterone are the drivers for about 70% of breast, ovarian and endometrial cancer patients. The industry has had great estrogen blockers for 30 or 40 years, but hasn’t yet developed a progesterone blocker,” Martin Lehr, co-founder and CEO, told BioSpace. That’s a problem, he explained, because “Cancer cells are very smart. If you block estrogen, they will make progesterone and will activate other signaling pathways to promote their survival.
“Progesterone is strongly immunosuppressive, which makes the tumors inherently cold and unresponsive to immunotherapies. Our collaborators at the University of Kansas Cancer Center showed at the American Association of Cancer Research (AACR) 2022 annual meeting that when you block the progesterone receptor, you potentially can turn the tumors from cold to hot,” Lehr said.
Courtesy of Context Therapeutics
Context Therapeutics’ lead compound, onapristone extended release (ONA-XR), is an oral progesterone receptor antagonist that is taken twice daily. ONA-XR prevents interaction between progesterone and its receptor, downregulates cancer stem cell mobilization and blocks immune evasion. Basically, it primes the cancer cells to be more responsive to combination therapy and to anti-hormonal therapy.
Phase Ib/II and Phase II trials are underway involving ONA-XR for:
- first-line metastatic breast cancer
- second-line metastatic breast cancer
- granulosa cell tumor in ovarian cancer (which has FDA Fast Track designation)
- recurrent endometrial cancer
Updates for each program are expected this year. Biomarkers are used for patient selection. “If a patient has the progesterone receptor, there is a better chance she will respond to this drug,” Lehr said.
ONA-XR data presented at AACR by Lauryn Werner, M.D./Ph.D. candidate showed nearly complete inhibition of progesterone-positive mammary gland tumors. At day 25 post-administration, tumor volume was near zero compared to a volume exceeding 150 cubic millimeters for placebo-treated subjects. Werner noted that depletion of T cells decreased the efficacy of ONA-XR, underscoring the role of the progesterone receptor in immune regulation.
Other data at AACR highlighted an immuno-oncology approach involving the CDK4/6 inhibitor and the progesterone receptor, which suggest another way to use ONA-XR.
That study, presented by Elisabetta Marangoni, Ph.D. from Institut Curie, indicated that the combination of fulvestrant, ONA-XR and palbociclib decreased tumor volume. When ONA-XR was administered alone, or when fulvestrant and palbociclib were administered in combination, however, tumor volume grew. Therefore, she concluded, “The triple combination decreased the interaction between progesterone receptors and estrogen receptors, down-regulated estrogen response and proliferation genes, and upregulated genes involved in cell death, interferon responses, Kirsten rat sarcoma virus (KRAS), tumor necrosis factor alpha (TNFα) and signal transducer and activator of transcription 3 or 5 (STAT3/5) signaling.”
ONA-XR also has the potential to be combined with selective estrogen receptor degraders or PI3Kα inhibitors.
“We’re also interested in bi-specific antibodies,” Lehr said. The company is developing an anti-claudin 6 x anti-CD3 bispecific monoclonal antibody known as CLDN6xCD3 bsAb. Currently in the preclinical stage, the goal of the program is to redirect T-cell mediated lysis toward malignant cells that express claudin 6.
“CD3 is a well-known T-cell engager that has wonderful efficacy, and clinicians are doing a much better job of managing its toxicity,” Lehr said, but, “Claudin 6 is a totally new target.” As an oncofetal protein, it is required for fetal development but is transcriptionally repressed at birth. “It is highly enriched in gynecologic cancers and, to a lesser extent, in testicular, lung and gastric cancers. It is a unique, cancer-only target.”
The challenge, however, is that claudin 6 is part of a family of about two dozen claudin proteins that Lehr said “are reasonably widely expressed” throughout our bodies. Inhibiting them causes significant toxicities, such as lipase activation “which is a hallmark of pancreatic stress and a precursor to pancreatitis. Our task, therefore, is to thread the needle.
“Selectivity is extremely important,” he said. Therefore, the claudin 6 binding arm Context Therapeutics designed is more than 100 times more selective for that antibody than for claudin 9 (which is expressed in the gut and ears), and possibly 10 times more selective than competing anti-claudin 6 therapeutics.
Other companies are also developing therapeutics targeting claudin 6. BioNTech, for example, is combining CAR T therapy with mRNA. The company reported an overall 43% response rate and a disease control rate of 86% in initial trials reported at the recent AACR annual meeting. That work further validated the claudin 6 target for Context Therapeutics.
Lehr’s goal, he said, is to build Context Therapeutics into “a strong, independent biotech company that is focused preclinical through Phase II projects, and that has a scalable team and infrastructure.”
“We don’t need a huge research team, because there’s more than enough good science to bring in, and we don’t need a huge commercial sales force because we can (hopefully) partner with large pharma.” It’s even comfortably funded. After going public last October, the company raised approximately $60 million in Q4 2021. “That gives us cash into 2024,” Lehr said.
To execute, he said, “We just need a well-oiled machine to focus on the middle area of drug development.”
