The Rise of the 2nd Gen Antihormonals
Context’s mission is to develop important drugs to treat hormonally-driven cancers. Any drug can be differentiated, but an important drug exhibits the attributes required to directly address unmet needs for patients. Until lately, there has been a dearth of important antihormonal drugs in development.
Why The Sudden Interest In Antihormonals?
The acquisitions of Medivation and Seragon respectively by Pfizer and Roche has had a profound impact on clinical, pharmaceutical, and investor interest in antihormonals. Prior to these acquisitions, there was a general belief that first generation antihormonals, including bicalutamide and fulvestrant, were good enough. The fact that over 75,000 Americans die each year of prostate cancer and hormone receptor positive breast cancer cuts against the notion that “good enough” is really good enough.
The assets that drove those acquisitions - enzalutamide and ARN-810 – were important advancements in our understanding of androgen receptor (AR) and estrogen receptor (ER) biology. In the case of enzalutamide, Medivation showed that by dialing in androgen receptor antagonism and dialing out agonism (a key liability for bicalutamide), patient outcomes in castrate resistant prostate cancer could be vastly improved.[i] In the case of ARN-810, Roche showed the life science community that failure can be just as important as success as both ARN-810 and its successor compound, ARN-927, failed clinically. In the aftermath of those failures, it is now better appreciated that oral SERDs carry toxicity liabilities not necessarily seen in preclinical studies and that full estrogen receptor antagonism is a more relevant determination of clinical activity than degradation.[ii] Despite these two clinical setbacks, Roche is now advancing a 3rd SERD into clinical development – a strong signal of the company’s long-term commitment to developing an oral antiestrogen.
With Medivation and Seragon paving the way, a new generation of companies are racing to develop the next generation of SERDs (AZ, Roche, Sanofi, G1, H3, and others), glucocorticoid receptor antagonists (ORIC), androgen receptor antagonists (CellCentric, Kronos), and progesterone receptor antagonists (Context, Evestra).
The Promise And Challenges Of Hormonally-Driven Cancers
Hormonally-driven cancers, including prostate, breast, gynecological, and some gastrointestinal, are responsible for >100,000 deaths per year in the US. Most patients are treated with antihormonals and chemotherapies that were developed decades ago. A prime example is Fulvestrant, which was discovered in 1984 by Imperial Chemical Industries (9 years before ICI spun out Zeneca!) and the drug is still marketed today thanks to some clever formulation patents.
If the market is so large and the unmet need is so clear, why haven’t more drugs been brought forward to treat hormone-responsive cancers?
There are a multitude of challenges associated with developing drugs to target hormonally-driven cancers:
- Hormonally-driven tumors are “cold” tumors, which limits the therapeutic utility of immune-oncology agents
- Lack of quality cell surface receptors for antibody or CAR-T targeting
- Small molecule inhibition of nuclear receptors is challenging due to off target effects, poor PK, and working with steroidal backbones that slow down analogue development and that increases CMC costs
- Activation of compensatory pathways – for example, blocking estrogen activity in breast cancer will result in stimulation of progesterone activity
With the renewed interest in antihormonals, researchers are receiving the funding and support to chip away at these challenges to deliver new and better antihormonals.
APRISTOR: A Selective PR Antagonist For PR+ Breast Cancer
There aren’t too many ligand receptor pairs wherein the ligand is a carcinogen and the receptor is an oncogene, but that is exactly the case with progesterone and progesterone receptor (PR). During puberty, progesterone is responsible for breast development. In cancer, progesterone levels rise in cancer cells thereby activating PR-mediated growth signaling pathways. There are even some cancer cells where PR is permanently turned on (constitutively active) even in the absence of progesterone.
The attractiveness of progesterone and PR as a breast cancer target has been known for decades, but the challenge has been to develop a pure PR antagonist. Current drugs that target PR (“antiprogestins”), including mifepristone and ulipristal, are dual PR agonists / antagonists. By both activating and inhibiting PR, mifepristone and ulipristal may inhibit PR activity for a period of time, but they ultimately drive their own resistance through their agonist activity. The duality of activity may explain why the clinical activity of antiprogestins thus far has been underwhelming.
Onapristone is the first pure PR antagonist. Onapristone was originally developed as an oral contraceptive by Schering AG. In the mid-1990s as the progesterone receptor became a validated cancer target distinct from the estrogen receptor, Onapristone was tested in two Phase 2 trials across 1st Line Locally Advanced / Metastatic Breast Cancer and 2nd Line Recurrent Metastatic Breast Cancer. The drug was found to be highly active as a monotherapy, but it also had pharmacokinetic (PK) drawbacks that limited its commercial viability – namely, it had a short half-life and high Cmax that resulted in low grade transient liver enzyme elevations in some patients. Due to its poor PK, Schering AG shelved the asset.
Almost a decade passed until the program was resuscitated by Arno Therapeutics. Arno reformulated Onapristone much in the same way that Cubist Pharmaceuticals reformulated and developed daptomycin. Daptomycin is an antibiotic that was developed by Eli Lilly in the 1980s. The drug had a high Cmax that resulted in musculoskeletal system toxicity in 2 of 5 volunteers during a Phase 1 study.[iii] After deprioritizing the asset, Lilly sold daptomycin to Cubist, which then reformulated it to improve the PK properties of the drug and resolve the muscle toxicity. The net result was a highly successful commercial product – Cubicin.
Arno Therapeutics spent considerable effort improving the synthetic route of Onapristone, which in turn generated a highly stable crystalline form that when combined with a unique formulation created a long-acting version of Onapristone – Apristor® – that exhibited ideal PK properties and no drug-associated liver enzyme elevations during Phase 1 trials. In 2017, Context Therapeutics acquired Apristor from Arno Therapeutics.
[i] Scher, 2012, NEJM.
[ii] Metcalfe, C. Not all “SERDs” are equal: Context-independent ER degradation and full ER antagonism define the next generation of ER therapeutics. Presentation, AACR 2018.
[iii] Tally FP, et al. Daptomycin: a novel agent for gram-positive infections. Expert Opin Investig Drugs, 1999, vol. 8 (pg. 1223-38).