Zenith Epigenetics: ZEN-3694: Resistance is Futile

TSX:RVX | NYSE:PFE

Zenith Epigenetics offers a differentiated approach to bromodomain extra terminal (BET) inhibition. The company’s lead candidate, ZEN-3694, has demonstrated a synergistic ability to resensitize the tumor environment to approved therapies in clinical trials with enzalutamide and talazoparib. The company’s programs focus on metastatic castration resistant prostate cancer (mCRPC) and triple negative breast cancer (TNBC) supported by partners Newsoara (private) and Pfizer (NYSE:PFE). Beyond extending the life of ARSi and PARPi therapies, ZEN-3694 also presents an attractive safety profile with limited and easily manageable adverse events.

The world of BET inhibition expanded in 2013 with the spin out of an oncology-focused group from Resverlogix Corp (TSX:RVX). At that time, Resverlogix had pioneered important advances in BET epigenetics, but was committed to cardiovascular disease; however, the field had a much broader application than just one therapeutic area. Realizing that the potential in oncology would be better realized in a stand-alone unit, management elected to separate the oncology-focused portfolio into a company called Zenith Epigenetics. The new group began using its technology to generate numerous compounds that were screened for specificity, potency, safety and optimal drug-like properties with the most promising candidates isolated for in vivo work. After several years advancing this process, Zenith identified a promising candidate and initiated both a single agent and combination study with enzalutamide in mCRPC patients in 2016. In the following two years, additional data published in scientific journals provided preclinical proof of concept that attracted Pfizer’s (NYSE: PFE) attention which came on as a partner in a Phase II trial. This was followed in August 2019 by a partnership with the Chinese drug developer Newsoara BioPharma Co. which provided upfront payments as well as future milestones and royalties in return for rights to commercialize ZEN-3694 in the greater China region. These successes are leading to further collaborations which will be announced in the near future.

Zenith’s focus on epigenetics is advancing one of the emerging drivers in the biotechnology space. The term epigenetics was first used in the 1940s by Conrad Waddington to explain the type of interactions between the environment and genes that yields a phenotype not associated with changes to DNA. The meaning of the word evolved over time as more was learned about these interactions. In current parlance, epigenetics is the study of the expression of genes into proteins.

Mechanism of Action

Bromodomain and extra terminal inhibitors, BETi, are a class of small molecules that can reversibly bind to bromodomain proteins BRD2, BRD3, BRD4 and BRDT. Their function is to inhibit protein-protein interactions between BET proteins and acetylated histones and transcription factors by binding to bromodomains. BET proteins are of interest due to their ability to target the expression of oncogenes such as MYC (1), AR and CDK6 among others. ZEN-3694 falls into the BETi class and functions as a pan-inhibitor of all four BET proteins.

Many cancers are bromodomain 4 (BRD4) dependent and BRD4 can also drive expression of multiple oncogenes at super-enhancer sites, which are enriched in bromodomain binding sites. Exposure of tumor cells to BETi reduces the level of BRD4 at superenhancer sites and downregulates the expression of key oncogenes (2). Zenith’s in vitro and in vivo experiments have shown that targeting BET proteins inhibits tumor growth in multiple cancer types.

Exhibit I – Chromosome, Chromatin and DNA

Based on our environment, biochemical processes take place in our DNA that deposit chemical tags (such as acetyl or methyl groups) on histone tails that can either stimulate or silence the expression of genes. Enzymes known as readers, writers and erasers are responsible for interacting with and modifying these chemical tags. The tags are identified and interpreted by readers, introduced by writers and removed by erasers. Acetylation, methylation and phosphorylation are the key mechanisms that attach the tags which in turn affect epigenetic expression. In one example, an acetylated lysine attaches to a histone tail which alters the chromatin structure to become more accessible and transcription increases in these regions. Bromodomains, which are amino acid chains, are specific to these acetylated sites and function as readers of lysine acetylation. Often the recognition of specific histone regions by bromodomains is necessary for protein histone association and chromatin remodeling.

Cancer cells hijack the epigenetic mechanism to drive expression of cancer causing genes also known as oncogenes. In some breast and prostate cancers, a signal for cell growth is given when oncogenes such as estrogen or androgen hormones bind to a protein receptor. Bringing the system back into balance is one of the potential benefits of BETi.

Combination therapies with ARS inhibitors and PARP inhibitors

ARSi

Most prostate cancers are dependent on androgen signaling for tumor growth and metastasis. Androgen receptor signaling inhibitors (ARSi), such as enzalutamide, apalutamide and darolutamide are prescribed for mCRPC and antagonize AR signaling. While ARSi are effective in prostate cancer, eventually the prostate cancer becomes resistant. The resistance can be due to the resumption of AR signaling, bypass of AR signaling or through AR independent mechanisms. There is a significant need for therapies that can address this resistance.

The market for ARSi is currently about $4 billion based on 2019 sales as reported in the Evaluate Pharma database. It is forecast to grow to over $5 billion in the next few years and can be materially expanded if a therapy such as ZEN-3694 is able to extend the utility of the ARSi class.

ZEN-3694 can sensitize resistant tumors to targeted therapies in mCRPC. There is even pre-clinical evidence supporting the use of ZEN-3694 in combination with checkpoint inhibitors to address resistance of tumors to this class of drug. Many companies in the space including Zenith are developing BETi in combination with checkpoint inhibitors for multiple tumor types.

Exhibit II – Forecasted Global Market Size for Enzalutamide (3)

Exhibit III - Forecasted Global Market Size for Apalutamide (4)

Exhibit IV - Forecasted Global Market Size for Darolutamide (5)

PARPi

In certain cases when DNA repair is not functioning properly, cancer cells rely on poly ADP-ribose polymerase (PARP) to thrive. PARP steps in when there is a BRCA mutation preventing DNA repair. PARP signals the recruitment of repair proteins which fix single strand breaks in cancer cell DNA thereby allowing the cancer to survive. It serves a backup role for DNA repair when BRCA is broken. A PARP inhibitor (PARPi) can inhibit PARP proteins, which prevents DNA repair and causes the death of the cancer cell. While PARPs work well in patients with BRCA mutations, they do not work so well when BRCA is functioning properly and are able to conduct DNA repair in cancer cells. Normal BRCA genes produce proteins that can repair a double stranded DNA break and stabilize a cell’s genetic structure thereby sidestepping the programmed cell death that occurs when there is a BRCA mutation. This allows cancer cells to progress and bypass the action of PARPi. PARPi as a monotherapy is most effective in triple negative breast cancer (TNBC) patients with the BRCA 1 or 2 gene mutation. However, the majority of TNBC patients do not have the BRCA mutation and do not see a response from PARPi.

Exhibit V – TNBC Addressable Market With and Without BRCA1/2 Mutation (US Patients/%) (6,7)

ZEN-3694 is able to modulate the epigenetic environment so that the cancer cells appear to have properties similar to a BRCA mutation. This change may allow PARP inhibitors to work in patients without the BRCA mutation, providing another line of therapy where few other options exist. This dramatically increases the size of the addressable market for PARPi from the approximate 15% to 20% of TNBC population to a much larger population. If successful, ZEN-3694 will be a very attractive partner for Pfizer and other PARPi players.

MYC Oncogene

One of the most important drivers of mCRPC and TNBC is the MYC oncogene. MYC, or MYC proto-oncogene BHLH transcription factor, encodes a nuclear phosphoprotein that impacts cell cycle progression, apoptosis and cellular transformation. MYC is present in a broad variety of cancers including Burkett lymphoma, carcinomas of the cervix, colon, breast, lung and stomach, mCRPC and TNBC. One of the hurdles faced in MYC-associated cancers is that MYC has long been thought to be undruggable as there is no pocket for binding; therefore, treatments must target the protein indirectly. MYC is a transcription factor that regulates cell proliferation. Aberrant MYC expression leads to cancer by the coordinated activation of transcriptional pathways involved in cell division, metabolic adaptation, and survival. In a research paper by Mertz et al. (8) the authors show that MYC gene expression can be reversed by BETi measured by transcriptional effects and apoptotic responses. Side effect profiles in the in vivo study were suggesting that normal cells are resistant to MYC suppression or function. Downregulating MYC with BETi may produce a potent suppressive effect in cancer cells by cell-cycle arrest and the halt of cellular division (9). MYC is thus viewed as a promising target for anti-cancer drugs.

A BETter Inhibitor

Early BET inhibitors for oncology were based on a benzodiazepine scaffold, a class of drug used as a tranquilizer with a variety of negative side effects and poor drug-like properties. In response, Zenith Epigenetics launched an effort to develop a better BET inhibitor. By using an orthogonal scaffold and a molecule with optimal potency, half-life, and drug like properties, ZEN-3694 was able to demonstrate better oral bioavailability, as well as improved drug interaction, efficacy and safety in pre-clinical models.

Also, many of the oncology studies initially launched with BETi were monotherapy, all-comer studies that were too broad to characterize activity in a well-defined clinical population. Zenith pursued a different clinical strategy, identifying combination therapies in targeted populations which allowed the company to show early clinical proof of concept in a defined indication. This allowed Zenith to move ahead of other companies and become a leader in developing BETi therapeutics for oncology.

Clinical Pipeline

Since it first became a stand-alone entity, Zenith has sought to differentiate itself in the advance of BETi epigenetics. The company’s BET inhibitor candidate, ZEN-3694, has distinguished itself in both preclinical and early clinical work demonstrating an ability to address both mCRPC and TNBC. The company is conducting multiple clinical programs in combination therapies, taking advantage of the synergistic characteristics of BETi to resensitize and expand therapeutic pathways for proven drug regimens.

Exhibit VI – Zenith Pipeline

Metastatic Castration Resistant Prostate Cancer (mCRPC)

Persistent AR signaling provokes cancer proliferation, tumor invasion, and metastasis in mCRPC. First line approaches for prostate cancer begin with chemical or surgical castration followed by androgen deprivation therapy (ADT). For mCRPC, AR antagonist enzalutamide and CYP17A1 (10) inhibitor abiraterone are used. As the cancer adapts to the therapies, patients become resistant to first-line treatments and the mCRPC progresses.

Zenith’s lead program is evaluating ZEN-3694 in patients with mCRPC that have progressed on an ARSi (enzalutamide or abiraterone). The asset is being investigated in a Phase II trial targeting patients that have progressed on an ARSi without having received chemotherapy (11). The trial enrolled 75 subjects and concluded that those on the combination therapy demonstrated a longer time to progression of 39 weeks as compared to an expected 12-24 weeks with other therapies. The data also provided significant insight into the mechanism of action in patients. Samples obtained and analyzed from tumor biopsies demonstrated that ZEN-394 can resensitize AR resistant tumors to enzalutamide.

Now that the Phase IIa combination trial in mCRPC has been completed, Zenith is exploring multiple options for advancing ZEN-3694 with enzalutamide to registration. The registration-enabling trial will be a randomized trial comparing ZEN-3694 and enzalutamide to standard of care. The pathway forward may also include the option for accelerated approval.

Zenith’s second trial targets TNBC. It is enrolling metastatic TNBC (mTNBC) patients that do not have a germline breast cancer (BRCA 1 or 2) mutation. This is approximately 80% of the TNBC market. The Phase Ib/II trial is being run in collaboration with Pfizer and combines ZEN-3694 with talazoparib, a PARP inhibitor. The study will enroll 50 patients and will start with a dose escalation phase followed by a Simon 2-stage design. Phase I, which focused on safety and determining maximum tolerated dose was completed. Now the study has progressed to Phase II which will determine objective response rate (ORR), duration of response (DOR) and rPFS at the recommended phase 2 dose. The first TNBC patient was dosed in June 2019 and an interim readout is expected in 2H:20 with the final readout in the first half of 2021. To date, 16 patients have been dosed and clinical activity is promising with several responses. Zenith and its partner are considering expanding the trial to test the combination of ZEN-3694 and talazoparib in other indications such as ovarian and HR positive breast cancer.

Partnerships

Zenith has developed several important relationships that will help advance ZEN-3694 through development and global commercialization. The lead program counts Shanghai-based Newsoara as a partner which will advance ZEN-3694 through the regulatory process and maintain commercialization rights in China, Hong Kong, Macau and Taiwan. Newsoara agreed to pay $15 million in upfront and near-term development milestones plus another $63 million in sales milestones. It will also make 6% royalty payments that will decline to 4% after exceeding certain sales thresholds.

The most important partnership is with Pfizer which is advancing the combination with PARPi for mTNBC. Pfizer will co-fund the TNBC study and provide talazoparib for use in the trial. Zenith has retained all rights to its drug. If this collaboration is successful and ZEN-3694 is able to sensitize wild-type BRCA patient tumors to PARPi, the therapies will be important companions and ZEN-3694 will likely benefit from Pfizer’s commercialization clout.

Pfizer first began commercializing talazoparib following its October 2018 approval. In the EMBRACA study that was used to support the new drug application (NDA), talazoparib provided a 50.2% objective response rate compared to an 18.4% rate for chemotherapy. The combination of talazoparib with ZEN-3694 can potentially expand the use of the therapy to wild type BRCA genotypes, which comprise the majority of TNBC patients. Research examining a broad selection of BET inhibitors found that the class may synergize with PARPi in HR-proficient cells and tumors to PARPi treatment (12).

Safety and Adverse Events

Safety is a strong point for Zenith’s candidate. The toxicity profile of ZEN-3694 in combination with enzalutamide was favorable in the mCRPC study. The main adverse events were gastrointestinal (GI) toxicity which was managed with the use of anti-emetics. The safety profile for the mTNBC study found thrombocytopenia and GI effects for the BETi/PARPi combo, as expected. The doses of ZEN-3694 and talazoparib were optimized to mitigate these adverse events and the study is on track to define a recommended Phase II dose in the second quarter of 2020.

Summary

Employing epigenetics to cure cancer addresses multiple disease pathways by eliminating problematic proteins and addressing the root of the malignancy. The ability to allow normal expression of healthy genes and discourage the impact of oncogenes provides efficacy while limiting severe side effects. ZEN-3694 is capable of sensitizing cancer pathways for approved drugs that normally encounter resistance after a period of treatment. ZEN-3694 may be able to dramatically extend and expand the ability of these proven therapies to thwart specific types of prostate and breast cancer as well as other cancer areas such as ovarian. The company’s impressive partnerships boast strong collaborators that can efficiently and effectively help ZEN-3694 advance through the development, registration and commercialization process. With good data and friends at large global pharmaceutical companies, Zenith has a clear pathway forward with ZEN-3694.

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1. MYC (MYC Proto-Oncogene, BHLH Transcription Factor) proteins are a family of transcription factors that regulate growth and cell cycle entry by their ability to induce expression of genes required for these processes

2. Stathis, A.; Bertoni, F. BET Proteins as Targets for Anticancer Treatment. Cancer Discov 2018;8:24-36. Published OnlineFirst December 20, 2017.

3. Source: Evaluate Pharma.

4. Source: Evaluate Pharma.

5. Source: Evaluate Pharma.

6. BRCA1/2 mutations were identified in 15.4% of patients in this small study. Sharma, P.; et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Research and Treatment, vol. 145, no. 3, pp. 707–714, 2014. Pie chart is author’s own work.

7. Based on its review, research conducted by Zenith finds the proportion of BRCA1/2 mutations as a proportion of TNBC to fall in between 20-30% of the total.

8. Mertz, J. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011 Oct 4; 108(40): 16669–16674.

9. Delmore, JE et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17. doi: 10.1016/j.cell.2011.08.017. Epub 2011 Sep 1.

10. CYP17A1: cytochrome steroid 17-alpha-hydroxylase/17,20 lyase

11. Chemotherapy patients were avoided for two reasons. The first is related to thrombocytopenia which can result from chemotherapy and associated damage to bone marrow. BETi is also associated with thrombocytopenia which would present an additional risk. The second is related to the target population. More aggressive prostate cancers are treated with chemotherapy while less aggressive types of mCRPC are treated with ARSi which are used in the population anticipated to benefit from the synergy with ZEN-3694.

12. Yang, Lu; et al. Repression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition. Sci Transl Med. 2017 Jul 26; 9(400): eaal1645.