SBIR-STTR Award

IND-enabling Studies of ZB716, an Orally Bioavailable SERD Project Summary Most patients with advanced metastatic breast cancer eventually develop resistance to tamoxifen or aromatase inhibitor (AI) treatment where the recurrent and/or progressive disease retains the expression of ER?. The standard treatment of breast cancer progressing after tamoxifen or AI therapy is fulvestrant which is the only FDA approved selective estrogen receptor degrader (SERD) as a second-line endocrine regimen. Due to its extremely poor oral bioavailability, fulvestrant was administered as a 250 mg/month by intramuscular injection, which was approved in 2002. It takes 3-4 month to reach the steady state serum concentration of fulvestrant at 15 ng/mL in patients. Subsequent clinical trials using 500mg/month with an additional loading dose on day 14 demonstrated significant clinical improvement, leading to the 2011 FDA approval of fulvestrant as a 500 mg injection regimen. However, even at this dosage, the peak blood concentration of fulvestrant remains below a modest 25 ng/mL, and the time to steady-state drug concentration remains about 30 days. These shortcomings of fulvestrant may account for the limited clinical efficacy low patient response rate. Thus, a potent, orally bioavailable SERD has potential for significantly higher receptor knockdown and for more durable clinical benefits than fulvestrant. To date, only two nonsteroidal oral SERDs, GDC-0810 (Genentech) and AZD9496 (AstraZeneca) are being tested in clinical trials. These oral SERDs have very different molecular structures from fulvestrant, are less potent than fulvestrant in preclinical studies, and are at least several years away from being proven clinically safe and efficacious. On the other hand, few reports have described attempts to make orally bioavailable steroidal SERDs and none has progressed to clinical studies. Indeed, these attempts focused on modifications made primarily to the long alkyl chain to increase polarity and solubility but failed to address the main problem that is responsible for the poor bioavailability of fulvestrant, that is, fulvestrant undergoes rapid and extensive O-glucuronidation and O-sulfation to form polar metabolites that are inactive and water soluble. Zenopharm has developed ZB716, a patented steroidal oral SERD that can effectively enhance systemic bioavailability while bypassing first-pass metabolism (glucuronidation and sulfation) of fulvestrant. Preclinical studies confirmed that this chemical modification can retain sufficiently high binding affinity of the steroidal moiety of fulvestrant while minimizing glucuronidation and sulfation. We found that ZB716 binds to ER with high affinity and exerts its antiestrogenic effect on ER-expressing breast cancer cells. In both tamoxifen naive and tamoxifen resistant breast cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose- dependent manner. Moreover, ZB716 is shown to have far superior oral bioavailability in mice compared to fulvestrant. Therefore ZB716 is a viable oral SERD, which can not only overcome the disadvantages associated with injection depot, but more importantly can improve therapeutic efficacy and achieve more durable treatment outcome than the current SERD regimen. To move ZB716 towards clinical trials we propose to conduct IND-enabling studies that will initiate CMC (chemistry, manufacturing, and control) work and investigate the in vivo efficacy of oral ZB716 in two xenograft models. The dose-dependent efficacy studies are the next key steps to determine if the oral bioavailability of ZB716 can be translated to in vivo efficacy. Optimization of synthetic procedure for use in scale-up preparation of GLP and GMP grade ZB716 is necessary to custom-manufacture the API.

Public Health Relevance Statement:
Project Narrative Fulvestrant is currently the only FDA approved selective estrogen receptor degrader (SERD) to treat breast cancer patients with progressing disease after previous endocrine therapy. The major limitation of fulvestrant suffers from the well-known poor bioavailability and the standard intramuscular route of administration have negatively impacted its widespread use. Development of orally bioavailable SERDs to improve therapeutic efficacy and to overcome clinical disadvantages associated with fulvestrant is an ongoing effort. Zenopharm has recently designed, synthesized, and tested ZB716, an orally bioavailable SERD that demonstrated superior bioavailability and pharmacokinetic profiles in mice. Compared to fulvestrant, ZB716 afforded over 10-fold higher plasma drug concentration at a modest dose of 5 mg/kg in mice. If such enhancement of oral bioavailability can be translated to humans, ZB716 holds the promise of being a viable oral SERD, which can not only overcome the disadvantages associated with high-dose intramuscular injection, but more importantly can further increase the therapeutic efficacy and achieve more durable treatment outcome than the current SERD regimen. In this SBIR phase 1 application we propose to optimize method of preparation for ZB716 and to investigate the dose-dependent efficacy of orally administered ZB716. The proposed IND- enabling studies are crucial pre-clinical studies to validate the therapeutic utility of ZB716 and to prepare for IND filing for clinical trials.

Project Terms:
Address; Adopted; Affinity; analytical method; Aromatase Inhibitors; Binding; Bioavailable; Biological Availability; Blood; Blood Circulation; Boronic Acids; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Bypass; Cell Line; Cell Proliferation; Chemicals; Chemistry; Chromatography; Clinical; clinical efficacy; Clinical Research; Clinical Trials; clinically significant; Collaborations; Contracts; Custom; design; Development; Disadvantaged; Disease; dosage; Dose; Dose-Limiting; Drug Exposure; Drug Kinetics; efficacy study; Endocrine; Ensure; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; FDA approved; Fulvestrant; Glucuronides; Health Sciences; Hormone Receptor; hormone therapy; Human; improved; in vivo; Injection of therapeutic agent; Intramuscular; Intramuscular Injections; knock-down; Laboratories; Legal patent; Louisiana; malignant breast neoplasm; Measures; Metabolic; Metabolism; Metastatic breast cancer; Methods; Modification; Molecular Structure; Mus; novel; Nude Mice; Oils; Oral; Patients; Pharmaceutical Preparations; Phase; Plasma; preclinical study; Preparation; PRKCA gene; Procedures; Process; Progressive Disease; Protocols documentation; Qualitative Methods; Quality Control; receptor; Recurrent disease; Regimen; Reporting; Reproducibility; research clinical testing; Resistance; Resistance development; response; Route; Sampling; scale up; Serum; Small Business Innovation Research Grant; Solubility; Spectrometry; standard care; Standardization; Steroids; sulfation; T47D; Tamoxifen; Testing; Therapeutic; therapeutic evaluation; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; treatment group; Treatment outcome; tumor; tumor xenograft; Universities; Unspecified or Sulfate Ion Sulfates; Water; Work; Xenograft Model; Xenograft procedure

Fulvestrant is the only FDA approved selective estrogen receptor downregulator (SERD) indicated for advanced metastatic breast cancer that has progressed after or during tamoxifen or aromatase inhibitor (AI) treatment. In July and August, 2017, fulvestrant was approved as a first line endocrine agent for breast cancer patients by the European Medicines Agency (EMA) and US FDA, respectively. However, the drug is not orally bioavailable; its high-dose monthly regimen of 500 mg as an intramuscular injection had limited drug exposure and ER turnover in patients. The low bioavailability of fulvestrant and its slow action presents clinical challenges because endocrine-resistant tumors require a significantly higher SERD exposure which is insufficient in the fulvestrant treatment. As a result, the clinical response rate to fulvestrant in the advanced metastatic setting remains below 20%. In the first line setting, an oral SERD with greater drug exposure and faster action would bring immediate clinical benefits to patients in numbers that far exceed those who are treated with fulvestrant only as a second line regimen. Thus, an urgent need exists for an orally bioavailable SERD that offers first-line therapy advantages over other endocrine regimens and higher clinical response rates in the second-line setting or beyond. Advances in oral SERDs development have been so far confined to nonsteroidal molecules, and all non-steroidal SERD candidates have yet to be advanced to phase II clinical trials. Zenopharm's lead compound, ZB716, will be the first oral steroidal SERD to enter clinical trials if we are successful in securing the funds to complete the proposed IND-enabling studies. ZB716 has shown promising preclinical data in bioavailability, efficacy, and toxicology. If clinically proven, ZB716 will bring substantial clinical benefits to advanced, metastatic breast cancer patients both as a first-line endocrine therapy and as ER-targeting treatment for recurring diseases after SERM and/or AI therapy. To bring this promising oral SERD candidate to clinical trials we propose to complete remaining FDA required studies both in the CMC (Chemistry, Manufacturing, and Control) and Toxicology category. In Specific Aim 1, Zenopharm will collaborate with Avista Pharma Solutions, a GMP manufacturer on a fee for service basis to optimize process scale up and manufacture 500 g of the API for GLP toxicity studies, and prepare 1 kg GMP batch of API for clinical studies. In Specific Aim 2, Zenopharm will collaborate with Covance to implement the nonclinical development plan following the ICH S9 guidance for the Nonclinical Evaluation for Anticancer Pharmaceuticals. The IND-enabling studies will be conducted to ensure approval for the First in Human study and support the confirmation clinical Proof of Concept study. Completion of the above proposed work will allow Zenopharm to prepare and file an IND application for ZB716 to be tested in the clinic for safety, tolerability, and pharmacokinetic studies. It will also enable the company to secure funds from venture capital firms to conduct the phase 1 clinical trial.

Thesaurus Terms:
Address; Advanced Breast Cancer; Advanced Malignant Neoplasm; Agreement; Animals; Anti-Cancer; Aromatase Inhibitors; Award; Bioavailable; Biological Availability; Breast Cancer Model; Breast Cancer Patient; Canis Familiaris; Capital; Categories; Chemistry; Clinic; Clinical; Clinical Paths; Clinical Research; Clinical Trials; Conduct Clinical Trials; Cyclic Gmp; Data; Development; Development Plans; Disease; Dosage; Dose; Drug Exposure; Drug Kinetics; Drug Metabolism; Drug Synthesis; Endocrine; Ensure; Estrogen Receptors; European; Evaluation; Fda Approved; Fee-For-Service Plans; First-In-Human; Fulvestrant; Funding; Grant; Hormone Therapy; Human; Human Study; In Vitro; In Vivo; Intramuscular; Intramuscular Injections; Investigational New Drug Application; Laboratories; Lead; Malignant Breast Neoplasm; Manufacturer Name; Manufacturing Facility; Medicine; Metastatic Breast Cancer; Methods; Modification; Operation; Oral; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase Ii Clinical Trials; Phase Ii Trial; Plasma; Pre-Clinical; Preclinical Study; Process; Process Optimization; Production; Rattus; Reaction; Recovery; Regimen; Research And Development; Resistance; Response; Rodent; Route; Safety; Safety Testing; Scale Up; Secure; Selective Estrogen Receptor Modulators; Small Business Innovation Research Grant; Stem; Steroids; Tamoxifen; Techniques; Testing; Toxic Effect; Toxicokinetics; Toxicology; Tumor; Work;