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.
Fulvestrant is currently the only FDA approved selective estrogen receptor downregulator (SERD) indicated for breast cancer progressing after previous endocrine therapy and as a first line endocrine agent for metastatic and locally advanced breast cancer. The major limitation of fulvestrant stems from its well-known poor bioavailability and the standard intramuscular route of administration, which could be addressed by the availability of an orally bioavailable, more efficacious SERD. Zenopharm has recently developed ZB716, an orally bioavailable SERD that demonstrated superior bioavailability, pharmacokinetic profiles, and efficacy in multiple breast tumor models. Compared to fulvestrant, ZB716 afforded over 10-fold higher plasma drug concentration in animals at lower dosage. Zenopharm was awarded an SBIR phase 1 grant to initiate key preclinical studies to further demonstrate the feasibility of developing ZB716 for first in human trials. In the phase 2 application we propose to complete all IND-enabling studies in order to obtain approval from FDA to conduct clinical trials. The proposed work includes manufacture of the API for GLP toxicology studies and GMP drug substance and product for clinical use. At the conclusion of this SBIR phase grant, Zenopharm will be able to file an Investigational New Drug application for ZB716 to test safety, tolerability, and pharmacokinetics in humans.