Preclinical validation of an effective oral fulvestrant product as the future standard of care endocrine therapy for ER+ metastatic breast cancer

ABSTRACT Breast cancer is the most commonly diagnosed form of cancer globally and, when progressed to the metastatic setting, remains an incurable disease. For the roughly 80% of patients with estrogen receptor positive (ER+) breast cancer, endocrine therapies (ETs) are effective at limiting tumor proliferation in both the adjuvant (i.e., preventative) and metastatic settings. However, ETs are susceptible to acquired resistance resulting in disease progression. Progression is addressed by changing treatment, which is repeated as necessary in order to maximize the duration of response, balanced by maintaining an acceptable quality of life. Therefore, improving survival of ER+ metastatic breast cancer (mBC) patients requires the development of new therapies or improvement of existing therapies to increase the potency and/or duration of each line of treatment. Fulvestrant is a potent and well tolerated selective estrogen receptor degrader (SERD), a type of ET, used as part of the standard of care, but the clinical efficacy is limited by its poor solubility, which currently requires administration as a painful monthly intramuscular injection at the maximum feasible dose. The resulting low, steady exposure yields sub-optimal efficacy and contributes to acquired resistance. To overcome these limitations, VeraMorph has leveraged its novel “DPOD” oral drug delivery technology to transform fulvestrant into an effective oral treatment with higher maximum plasma concentrations that simultaneously can improve patient quality of life. Since optimizing the oral formulation, preclinical studies have shown that oral fulvestrant is well tolerated and significantly improves exposure. PK studies with oral fulvestrant in rodents achieved maximum plasma concentrations up to 400 ng/mL, roughly 20 times that achieved clinically by IM fulvestrant, which resulted in 55% more effective tumor growth inhibition than IM fulvestrant in a cell derived xenograft (CDX) study using MCF7-based tumors. This Fast Track project will expand this proof of concept in a metastatic and ET-resistant CDX model (Phase I) before progressing into IND-enabling safety studies of the oral fulvestrant product and the DPOD technology, additional efficacy studies in a patient derived xenograft (PDX) and immunocompetent mouse model, which all resemble real world conditions, and prepare an IND for clinical translation (Phase II). The end goal is to commercialize oral fulvestrant as the new standard of care oral ET for ER+ mBC that can also complement existing ETs in order to prolong patient response and improve survival statistics. Alternative novel oral SERDs have only shown superiority over IM fulvestrant for patients that have progressed on prior ET and have developed ESR1 mutations, which only account for about 20% of ER+ mBC patients. Thus, for the majority of these patients, oral fulvestrant provides an opportunity to improve clinical outcomes with minimal risk. Additionally, development of oral fulvestrant will simultaneously validate the DPOD platform as a safe and effective oral delivery system for poorly soluble drugs, which account for 9 out of 10 drugs in pharmaceutical pipelines and 4 out of 10 approved products. Therefore, a secondary outcome of this SBIR Fast Track project will be to enable the development of more effective oral therapies across a broad swath of diseases currently addressed by poorly soluble drugs.