Zenopharm, LLC — Department of Health and Human Services SBIR Phase I: 102

Description

IND enabling Studies of ZB 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 mg month by intramuscular injection which was approved in It takes month to reach the steady state serum concentration of fulvestrant at ng mL in patients Subsequent clinical trials using mg month with an additional loading dose on day demonstrated significant clinical improvement leading to the FDA approval of fulvestrant as a mg injection regimen However even at this dosage the peak blood concentration of fulvestrant remains below a modest ng mL and the time to steady state drug concentration remains about 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 Genentech and AZD 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 ZB 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 ZB 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 ZB potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose dependent manner Moreover ZB is shown to have far superior oral bioavailability in mice compared to fulvestrant Therefore ZB 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 ZB 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 ZB in two xenograft models The dose dependent efficacy studies are the next key steps to determine if the oral bioavailability of ZB can be translated to in vivo efficacy Optimization of synthetic procedure for use in scale up preparation of GLP and GMP grade ZB is necessary to custom manufacture the API 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 ZB an orally bioavailable SERD that demonstrated superior bioavailability and pharmacokinetic profiles in mice Compared to fulvestrant ZB afforded over fold higher plasma drug concentration at a modest dose of mg kg in mice If such enhancement of oral bioavailability can be translated to humans ZB 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 application we propose to optimize method of preparation for ZB and to investigate the dose dependent efficacy of orally administered ZB The proposed IND enabling studies are crucial pre clinical studies to validate the therapeutic utility of ZB and to prepare for IND filing for clinical trials