Company
Portfolio Data
Back to Company SearchZenopharm, LLC
UEI: H8MEQ3719HM3
Number of Employees: 2
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
SBIR/STTR Involvement
Year of first award: 2017
1
Phase I Awards
1
Phase II Awards
100%
Conversion Rate
$298,524
Phase I Dollars
$1,994,552
Phase II Dollars
$2,293,076
Total Awarded
Awards
IND-Enabling Studies of ZB716, an Orally Bioavailable SERD
Amount: $1,994,552 Topic: 102
Project Summary Fulvestrant is the only FDA approved selective estrogen receptor downregulatorSERDindicated for advanced metastatic breast cancer that has progressed after or during tamoxifen or aromatase inhibitorAItreatmentIn July and Augustfulvestrant was approved as a first line endocrine agent for breast cancer patients by the European Medicines AgencyEMAand US FDArespectivelyHoweverthe drug is not orally bioavailableits high dose monthly regimen ofmg as an intramuscular injection had limited drug exposure and ER turnover in patientsThe 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 treatmentAs a resultthe clinical response rate to fulvestrant in the advanced metastatic setting remains belowIn the first line settingan 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 regimenThusan 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 beyondAdvances in oral SERDs development have been so far confined to nonsteroidal moleculesand all non steroidal SERD candidates have yet to be advanced to phase II clinical trialsZenopharmandapos s lead compoundZBwill be the first oral steroidal SERD to enter clinical trials if we are successful in securing the funds to complete the proposed IND enabling studiesZBhas shown promising preclinical data in bioavailabilityefficacyand toxicologyIf clinically provenZBwill bring substantial clinical benefits to advancedmetastatic breast cancer patients both as a first line endocrine therapy and as ER targeting treatment for recurring diseases after SERM and or AI therapyTo bring this promising oral SERD candidate to clinical trials we propose to complete remaining FDA required studies both in the CMCChemistryManufacturingand Controland Toxicology categoryIn Specific AimZenopharm will collaborate with Avista Pharma Solutionsa GMP manufacturer on a fee for service basis to optimize process scale up and manufactureg of the API for GLP toxicity studiesand preparekg GMP batch of API for clinical studiesIn Specific AimZenopharm will collaborate with Covance to implement the nonclinical development plan following the ICH Sguidance for the Nonclinical Evaluation for Anticancer PharmaceuticalsThe IND enabling studies will be conducted to ensure approval for the First in Human study and support the confirmation clinical Proof of Concept studyCompletion of the above proposed work will allow Zenopharm to prepare and file an IND application for ZBto be tested in the clinic for safetytolerabilityand pharmacokinetic studiesIt will also enable the company to secure funds from venture capital firms to conduct the phaseclinical trial Project Narrative Fulvestrant is currently the only FDA approved selective estrogen receptor downregulatorSERDindicated for breast cancer progressing after previous endocrine therapy and as a first line endocrine agent for metastatic and locally advanced breast cancerThe major limitation of fulvestrant stems from its well known poor bioavailability and the standard intramuscular route of administrationwhich could be addressed by the availability of an orally bioavailablemore efficacious SERDZenopharm has recently developed ZBan orally bioavailable SERD that demonstrated superior bioavailabilitypharmacokinetic profilesand efficacy in multiple breast tumor modelsCompared to fulvestrantZBafforded overfold higher plasma drug concentration in animals at lower dosageZenopharm was awarded an SBIR phasegrant to initiate key preclinical studies to further demonstrate the feasibility of developing ZBfor first in human trialsIn the phaseapplication we propose to complete all IND enabling studies in order to obtain approval from FDA to conduct clinical trialsThe proposed work includes manufacture of the API for GLP toxicology studies and GMP drug substance and product for clinical useAt the conclusion of this SBIR phase grantZenopharm will be able to file an Investigational New Drug application for ZBto test safetytolerabilityand pharmacokinetics in humans
Tagged as:
SBIR
Phase II
2018
HHS
NIH
IND Enabling Studies of ZB an Orally Bioavailable SERD
Amount: $298,524 Topic: 102
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
Tagged as:
SBIR
Phase I
2017
HHS
NIH