Development of Superactive Analogs of FSH for Human Infertility

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$2,931,156.00
Award Year:
2011
Program:
SBIR
Phase:
Phase II
Contract:
2R44HD060321-04A2
Award Id:
n/a
Agency Tracking Number:
R44HD060321
Solicitation Year:
2011
Solicitation Topic Code:
NICHD
Solicitation Number:
PA10-050
Small Business Information
6 TAFT CRT, STE 150, ROCKVILLE, MD, -
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
063841477
Principal Investigator:
BRUCE WEINTRAUB
(301) 838-1936
bweintraub@trophogen.com
Business Contact:
BRUCE WEINTRAUB
(301) 838-1936
bweintraub@trophogen.com
Research Institution:
Stub




Abstract
DESCRIPTION (provided by applicant): Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, human(h) follicle-stimulating hormone (FSH). Although available urinary and recombinant hFSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularly for older patients and those relatively unresponsive to current therapies. We have previously described the first superactive analogs of glycoprotein hormones that considerably increase receptor binding affinity as well as both in vitro and in vivo biopotency and maximal efficacy. During our successfully completed phase 2 SBIR study we have achieved or exceeded all the aims including screening additional FSH analog candidates and identifying the optimal FSH analog TR 4401 for clinical trials, using multiple in vitro and in vivo rodent bioassay models including the classic ovarian weight response as well as those of oocytes, blastocysts and newborn pups resulting from embryo transfer. In all these rodent models 4401 greatly outperformed all currently available recombinant FSH preparations both in potency and efficacy related to both quantitative endpoints as well as qualitative endpoints related to oocyte or embryo quality. In addition we have shown such superior efficacy of TR4401 to standard FSH in human cell lines with reducedFSH receptor expression representing two models of human infertility, in two bovine models of infertility and in Rhesus monkeys using methods emulating human assisted reproductive technology. We have also shown that one injection of TR4401 in cows could produce comparable superovulation to the standard 8-injection regimen of porcine FSH with no attenuation of response after repeated administration. These nonhuman primate and bovine studies showed no evidence of ovarian hyperstimulation by TR4401 at neithera presumably maximal dose, nor any evidence of immunogenicity, the only two side effects of concern to FDA for this minimally modified, and thus presumably safe, FSH analog. Using an HPLC-validated immunoassay we have discovered superior pharmacokinetic properties of TR4401 in comparison to standard FSH both in rodents and monkeys, apparently the result of delayed absorption. We have also achieved development of a stable Chinese Hamster Ovary (CHO) cell line producing high levels of the final TR4401 analog; optimization of large scale bioreactor production methods; development of novel, high capacity purification methods suitable for commercial scale-up; rigorous quantification and characterization of purified analogs by multiple physicochemical methods including carbohydrate analysis. In the current application, following specific directives from FDA obtained in our highly successful Pre-IND Meeting with them, we propose all steps, including specific timelines indicated on a detailed Gantt chart, required by FDA for further commercial development of this novel FSH analog. These include establishment and characterization of a master and working CHO cell bank; manufacturing of two additional large batches of TR4401 (gt200 mg each): the first under GLP and thesecond under GMP compliant conditions; performance all FDA-required efficacy, specificity, stability, metabolic, pharmacokinetic, pharmacodynamic and analytic studies; performance of all FDA-required toxicology studies including two-generation reproductivetoxicology assessment in rats and rabbits; and submission of IND to initiate clinical trials. We have licensed TR4401 to the worldwide leading veterinary superovulation company, Bioniche, Inc. for veterinary use, with a possible option to also co-developthe analog for human use. PUBLIC HEALTH RELEVANCE: Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, human (h) follicle-stimulating hormone (FSH). Although available urinary and recombinant hFSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularlyfor older patients and those relatively unresponsive to current therapies. We have shown in previous phase one and phase two SBIR grant studies that our novel FSH superagonist, TR4401, engineered to increase binding affinity to the FSH receptor, shows greatly increased potency and efficacy compared to currently available FSH products, in multiple quantitative and qualitative oocyte endpoints in rodents, monkeys, and bovines, with no apparent side effects. We now propose to commercialize this novel FSH analog by following all the specific FDA guidelines given to us in a pre-IND meeting in order to submit an IND to that agency to initiate clinical trials.

* information listed above is at the time of submission.

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