Background

Infertility is a large and growing issue in the Western world as the birth rate slows down and populations age. It is estimated that there are almost 13 million infertile women in Europe and US. According to Harris Williams and Co., the fertility pharmaceutical sector is estimated to be $1.5bn in the U.S. alone and primarily consists of drugs that induce ovulation.

Technology Overview

Changes in Th1/Th2 immunity during reproduction are well established and the role of immune dysfunction related to infertility is well known. For example there is general agreement that pregnancy is associated with Th2 dominance while Th1 immune response is associated with embryonic rejection.

Figure 1: Low Dose Tacrolimus Significantly Improves Egg Implantation.

To that end Queen’s University researchers have discovered that low dose tacrolimus (well below current clinical doses), and related macrolides, have vast potential for treating infertility across the whole treatment paradigm. This includes treating diseases related to causing infertility and the current last hope for infertile women – in vitro fertilization (IVF). Major causes of infertility include endometriosis and polycystic ovarian syndrome (PCOS). In preclinical mouse models of PCOS, notorious for being infertile, low dose tacrolimus enhanced both ovulation AND egg implantation. This is unlike any other drug currently used in the marketplace which simply stimulate ovulation. In fact, enhancing implantation is the “holy grail” of infertility and IVF. In these animals, fed a continuous 60% high fat diet, low dose tacrolimus completely corrected underlying defects associated with infertility including preventing weight gain/inducing weight loss, normalizing blood lipids, significantly reducing androgens and corrected glucose homeostasis. Developmental toxicology studies supported the safety of low dose tacrolimus and other macrolides in reproduction.

Figure 2: Normalization of Androgens in Low Dose Tacrolimus Treated PCOS Mice.

Associated with these remarkable effects were correction of Th1 cytokines and restoration of a Th2 phenotype. For example treatment reduced levels of Th1 cytokines such as interferon-gamma, TNFα and IL-16 while increasing Th2 cytokines such Il-4 and Il-6. Furthermore measurable changes in these and other biomarkers will enable for optimizing embryo implantation in IVF and following treatment efficacy.

Further Details

A recently published clinical trial demonstrated that low dose tacrolimus can successfully treat women with repeated implantation failure.¹ The pregnancy success rate in treated women exceeded 60% compared to 0 in untreated women.

Nakagawa K et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015 Apr;73(4):353-61.

State of Development

Clinical development (505(b)(2) pathway in US

Benefits

Increase success rate of IVF by stimulating ovulation AND enhancing implantation
Treats underlying causes of female infertility including PCOS, type II diabetes, obesity, dyslipidaemia, correcting dysfunctional glucose homeostasis
Corrects female hormone imbalances - significantly reduces androgens

Applications

Treatment of causes of female infertility including: Polycystic Ovarian Syndrome (PCOS), endometriosis, recurrent implantation failure, obesity and type II diabetes
Enhance success rest of IVF: by stimulating ovulation AND enhancing egg implantation

Opportunity

Available for exclusive licensing

Novel Treatment for Female Infertility

Patents

IP Status

Seeking