While in vitro fertilization (IVF) rates have improved dramatically, they certainly have plenty of room for improvement.

"There's still about 30 percent of patients who aren't having positive pregnancy tests and around 40 percent who aren't having a live birth" after embryo transfer, Lucky Sekhon, a reproductive endocrinologist at Reproductive Medicine Associates of New York, told BioWorld Insight. And that's for the most viable embryos and doesn't include patients who fail before getting to that stage.

Earlier this month, at the 74th annual meeting of the American Society of Reproductive Medicine (ASRM), in Denver, researchers presented studies on drugs and basic research to help improve the success of in vitro fertilization at every stage of the process.

Starts with the eggs

To improve the egg retrieval step, Basel, Switzerland-based Myovant Sciences Ltd. is developing MVT-602, a kisspeptin-1 receptor agonist.

Kisspeptin is an upstream orchestrator of reproductive hormones. Stimulating the kis-speptin-1 receptor leads to gonadotropin-releasing hormone secretion, which, in turn, triggers the release of follicle-stimulating hormone and luteinizing hormone (LH) that stimulate egg maturation and ovulation, respectively.

By working upstream, Myovant believes it can produce an LH surge that more closely mimics the normal menstrual cycle, thereby avoiding the likelihood of ovarian hyper-stimulation syndrome, a side effect of some ovulation triggers that results in swollen, painful ovaries.

"People in the field are very interested in finding triggers that don't cause this," Lynn Seely, president and CEO of Myovant, told BioWorld Insight.

At ASRM, Myovant presented phase I data testing three doses of MVT-602 in 24 healthy female volunteers, showing median peak serum LH increases from baseline of 3.5 IU/L, 10 IU/L and 8.1 IU/L for the 0.3-ug, 1-ug and 3-ug doses, respectively, compared to 3.6 IU/L for placebo. The peak occurred about 24 hours after dosing and returned to baseline approximately 72 hours after dosing, a duration that Seely said was what the company was hoping to see.

Myovant has started enrolling a phase IIa study in 70 healthy female volunteers using a mini ovulation stimulation protocol testing four different doses of MVT-602. Myovant hopes to determine the best dose and optimal time of administration relative to other medications used in the stimulation process and then move into a trial testing the drug in patients undergoing IVF.

Growing longer

"The thing that's considered most cutting edge currently in our field, which has really changed the game, is the ability to extend the culture of embryos past day two, day three, all the way up to day five, six and seven," Sekhon explained.

Growing the embryos longer allows doctors to genetically test some of the cells from the layer of the embryo that eventually gives rise to the placenta, which can help doctors avoid using embryos with genetic adorations, such as chromosomal copy number that will make them unviable.

Also, by day five, the embryo has become a more differentiated blastocyst that can be graded based on morphology, allowing for the selection of embryos with the best likelihood of implantation and development.

"While we know that we can do it, we know that only 60 percent of fertilized eggs actually make it to that stage and are eligible for that genetic testing," Sekhon said. "If there was a way to improve the rate of blastulation – the rates of embryos getting to that developmental stage – then a lot more patients would have success with IVF."

To help understand the growth process, Sekhon and colleagues measured gene expression of 81 embryos at different stages of development, noting that genes mediating mitochondrial function, such as CISD1, ISCA1, MFN2, MRPL42 and SUCLG1, are up-regulated at the morula stage, which occurs between the cleavage stage on day three and the development of a blastocyst.

"This corroborates the theory that the morula stage is where the conversion of anaerobic metabolism changes to aerobic metabolism," Sekhon explained. "We know that energy mobilization pathways are key to that transition, so perhaps we need to make culture media more energy rich."

Implantation

To improve fetus implantation, Obseva SA, of Geneva, is developing nolasiban, an oxytocin receptor antagonist. Oxytocin stimulates contraction of muscles of the uterus during child delivery, but it's also present in non-pregnant women and can cause some compaction of the uterus, which has been associated with lower embryo implantation rates. Inhibiting the oxytocin receptor also increases blood flow in the endometrium, which may aid in embryo transfer as well.

In the phase III Implant 2 study, nolasiban improved the chance of ongoing pregnancy 10 weeks after embryo transfer with a rate of 35.6 percent, compared to 28.5 percent for patients who got placebo (p=0.031). Just looking at women who were able to transfer embryos that developed to day five, nolasiban resulted in a higher ongoing pregnancy rate of 45.9 percent, compared to 34.7 percent for placebo (p=0.034). (See BioWorld, Feb. 27, 2018.)

At ASRM, Obseva presented additional data from Implant 2 showing the improved pregnancy rates resulted in more live births. The live birth rate for nolasiban-treated patients was 34.8 percent, compared to 27.7 percent for patients receiving placebo (p=0.025). Again, looking at the subset of patients who had transfers of day five embryos, the live birth rate was 44.8 percent for patients receiving nolasiban, compared to 33.2 percent for those receiving placebo (p=0.025).

EU regulators have indicated that they need to see a second phase III trial before approving nolasiban, which Obseva plans to start by the end of the year. The study will focus on day five embryos using ongoing pregnancy rate as the primary endpoint. With the blessing of the EMA, Obseva plans to submit the MAA with those data and then add the live birth rate during the review process.

In the U.S., Obseva is still in talks with the FDA, but Ernest Loumaye, co-founder and CEO of Obseva, told BioWorld Insight he expects the agency will also want a second study run in the U.S., and the company plans to run that as a separate study.

With the EU market about four times larger than the U.S. in terms of number of cycles – largely because IVF cycles are usually covered by health insurance in Europe – Obseva is understandably in a hurry to launch in the EU.

"We don't want to delay the European submission pending the U.S. trial," Loumaye said, noting that Obseva can run the European study "from start to finish within 12 months" and at one-third the cost compared to the U.S.