The following is part one in a two-part series examining the state of the fertility market. This part focuses on biotechnology companies' development of new drugs to improve the success and safety of in vitro fertilization, the most commonly used assisted reproduction method. The second part will center on a new assisted reproduction technology that could reduce the high costs associated with IVF.

In vitro fertilization is viewed as the high-tech, gold standard of fertility treatment, and yet the procedure relies on drugs that are decades-old and prone to side effects.

Infertility is defined as difficulty or inability getting pregnant after a year of trying. The condition — which impacts up to 15% of couples, according to the Mayo Clinic — has a variety of causes in both sexes, and oftentimes is not fully understood. One of the most commonly cited causes in women is failure to ovulate, while low or abnormal sperm production is commonly diagnosed in men.

The fertility market is a fast-growing sector of the healthcare industry, climbing at a compound annual growth rate of slightly above 10% per year, according to Grand View Research and investment bank Harris Williams. And yet, conditions of infertility have seen virtually no new pharmaceutical entrants since the revolutionary treatment was introduced 40 years ago. Currently, the global fertility services market is valued at about $20.4 billion, MarketWatch reported in April 2019.

Big pharma has "vastly abandoned" the infertility space, according to Ernest Loumaye, CEO of women's health-centric company ObsEva SA. This could be due to a lack of innovation and concerns about liability when developing drugs related to pregnancy, Loumaye said. In their absence, fertility clinics and services providers have stepped up and represent a larger portion of the fertility sector.

The ART of infertility

Despite the wide range of conditions that can lead to infertility, a small handful of pharmaceutical products are used to treat the conditions. Infertility in women is most often treated with medications like estrogen modulators and hormones, particularly gonadotropins and human chorionic gonadotropin. Most of these drugs have been around for decades, as early as the 1960s.

Some of the drugs are approved by the U.S. Food and Drug Administration specifically for ovulation stimulation in women with failure to ovulate, but physicians use many therapies on an off-label basis. Prescribing medications beyond their FDA-approved use is legal in the U.S., and is known as off-label prescribing because the indication is not on the product's label. Erectile dysfunction therapy Viagra, produced by Pfizer Inc., and hormone-based chemotherapy letrozole are examples of products used off-label to treat conditions of infertility.

The same ovulation- and hormone-stimulating drugs are also used to assist the more active and innovative field of assisted reproductive technology, or ART, of which IVF is one of the more common procedures.

According to the National Institute of Child Health and Human Development, ART is most often employed by those who cannot be treated with infertility drugs alone, such as women with damage to the fallopian tubes or severe endometriosis, or who have already tried other treatments without success. IVF has the highest success rate compared to other methods like intrauterine insemination. Approximately 1 in 3 women ultimately achieve live birth following IVF, said Loumaye.

A typical IVF cycle involves stimulation of the ovaries to produce many eggs at once, then an outpatient surgery to remove the eggs from the ovaries. The eggs are fertilized in a lab, then transferred back into the woman's uterus. Transfer can occur either in the same cycle, or the embryos are frozen for later.

"We're basically harnessing the body's natural hormones to trigger egg maturation," said Lynn Seely, CEO of Brisbane, Calif.-based Myovant Sciences Ltd., which is developing potential treatments to improve the IVF process. "The hormones they have now are quite old, and there hasn't been a lot of innovation in this space. And they were not ideal."

Human chorionic gonadotropin, which is commonly used to stimulate the ovaries to produce multiple eggs and trigger ovulation, can cause over-stimulation of the ovaries, leading in severe cases to ovarian hyperstimulation syndrome. OHSS is one of the most serious risks of IVF, and can cause rapid weight gain, severe pain, kidney failure, and pregnancy loss and miscarriage. Severe OHSS occurs in just 1% to 2% of women undergoing ovarian stimulation, while a mild form of the disorder can occur in as many as 33% of women, according to the U.K.'s Royal College of Obstetricians and Gynaecologists.

Women at high risk, such as those with polycystic ovarian syndrome, have an estimated 20% chance of developing severe OHSS, according to Myovant.

"Reproductive endocrinologists have to track very carefully the number of follicles that are maturing," Seely said. "If there are too many or they become concerned, they have to abort the cycle."

Myovant is developing MVT-602, which could provide a different pathway to ovulation, to address the hormonal preparation and egg retrieval portion of IVF. The drug is a kisspeptin agonist that stimulates the kisspeptin pathway, a hormonal pathway responsible for the onset of puberty in males and females. The pathway also leads to ovulation each month in women. Seely said the product, now in phase 2 trials, could stimulate the hypothalamus in the brain to produce a hormone, which goes to the pituitary and then makes the luteinizing hormone that ultimately triggers ovulation.

Addressing the 'black box'

ObsEva, meanwhile, is aiming to improve outcomes of the embryo transfer step in IVF, which is a major reason for the treatment's failure. Once the embryo is transferred to the uterus, it should implant into the lining to establish a pregnancy.

"Nobody understands why so few embryos implant," Loumaye said. "That's a black box."

Chromosome abnormalities can affect implantation of the embryo, Loumaye said, but even after adjusting for such events, the rate of successful embryo transfer is still about 50%.

"All the quality embryos that we now have, the quality labs, the quality procedures, the efforts clinics put into guiding the patients — they seem to hit the ceiling," ObsEva Chief Commercial Officer Wim Souverijns said.

Uterus contractions and insufficient blood flow during embryo transplant are two likely causes of implantation failure, according to Loumaye. The two may be related, as uterus contractions can affect blood flow. ObsEva's nolasiban seeks to address these two issues as an antagonist of oxytocin, the natural hormone that induces contractions and reduces blood flow in the uterus.

"Maybe if we inhibit that hormone, the uterus will be more relaxed, there will be more blood, and we will have more pregnancies," Loumaye said.

Nolasiban was shown in a phase 3 study to increase live birth rates compared to placebo in couples undergoing IVF. According to Souverijns, including nolasiban in the treatment plan could reduce the average number of cycles for success from three cycles to two.

"It's a huge physical pain, there's a strong emotional pain, and there's a financial cost to it as well, particularly in countries like the U.S. ... where most of the time it's out of pocket," Souverijns said.

Due to the high cost of IVF, Souverijns said patients will sometimes elect for a double or multiple embryo transplant to increase the live birth rate. Almost 55% of embryo transfers are double embryo transfers, according to Leerink analyst Ami Fadia, which is "not ideal from a patient safety perspective." Double transfers are controversial, and many countries have urged fertility care providers to go with a single embryo transfer as the standard of care.

A double transfer ups the risk of a multiple pregnancy to about 40%, putting the woman at risk of severe complications including death. Multiple births are also more costly, and typically end in a preterm delivery and time in the neonatal ICU, placing the cost of birth into the hundreds of thousands of dollars, Souverijns said.

While IVF itself is typically an out-of-pocket expense in the U.S., payers often pick up the bill for costs related to multiple births. Souverijns said nolasiban could become an attractive option to payers due to the potential reduction in multiple embryo transfers and multiple births.

"It could change the landscape in that respect," he said.

ObsEva's nolasiban is in a second phase 3 trial in Europe to support a possible 2021 EU approval and launch. The Swiss biotech will initiate a U.S.-based phase 3 trial in late 2019 or early 2020 for FDA filing, according to a June 19 release.

"Nolasiban will likely be the only treatment option to increase IVF success rates, an unmet need that has been increasing in recent years," Fadia said. She expects the drug to cost $1,400 to $2,000. IVF patients are willing to pay $3,000 to $4,000 for pre-implantation genetics testing, which suggests nolasiban's price tag is reasonable if it can reduce miscarriage or failure rates.

Treating infertility before IVF

Both Myovant and ObsEva also have drug candidates that may treat endometriosis and uterine fibroids, two common women's health conditions that can lead to infertility.

According to the companies, endometriosis and infertility in particular have a major overlap. Approximately half of the women evaluated for infertility have endometriosis, and oftentimes are diagnosed for the first time only when they become aware of their infertility, Seely said.

"The best way to really decrease our rates of infertility over time is to start to address some of these diseases which result in infertility at an earlier stage, before women have to have IVF," Seely said.