Femtechs take on women’s health

The once-neglected areas of pregnancy loss and fertility are now hot new areas of research. Hoffmann has collaborated with Henriette Svarre Nielsen, a specialist in obstetrics and gynecology at Copenhagen University Hospital Hvidovre, to analyze DNA in the blood of hundreds of women who had miscarriages.

Their work has focused on cell-free fetal DNA circulating in the maternal bloodstream, which can reveal the health of the fetus while avoiding the need for invasive (and often inaccurate) biopsies, such as amniocentesis, which carry a risk of miscarriage.

Hoffmann and Nielsen used a structural quirk of fetal chromatin to distinguish it from maternal DNA. “You get different chromatin structures, and that means you get different fragment sizes for specific sequences,” says Hoffmann. The pair led the first large-scale validation of cell-free fetal DNA² and found that this non-invasive blood test can detect aneuploidy (where the fetus has an incorrect number of chromosomes) to provide an explanation for pregnancy loss.

The underlying cause of these chromosomal abnormalities, however, remains largely unknown. Hoffmann was involved in a genome-wide association study of more than 100,000 women in the UK Biobank³, which identified mutations in the SYCE2 gene associated with an increased risk of pregnancy loss. SYCE2 is part of a multi-protein complex that controls genetic recombination during meiosis.

Hoffmann is forming a femtech startup to commercialize biomarkers and diagnostics for pregnancy loss. It is funded by the Bioinnovation Institute in Denmark, part of the Novo Nordisk Foundation. The startup will also focus on proteome analysis of plasma using AI to develop predictive models, which should lead to new diagnostics and therapeutics for pregnancy loss further down the line.

For some miscarriages, the cause is not necessarily fetal chromosomal alterations, but the mother’s vaginal microbiome. In 2019, a team led by Gregory Buck at Virginia Commonwealth University showed that preterm birth was associated with vaginal dysbiosis⁴, including the depletion of Lactobacillus species. Lactobacilli, as the name suggests, produce lactic acid, which brings the vaginal pH down to around 4.5 — a range that keeps infections at bay. Several research groups have found depletion of lactobacilli in the vaginal microbiomes of women who experience pregnancy loss, and some studies have associated this microbial imbalance with higher levels of proinflammatory cytokines⁵. These cytokines lead to inflammation, which could be responsible for the symptoms seen in some women with recurrent pregnancy loss, who often have vaginal discomfort and dysbiosis, including discharge during pregnancy. In the same year, the first small trial of vaginal microbiome transplantation took place⁶. A team of microbiologists and gynecologists in Israel treated five women with intractable bacterial vaginosis, four of whom saw remission.

If vaginal microbiome transplantation can treat dysbiosis, then the next logical step would be to treat pregnancy loss with a microbiome transplant. This is precisely what Nielsen aimed to do in 2021 in a proof-of-principle n-of-1 trial, in part funded by Copenhagen-based Freya Biosciences. The cervicovaginal secretions from a healthy donor were safely administered to a woman who had previously experienced recurrent pregnancy loss, resulting in a successful pregnancy. Although the precise bacterial composition of the microbiome transplant was not known, the mother’s vaginal microbiome shifted from a dominance of Gardnerella bacterial species to a mix of Lactobacillus species (dominated by L. crispatus and L. jensenii). Freya secured $38 million in series A funding in December 2023 for further clinical trials using the FB101 microbiota product in women who are undergoing assisted reproduction, with funding led by Sofinnova Partners and OMX Ventures.

Including pregnant women in clinical trials⁷ is a regulatory hurdle most companies have struggled to overcome. The thalidomide scandal, where more than 10,000 children were born with severe deformities after their mothers took the drug during pregnancy, led to tight restrictions on clinical trials from the US Food and Drug Administration (FDA) and global regulators. Some consider such restrictions responsible for slowing the flow of capital into the area: “If the regulatory risk is too high, the investors aren’t willing to put money in,” Obremskey says.

After decades of neglect, female biology is catching up. Geneticist Stasa Stankovic who did her PhD with John Perry at the University of Cambridge, UK, is hoping for commercial opportunities for her discoveries on ovarian aging and menopause timing.

Studies from their team revealed hundreds of genetic determinants of menopausal timing from hundreds of thousands of women of European ancestry, based on data from UK Biobank⁸. What surprised Stankovic was that most of the genes had a shared function: DNA repair. “This is probably one of the unique examples where a single mechanism is so prevalent in the genetic architecture of an individual trait, driving certain risks,” in this case for early menopause, says Stankovic, showing that the ovaries are especially vulnerable to DNA damage. Of particular interest were two DNA damage response genes: Chek1 and Chek2, which repair single-stranded and double-stranded breaks, respectively.

Follow-up studies in mice found that Chek2 knockouts had an increased ovarian reserve, due to reduced rates of apoptosis in the eggs, whereas Chek1 overexpression led to an increased size of the ovarian reserve from birth, with more eggs later in life. Modulating these genes could mean that boosting fertility and delaying menopause is possible.

Because mice neither menstruate nor go through menopause, they are poor models for ovarian health. But human ovarian tissue is precious and rarely used in research, and there are no ovarian cell lines in existence either. Stankovic hopes their cell engineering work, including making cells that produce hormones in vitro, can help to validate targets for drug discovery and speed up preclinical studies. Recent changes at the FDA that allow preclinical testing in organoids, in lieu of animal experiments⁹, will be another boost for the sector.

The in vitro fertilization (IVF) sector, a booming global market that is expected to be worth almost $1 billion by 2026, will benefit from this research, too. Forty percent of women respond poorly to the hormonal stimulation needed to boost the number of eggs needed for IVF. Stankovic and Perry’s research showed that genetic modulation of Chek1 and Chek2 can also increase egg retrieval in mice; such targets could be used to improve the success of IVF. .

Treatments for the menopause — long a drug development desert — will also benefit from new biological insights into ovarian aging. Treatments to target specific symptoms of the menopause, as well as to delay it, would be especially beneficial for the 10% of women who experience early menopause (between the ages of 40 and 45 years) or the 1% who have primary ovarian insufficiency. The May 2023 approval of Astellas Pharma’s Veozah (fezolinetant), a neurokinin 3 receptor antagonist as a treatment for moderate to severe vasomotor symptoms or hot flashes, is a step in this direction.

Several femtechs are pinning their hopes on RNA therapeutics. One of them is Comanche Biopharma, a company developing an siRNA to treat pre-eclampsia — a complication of pregnancy due to high blood pressure that can be fatal to the mother and the baby. The company’s siRNA targets the mRNA encoding a protein called sFlt1, which in 2003 was identified in the blood of women with pre-eclampsia¹⁰. sFlt1 is thought to be produced by the placenta, where it damages blood vessels.

Comanche’s therapy, CBP-4888, is made up of two lipid-conjugated siRNAs, each of which targets a different isoform of sFlt1. CBP-4888 received US FDA fast-track designation last August, after which the biotech raised $75 million of series B financing in January 2024 for further trials to follow its successful phase 1 trial in healthy women of childbearing age.

An sFlt1-based pre-eclampsia test developed by Hennigsdorf, Germany-based Brahms (part of Thermo Fisher Scientific) was approved in 2023 by US regulators. This test will be essential for Comanche’s clinical trials, the company said in a press release. Comanche’s scientific advisors include Nobel Prize-winner Craig Mello, who discovered RNA interference in mammals; Ananth Karumanchi, who identified sFlt1 in pre-eclampsia; and former FDA commissioner Scott Gottlieb, who joined the board at the start of this year, coinciding with the new funding announcement. As with many women’s health conditions, the prevalence of pre-eclampsia is huge, affecting around 2–10% of women in their first pregnancy. Despite identification of sFlt1 as a biomarker, the exact cause of pre-eclampsia is unknown. The only treatment is delivery of the baby.

A growing cadre of companies is focused on urinary incontinence, a much neglected condition that affects between 5% and 69% of women. Weakened muscles in the pelvic floor or urinary sphincter, often as a result of childbirth, lead to reduced pressure in the urethral closure and result in leakage of urine when laughing, exercising or having sex. Versameb, in Basel, Switzerland, hopes to tackle this common condition using mRNA. The company’s research builds on studies of insulin-like growth factor 1 (IGF-1), a signaling molecule that can regenerate the urethral sphincter in animal models¹¹. Levels of IGF-1 fall with age, and so less regeneration occurs as women age. “By the time women have children, we’re really well into the decline of IGF,” says company’s CEO, Klaas Zuideveld. This decline of IGF-1 with age helps explain why postmenopausal women have higher levels of urinary incontinence.

Several teams have tried supplementing levels of IGF-1, but its short half-life means that regular injections of the growth factor are needed. Using IGF-1 mRNA increases the half-life up to 17–20 h and triggers regeneration of the sphincter in preclinical testing, says Zuideveld.

Versameb’s mRNA is shockingly naked compared with the lipid nanoparticles used to deliver COVID-19 mRNA vaccines. The mRNA has a cap and a poly(A) tail added for intracellular stability, along with modified uridines to reduce immunogenicity, and is simply suspended in a citrate buffer. Zuideveld explains that muscle cells are perfect for mRNA therapy, as they actively take up naked mRNA. The lack of a delivery vehicle helps to reduce immunogenicity, which for a treatment, as opposed to a vaccine, is important for the avoidance of side effects. Versameb has received $30 million from international private investors for its first-in-human clinical trials¹², which it hopes will start in the United States this year. After stress urinary incontinence, the biotech will aim for further indications in women’s health, including uterine scarring after caesarean delivery.

Also in Switzerland, Zurich-based Muvon Therapeutics is taking a different approach to regenerating the urinary sphincter: tissue engineering. Muvon was spun out of research at the University of Zurich, where researchers spent over a decade perfecting the cultivation of muscle cells. The process begins with a small muscle biopsy from the lower leg, which is then digested in the lab to isolate muscle precursor cells. Those cells are grown until there are enough to inject into the muscle surrounding the urethra. CEO Deana Mohr was keen to point out that this is not an expensive cell therapy: “We are really doing regenerative medicine designed for scale,” she says, with no genetic modifications of the cells, which allows easy automation of the femtech’s production process. This brings down the cost compared to, say, CAR-T cell therapy, with its half a million dollar price tag.

Muvon has treated nine patients so far in a phase 1 trial¹³, with all patients having an increase in their functional urethral length and a thicker muscle. Mohr and her colleagues are now testing this approach in a larger phase 2 trial¹⁴ of patients with urinary incontinence, with results expected sometime in 2025. Funding is led by “some generous foundations and high-net-worth individuals,” explains Mohr, but remains a challenge. Another challenge is that their approach is new, with no comparable products already on the market. “Although we have so far shown a very good safety and efficacy profile, investors seem to require further de-risking than for other types of technologies,” says Mohr.

Biotechs should listen carefully to women’s needs to shape and drive their innovation, says consultant and patient advocate Fiona McKenzie, who lived for many years with endometriosis. She says that when she received treatments for endometriosis, her doctors were usually interested in her fertility, whereas she “wanted to be able to go back to work. I wanted to live and function, and that was just as important as my fertility.”

Reproductive health scientist Joyce Harper, at the Institute for Women’s Health, University College London, says patient advocates, academic scientists and biotechs should all be encouraged to collaborate to develop evidence-based diagnostics and therapeutics.

All femtechs agree that investment is a challenge, despite the recent uptick in enthusiasm. A women’s health investor forum in 2023 at the New York Stock Exchange attracted 90 potential investors, representing hundreds of millions of investor dollars. But many potential investors are watching and waiting, rather than opening their wallets, says Obremskey, who attended the event. “They are sitting on the sidelines watching for that proof point.”

What the femtech sector really needs is a blockbuster drug, says Obremskey. “We need a success story … that will drive more capital to those kinds of unmet needs and women’s health,” she predicts. Another major boost would come when small femtech companies get acquired by big pharma or go to an initial public offering. This would then lead to a virtuous cycle of more capital flowing into the sector, as rivals look to add fresh women’s health assets to their portfolios, but, she says, “we don’t have that virtuous cycle yet.”