Can We Fix Ovarian Aging? Here Is One Startup Up For The Task!
The field of female reproductive longevity and inequality is getting more and more attention. In fact, it is one of the hottest areas of the emerging longevity biotechnology industry, and every venture firm in the field is either investing, incubating, or looking for projects in this area. Companies like BOLD Capital, Future Ventures, LongeVC, and iconic biotechnology investors including Bob Nelsen and Christian Angermayer, are all active and significant partners in this area of science. While females generally live longer than men, their reproductive period is limited—something that is often overlooked. A female’s peak reproductive years are between the late teens and late 20s. Fertility starts to decline by age 30, and this decline becomes more rapid once women reach the mid-30s. By 45, fertility declines so much that getting pregnant naturally is unlikely for most women. Likewise, women begin life with a fixed number of eggs in their ovaries, usually around one million. This number decreases as women age. Ovaries age faster than the rest of a woman’s body—an understudied phenomenon of a neglected organ. None of us would be here without them. Yet surprisingly little is known about the avocado-shaped organ that’s nestled inside half of all humans.
What’s up with the ovaries?
The ovaries also influence a woman’s overall health and well-being. This includes how they age, since this organ tends to lose its function with age faster than any other tissue. This is called asynchronous aging, and it’s one reason why a woman’s fertility declines, and menopause strikes, while they are still relatively young.
In one of my previous articles, I wrote about Gameto, a biotechnology company that is translating the impact of ovarian aging to develop solutions to improve fertility and stop the impact of menopause on female health. Gameto’s co-founder and CEO Dina Radenkovic told me about her intention to redefine the narrative around female reproductive longevity and making it more around health and longevity. Gameto is building a platform for ovarian therapeutics to address menopause and improve assisted fertility. Dina told me she hopes it will make women suffer fewer health problems in their later lives. Neglecting the ovaries—except for their crucial role in IVF treatments—has been part of a general disregard for many aspects of women’s health in the biomedical world.
What surprises me is this: If overall life expectancy is increasing, and it has consistently over the past decade, then shouldn’t there be more focus on extending female reproductive life too? Without extending female reproductive life, we are worsening gender inequality in society.
Just two years ago, Nature published a major study out of Stanford University on the variability in rates of cellular aging in 17 major organs. These included the heart, kidney, and spleen—but not the ovaries, despite it being #1 among organs that rapidly age and are known to influence cellular aging in the rest of the body upon their decline.
Investing in Female Reproductive Longevity
Luckily, tides are turning, and female reproductive longevity and inequality are rapidly turning into the hottest research areas in longevity science and investment themes in longevity venture capital.
“I think women’s reproductive longevity is becoming an interesting investment sector because it’s at the nexus of several important trends. Research in this space is finally getting the recognition and influx of talent that it so desperately needs, thanks in large part to efforts of people like Jennifer Garrison who have been championing the needs of the field. Second, investors are recognizing that addressing longevity without attending to women’s reproductive longevity is a laughably incomplete picture. Finally, in the last few years incredible entrepreneurs are taking the risk and entering the space with scientifically credible companies”, says Maryanna Saenko, a celebrity venture capitalist who co-pilots Future Ventures together with Steve Jurvetson. Saenko and Jurvetson recently backed Gameto and Cambrian Biosciences.
Oviva Therapeutics – Longevity Through Ovarian Health
In 2020, molecular biologist Daisy Robinton, while working with a biotechnology company to help develop a potential treatment for COVID-19, was told by male colleagues on a Zoom call to consider excluding female mice from testing to avoid unpredictable ‘noise’ that they believe can obfuscate clear conclusions. Daisy—a 35 year-old Harvard PhD who is fast becoming a Millennial firebrand on the topic of women’s health in TEDx and other talks—kept her cool so as not to be labeled “difficult,” “something that women in science—or any discipline—have to always be aware of,” she said. Taking a deep breath on the Zoom call, she suggested as calmly as possible that including female physiology is critical to developing any therapeutic to be used for a general population.
In the Spring of 2020 Daisy joined Cambrian Biopharma, which is developing therapeutics to combat the diseases of aging like cancer, heart disease, and Alzheimer’s disease. She convinced Cambrian co-founder and CEO James Peyer, a biologist and former venture capitalist, to add the aging of ovaries to his company’s roster. This led a few months later to the formation of a new company under the Cambrian umbrella co-founded by Daisy called Oviva Therapeutics, powered by $11.5 million in seed funding—a big number for a just-hatched company.
The focus of Daisy’s company emerged out of her concern and curiosity about her own fertility. In 2018, at age 31, she began to wonder about her own prospects for having children in the future—since kids now seemed a ways off—she began a deep-dive into issues of fertility. This included what was known, and not known, about the ovaries. “I discovered that the ovaries are the first organ that really goes kaput,” she said, “leading to an accelerated decline in health for women—affecting bone density, cardiovascular health, sexual function, metabolism, and on and on.”
Overall, she noted, cellular aging accelerates an average of six percent after women reach menopause, typically beginning at age 52. “And yet we have not put a lot of funding or effort into studying and understanding what this means for our health or how to create solutions to improve the negative consequences,” she said.
Teaming up with Harvard molecular biologist and reproductive biology expert David Pépin, Daisy learned that a hormone produced by the ovaries called Anti-Mullerian Hormone (AMH) might be used to extend the functional life of the ovaries. Normally, AMH is used in IVF to measure the fertility of a patient. Pépin was experimenting with it to see if it would slow the progression of ovarian cancer.
That’s when he noticed that flooding ovaries with AMH also suppresses a process known as “folliculogenesis.” “This is a process where some of the immature–or ‘primordial’ follicles—are recruited for maturation,” explained Daisy. “Each month of an adult woman’s reproductive cycle, a group of roughly 1,000 follicles will mature, ultimately leading to ovulation of a single egg from just one follicle, the ‘dominant’ follicle.’ The remaining follicles then die and wither away.” This process eventually leads to a depletion of most of a woman’s follicles and the subsequent triggering of menopause. “Using AMH to limit folliculogenesis preserves the possibility in the future that the follicles which women are born with and slowly lose over time do not get fully depleted,” said Daisy.
“We stumbled on this accidently,” said Pépin. “The result astonished us. When we added AMH, almost all of the immature follicles stopped growing,” meaning the ovulation process largely froze in place, thus preserving the ovaries’ ability to produce mature eggs at a later date.
Harvard pediatric surgeon Patricia Donohoe, one of the great pioneers of reproductive medicine, also has worked closely with Pépin and is a co-founder and key advisor to Oviva and to Daisy. Pépin and Donoahoe developed a bio-engineered version of the naturally occurring AMH hormone. Pre-clinical data indicate that this bio-engineered AMH can protect the immature follicles during chemotherapy treatment, and potentially be used to improve IVF protocols by increasing the yield of viable eggs by 2-3x, a huge deal for women over the age 35.
The bioengineered form of AMH remains experimental, with the company running pre-clinical trials in mice and non-human primates. “It is possible this will not succeed,” said Daisy, “most drug candidates don’t, even those that reach human clinical trials.” If this happens, she added, “Oviva is poised to pivot to develop alternative treatments that would extend ovarian function and ultimately female healthspan.”
“I’m excited about getting support and funding for studying the ovaries,” said Daisy. “It’s a watershed moment in the history of women’s health.” She also welcomes others to join in.
To understand this field a bit better, I recently chatted about this topic with Daisy.
1. Female reproductive longevity and inequality seem to be a very hot topic. Why now? In your opinion, what triggered this sudden interest from the VCs?
There has been a growing wave of interest in women’s health over the last few years. In some ways COVID highlighted this — in a somewhat backwards way. Early on there were statistics suggesting that more men were dying from COVID19 infection than women. This spurred an influx of funding to study female physiology to better understand why and potentially leverage these mechanisms to help men. Because we have historically overlooked females in biomedical research and clinical development, there is so much we don’t know.
I think women are being more vocal about their needs, and an increase of women in power or positions of authority to help drive this change. And – there has also been a growing recognition that women have a lot of economic power behind them and the market for women’s health is huge. Menopause alone has a market size of 14.7 billion and is growing. The US fertility market alone is $8 billion. And this doesn’t even touch the various indications women suffer from that have little to no resources – things that I know patients would pay an arm and a leg to feel better from (endometriosis, PCOS, etc).
And then there’s Roe v Wade, which of course is more immediate but brings into stark urgency the threat to women’s health, reproductive freedoms and agency. This is a flashpoint and I am both furious and passionate about helping drive change so that females have more opportunities to live healthy, vibrant, resilient lives, so that we can feel and experience agency throughout our lives no matter our age.
2. Can you shine some light on how Oviva approaches the ovarian longevity challenge?
Our fundamental hypothesis is that ovarian function is inherently linked to healthspan, and by preserving or extending ovarian function we will also extend healthspan. Our first hypothesis that we are working on to address this is that through protecting or preserving the ovarian reserve – and therefore not depleting the ovarian reserve which ultimately triggers menopause and ovarian decline — will prevent the ovaries from declining in function. Without the signal from a depleted ovarian reserve to shut down, the ovaries will ‘believe’ that they should keep working rather than senescing and triggering menopause. The AMH/AMHR2 axis is the earliest known point where we can influence this — AMH works by preventing immature (or primordial) follicles, each housing a single egg, from leaving the ovarian reserve. By leveraging this mechanism we aim to prevent the attrition of eggs (and primordial follicles) and thus preserve the ovarian reserve.
3. You share some investors with Gameto, can you please expand on how you are different?
Cambrian is our sole investor — we are approaching this goal through the lens of longevity and with the hypothesis that extending ovarian function will significantly impact female health. Additionally, we are developing a candidate targeting the AMH/AMR2 axis — which has yet to have any clinical development around it to date — and are taking a very focused approach to this. The mechanism is fundamentally different from what Gameto is doing (cellular reprogramming), though the goals are similar. Frankly I think this is actually very important – ultimately what will serve women and patients best is having options to choose from. Much like birth control, different people will want or need distinct methodologies/therapeutics to support their health, so I am thrilled that we have a growing field working towards this goal of ovarian longevity. Gameto is working to reconstitute the ovaries, whereas we are looking to support and preserve the endogenous ovaries.
Also, we decided early on to develop a focused, rigorous program that was built out to thoughtfully de-risk as much as possible and to take us to clinic efficiently and effectively. We are initiating talks with the FDA this year, and this seed funding will take this program to IND submission. We have additional programs in early stages of development (more on that later this year… will be tied to our Series A), but we felt strongly that we want to devote our attention to this first program and indication in order to drive it forward effectively without diluting our attention across multiple assets to start. We believe this allows us to take a deeper, more rigorous approach to what we are doing and build from a strong foundation. This focused approach sets us apart from other companies in the space that share our mission — and who I hope succeed! — and who are working on several things simultaneously. For us this seed round and focused approach – we believe – is the most effective strategy to get to clinic and be successful. Related to this, our candidate is closest to clinic and we are excited to test in humans soon and determine whether this has the potential for our broader vision of extending ovarian function – but one step at a time.
4. What do you see as the major obstacles to achieving ovarian longevity?
There are many fundamental questions about ovarian physiology – and women’s health more broadly – that remain unanswered. In order to make a positive impact on ovarian biology we also have to understand the consequences of extending ovarian function (positive and negative) to ensure what we’re doing is safe in humans and achieving the desired goal, which is ultimately to provide therapeutic options to women that preserve agency over their bodies and reproductive health.
5. In the pharmaceutical industry we usually go after specific diseases. And in longevity biotechnology, most companies try to go after dual-purpose targets that may work in aging and disease. What indications are you targeting?
For our first program we are targeting poor responders to IVF. Similar to the longevity field we view this as an important stepping stone to advance our broader goal of prolonging ovarian function and forestalling the negative consequences that occur as the ovaries decline with age. This first indication (and those to follow, currently confidential) will enable us to establish safety and efficacy (evaluating efficacy and function in humans).
Oviva is one of 19 offspring companies tucked into the Cambrian fold that address certain system-wide triggers of aging. These include using stem cells to regenerate damaged or aging tissue; a treatment that counters the effects of those dwindling telomeres; and yet another that inhibits the formation of fibrotic cells that thicken and cause damage to the lung, uterus and other organs. To learn about longevity biotechnology, Cambrian biosciences, and many other cutting-edge academic and industry projects, consider registering for the 9th annual Aging Research and Drug Discovery conference, 29.08-2.09 in Denmark, hosted by the University of Copenhagen.