In Vivo: strategic insights for life sciences decision-maker...
By David Wallace 04 Dec 2019
As the US generics market continues to experience turbulence, the industry’s largest players are adopting a wide range of strategies...
Key players developing new treatments for women effected by diseases such as endometriosis talk to In Vivo about the hurdles preventing novel therapies from reaching the market.
The vicious investment cycle affecting biopharma start-ups is a central issue in women’s health drug development, where a lack of clear exits means no money for innovation to attract larger pharma interest.
So what? Times are changing, and movements outside the pharma industry could have ripple effects on drug developers. Consensus opinion is optimistic for the future but the decades-long challenges and stigmas remain.
Investment into research for conditions like endometriosis, polycystic ovary syndrome and the symptoms of menopause has been limited, according to key players in the field, with some expressing concerns that exploration in these areas receives less attention because the outcome of these conditions is not fatality.
However, the market is shifting as women’s suffering is being better understood and accepted culturally. “It has always been the situation in women’s health that you have a few pharma companies being experts in the space,” the CEO of Evotec AG, Werner Lanthaler, noted in an interview with In Vivo. Evotec is involved in a long-term partnership with Bayer AG (one of the longest-standing developers in the area of women’s health). However, despite the history of this field, Lanthaler says the market has been evolving. “Twenty years ago, those making contraceptives pills were considered to be the women’s health companies and the experts. That has really changed in the last five to 10 years.” There is a greater focus now on diseases effecting women’s health outside of conditions related to fertility only. Lanthaler believes this has come from cultural changes and greater diagnostic capabilities.
According to data from Informa's Pharma Intelligence's Pharmaprojects, the more popular indication for pharma R&D is menopausal symptoms, with a greater number of companies pursuing clinical studies for this condition than others that fall under the spectrum of women’s health. Excluding fertility and oncology indications and instead focusing on those only occurring in women, the pipeline for drugs in the later stages of development appears sparse (see Exhibit 1). The conditions in focus are uterine fibroids, endometriosis, polycystic ovarian syndrome and menopausal symptoms.
Compounds In Development For Key Indications* In Women’s Health
*Uterine fibroid, endometriosis, polycystic ovary syndrome, menopausal symptoms.
SOURCE: Pharmaprojects | Pharma Intelligence 2018
The pipeline overview highlights two drugs in the pre-registration stage that is targeting both uterine fibroids and endometriosis. Myovant Sciences Ltd. has filed relugolix with the Ministry of Health, Labor and Welfare in Japan for the treatment for uterine fibroids, where a regulatory decision is expected either in late 2018 or early next year. US filings for relugolix in uterine fibroids and endometriosis are slated for 2019. The drug is partnered with ASKA Pharmaceutical Co. Ltd. in Japan for both commercialization in uterine fibroids and development and commercialization in endometriosis. Myovant was formed by Takeda Pharmaceutical Co. Ltd and Roivant Sciences GMBH in June 2016. Relugolix is an oral, once-daily, small-molecule, gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits pituitary release of luteinizing hormone and follicle-stimulating hormone. The second product in the pre-registration phase is BL&H’s BLNP-017, which is being developed for menopausal symptoms.
Elsewhere, in July this year, AbbVie Inc.won US FDA approval for Orilissa (elagolix), also a GnRH inhibitor, for the treatment of endometriosis. Phase III trials in uterine fibroids are ongoing for the drug in the US. Orilissa represents the first new treatment for endometriosis, in a pill form, to reach the market in more than a decade. AbbVie has set the price for Orilissa at about $850 per month in the US, with a view toward enabling patient access – the product launched in retail pharmacies in early August. (Also see "AbbVie Prices Oral Endometriosis Drug Orilissa In Value Range, Focusing On Access" - Scrip, 24 Jul, 2018.)
Furthermore, there are several novel approaches to menopausal symptoms being explored in the clinic, according to data from Pharmaprojects. One company with a Phase II asset in development is the young biotech KaNDy Therapeutics, which is developing NT-814, a dual neurokinin-1 (NK1) and neurokinin-3 (NK3) antagonist.
Mary Kerr, managing director of KaNDy Therapeutics, told In Vivo during an interview at the 2018 Anglo-Nordic Life Science Conference that the majority of conditions under the umbrella of women’s health have been seen as symptoms and not serious diseases. However, she highlighted that these conditions cause debilitating symptoms for a large percentage of women. “They're seen as symptoms, but you can have symptoms that debilitate your life for 10 years,” Kerr points out. She cites menopause as an example, which can cause women to wake multiple times at night. This symptom alone could put women at risk for other comorbidities, Kerr states. “It's well known that people who wake at night are more prone to obesity. And there's been data published recently in the journal Menopause that women who have night-time awakening and hot flashes are at higher risk for diabetes.”
“Why is it less important that women have flashes, they don't sleep, they're depressed, they're anxious, they gain weight? Why's that less important than, as an example, erectile dysfunction?” Kerr asks. She also adds that in her opinion and experience, “women's health has been under-funded for many years.” Since hormone replacement therapy (HRT) was discredited in 2002, wrongly or rightly, there has been limited focus on developing an effective non-hormonal alternative to HRT. In the report by the Women's Health Initiative at that time, HRT was associated with an increased risk for breast cancer and cardiovascular events in some women. Kerr asserts this was one of the major drivers that pushed pharma away from women’s health R&D. “The HRT market plummeted and has never recovered,” she notes.
Kerr believes the research area of diseases effecting women’s health has since suffered from being trapped in a vicious circle of under-funding. “We know that two thirds of novel drugs that are approved are started in biotech, and VC funding of private biotech companies is super important in the food chain. VCs like to invest where they can see an obvious exit, and there hasn’t historically been a lot of pharma companies strategically present in women's health. Historically, VCs couldn't see that potential exit,” she observes, noting that this had been her experience when seeking funding for biotechs developing new drugs in women’s health.
As such, with KaNDy Therapeutics, Kerr says the company is focused on generating strong data to draw in venture capital financing. “We will generate the data and the interest will follow,” she predicts. Despite the difficulties of getting investors to buy into a disease space where big pharma activity is more limited, Kerr believes the market is changing. “There is an appetite to move back into women’s health,” she says.
Kerr notes the recent "Times Up" movement as an example of a driven societal shift that may be able to motivate change in various industries. “It's about time that women were treated equally, and their health issues were invested in equally,” she insists. Kerr adds that if investment continues, novel targets with strong data would draw in more players and financiers. She cites early clinical data reported by KaNDy in June 2018, noting that the company has had interest from groups that are not traditional players in the women’s health R&D arena.
KaNDy Therapeutics announced promising Phase Ib/IIa clinical trial data this year for its oral, once-daily neurokinin antagonist, NT-814, in women with debilitating menopausal symptoms. The drug candidate may have a more rapid onset of action than current hormone replacement therapies, which can take weeks to months to become fully effective. NT-814 is KaNDy's lead candidate in the clinic, and is an orally active and selective dual antagonist at neurokinin-1 and -3 receptors. It is thought to block estrogen-sensitive "KNDy"neurones in the hypothalamus, which become hyperactive because of the absence of estrogen, disrupting the way body temperature is controlled.
KaNDy was spun out in 2017 from NeRRe Therapeutics Ltd., itself a spin out from GlaxoSmithKline PLC. KaNDY is backed by a number of life sciences venture capital investors, including Advent Life Sciences, Fountain Healthcare Partners, Forbion Capital Partners, and OrbiMed Advisors. GSK had been assessing the compound in neuroscience indications but KaNDy is looking at the asset through another lens. “It's really an example of, I think, innovation from just taking a slightly different perspective.”
Neurokinin-1 receptor antagonists have been indicated as antiemetics for more than a decade, including most notably Merck & Co. Inc.'s Emend (aprepitant). However, the use of neurokinin antagonists for endocrine disorders is not a particularly popular research strategy, according to Informa's Pharma Intelligence's drug development pipeline database, Biomedtracker. One company, Astellas Pharma Inc., is evaluating a neurokinin-3 receptor antagonist, fezolinetant, in Phase II studies for the treatment of menopause-related vasomotor symptoms. The drug was sourced by the Japanese company through its €800 million ($926 million) acquisition in 2017 of Belgian biotech Ogeda SA. (Also see "Menopausal Symptoms Cooled By KaNDy's Dual Neurokinin Antagonist" - Scrip, 7 Jun, 2018.)
As well as having had an effect on hot flashes, Kerr highlights that NT-814 had a rapid effect on night-time awakening. “We saw in our study that, on average, the women enrolled were waking up five or six times a night. They end up waking less than once on the optimal dose tested. There's nothing else out there that specifically targets the night-time awakening that comes with menopause,” Kerr says.
KaNDy expects to start a Phase IIb trial for NT-814 in October. Kerr acknowledges that the biology around NT-814’s effects in menopause is yet to be fully understood. “Nobody was looking at neurokinin as a potential treatment for menopause, so this is very cutting-edge biology and it’s not very well understood. The clinical data have overtaken the understanding of the biology, but if we look at clinical data, we can deduce that a neurokinin antagonist shuts the pathway down.”
Kerr believes that NT-814 will be able to compete if it gets to market and that there is room for multiple novel treatments for women suffering side effects of menopause. She nods to Astellas as KaNDy’s closest competitor but adds that “at peak there were multiple HRT players, so two new players in this space is very valuable.” Kerr says that NT-814 was differentiated because of its once-daily dosing potential and additional benefits on top of the management of hot flashes – notably effects on night time awakening, mood and anxiety. Kerr notes that there is a “huge” market for menopause therapies; she cites the HRT Premarin (conjugated estrogens), which had a peak valuation of $2 billion – equivalent of around $10 billion in today’s money. “Premarin was one of the original blockbusters,” she points out.
As investment interest grows in women’s health, Kerr expects researchers to turn their attention to uncovering new targets and new mechanisms to provide options for patients. Lanthaler, though, expects this to be in new directions, away from hormonal therapies. “If you want to go a step beyond current medicine and current thinking, then you have to go beyond hormonal treatment." Evotec’s leading R&D area under its partnership with Bayer is novel targets for endometriosis. “A non-hormonal treatment that reduces pain would be a massive success in the treatment of endometriosis. The whole idea is to get beyond the ancient therapies that are out there,” he states.
Henk Jan Out, VP of reproductive medicine and women’s health, global clinical R&D at Ferring Pharmaceuticals AS, also highlights concerns about how to move the innovative drug development sector forward in women’s health.
He told In Vivo a key challenge for research in women’s health is the lack of understanding as to what causes some conditions. “In terms of endometriosis, for instance, there have not been many biological breakthrough insights into its causes, and the lack of an easy-to-use diagnostic in this particular field is also hampering scientific research,” he asserts. Jen Out adds that for pre-term birth, the largest cause of infant death, in more than half of all cases no explanation exists. “So, research and development is challenging from this perspective.”
However, he says Ferring has significantly invested in the field of fertility and women’s health. “We are committed to becoming the world-leading company in reproductive medicine and women’s health, and last year the majority of our R&D spend was dedicated to this area.”
Jen Out believes patients and advocacy groups will propel investment and, in parallel, innovation in drug development for diseases in women. “We’re at a tipping point with certain conditions thanks to patient advocacy.” Regarding endometriosis for instance, there has been more media coverage on the condition, with celebrity influencers sharing their experiences with huge online audiences. “We are also seeing women sharing advice with each other on forums and blogs, forming powerful patient groups who are demanding that this condition be prioritized,” he notes.
“Patient involvement will stimulate basic researchers to intensify their activities in endometriosis, in addition to research into diagnostics to test for the condition, which will in turn help with the development of new therapeutics,” Jan Out says.
Endometriosis, a gynecologic disease defined as the presence of endometrial tissue located in places other than physiologically appropriate, affects about 10% of women worldwide. Bleeding is one of the consequences of the response of the endometrial tissue to hormonal stimulation, and can lead to inflammation and scarring, and consequently to complications such as dysmenorrhea, infertility, chronic pelvic pain and dyspareunia. According to the National Institutes of Health, the disease can only be diagnosed accurately by laparoscopy, laparotomy or hysterectomy, and magnetic resonance can be used only for lesions larger than 1 cm in diameter. According to the charity Endometriosis UK, on average it takes 7.5 years from onset of symptoms to obtaining a diagnosis.
Hakan Goker, senior investment director for health care at M. Ventures, the strategic investment arm of Merck KGAA formed in 2009, told In Vivo that the recent increase in investment and interest in women’s health R&D was driven by patients as well as researchers. “The voice of the patient is getting louder,” he said. “Women want better treatments in a field that has been largely ignored.”
Goker, who has worked in the health care industry for more than a decade, having started at Atlas Venture in 2006, says there has been a resurgence in the last three years for women’s health investment. For indications such as endometriosis, polycystic ovary syndrome infertility and menopausal symptoms, there have not been significant drug launches in some time with a “paradigm changing effect,” Goker notes.
Agreeing with Kerr’s assessment of the investment landscape, Goker believes it was an “action-reaction situation.” He says that around a decade ago, many pharmas disbanded R&D activities in the space and stopped deal-making in this area; in parallel, venture capitalists stopped investing because they could not see an exit. Goker also notes that “when you look at women’s health because they are not deadly diseases and the target population is women at fertile age, the safety portion of trials that regulators want are lengthy and expensive. As such, we have seen more activity in areas like cancer and rare diseases, in chronic and acute illness, where the cost of capital is a little less.” Nonetheless, the portion of the population that is suffering from these indications is not getting smaller and the higher demand from patients are encouraging pharma to re-enter this space with novel approaches, he says.
Lanthaler concurs that women’s health has been an overlooked field of medicine for innovative drug developers, and although disease areas such as immuno-oncology have dwarfed all other development sectors in more recent times, “diseases that reduce quality of life” require greater attention. The probability of getting pregnant between the age of 20 and 45 is reduced by around 50% if you suffer from endometriosis, Lanthaler highlights. “Many interventions today can only be done through invasive surgery, that’s not modern medicine. The awareness of specific diseases affecting women is still too low.”
Goker cites Forendo Pharma Ltd. as an example of a smaller drug developer aiming to bring something new to the market. Endometriosis is currently treated with systemic hormone therapies, ablating estrogen in the whole body and giving rise to unwanted side-effects such as menopausal symptoms including bone degredation. But Finland-based Forendo is targeting an enzyme responsible for converting low-active estrone precursor to highly active estradiol locally in endometriotic lesions. Finding a very specific target to inhibit only the local conversion of estrone to estradiol rather than eliminating estradiol systemically has been challenge for many for decades. There are 14 enzymes in the HSD17beta family and closely related family members in addition to other mechanisms that have different roles in steroid metabolism. However, HSD17B1 is the only enzyme present in endometrial tissue that helps produce estrogen. Forendo’s lead program targeting HSD7B1 enzyme is aiming to ablate estrogen in the endometrium only, therefore it could avoid the systemic side-effects of current approaches. The company recently received CTA approval for its HSD17B1 candidate, FOR-6219, and is entering into the clinic soon. (Also see "Forendo Pharma: Tackling The Endometriosis Challenge" - Scrip, 9 Nov, 2017.)
“If what it says on the tin comes true, then Forendo will have an oral drug that has the same, or greater, benefits as the injectable treatments that are already on the market or the oral systemic therapies in late-stage development. It had the advantage that it can be administered long-term to put a stop to the suffering of this large group of patients” Goker predicts.
“As the founders of Forendo, we have optimized systemic hormones for benefit of women’s health in other companies. Now we are working on these precision medicines in Forendo, enabled by the activities of the HSD enzyme family to target the intracrine regulation of hormone levels in target organs. This work, supported by multiple independent academic research findings, is now bearing fruit to enable such next generation medicines for treating endometriosis, fibroids, menorrhagia and even PCOS more selectively,” added Risto Lammintausta, CEO of Forendo.
While M Ventures, based in Amsterdam, is an investor in Forendo Pharma, in women’s health the VC usually has a greater focus on fertility investments. Other M Ventures investments in this field include ObsEva SA, a Swiss drug development company focused on therapies for pre-term labor, and TocopheRx, a company developing an oral follicle stimulating hormone (FSH) agonist for the treatment of infertility. Endometriosis is dealt with by gynecologists not fertility specialists, which is why the disease falls at the edges of M Ventures’ usual remit. However, “endometriosis causes a lot of infertility cases, but once it is treated some patients can conceive naturally or have better chances with IVF, and our mother company is a leader in IVF. This is why we invested in technology here,” Goker explains. Some of ObsEva’s programs came from Merck originally, when the German pharma was downsizing its activities in women’s health R&D.
In endometriosis, Ferring’s Jan Out expects the new generation of GnRH-antagonists to create more awareness for the disease and stimulate basic researchers to intensify their activities. Also, infertility treatment should become more individualized. At Ferring, Jan Out says, the company recognized early on that many unmet needs in fertility treatment were due to individual patient differences. In response, it pioneered a more personalized approach to treatment, designed for predictable ovarian response. “Last year we launched the first fertility treatment approved in conjunction with a companion diagnostic. This brought the first approved, evidence-based approach to personalization to the market.”
But Jan Out foresees little to no innovation for the contraceptive market in the coming years, because this space is “already quite saturated with effective and relatively cheap products.” However, he predicts that the market for treatments for menopause will change with the arrival of a new generation of non-hormonal drugs. “New developments that have caught my attention include newly discovered hypothalamic pathways to treat hot flushes in menopausal women,” he notes.
The field in general though is expected to grow, and success for businesses such as ObsEva, Myovant and Ferring could draw other, larger pharma companies back into R&D for diseases affecting women’s health. “Merck for one is expanding its reach, and we have seen groups like Astellas diving back into the space. There are more companies showing interest now than there were five years ago,” M Ventures’ Goker says. The investor adds that he thinks AbbVie’s elagolix could be successful in driving patient acceptance now that is has been approved, which would open up the endometriosis market. This market will grow as better tools for diagnosis of the condition come through and as patients become more familiar with the disease through communication on social media and other sources. “Time to diagnosis currently is too long; specialist gynecologists are able to diagnose patients very quickly, but there is an awareness issue around endometriosis that must be addressed,” Goker maintains.
“AbbVie, Pfizer Inc.and Bayer are three of the large players in this field currently,” Lanthaler notes, but he adds that patients are still under-served. “One area that we are yet to understand and focus research on, is women’s health and age-related diseases. This is an area I expect companies to move into,” he highlighted when setting out his expectations for the future of R&D in women’s health.
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