Debra Duke had found herself among the two-thirds or more of menopausal women who get hot flashes. Several times a day, she abruptly heated up as if she’d been dropped on some invisible skillet.
Hot flashes are uncomfortable, they’re disruptive, and they are pervasive, affecting some 10 million women in the United States alone on any given day. As of 2008, when Duke noted that her hot flashes had quite suddenly dissipated, there was a single U.S. Food and Drug Administration-approved drug to treat hot flashes: hormone replacement therapy.
But Duke wasn’t taking hormones or anything else to ice her hot flashes. Rather, during a workup, the late University of Colorado School of Medicine oncologist Fred Kolhouse, MD, had diagnosed mild neutropenia – a deficit of white blood cells called neutrophils – and prescribed granulocyte colony-stimulating factor (G-CSF) to stimulate her body’s neutrophil production.
G-CSF had been FDA-approved since 1991, when Amgen brought the drug Neupogen to market. Countless women, many of them coming off cancer therapy, have taken it since. Some may have noticed their hot flashes cooling as a result. Only Duke acted on that insight – in her case, launching a company, MenoGeniX, that aims to help women everywhere douse their hot flashes with a customized form of G-CSF.
So far, so good: an initial clinical trial in 30 women provided supportive data that G-CSF could reduce hot-flash frequency and severity in other women. Duke is now working on funding for a much larger trial that she aims to launch in 2017.
Sit down with Duke in the Fitzsimons Bioscience Park Center’s main conference room and she’ll tell you right away that the story isn’t about her, and that MenoGeniX wouldn’t have gotten far without help ranging from her spouse and several other CU School of Medicine faculty serving as advisors. And that’s a fact.
Her spouse is Richard Duke, PhD, a tenured CU School of Medicine immuno-oncologist, serial biotech entrepreneur, and founder of the Colorado Institute for Drug, Device and Diagnostic Development (CID4). When Debra mentioned to Rick, “You know, I don’t know if it has anything to do with the shot [of G-CSF], but my hot flashes seem to be going away,” he answered not with an absent, “That’s nice, Debra.” Rather, Rick suggested they sit down with a well-known life science patent attorney, Gladys Monroy, PhD, which they did. In time that yielded patents now issued and pending across the world’s major markets.
The Dukes had recognized that, despite Amgen’s holding the patent on the composition of synthetic G-CSF (since expired, in 2013), one can acquire a patent for a label expansion – that is, a new clinical use for someone else’s drug. In this case, they did that for G-CSF as it relates to menopause, and in 2012 they founded MenoGeniX to turn that intellectual property into a real therapy. CU has successfully commercialized other therapies this way, including Botox to treat overactive bladder and the Zostavax vaccine to prevent shingles in adults, according to Richard Duke.
Debra Duke raised $500,000 from angel investors and poured it into that first pilot trial – a randomized, placebo-controlled, double-blind clinical trial involving 30 women with naturally occurring or surgically induced menopause. CU School of Medicine OB/GYN and women’s health physician Maryam Guiahi, MD, MSc, who practices at University of Colorado Hospital, led the effort.
While MenoGeniX is keeping the details quiet pending publication, the subjects who received a single injection of G-CSF reported a significant reduction in their hot flash frequency and severity within two weeks as compared to those who received a placebo. The two subgroups of women in the study that have been reported to have the most severe hot flashes – African American women and women with surgically induced menopause – appeared to respond particularly well to G-CSF vs. placebo. Surgically induced menopause tends to bring worse hot flashes – and for many such patients, who like Angelina Jolie have had their ovaries removed to lower their risk of developing breast and ovarian cancer, hormone replacement therapy isn’t an option.
Should the initial clinical trial’s numbers hold up in future trials, they would compare favorably to those of hormone replacement therapy and outclass those of Brisdelle, the second FDA-approved (in 2013) therapy for hot flashes, which is a weaker version of the antidepressants Paxil and Pexeva. In addition, Guiahi also had patients fill out menopause-related quality of life questionnaires such as the Hot Flash Daily Related Interference Scale and the Fatigue Severity Score. Patients on G-CSF reported much higher scores than those on the placebo, Duke said, suggesting that G-CSF is having a positive effect on their day-to-day lives.
Help in high places
MenoGeniX has harnessed CU School of Medicine expertise beyond that of her husband and Guiahi. Advisors include CU endocrinologist Margaret Wierman, MD, and medical oncologist William Robinson, MD, PhD, whose work with G-CSF harkens back to the discovery of the first human colony-stimulating factors in the 1960s. Nanette Santoro, MD, chair of the CU School of Medicine’s Department of Obstetrics and Gynecology, heads up the startup’s scientific advisory board. All practice at UCH.
Santoro says the MenoGeniX phase 1B trial results were “a signal that it’s effective. Is it worth looking into further? I think the answer is ‘yes,’ that it should be worked up more carefully,” Santoro said.
She added that while she doesn’t hesitate to prescribe hormone replacement therapy for women close to menopause and considers it safe, she recognizes that “lots of women have a fear and loathing of hormones” stoked by research that has linked long-term hormone replacement therapy to breast cancer, heart disease, stroke and blood clots. Either way, Santoro said, “We really are badly in need of alternatives.”
As to why G-CSF seems to quell hot flashes as it prods white blood cell production, no one can say. Santoro says the vasodilation (opening of blood vessels) that brings hot flashes is probably a central nervous system phenomenon. That the root cause remains a mystery explains why serendipitous discoveries have been the norm in formal hot flash therapy. Brisdelle, she says, came about when Mayo Clinic oncologists noted that breast cancer patients taking the antidepressant Paxil reported a slight improvement in their hot flashes. It was much the same with the anti-seizure medication gabapentin, whose use for hot flashes was also discovered anecdotally in a woman taking the drug to treat migraine. In the case of gabapentin, though, an FDA advisory panel recommended against the drug’s approval in 2013.
To move G-CSF a big step closer to FDA approval, Duke is planning a phase 2 clinical trial to test repeat administration of the drug, dosing, and durability – that is, what’s the right amount of G-CSF to give women and how often to safely suppress hot flashes in otherwise healthy women. With 300 patients expected to take part, it will be a multimillion-dollar affair, for which Duke is rounding up funding and looking for partners. A much larger phase 3 trial would cost even more. By that point, she’s hoping a major biopharmaceutical firm, one capable of bringing the drug to a big market in dire need of relief, can take the reins.
For now, the work to build MenoGeniX, she said, “has basically taken over my life. And that’s okay, because what can be more important?
“Hot flashes affect peoples’ lives,” Duke said. “You go on the internet and what do you see? People are talking about yoga and teas and Chinese herbs and massages. Women are suffering and deserve more alternatives.”