Beyond Hormone Therapy: Signs Of Life In Pipeline For Menopausal Women

Conditions associated with menopause represent a huge market, yet the R&D pipeline has long been slim, despite the well-known drawbacks of marketed hormone replacement therapies. But new approaches with a tissue-selective estrogenic effect are emerging: Shionogi’s Osphena for menopause-related sexual dysfunction broke the long drought in NME approvals, and Pfizer’s broad NDA for bazedoxifene/conjugated estrogens is under review. Emerging companies like EndoCeutics are exploring new hormonal approaches.

The potential market may be huge, but advances in pharmacotherapy for conditions associated with menopause have been few in recent years – rocked by the safety issues uncovered by the Women’s Health Initiative and with disappointing results out of the major class in development. But a new crop of more selective and non-hormonal agents shows that it might again become a profitable sector.

A small core of companies has continued to work in the field and could produce a new crop of products to build on recent activity like the February approval of Shionogi Inc./QuatRx Pharmaceuticals Co.’s Osphena (ospemifene) for sexual dyspareunia associated with menopause and Pfizer Inc.’s October 2012 NDA submission of bazedoxifene plus conjugated estrogens for a range of conditions associated with menopause.

But even as Osphena represented a step forward, FDA advisory committee rejection of two products vying to become the first non-hormonal treatments for vasomotor symptoms of menopause (hot flashes) signals that drug development in this area is still challenging (Also see "Gabapentin Cannot Navigate Efficacy Hurdles At Advisory Committee" - Pink Sheet, 4 Mar, 2013.).

Agents with tissue-selective estrogenic activity aim to provide the benefits of hormone replacement therapy with fewer risks.

Osphena is the first NME for an obstetric, gynecologic or menopause-related indication since the 2010 approval of Amgen’s Prolia (denosumab) for postmenopausal osteoporosis. Despite well-known (and comprehensively litigated) risks associated with hormone-based therapy, new formulations of hormonal products count for most women’s health products that have cleared FDA, like the Oct. 29, 2012 approval of Noven Pharmaceuticals Inc.’s Minivelle (estradiol) extended-release transdermal estrogen for menopausal symptoms.

The highly generic commercial environment for women’s health products exerts a dampening effect on R&D in the area. Few major pharmaceutical companies are pursuing significant new products in the U.S., and the smaller firms that are active have often struggled with the resource needs of late-stage development. Bone-focused treatments for osteoporosis have proven a more attractive area for R&D investment (see related story, (Also see "Regenerating Interest In Novel Drugs For Postmenopausal Osteoporosis" - Pink Sheet, 19 Mar, 2013.)). But therapies that target a broader range of the conditions associated with menopause’s declining hormone production, including vasomotor symptoms and vaginal and vulvar atrophy, still hold enough commercial promise to support meaningful development activity.

[Editor’s note: Women’s health R&D for conditions affecting women before menopause are another underserved market. But novel late-stage products for endometriosis, uterine fibroids and female sexual dysfunction unrelated to menopause are advancing. Next month’s issue of Pharmaceutical Approvals Monthly will look at the pipeline in pre-menopausal women’s health.]

Vasomotor Symptoms & The Perils Of Patient-Reported Outcomes

Hormone replacement is the foundation therapy for menopausal symptoms. FDA notes that estrogen therapy has been used for half a century for vasomotor symptoms and vulvar and vaginal atrophy, and it started being used for prevention of bone mineral density loss in the 1980s. However, estrogen has well-known risks that make development of non-hormonal treatment options a medical need.

“While there are a variety of drug products in different formulations … approved for the treatment of menopausal symptoms (including both VMS and symptoms related to vulvar/vaginal atrophy), all contain either estrogen alone or estrogen plus a progestin,” FDA explained in background documents for the March 4 advisory committee review of two non-hormonal hot flash NDAs based on CNS-active drugs, Depomed Inc.’s Sefelsa (gabapentin, formerly Serada), and Noven’s low-dose paroxetine mesylate.

Estrogen-only products carry a boxed warning about endometrial cancer; the addition of a progestin mitigates that risk, but as the landmark Women’s Health Initiative study found, combination products may be associated with increased risk of breast cancer, thromboembolic events and myocardial infarction. Extensive contraindications mean that there are “significant subgroups of women … who may be symptomatic during menopause but unable to use the hormonal preparations,” FDA said.

Following the advisory committee vote of 12-2 against approval for Sefelsa, Depomed’s oral twice-daily formulation of gabapentin for moderate to severe vasomotor symptoms due to menopause, Depomed said it would not actively seek approval of the NDA, even though FDA is not bound by committee recommendations. The committee also voted 10-4 against approval of Noven’s paroxetine formulation. High placebo response rates in clinical trials plagued both NDAs (Also see "Placebo Effect Raises Questions About Clinical Value For Depomed, Noven Hot Flash Treatments" - Pink Sheet, 11 Mar, 2013.).

“Based on today’s meeting, we believe the hurdles for approval of a non-hormonal treatment for hot flashes remain high,” Depomed announced March 4. “Until we believe there is a positive direction for Sefelsa, we will cease all spending relating to the product candidate.”

Pfizer had previously tried to bring a CNS-targeting non-hormonal option for VMS to market via an sNDA for its serotonin-norepinephrine reuptake inhibitor Pristiq (desvenlafaxine), but the company withdrew the application in February 2012 after receiving two “complete response” letters for the VMS claim.

Improved Targeting Of Estrogenic Activity To Treat Vulvar/Vaginal Atrophy

Another condition associated with menopause that historically has been treated with hormone replacement therapy is vaginal and vulvar atrophy, which encompasses a constellation of symptoms including sexual pain or dysfunction, vaginal dryness and discomfort.

While Osphena is not a hormone, as a tissue-selective estrogen agonist/antagonist it does not entirely evade the risks associated with estrogen supplementation. Osphena, for example, carries a boxed warning about risk of thrombosis, but the warning points out that the ospemifene findings “represent low risks in contrast to the increased risks of stroke and deep vein thrombosis seen with estrogen-alone therapy” (Also see "Shionogi’s Osphena May Offer Safer Alternative To Estrogen" - Pink Sheet, 26 Feb, 2013.).

Osphena is approved for a specific symptom related to VVA – painful sexual intercourse – unlike other treatments (chiefly topical estrogens) that are indicated for the underlying physical condition. Osphena’s dyspareunia indication may represent a narrowing of Shionogi’s initial claim. In announcing the ospemifene NDA submission June 27, 2012, Shionogi described the NDA as for “treatment of vulvar and vaginal atrophy (VVA) due to menopause, including moderate to severe symptoms of dyspareunia (painful sexual intercourse) and/or vaginal dryness and physiological changes (prebasal cells, superficial cells, and pH).”

Bayer HealthCare LLC, one of the biggest women’s health pharmas worldwide, has placed a modest bet on a hormonal treatment for VVA that is not estrogenic via EndoCeutics Inc., based on the finding that dehydroepiandrosterone (DHEA) is also “major factor in the hormonal deficit underlying menopausal problems.” Endoceutics’ DHEA formulation Vaginorm (intravaginal prasterone) is “without intrinsic estrogenic activity,” but “is transformed intracellularly into androgens and/or estrogens only in the tissues physiologically in need of these compounds,” according to the company. Vaginorm replaces local deficiencies in sex steroids without increasing circulating estrogens, EndoCeutics says.

Bayer licensed worldwide rights to Vaginorm in 2010 and is funding Phase III, but EndoCeutics is responsible for running the Phase III program for treatment of symptoms of VVA and female sexual dysfunction in postmenopausal women. The company has conducted two three-month treatment trials and is analyzing data from a 12-month safety study.

Can Addition Of Hormones Save SERMs?

The re-emergence of Pfizer’s troubled selective estrogen receptor modulator bazedoxifene in an October 2012 NDA submission for a combination with conjugated estrogens (Premarin) to treat vasomotor symptoms and vulvar and vaginal atrophy as well as to prevent postmenopausal osteoporosis is an endorsement for a strategy combining hormone replacement with an estrogen agonist/antagonist to provide the broad benefits of HRT for women undergoing menopause with less risk.

Pfizer describes the combination of bazedoxifene and conjugated estrogens as a tissue-selective estrogen complex that is an antagonist to estrogen’s effect on the breast and uterus while preserving its CNS effect on hot flashes. Development has also, apparently, been complex: NDA filing for the combination product, once known as Aprela, had once been targeted for 2007 (Also see "Wyeth Pushes Back NDA Filing Timeline For Aprela For Vasomotor Symptoms" - Pink Sheet, 5 Oct, 2007.).

Selective estrogen receptor modulators emerged almost 20 years ago, offering estrogen-like benefits for postmenopausal women with a better safety profile. Eli Lilly & Co.’s Evista (raloxifene) received approval for prevention and treatment of postmenopausal osteoporosis in the late 1990s, then added a breast cancer risk reduction claim. But the second-generation SERM pipeline, initially focused on postmenopausal osteoporosis, hit rough seas a decade later. Lilly axed its planned follow-on to Evista, arzoxifene, in 2009, leaving the company with no successor when Evista faces patent expiration in 2014. Arzoxifene met Phase III primary efficacy endpoints but missed key secondary outcomes measures and was associated with VTE and hot flashes (Also see "Almost At The Phase III Finish Line, Lilly Cuts Arzoxifene Losses" - Pink Sheet, 24 Aug, 2009.).

Pfizer ended up with two SERM candidates licensed from Ligand Pharmaceuticals Inc. after acquiring Wyeth. Pfizer stuck with Wyeth’s bazedoxifene program, returning its own candidate, Fablyn (lasofoxifene), to Ligand after its NDA for prevention of PMO received a January 2009 “complete response” letter due to an apparent increase in mortality with the drug. Bazedoxifene, known as Viviant as a single agent, had also collected “approvable” letters, most recently in May 2008 concerning risk of stroke and VTE with its PMO treatment NDA; a claim for prevention of PMO had already received a similar request in an “approvable” letter after responding to an earlier “approvable” action seeking more fracture data (Also see "Wyeth’s Viviant “Approvable” For Osteoporosis" - Pink Sheet, 23 May, 2008.). Pfizer’s most recent pipeline and investor materials still list single-agent bazedoxifene as an active project.

Pfizer’s clinical activity in the SERM area appears to have focused on the bazedoxifene/conjugated estrogens project. It has been gradually rolling out safety analyses of the pivotal SMART trial series, including data showing no significant increase in breast density, a risk factor for breast cancer , a low incidence of venous thrombosis and cerebrovascular events , and a favorable metabolic profile .

DHEA-focused EndoCeutics is following a similar strategy, combining its hormonal alternative to estrogen with a SERM “to relieve symptoms of menopause without the risks of breast cancer.” EndoCeutics’ SERM acolbifene is a “complete blocker of estrogens in the breast and uterus” and also slows down bone loss, the firm maintains.

Current clinical investigation of EndoCeutics’ oral prasterone/acolbifene product, Femivia, is centered on hot flashes with a Canadian Phase III trial in 202 postmenopausal women with VMS. The 12-week, placebo-controlled study kicked off in late 2011 and is fully enrolled.

Radius Health Inc. sees continued potential with a single-agent SERM for hot flashes. The company hopes to find a partner to further develop a SERM for vasomotor symptoms, RAD1901, that it licensed from Eisai Co. Ltd. in June 2006. Radius has brought RAD1901 through a Phase II proof-of-concept study in 100 postmenopausal women with moderate to severe hot flashes. “While a classic dose-response effect was not demonstrated, efficacy was determined to occur at the 10 mg dose level,” the lowest of the four doses tested, the company reported in a prospectus for its recently withdrawn initial public offering.

The Continuing Fallout Of The Women’s Health Initiative Study

The women’s health field is still reeling from the results a decade ago of the landmark Women’s Health Initiative study, which found that long-term estrogen and estrogen/progestagen use raised the risk of cardiovascular events and stroke to a degree that outweighed benefits, including fewer osteoporotic hip fractures. Sales of Wyeth’s (now Pfizer’s) Premarin family of products, by far the biggest HRT brand, plunged from $2.07 billion in 2001, before the WHI finding, to around $1 billion in 2004 (Also see "Prempro DTC Campaign Touts Lowest Approved Dose Of Hormone Therapy" - Pink Sheet, 23 Aug, 2004.). Pfizer’s reported annual revenue from the HRT line has held to just above $1 billion in 2010, 2011, and 2012, according to the firm’s annual SEC filing for 2012.

Prescriptions for HRT in the U.S. are on a “slow but steady downward trend,” the North American Menopause Society reports based on IMS Health data. Estrogen-only preparations, the largest segment of the market, slid from 33.68 million prescriptions dispensed in 2006 to 26.46 million in 2010.

Research into HRT’s risks continues – a Danish osteoporosis prevention study published in the British Medical Journal October 9, 2012, for example, did not find greater cardiovascular, stroke or breast cancer risk – but the medical consensus is still against use in postmenopausal women. The Agency for Healthcare Research & Quality’s U.S. Preventive Services Task Force issued final recommendations against use of HRT for primary prevention of chronic conditions in October 2012.

Efforts are underway to rehabilitate the perception of shorter-term HRT use during menopause to treat symptoms, including a March 15, 2013 “Global Consensus Statement On Menopausal Hormone Therapy” from an international coalition of organizations related to women’s health. The consensus statement endorses HRT to treat VMS and VVA and finds it “effective and appropriate for the prevention of osteoporosis-related fractures in at-risk women before age 60 years or within 10 years after menopause.”

Nonetheless, the tsunami of lawsuits that followed the WHI announcements also speak loudly to industry and the medical community. In the Feb. 28 SEC filing, Pfizer also reported aggregate charges of $1.6 billion in settlement of HRT lawsuits with another $100 million in charges for expected costs to resolve remaining lawsuits.

Treating the repercussions of the declining estrogen levels of menopause without incurring the negative systemic effects of estrogen replacement has proven a challenging task for drug development, as the less-than-stellar clinical performance of the SERM class showed. But the size of the market maintains the interest of a few firms, including Bayer and Pfizer; the North American Menopause Society estimates that 2 million women reach menopause each year, and about three-quarters will experience hot flashes and vaginal symptoms. Should any of these products prove successful, it might once again be a significant source of sales growth for the pharmaceutical industry.