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Women’s Health Medicine Review 2013

Written by: | andrew.humphreys@medadnews.com | Dated: Friday, February 1st, 2013

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As new blockbuster drugs emerge in the breast cancer setting, the industry is awaiting the next breakthrough products to reach the marketplace in the osteoporosis, oral contraceptive and hormone therapy areas.

This article reviews the current marketplace for several women’s health categories: breast cancer, osteoporosis, and oral contraceptives/hormone therapies. Each of these multi-billion dollar therapeutic markets are expected to continue growing in the next few years.

Price erosion of the current breast cancer drug leaders will be offset by the uptake of novel premium-priced therapies and growth of diagnosed breast cancer cases due to the aging population. For osteoporosis, companies are looking to gain market advantages by developing cost-competitive medicines with easy dosage patterns that effectively promote bone building, as many patients have trouble complying with the strict dosage schedules of traditional drug treatments. The oral contraceptive market continues to grow based on demographic and sociological factors, including population growth as well as the proportion of the young population.

Breast cancer

As the world’s most common female cancer, about 1.4 million new cases of this disease are diagnosed globally every year. More than 450,000 women die because of breast cancer on an annual basis.

The world’s leading breast cancer medicine is Herceptin, which contains trastuzumab as its main ingredient. The Roche/Genentech drug was introduced to the U.S. market during October 1998. Herceptin has been approved for adjuvant breast cancer, metastatic breast cancer, and metastatic gastric/gastroesophageal junction cancer. The targeted therapy is available for treating people with certain Human Epidermal growth factor Receptor 2-positive (HER2+) cancers.

One in four patients with breast cancer has HER2+ breast cancer. HER2+ cancer cells contain more HER2 receptors (a particular protein found on the surface of cells) than normal cells. An especially aggressive type of breast cancer, HER2+ cancer quickly grows and spreads.

Global sales for all Herceptin cancer indications totaled SFr5.25 billion ($5.93 billion) during 2011 and SFr4.43 billion ($5 billion) in January-September 2012. The 12 percent growth during the first three quarters of 2012 versus same-time 2011 was largely due to an improvement in the quality of HER2 testing in the United States and Western Europe, as well as programs to help improve access to the product in emerging markets. Japanese and U.S. sales were spurred by continued uptake for the stomach cancer indication.

Roche is building on the long-term success of Herceptin as the standard of care for women with HER2-positive breast cancer with two innovative medicines: Perjeta and T-DM1. According to the company, these two drugs have the potential to offer the thousands of women affected by this type of breast cancer an even more effective and better-tolerated treatment.

Perjeta was approved by FDA during June 2012 in combination with Herceptin and docetaxel chemotherapy for treating people with HER2-positive mBC, who have not received previous anti-HER2 therapy or chemotherapy for metastatic disease. As a personalized medicine, Perjeta targets the HER2 receptor. The drug is believed to work in a way that is complementary to Herceptin, as the two products target different areas on the HER2 receptor.

Perjeta is designed specifically to prevent the HER2 receptor from pairing with other HER receptors (EGFR/HER1, HER3 and HER4) on cell surfaces. This process is thought to play a role in tumor growth and survival. Perjeta binding to HER2 may additionally signal the body’s immune system to destroy cancer cells. The combination of Perjeta, Herceptin and chemotherapy is believed to provide a more comprehensive blockade of HER signalling pathways.

Perjeta has been recommended for approval in the European Union in combination with Herceptin and docetaxel in patients with HER2-positive metastatic or locally recurrent unresectable breast cancer (mBC). During December 2012, Genentech filed a supplemental Biologics License Application to U.S. regulators for inclusion of updated overall survival results in Perjeta’s drug label. The results stem from the Phase III CLEOPATRA study. This clinical trial demonstrated that the combination of Perjeta, Herceptin and docetaxel chemotherapy significantly extended the lives (overall survival) of individuals with previously untreated HER2-positive mBC versus Herceptin, chemotherapy and placebo.

Bernstein Research has projected Perjeta sales of $1.91 billion for 2016 compared to the industry analyst consensus of about $1.6 billion.

Potential market-leader trastuzumab-DM1 has produced impressive results in clinical trials for HER2-positive breast cancer. This antibody-drug conjugate contains the antibody trastuzumab and the chemotherapy DM1, joined together using a stable linker. Trastuzumab emtansine is designed to target and inhibit HER2 signaling, as well as deliver the DM1 directly inside HER2-positive cancer cells. Trastuzumab emtansine binds to HER2-positive cancer cells, and is believed to block out-of-control signals that make cancer grow while calling on the body’s immune system to attack cancer cells. Once trastuzumab emtansine is taken up by those cancer cells, it is designed to destroy them via the release of DM1.

T-DM1 was submitted for regulatory clearance in the European Union and United States during August 2012. U.S. marketing clearance based on a priority drug review is anticipated during February 2013, and EU approval is projected to occur by mid-2013. The drug is expected to eventually replace Herceptin as the standard of care (perhaps in combination with Perjeta) for second-line mBC. Bernstein Research analysts forecast that T-DM1 will exceed $1 billion in sales during 2016.

Eisai’s novel anticancer agent Halaven has produced solid sales since its major-market regulatory approvals occurred in 2010 and 2011. The green light was given by FDA during November 2010, the European Commission in March 2011, and Japanese health regulators in April 2011. Eisai announced its filing of simultaneous regulatory applications for approval of eribulin mesylate in the United States, European Union, and Japan during March 2010. As of early November 2012, Eisai forecasted Halaven fiscal 2012 worldwide sales of ¥28.5 billion ($346 million) for the 12-month period ending March 31, 2013.

According to Eisai, Halaven is the first single-agent chemotherapy to show a statistically significant overall survival benefit in pretreated metastatic breast cancer patients. Halaven is a non-taxane microtubule dynamics inhibitor. The drug is a synthetic analog of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai. Halaven is indicated for treating patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease

Osteoporosis

The osteoporosis drug arena consists of products that either enhance bone formation or minimize bone resorption. Anabolic /bone-forming products include recombinant human parathyroid hormones. Antiresorptive agents include bisphosphonates, calcitonin, estrogen, and selective estrogen receptor modulators (SERMs).

The osteoporosis marketplace leaders include Forteo, which contains the active chemical teriparatide. Forteo is one of Eli Lilly and Co.’s best-growing products and key franchises. Launched in the United States during December 2002, the drug produced worldwide sales of $836.4 million in the first three quarters of 2012, an increase of 22 percent compared to the corresponding January-September 2011 period. Forteo is a recombinant human parathyroid hormone administered via subcutaneous injection. The naturally occurring protein regulates calcium metabolism in the body.

Evista was previously the best-selling osteoporosis drug for Lilly, as recently as fourth-quarter 2011. During the first nine months of 2012, global sales were down 4 percent year over year to $769.2 million. Composed of the active ingredient raloxifene, Evista is a member of the benzothiophene class of compounds. The selective estrogen receptor modulator is taken as a tablet.

The product was introduced to the U.S. market in January 1998 for the prevention of postmenopausal osteoporosis. During 1999, the medicine was cleared by FDA for treating postmenopausal osteoporosis. Evista is available for the treatment and prevention of postmenopausal osteoporosis in about 100 countries. In Japan, Evista is indicated only for treating postmenopausal osteoporosis. As of Dec. 31, 2012, Lilly is solely responsible for the distribution and commercialization of the medicine in Japan. Previously, Lilly and Chugai Pharmaceutical jointly marketed Evista 60-mg tablet in Japan.

The worldwide osteoporosis product market has been led by the bisphosphonate drug class in recent years. Bisphosphonates aid in increasing bone mass and reducing the chance that an individual has a spinal fracture.

Actonel has been a competitor to Evista since its U.S. launch in September 1998. Hailing from the pyridinyl bisphosphonate drug class, Actonel is administered in tablet form. Containing risedronate, Actonel inhibits osteoclast-mediated bone resorption and modulates bone metabolism.

Actonel is marketed for treating osteoporosis in about 100 countries. The medicine generated annual blockbuster sales for a number of years through 2011, with the 2012 total projected to fall short of $1 billion. Actonel is marketed globally between Sanofi, Warner Chilcott, and Eisai. According to Warner Chilcott, this is the leading branded product in the U.S. non-injectable osteoporosis market for the prevention and treatment of osteoporosis in women.

The Ministry of Health, Labour and Welfare in Japan during December 2012 approved Actonel 75-mg tablet. The once-monthly form of risedronate sodium hydrate was cleared for the treatment of osteoporosis. In Japan, the drug is manufactured by Ajinomoto Pharmaceuticals and distributed by Eisai.

Fosamax is a former billion-dollar yearly sales producer. Merck launched the tablet product in the United States during October 1995. The drug, containing alendronate, is marketed by Teijin in Japan under the brand name Bonalon. As a bisphosphonate, Fosamax acts as a specific inhibitor of osteoclast-mediated bone resorption. Merck reported January-September 2012 sales of $522 million for the medication, compared to $644 million during the first three quarters of 2011.

Boniva/Bonviva is another osteoporosis brand that once generated annual sales exceeding $1 billion, but came in under that amount for 2012. For the first nine months of 2012, Roche reported Boniva/Bonviva sales of SFr258 million ($291 million), down 53 percent versus the corresponding one-year-earlier period. For full-year 2011, Roche reported sales of SFr696 million ($785 million). GlaxoSmithKline reported 2011 Boniva/Bonviva sales of £65 million ($104 million); the product’s 2012 sales for the company were unavailable as this magazine went to press. Boniva debuted in the U.S. marketplace in April 2005 and Bonviva was introduced in the European Union during September 2005. The medicine is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Containing the active chemical ibandronate, Boniva is administered through an intravenous injection as well as via a tablet. The bisphosphonate drug inhibits osteoclast activity as well as reduces bone resorption and turnover. In postmenopausal women, ibandronate reduces the elevated rate of bone turnover, resulting in (on average) a net gain in bone mass.

During March 2012, the U.S. Food and Drug Administration approved for marketing the first generic versions of the once-monthly Boniva tablet. Apotex, Orchid Healthcare, Mylan Pharmaceuticals, Watson Laboratories, and Dr. Reddy’s Laboratories are some of the manufacturers that have obtained U.S. marketing clearance for generic 150-milligram ibandronate tablet.

Novartis’ bisphosphonate Reclast was launched in the United States during September 2007. Composed of zoledronic acid, the brand is marketed in Europe under the trade name Aclasta. Intravenously administered zoledronic acid rapidly partitions to bone and as other bisphosphonates, localizes preferentially at sites of high bone turnover. Novartis reported Reclast/Aclasta sales of $613 million for full-year 2011 and $437 million during the first nine months of 2012.

Unlike the previously mentioned osteoporosis medications, Prolia (denosumab) is in the early stages of a growth path. Prolia represents a new-generation osteoporosis treatment. Marketed by biotech leader Amgen, the RANK ligand inhibitor was granted U.S. and EU regulatory approval during second-quarter 2010 for treating postmenopausal women with osteoporosis at high risk for fracture. The subcutaneous injection is administered by a health-care professional every six months. Global sales totaled $203 million during 2011 and $318 million for the first three quarters of 2012.

Denosumab represents the first approved therapy that specifically targets RANK Ligand, an essential regulator of osteoclasts – the cells that break down bone. RANK Ligand is a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts. The drug prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival. This process leads to decreasing bone resorption and increasing bone mass as well as strength in cortical and trabecular bone.

FDA approved a new indication for Prolia in September 2012: the treatment of bone loss in men with osteoporosis at high risk for fracture. Male osteoporosis has recently been recognized as a significant public-health issue. Between 2010 and 2020, the amount of males with osteoporosis is expected to grow by 17 percent. One in four American men older than 50 years will have an osteoporosis-related fracture in his remaining lifetime.

Prolia is being studied across a range of conditions, including Phase II studies for the treatment of rheumatoid arthritis. The drug is expected to generate global sales of more than $1 billion in 2018.

EffRx Pharmaceuticals during March 2012 was granted FDA approval for Binosto (alendronate) Effervescent Tablets, a new alternative to pill therapy for osteoporosis. Previously known by the product code EX101, the drug was approved for treating osteoporosis in postmenopausal women and increasing bone mass in men with osteoporosis. The once-weekly, strawberry-flavored effervescent tablet rapidly dissolves in a four-ounce glass of plain room temperature water to make a buffered solution. Using EffRx’s formulation technology, Binosto is the first buffered effervescent therapeutic to deliver the gold standard in osteoporosis treatment and fracture prevention of alendronate in an easy-to-swallow solution.

Binosto was launched in the U.S. market by Mission Pharmacal in October 2012. Mission Pharmacal reached a pact with EffRx in April 2012 for the manufacturing and commercialization of the drug in the United States and Canada.

The medicine was developed by the Swiss drug-delivery company EffRx based on a deal with Merck. EffRx holds the global rights to all effervescent and related patents of Fosamax. Patents have been granted to EffRx providing exclusivity for Binosto until February 2023, with other patents pending.

The next blockbuster osteoporosis medicine to emerge from the industry pipeline might be Merck’s odanacatib. The reversible cathepsin-K (cat-K) inhibitor with a novel mechanism of action is undergoing Phase III development for treating osteoporosis in post-menopausal women. The new drug candidate works differently than other osteoporosis treatments by targeting cat-K, a specific enzyme within bone cells. Odanacatib selectively inhibits cat-K, which is the main enzyme in the osteoclasts that digests proteins during bone resorption. Progressive increases in bone mineral density have been shown with odanacatib.

Phase II trial results revealed during October 2012 showed that odanacatib (compared to placebo) significantly increased bone mineral density during a two-year period in post-menopausal osteoporotic women who previously had three or more years of treatment with alendronate. Patients were allowed to have been off alendronate therapy for up to three months immediately before enrollment in the clinical trial.

Merck anticipates submitting U.S. and EU regulatory filings for odanacatib during first-half 2013, and in Japan during second-half 2013. Bernstein Research analysts have projected 2016 sales of about $418 million for the product based on market launches occurring in 2014.

Tarsa Therapeutics is developing an oral version of calcitonin for treating and preventing postmenopausal osteoporosis. Despite having a long history of safety and efficacy as an osteoporosis therapy, calcitonin is only available in injectable and intranasal forms. According to Tarsa, its tablet version has the potential to provide calcitonin’s proven safety and efficacy with the major advantage of once-daily oral dosing. The company’s Phase III clinical study ORACAL investigating its oral calcitonin as a treatment for postmenopausal osteoporosis has yielded positive safety and efficacy results. Additionally, a Phase II osteoporosis prevention study is under way.

“Our product has the potential to be the first FDA-approved oral formulation of calcitonin to be marketed as a treatment for postmenopausal osteoporosis, and we are pleased that it also appears to work well for osteoporosis prevention,” noted David Brand, Tarsa president and CEO of Tarsa. “We believe that our oral calcitonin could address an important unmet need for safe and effective therapies to prevent osteoporosis, and we are assessing options for conducting a Phase III registration trial.”

Oral contraceptives and hormone therapy

The U.S. oral contraceptive market is valued at more than $5 billion, and reportedly is growing at about 8 percent per year. Globally, the OC market exceeds $10 billion and is increasing more than 2 percent annually. The marketplace includes a wide array of contraceptive methods (monophasic and triphasic combined oral contraceptives and progestogen-only products), injectables (one-monthly and three-monthly), implants, and intrauterine devices/systems.

Bayer HealthCare is a global market leader in the contraceptive arena. Two of the company’s five best-selling prescription product lines are oral contraceptives. Ranking No. 3 for the company during the first nine months of 2012 was the YAZ/Yasmin/Yasminelle franchise with global sales of EUR775 million ($1.08 billion), down less than 1 percent compared to the same-time 2011 amount. According to Bayer, this oral contraceptive line during third-quarter 2012 was hampered by generic competition, particularly in Western Europe. The company reported that 3Q 2012 sales gains in the Asia/Pacific and Latin America regions only partly compensated for this effect.

YAZ Flex Plus is awaiting FDA market clearance. The oral contraceptive offers a flexible dosage regimen and folic acid supplementation.

Launched in the United States during February 2001, Mirena can be placed in a uterus to prevent pregnancy for as long five years. The product additionally treats heavy periods in women who choose intrauterine contraception.

Mirena during 2012 was on pace to potentially break the billion-dollar annual sales barrier for the first year ever. The hormone-releasing intrauterine device generated worldwide sales of EUR542 million ($755 million) during January-September 2012, an increase of 27.8 percent versus same-time 2011. The 2012 revenue growth was based primarily on higher U.S. volumes.

Containing ethinyl estradiol and cyproterone, Diane represents another Bayer oral contraceptive. The product accounted for global sales of EUR182 million ($254 million) during 2011 and EUR145 million ($202 million) for the first three quarters of 2012.

Another company leader in the oral contraceptive field is Merck, by way of various brands formerly marketed by Organon/Akzo Nobel and then Schering-Plough. Approved by FDA in October 2001, NuvaRing generated worldwide sales of $623 million for full-year 2011 and $459 million during the first nine months of 2012. Initially introduced internationally in 1998, Implanon sales totaled $294 million in 2011 and $254 million during January-September 2012. Launched in the European Union during June 2000, Cerazette sales reached $268 million for 2011 and totaled $202 million for the first nine months of 2012.

Merck also markets the infertility agent Follistim AQ. Launched in the United States during August 2005, the glycoprotein hormone produced sales of $530 million for 2011 and $352 million during January-September 2012

Warner Chilcott is a strong player in the women’s healthcare arena. The company’s top-selling oral contraceptive is Loestrin 24 FE, which is composed of norethindrone acetate, ethinyl estradiol and ferrous fumarate. This is the first oral contraceptive featuring 24 days of active therapy compared with the traditional 21-day dosing regimen. First approved by U.S. regulators in February 2006, the drug accounted for sales of $396 million in 2011 and $300 million during January-September 2012. Warner Chilcott’s oral contraceptive portfolio additionally consists of Femcon Fe, Ovcon 35, Ovcon 50, and Estrostep Fe.

Warner Chilcott’s top-selling hormone therapy is Estrace Cream. This leading topical product is available for treating urogenital menopausal symptoms. Estrace Cream accounted for sales of $157 million in 2011 and $143 million during the first nine months of 2012, which was up 24.3 percent versus January-September 2011.

The Premarin line of conjugated estrogen products is the leading therapy for women with moderate to severe menopausal symptoms. Marketed by Pfizer, the Premarin family generated sales of $1.01 billion during 2011 and $797 million in the first three quarters of 2012.

A potential first-in-class medicine is the bazedoxifene and conjugated estrogens combination product. Pfizer and Ligand Pharmaceuticals announced in December 2012 that FDA accepted for review a New Drug Application for bazedoxifene/conjugated estrogens (BZA/CE). This drug is intended for non-hysterectomized women for treating moderate-to-severe vasomotor symptoms as well as vulvar and vaginal atrophy associated with menopause, and for the prevention of postmenopausal osteoporosis. FDA’s Prescription Drug User Fee Act date for the product is Oct. 3, 2013.

BZA/CE combines the novel, chemically distinct selective estrogen receptor modulator bazedoxifene with conjugated estrogens. Bazedoxifene was specifically developed to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes, without stimulating the uterus or the breast.

BZA/CE was studied in Phase III studies that included 7,500 postmenopausal women. The new drug candidate was developed by Wyeth Pharmaceuticals and was part of a broader research collaboration with Ligand on SERMs. Pfizer acquired the rights to BZA/CE upon its acquisition of Wyeth. The product is expected to be branded under the trade name Aprela.

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