Regenerating Interest In Novel Drugs For Postmenopausal Osteoporosis

New bone-targeted agents for osteoporosis must clear significant obstacles to succeed in a highly generic market, but safety concerns with established agents like bisphosphonates and calcitonin offer a foothold. Phase III anabolic candidates from Amgen and Radius Health aim to build new bone, the holy grail of osteoporosis treatment, but R&D in new anti-resorptive mechanisms to halt bone breakdown also continues.

The fractures that continue to weaken the foundation for currently marketed postmenopausal osteoporosis drugs offer a foothold to sponsors of new bone-building or bone-strengthening agents – but they’ll need to provide data sufficiently compelling to win over insurers who already have a wide choice of low-cost generic options.

Major Phase III programs are underway for new mechanisms to treat osteoporosis, including the partnership of Amgen Inc. and UCB Group, as well as Merck & Co. Inc., even though postmenopausal osteoporosis is considered a forbidding market to enter thanks to the wide range of generic drug therapies on offer. A GlobalData analysis of the osteoporosis market released March 7 predicts slow growth globally, rising from just under $6 billion in 2012 to $8 billion in 2022.

Big company experience and resources make Amgen’s romosozumab and Merck’s odanacatib the top bets among osteoporosis NMEs, but emerging companies Radius Health and Tarsa Therapeutics are also trying to bring Phase III candidates to FDA.

However, medical costs associated with osteoporosis are expected to rise more rapidly, and therein lies the opportunity. The National Osteoporosis Foundation’s clinical guidelines, updated in early 2013, report that the cost of osteoporosis-related fractures to the U.S. health care system, estimated at $17 billion for 2005, could “double or triple” by 2040.

“Too many patients are not being prescribed any of the FDA-approved, effective therapies,” the foundation maintains. Adherence to treatment is complicated by inconvenient dosing and well-publicized safety concerns. Use of the most popular anti-osteoporotic class, the mostly-generic oral bisphosphonates, is in decline thanks to concerns about osteonecrosis of the jaw and atypical femoral fractures (Also see "Waiting For Blockbusters: Osteoporosis Market Burdened With Black Box Warnings, Reimbursement Woes, And Spare Pipelines" - Pink Sheet, 2 Jan, 2012.).

The market has been cold to new formulations that improve on the gastrointestinal tolerability issues that make oral bisphosphonate dosing a chore. Warner Chilcott PLC launched Atelvia, a once-weekly version of its Actonel (risedronate) without food and drink restrictions, in the U.S. in early 2011; Atelvia posted annual sales of only $62 million in 2012. Now EffRx Pharmaceuticals SA/Mission Pharmacal Co.’s Binosto is taking another run at the market for an improved bisphosphonate: the once-weekly effervescent solution of alendronate (Merck’s Fosamax and generics) launched in the U.S. on Oct. 1, 2012.

Even calcium and vitamin D, the OTC foundation of osteoporosis prevention, has taken a hit, with the Feb. 25 release of a U.S. Preventive Service Task Force meta-analysis concluding that evidence is insufficient to support use of the nutrients for fracture prevention (Also see "AHRQ Vitamin D/Calcium Report Draws Industry Fire" - Pink Sheet, 4 Mar, 2013.).

In addition to agents that target bone, postmenopausal osteoporosis is also addressed by therapies that target the hormonal deficits associated with menopause. Pfizer Inc. is making another attempt to get its selective estrogen receptor modulator bazedoxifene through FDA; submissions for the SERM for PMO have languished after receiving multiple action letters, but a recent NDA for bazedoxifene plus conjugated estrogens is under review for PMO prevention as well as vasomotor and vaginal symptoms of menopause (see related story, (Also see "Beyond Hormone Therapy: Signs Of Life In Pipeline For Menopausal Women" - Pink Sheet, 19 Mar, 2013.)).

Waiting For The Anabolic Wave In Osteoporosis Treatment

While the armamentarium for postmenopausal osteoporosis is large, its range is narrow: anti-resorptive drugs, which target osteoclast activity to block bone resorption and consequent bone breakdown, dominate. Anabolic agents that build bone are desired, but only one has made it to the U.S. market – Eli Lilly & Co.’s Forteo (teriparatide), approved a decade ago, stimulates formation of new bone by activating osteoblasts. Its use is limited by an increased risk of osteosarcoma, which earned the drug a REMS in 2009 (Also see "Lilly Gains New Indication For Forteo, But Also A REMS And Patient Registry" - Pink Sheet, 24 Aug, 2009.).

Amgen/UCB’s Phase III osteoporosis candidate romosozumab increases osteoblast-mediated bone formation by inhibiting sclerostin, a different anabolic mechanism of action than teriparatide, a version of human parathyroid hormone. Two pivotal postmenopausal osteoporosis trials of the once-monthly subcutaneous injection started in 2012, a 6,000-patient placebo-controlled trial and an active controlled trial comparing romosozumab with alendronate in 4,000 patients. Both trials will collect 24-month vertebral fracture data, as FDA desires; the active control trial has an event-driven clinical fracture co-primary endpoint.

Romosozumab is a key element of Amgen’s goal of bringing biologics to primary care (Also see "On Amgen’s Agenda: Bring Biologics To Primary Care" - Pink Sheet, 18 Feb, 2013.). To support romosozumab marketing, Amgen aims to leverage its emerging primary care presence with Prolia (denosumab), an anti-resorptive RANKL inhibitor approved for prevention of PMO in 2010. Prolia was the first biologic introduced into a primary care market, and has seen a slow start. Annual sales reached $472 million in 2012, lagging behind the MAb’s sales as Xgeva in the less price-sensitive oncology market.

The Persistent Allure Of Parathyroid Hormone

Without Amgen and UCB’s considerable resources, Radius Health Inc. is trying to bring a novel anabolic candidate for PMO through Phase III. The company is facing limited financial resources after it cancelled an IPO late last year citing the deteriorating market for biotech IPOs (Also see "After Canceling IPO, Radius May Tap Institutional Investors" - Pink Sheet, 19 Nov, 2012.). BA058, in-licensed from Ipsen in 2005, is a synthetic peptide analog of human parathyroid hormone-related protein. According to Radius, hPTHrP activates the same PTHR1 receptor as parathyroid hormone (teriparatide, or PTH 1-34, is an 84-amino acid sequence of hPTH) but has different effects in bone thanks to downstream cell signaling differences. The company touts Phase II data showing BA058 to have faster and larger increases in BMD at the spine and hip with less hypercalcemia than Forteo.

The 2,400-patient Phase III trial that Radius kicked off in April 2011 is comparing daily subcutaneous injections of BA058 with placebo and Forteo for prevention of vertebral fractures. On Jan. 7, Radius reported that an interim safety analysis supported continuing the trial unmodified; the company expects to complete enrollment in the first quarter and report data in the fourth quarter of 2014, followed by NDA submission in mid-2015.

Radius had discussed its Phase III plan with FDA at an end-of-Phase II meeting on Jan. 21, 2010 and submitted the revised protocol at the end of that year, but its plans were upended when it received a letter from FDA on Feb. 15, 2012 “stating that, after internal consideration, the agency believes that a minimum of 24-month fracture data are necessary for approval of new products for the treatment of postmenopausal osteoporosis,” the IPO prospectus says. Radius’ Phase III trial had an 18-month fracture data primary endpoint.

After meeting with FDA on March 21, 2012, “we believe that continued use of the 18-month primary endpoint will be acceptable, provided that our NDA includes the 24-month fracture data derived from a 6-month extension of the BA058 and placebo groups of the Phase III trial, which will provide alendronate for osteoporosis management,” the prospectus reports.

A follow-on product, a transdermal formulation of BA058, started a 250-patient Phase II trial in the third quarter of 2012, with top-line data expected a year later. The microneedle patch, worn for five minutes daily, uses 3M Co.’s Microstructured Transdermal System.

The search for a better parathyroid hormone product dominated anabolic R&D in osteoporosis for years, but with little success (Also see "After D-mab: Next-Generation Osteoporosis Drugs Focus On Building Bone" - Pink Sheet, 1 Jun, 2009.). NPS Pharmaceuticals Inc. submitted a BLA for a recombinant version of the full length peptide (rhPTH 1-84) for PMO as Preos, but it never progressed beyond a 2006 “approvable” letter (Also see "NPS Seeks Development Partners For Preos And Teduglutide, Reduces Force" - Pink Sheet, 15 Apr, 2007.). NPS aims to submit a BLA for rhPTH 1-84 as Natpara for the rare endocrine disorder hypoparathyroidism in mid-2013, but says the PMO program would need a partner to continue.

The potential for improved formulations of the shorter PTH 1-34 peptide – without Forteo’s daily subcutaneous injections – once spurred big pharma licensing activity, but in 2011 those deals largely fell apart: Lilly dropped TransPharma Medical Ltd.’s transdermal ViaDor-PTH1-34 after it did not meet the primary endpoint in Phase II; Novartis AG terminated an oral formulation of PTH 1-34 with the absorption enhancer 5-CNAC from Emisphere Technologies Inc. after an early stage trial showed safety but did not meet several clinical endpoints; and GlaxoSmithKline PLC returned rights to Unigene Laboratories Inc.‘s oral PTH program.

Zosano Pharma Corp. has defined a Phase III strategy for a rapid transdermal formulation of PTH 1-34 using its needle-free ZP Patch technology with FDA, but the company lacks resources to continue alone and development has not proceeded since Phase II results were announced in 2009. Based on a late 2008 EOP2 meeting, Zosano expects to support a 505(b)(2) NDA with a Phase III trial using BMD as a surrogate endpoint to bridge Forteo’s fracture efficacy data.

A start-up formed in September 2012, [SkelRegen LLC] is targeting different bone-building proteins, known as bone morphogenetic proteins (BMPs). The company will focus on small molecules that block specific inhibitors of BMPs as well as molecules that directly activate the BMP pathway.

Advancing Anti-Resorptives With New Mechanisms

R&D in anti-resorptives continued with investigation into new mechanisms that could maintain bone density without hindering the creation of new bone, a drawback of osteoclast inhibitors like the bisphosphonates and Prolia.

Merck’s odanacatib, which inhibits cathepsin K, an enzyme responsible for breakdown of bone tissue, had been the leading light of the osteoporosis pipeline, especially after a pivotal trial was halted early thanks to “robust efficacy” with a “favorable risk-benefit profile,” as Merck announced in July 2012 (Also see "Odanacatib Phase III Success Suggests Merck’s Primary Care Gamble Is Paying Off" - Pink Sheet, 12 Jul, 2012.). But even then, Merck noted that “safety issues remain in certain selected areas,” and those issues apparently proved more serious than expected. In early 2013, Merck announced that NDA filing would be delayed from the first half of 2013 to 2014 so the firm could include safety results of an ongoing extension trial in 8,000 women in the filing along with the 16,000-patient pivotal trial (Also see "With Odanacatib Filing Pushed Back, Merck Reports Flat Top-Line Growth In 2012" - Pink Sheet, 1 Feb, 2013.).

Merck is already an established player in osteoporosis with Fosamax, but the recent appointment of a new R&D chief brings more recent regulatory experience in the sector: Roger Perlmutter shepherded denosumab while at Amgen (Also see "A Changing Of The Guard At Merck R&D As Perlmutter Succeeds Kim" - Pink Sheet, 11 Mar, 2013.). Nonetheless, echoes of the safety issues, especially related to skin, that derailed previous cathepsin K inhibitor candidates from Novartis and GSK have cast a pall on the project.

Biotech approaches to anti-resorptive therapy of osteoporosis are emerging in early-stage R&D. Alethia Biotherapeutics Inc. identified a cell surface protein, Siglec-15, specifically expressed on osteoclasts. A November 2012 financing round will fund IND-enabling studies of AB-25E9, a monoclonal antibody targeting Siglec-15 that may increase bone mineral density by inhibiting osteoclast differentiation and bone resorption without also impairing bone formation. Earlier last year, Novo Nordisk AS licensed rights to technology related to an anti-interleukin-20 antibody identified by Taiwan’s National Cheng Kung University. IL-20 has a role in osteoclast differentiation; when overproduced, the cytokine causes a decrease in bone mass, and the hope is that blocking IL-20 production could improve bone density [See Deal].

Goodbye Calcitonin?

The osteoporosis market may be on the verge of losing one of the oldest anti-resorptive therapies, salmon calcitonin, a more potent synthetic version of the human thyroid hormone calcitonin that inhibits osteoclast activity. A March 5 FDA advisory committee review of calcitonin benefits and risks was sparked by a cancer signal identified by a European pharmacovigilance review ( (Also see "Salmon-Derived Osteoporosis Drugs Face Upstream Struggle Against Cancer Concerns" - Pink Sheet, 16 Jan, 2013.). The European Medicines Agency eliminated osteoporosis indications for calcitonin in July 2012.

While the FDA committees split on whether the agency should withdraw marketed salmon calcitonin nasal sprays (Novartis’ Miacalcin, Upsher-Smith Laboratories Inc./Unigene’s Fortical, and generics), the committee agreed 20-1 that fracture efficacy data should be required to support approval of calcitonin salmon products for PMO (Also see "Committee Clear On Need For Fracture Data For New Calcitonin Drugs" - Pink Sheet, 11 Mar, 2013.). Calcitonin products entered the market before FDA switched from allowing approvals based on surrogate endpoints like bone mineral density to requiring a fracture endpoint in a 1994 guidance.

The advisory committee decision is a blow to Tarsa Therapeutics Inc. and its lead product, an oral recombinant salmon calcitonin. The company had completed a pre-NDA meeting with FDA and was preparing to file an NDA for treatment of PMO in 2013 based on the Phase III ORACAL trial showing superiority to both placebo and nasal calcitonin in increasing BMD at the lumbar spine at 48 weeks.

To defend its oral calcitonin against cancer concerns, Tarsa presented a poster at the October 2012 annual meeting of the American Society for Bone and Mineral Research analyzing cancer data from its two year-long calcitonin trials (ORACAL and a Phase II study for prevention of PMO) that found no carcinogenicity signal in the 694-patient database.

But without fracture data, even an oral calcitonin product could have a difficult time competing in the crowded PMO market – so if FDA requires Tarsa to go back and show an effect on a fracture endpoint, it will be gaining a stronger foothold for competition. And with the range of new mechanisms that could hit the market and an array of well-established, low-cost generics available, new entrants are going to need all the help they can get.