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Merck halts Ph III trial of osteoporosis drug on success
 
 
  World News | July 13, 2012
pharmatimes.com

Merck & Co is closing a Phase III trial assessing its osteoporosis drug odanacatib ahead of schedule after the drug hit all of its efficacy targets.

The US pharma major said that after an interim analysis of data from the study, an independent Data Monitoring Committee (DMC) recommended that it should be closed early "due to robust efficacy and a favorable benefit-risk profile".

Odanacatib is a novel drug that works by inhibiting cathepsin K, an enzyme found within osteoclast cells that breaks down bone tissue.

The Phase III randomised, placebo-controlled trial involved more than 16,000 patients and was designed to gage the safety and efficacy of the medicine in lowering the fracture risk of post-menopausal women with osteoporosis.

Despite considering the benefit-risk profile to be positive, the DMC did note that safety issues remain "in certain selected areas", and therefore made recommendations to follow up on them.

But Merck said that its original plan to carry out a blinded extension trial will enable further monitoring of safety issues anyway, in addition to providing extra efficacy data.

On the back of its positive performance in the multicentre trial, which Merck said will take "a number of months" to wind down, the company intends to file for approval of odanacatib in the US, Europe and Japan sometime in the second half of next year.

Investors welcomed news of the drug's ability to cut the risk of fractures in this subset of patients with osteoporosis as well as its step towards the market, pushing Merck's share price up 3%.

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Update on Phase III Trial for Odanacatib, Merck's Investigational Cat-K Inhibitor for Osteoporosis

Study met its primary efficacy outcomes at first planned interim analysis and is being concluded early

WHITEHOUSE STATION, N.J., July 11, 2012 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today an update on the Phase III trial assessing fracture risk reduction with odanacatib, Merck's investigational cathepsin K (cat-K) inhibitor. The Data Monitoring Committee (DMC) for the study recently completed its first planned interim analysis for efficacy and recommended that the study be closed early due to robust efficacy and a favorable benefit-risk profile. As a result, Merck will begin taking steps to close the trial. The DMC noted that safety issues remain in certain selected areas and made recommendations with respect to following up on them. Merck's previously announced plan to conduct a blinded extension trial will allow further monitoring of the issues. The extension trial will also continue to measure efficacy. Merck anticipates submitting regulatory applications for approval of odanacatib in the U.S., European Union (EU) and Japan in the first half of 2013.

"We are encouraged by the Data Monitoring Committee's recommendation to close the trial early," said Peter S. Kim, Ph.D., executive vice president, Merck and president, Merck Research Laboratories, "and look forward to reviewing the data with the scientific community to bring forward this innovation."

The Phase III randomized, placebo-controlled trial with over 16,000 patients was designed to assess the safety and efficacy of odanacatib in reducing fracture risk in post-menopausal women with osteoporosis. This event-driven trial started in 2007 and was expected to continue until hip fractures had been reported in a total of 237 patients. The interim analysis was conducted by the DMC as planned when approximately 70 percent of the targeted number of hip fractures had been reported.

Merck expects the process of closing this large, multi-center trial to take a number of months. Trial investigators will schedule final assessments for trial participants at 387 sites in 40 countries. Data from these visits will be collected and reviewed to allow a full and complete analysis, and final results of the study will be submitted for presentation and publication in 2013 once the analysis is complete.

About Odanacatib In osteoporosis, bone loss occurs because of an imbalance in bone remodeling (the rate of bone resorption exceeds that of bone formation). Osteoclasts, cells that resorb bone, secrete signaling factors to stimulate osteoblasts, cells that form bone. Odanacatib selectively inhibits cat-K, the primary enzyme in the osteoclast that digests proteins during bone resorption, while maintaining the number of osteoclasts. This novel mechanism of action of odanacatib leads to improved balance in bone remodeling and bone formation is preserved while bone resorption is reduced, resulting in progressive increases in bone mineral density over time.

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New Data on Odanacatib, Merck's Phase III Investigational Cat-K Inhibitor for Osteoporosis, Presented at the Annual Meeting of The American Society for Bone and Mineral Research

Merck press release. SAN DIEGO, Sept. 19, 2011 - New clinical and pre-clinical data on Merck's odanacatib, an investigational cathepsin K (cat-K) inhibitor for the treatment of osteoporosis in post-menopausal women, were presented at the 33rd Annual Meeting of The American Society for Bone and Mineral Research (ASBMR) in San Diego. The data were presented in an oral presentation and five posters.

"Merck is pleased to continue building scientific knowledge about odanacatib with new data showing this investigational medication's effects on increasing bone mineral density (BMD) and impacting bone strength and formation," said Albert Leung, M.D., Ph.D., executive director, Clinical Research, Merck Research Laboratories. "Merck has a strong and long-standing commitment to the field of osteoporosis as evidenced by our large and rigorous Phase III program to evaluate the long-term efficacy and safety of odanacatib."

Odanacatib selectively inhibits cathepsin K, the major enzyme in osteoclasts that is responsible for the breakdown of existing bone tissue. Odanacatib is currently in a large-scale Phase III clinical program to determine its safety and potential effects on hip, vertebral and non-vertebral fractures.

The following are highlights from the presentations at ASBMR. Abstracts can be viewed by visiting the ASBMR website at www.ASBMR.org.

Abstract # FR0453; Plenary Poster Session, September 16, 2011, 5:45 PM -7:00 PM PT/ Abstract # SA0453; Poster Session I, September 17, 2011, 11:00 AM - 1:00 PM PT - 5 Year Results of a Phase 2 Study of Odanacatib in Postmenopausal Women with Low Bone Mineral Density (BMD)

In a Phase IIb clinical study extending to five years, odanacatib continued to increase bone mineral density (BMD) and reduce bone resorption markers in postmenopausal women with low BMD (N=141). The two-year Phase IIb base study of postmenopausal women (mean age 63 years) with low bone mass (BMD T-scores initially between -2.0 and -3.5 at the lumbar spine, femoral neck, trochanter or total hip) was extended for three additional years to further assess the efficacy and long-term safety of odanacatib. The primary endpoint was BMD at the lumbar spine. Secondary endpoints included BMD at the femoral neck, trochanter, hip and distal radius; levels of bone resorption markers including urine NTx/creatinine, levels of bone formation markers including serum BSAP; and assessments of safety. Results from years four and five were presented.

In postmenopausal women who received odanacatib 50 mg weekly continuously for five years (N=13), there were BMD increases from baseline of 11.9 percent at the lumbar spine, 9.8 percent at the femoral neck, 10.9 percent at the hip trochanter, and 8.5 percent at the total hip. Additionally, women treated continuously with odanacatib 50 mg maintained a low level of urine NTx/creatinine (-67.4% from baseline) through five years of treatment; while levels of serum BSAP remained only slightly reduced relative to baseline ( 15.3%). In women who were switched from odanacatib to placebo after the two-year base study (n=14), BMD returned to near baseline levels.

Because of the small sample size in each individual treatment group, groups were pooled for comparison on the incidence of adverse experiences in the placebo and odanacatib groups. Among the 114 women treated with the 10, 25 or 50 mg weekly dose of odanacatib at any time during the first three years of the study, 41 were treated with placebo and 73 with odanacatib 50 mg during years 4 to 5 of the study. The incidence of adverse experiences and serious adverse experiences were 81 percent and 20 percent, respectively, in the placebo group and 89 percent and 22 percent, respectively, in the odanacatib group. None of the women in the placebo group and two women (3%) in the odanacatib group discontinued the study drug due to an adverse experience. The incidence of skin-related adverse experiences was 17 percent and 12 percent in the placebo and odanacatib groups, respectively.

Abstract # 1030; Oral Session 05: New Approaches to Osteoporosis Treatment (Preclinical), September 17, 2011, 10:45 - 11:00 AM PT - Efficacy of the combination regimens of the cathepsin K inhibitor odanacatib versus alendronate with parathyroid hormone in estrogen-deficient rabbits

This preclinical study in estrogen-deficient rabbits (n=12/group) compared the effect of five different treatment regimens on bone mineral density (BMD), bone histology and bone strength: the combinations of human parathyroid hormone 1-34 (PTH) and odanacatib, PTH and alendronate, and the monotherapies including odanacatib, alendronate or PTH. The data showed that treatment with PTH+odanacatib resulted in the fastest rate of BMD gains.

After three months of treatment, both the PTH+odanacatib and PTH+alendronate groups increased lumbar vertebrae bone mineral density from baseline by 13.4 percent and 9 percent from baseline, respectively, while odanacatib, alendronate, and PTH resulted in increases from baseline of 8.7 percent, 2.9 percent, 1.9 percent, respectively. By six months of treatment, the PTH+ odanacatib and PTH+alendronate groups increased bone mineral density from baseline in the lumbar vertebrae by 17.6 percent and 18.4 percent, respectively. Odanacatib, alendronate and PTH monotherapies increased lumbar spine bone mineral density from baseline by 11.3 percent, 8.3 percent, and 6.2 percent, respectively. Bone histology showed that although both the PTH+odanacatib and PTH+alendronate combinations resulted in increases in BMD, the PTH+alendronate combination eventually halted bone formation in the trabecular lumbar vertebrae, whereas the PTH+odanacatib combination increased BMD and bone formation rate. Positive correlations between BMD and bone mineral content and bone strength were seen in both the hip and the spine.

Abstract # FR0473; Plenary Poster Session, September 16, 2011, 5:45 PM -7:00 PM PT/ Abstract # SA0473; Poster Session I, September 17, 2011, 11:00 AM - 1:00 PM PT Differential effects of odanacatib and alendronate on bone turnover in the femoral neck of adult ovariectomized rhesus monkeys

This preclinical study evaluated the effects on bone mass and turnover in the femoral neck of ovariectomized rhesus monkeys (n=48) after 20 months of treatment with odanacatib, alendronate or placebo. Both odanacatib and alendronate significantly decreased trabecular bone formation rate at 12 months (p<0.01) and 20 months (p<0.05) compared to placebo. On the cortical bone surface, odanacatib significantly increased the cortical bone formation rate, a parameter which was not affected by treatment with either alendronate or placebo. The increased long-term bone formation rate with odanacatib, determined within 8-months of odanacatib treatment, resulted in a significant increase in cortical thickness by 23 percent (p<0.05), cortical area per tissue area by 18 percent (p<0.05) and a decrease in marrow area per tissue area by 11 percent (p<0.05) versus placebo.

Abstract # MO0472; Poster Session III, September 19, 2011 from 11:30 AM - 1:30 PM PT Effects of odanacatib versus alendronate on bone remodeling and biomechanical properties of the lumbar spine in estrogen-deficient rhesus monkeys.

This preclinical study evaluated the effects of odanacatib and alendronate on bone mineral density (BMD), bone turnover, strength and collagen organization in the lumbar spine of estrogen-deficient rhesus monkeys (n=48). Compared to placebo, significant increases in lumbar spine BMD were observed in the odanacatib (6.7%) and alendronate groups (6.4%). Both odanacatib and alendronate were also shown to significantly reduce (p<0.001) trabecular bone remodeling rate as compared to placebo. Increases in lumbar spine strength were also shown in the odanacatib and alendronate treated groups as compared to placebo.

Abstract # MO0037; Poster Session III, September 19, 2011, 11:30 AM - 1:30 PM PT Differentiation of treatment effects of odanacatib from alendronate in ovariectomized rhesus monkeys using voxel based morphometry of quantitative computed tomography images

This preclinical study examined volumetric bone mineral density (vBMD) in ovariectomized rhesus monkeys (n=48) treated with odanacatib, alendronate or placebo. Both odanacatib and alendronate produced significant increases in vBMD in the femoral neck from baseline; however, the positive effect of odanacatib was shown to be greater on cortical bone compared to alendronate.

Additionally, the following data will also be presented:

· Abstract # SU0066 - Evaluation of HR-pQCT in non-human primates for monitoring effect of odanacatib on bone microarchitecture

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World osteoporosis market forecast to reach $11.4B in 2015

World News | February 08, 2012


The world market for drugs to treat osteoporosis is set to rise from a value of $7.3 billion in 2010 to $11.4 billion by 2015, according to new forecasts.

The world market will grow by a yearly average of 9.2% during the period, according to the report, which is published by Transparency Market Research. The study also expects the market in China for osteoporosis treatments to increase by an annual average of 13.5% from 2010 to 2015, reaching a value of $2.5 billion by the end of the period.

Currently, the global osteoporosis drugs market is dominated by the bisphosphonate class, with Roche's Bonviva/Boniva (ibandronic acid) and Novartis' Aclasta/Zometa (zoledronate) accounting for healthy market shares and showing an average sales growth rate of about 20% in the past two years, according to the study.

Amgen's Prolia (denosumab) is the most recent entrant to the osteoporosis treatment market, following approval from the US Food and Drug Administration (FDA) and the European Commission, and is expected to compete directly with the bisphosphonate products, although its initial uptake is likely to be in second-line therapy, mostly in patients who are intolerant to these treatments, says the report. However, after this year, growth in the drug's use is expected to lead to a decline in the market for parathyroid hormone and selective oestrogen receptor modulator (SERM) drugs used in the treatment of osteoporosis, it notes, and goes on to point out that there is also substantial potential for Prolia in the treatment of bone loss in cancer patients.

Sales of the drug are expected to reach $3.5 billion in 2015, it says.

Drugmakers have various promising osteoporosis treatment candidates in R&D, including a number of first-in-class products currently in Phase III. Among these are Merck & Co's cathepsin K (cat-K) inhibitor odanacatib, which possesses a novel mechanism of action against osteoporosis, and Pfizer's Aprela, which combines the SERM bazedoxifene with conjugated equine oestrogens.

The anticipated fast growth of the market in China will largely be due to the increasing prevalence of osteoporosis among the female population, as well as the growing elderly population, rising standards of living and increasing awareness of, and education in, bone health.

Therefore, the report sees huge growth potential for osteoporosis drug treatments in many Chinese cities, including Shanghai, Beijing, Guangzhou and Hangzhou.

Drug developers can obtain market advantages by developing cost-competitive drugs with easy dosage patterns which effectively promote bone-building, as many patients find it difficult to comply with the strict dosage schedules of traditional drug treatments, the report advises. They should also work to address unmet needs in the market by developing treatments that combine convenient dosing schedules with efficacy and safety profiles which represents improvements over currently-available products, it adds.

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Has Merck Found The Heir To Fosamax?

forbes.com 7/11/2012

Merck's new bone drug appears to work, according to a clinical trial of the osteoporosis treatment that was stopped early tonight, although investors will have to wait to see full results of the study.

Full results won't be available for some time. But the news that an independent data safety and monitoring committee - a group of outside gatekeepers charged with making sure the clinical trial remains ethical - decided to stop the study could cheer investors. Shares of Merck were up 2.6% in after-market trading. Some on Wall Street hope the new medicine, odanacatib, could be an heir to the company's previous bone drug, Fosamax, which generated $3 billion in annual sales before its patent expired in 2008.

The data monitoring committee recommended the study be closed early due to "a favorable benefit-risk profile" but also noted that "safety issues remain in certain selected areas." Merck says the committee made recommendations as to how to follow up on those issues, and that it will conduct a blinded extension trial that will continue monitoring those issues.

Among Merck's pipeline of experimental drug, odacatinib has been generating considerable excitement among industry analysts, who have been talking up the drug to skeptical investors.

On July 9, Mark Schoenebaum at ISI Group wrote:

Most people have viewed "odana" as likely to work, but not likely to sell well given generic competition. However, if the phase 3 is stopped early for efficacy, it could begin to change Street opinion.

On June 25, Catherine Arnold at Credit Suisse First Boston, who rates Merck Outperform, wrote raised her estimates on the drug's sales in 2020 form $550 million to $1.1 billion. She wrote:

· The Market is overlooking the potential for Merck's phase 3 osteoporosis drug odanacatib considering the clinical unmet needs in osteoporosis, the potential fracture benefit given surrogate data for the drug and the positive demographic (aging) trends relevant to this market.

· Attention on odanacatib should increase soon with 2 interim looks at the drug's efficacy expected this year; 70% of events (likely imminent) and 85% of events (by year end) with regulatory filing expected in 2013. Positive data is likely to lead to upward revisions to 2015+ estimates and improved sentiment on MRK's pipeline.

· Post diligence with opinion leaders, we are raising our estimates in 2020 from $350MM to ~$1.1Bn, which we still see as conservative with meaningful differences in fracture rates to bisphosphonates and the likelihood of category expansion, with a new potentially safer option to treat osteoporosis. Our target price increases from $44 to $45 (Exhibit 28) with these sales changes and another $2 in valuation is plausible from our upside odanacatib forecast ($3.4Bn revenues).

On May 31, Christopher Schott of J.P. Morgan wrote:

Odanacatib (osteoporosis, phase III) represents one of Merck's key late-stage pipeline assets and expectations for both clinical and commercial success for the product are low. While clinical risk clearly remains for the asset, we believe positive phase III results are likely based on five-year phase IIb follow-up data. Importantly (and the focus of this report), we do not share the market's commercial concerns on odanacatib and believe bisphosphonate category concerns represent a meaningful opportunity for a new mechanism of action such as odanacatib. We remain Overweight MRK shares.

Our survey on odanacatib (pages 9-16) supports our view that safety fears surrounding the bisphosphonates have created an opening in the osteoporosis market, which we see odanacatib well-positioned to fill. The product offers a differentiated mechanism of action, which if supported by solid outcomes data, could translate into a multi-billion product opportunity for Merck over time, in our view. We are forecasting a 2014 launch for odanacatib and see sales reaching roughly $1bn by 2017.

 
 
 
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