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September 15, 2014 12:30 pm ET

Merck now expects to submit the New Drug Application for odanacatib with the U.S. Food and Drug Administration (FDA) in 2015

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced data from the pivotal Phase 3 fracture outcomes study
for odanacatib in postmenopausal women with osteoporosis. Odanacatib is
Merck’s investigational once-weekly cathepsin K inhibitor. In the
Long-Term Odanacatib Fracture Trial (LOFT), odanacatib met its primary
endpoints and significantly reduced the risk of osteoporotic hip, spine
and non-vertebral fractures compared with placebo. The results from this
trial were presented today at the American Society for Bone and Mineral
Research (ASBMR) Annual Meeting in Houston, Texas.

The rates of adverse events overall in LOFT were generally balanced
between patients taking odanacatib and placebo. Adjudicated events of
morphea-like skin lesions and atypical femoral fractures occurred more
often in the odanacatib group than in the placebo group. Adjudicated
major adverse cardiovascular events were generally balanced overall
between the treatment groups. There were numerically more adjudicated
stroke events with odanacatib than with placebo.

“Despite the important and serious consequences of fractures related to
osteoporosis and our ability to identify patients who would benefit from
therapy, many patients with osteoporosis are not being treated. There is
a need for additional treatment options. The effects of odanacatib on
fracture risk from the LOFT study are very encouraging,” said Michael
McClung, M.D., LOFT leader and founding director of the Oregon
Osteoporosis Center, Portland, Oregon.

In the study, odanacatib significantly reduced osteoporotic fracture
risk

In LOFT, odanacatib significantly reduced the risk of three types of
osteoporotic fractures compared to placebo in the primary efficacy
analysis, and also reduced the risk of the secondary endpoint of
clinical vertebral fractures. Specifically, compared to patients
receiving placebo, patients who received odanacatib had a:

• 54% relative risk reduction of new and worsening morphometric
  (radiographically-assessed) vertebral fractures (p<0.001),
• 47% relative risk reduction of clinical hip fractures (p<0.001),
• 23% relative risk reduction of clinical non-vertebral fractures
  (p<0.001), and
• 72% relative risk reduction of clinical vertebral fractures (p<0.001).

In addition, treatment with odanacatib led to progressive increases over
five years in bone mineral density (BMD) at the lumbar spine and total
hip. Compared to placebo, the change in BMD from baseline at five years
with odanacatib for lumbar spine was 11.2% (p<0.001) and for total hip
was 9.5% (p<0.001).

Safety and tolerability data from LOFT

Prior to the start of the study, certain adverse events of interest were
identified for adjudication: morphea-like skin lesions, systemic
sclerosis, serious respiratory infections, osteonecrosis of the jaw,
atypical femoral shaft fractures, delayed fracture unions, atrial
fibrillation and major adverse cardiovascular events (MACE). Adjudicated
morphea-like skin lesions occurred more frequently on odanacatib: in 12
patients in the odanacatib group (0.1% incidence) and 3 patients in the
placebo group (<0.1% incidence). These skin lesions resolved or improved
after discontinuation of the study drug. Adjudicated atypical femoral
shaft fractures were reported for 5 patients in the odanacatib group
(incidence of 0.1%) and not reported in patients in the placebo group.
No meaningful differences were observed in adjudicated events of
systemic sclerosis, serious respiratory infections or delayed fractured
unions between groups. There were no adjudicated cases of osteonecrosis
of the jaw.

Adjudicated atrial fibrillation was reported in 92 patients in the
odanacatib group (incidence of 1.1%) and 80 patients in the placebo
group (incidence of 1.0%). In the MACE analysis, events were reported
for 215 patients in the odanacatib group and 194 patients in the placebo
group (hazard ratio 1.12 (95% confidence interval (CI) 0.93, 1.36)).
There were 271 deaths reported in the odanacatib group and 242 deaths in
the placebo group (hazard ratio 1.13 (95% CI 0.95, 1.35)); this numeric
difference does not appear to be related to a particular reported cause
or causes of death. There was a numeric imbalance in adjudicated strokes
with more events occurring in the odanacatib group. Based on the
adjudication committee assessment, 109 patients in the odanacatib group
experienced stroke (incidence 1.4%) and 86 patients (incidence 1.1%) in
the placebo group (hazard ratio 1.28 (95% CI 0.97, 1.70)).
Investigator-reported cerebrovascular events occurred in 305 patients in
the odanacatib group (incidence 3.8%) and 290 patients taking placebo
(incidence 3.6%) (hazard ratio 1.06 (95% CI 0.91, 1.25)).

Merck continues to collect data from the blinded extension study and is
planning additional analyses of data from the trial, including an
independent re-adjudication of major adverse cardiovascular events, in
support of regulatory submissions.

“Merck believes the currently available data support a favorable
benefit/risk profile for odanacatib,” said Dr. Keith Kaufman, vice
president, Clinical Research, Diabetes and Endocrinology, Merck. “We
want to thank our investigators who conducted the study and the
thousands of patients who participated in this study, which is yielding
critical insights into the potential of odanacatib in the treatment of
postmenopausal osteoporosis.”

Largest outcomes study in postmenopausal women with osteoporosis

LOFT is a randomized, double-blind, placebo-controlled, event-driven
trial, including a pre-planned, blinded placebo-controlled extension
study. The trial enrolled 16,713 women, 65 years of age or older,
diagnosed with osteoporosis, who have been postmenopausal for five years
or more. Patients were randomized to receive odanacatib 50 mg/week
(n=8,357) or placebo (n=8,356). All patients received vitamin D (5600
IU/week) and calcium up to 1200 mg/day, if required. Safety and efficacy
analyses were conducted for 16,071 patients randomized at 387 centers in
40 countries, with patients enrolled across the Americas, Europe and the
Asia-Pacific region.

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 cathepsin K, the primary enzyme in the osteoclasts that digests
proteins during bone resorption. Progressive increases in BMD have been
demonstrated with odanacatib.

Merck now plans to submit a New Drug Application to the Food and Drug
Administration for odanacatib in 2015. Merck also plans to submit
applications to the European Medicines Agency and the Ministry of
Health, Labour, and Welfare in Japan.

About Merck

Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
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