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. Through our prescription medicines, vaccines, biologic
therapies, and consumer care and animal health products, we work
with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit
www.merck.com and connect with us on Twitter, Facebook and
YouTube.
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