2014年9月19日訊 /生物谷BIOON/ --近幾個月來，癌症免疫治療領域異常火熱。百時美施貴寶（BMS）的PD-1抑制劑Opdivo（nivolumab）率先在日本上市，而默沙東的PD-1抑制劑Keytruda（pembrolizumab）又於9月初獲得FDA批准，是美國上市的首個PD-1抑制劑。這2者分別以60億美元和41億美元的銷售預期摘得《即將結束臨床試驗的全球重磅藥物TOP 15》的狀元和榜眼。
不過，在pembrolizumab癌症免疫項目之前，默沙東另一種骨質疏鬆症藥物odanacatib實際上一直排在後期管線的前排。此前，默沙東一直對odanacatib寄予厚望，該藥也被市場預期為年銷售額高達25億美元的重磅炸彈。然而，因安全性問題，odanacatib的臨床推進緩慢，讓默沙東一度如坐針氈。而且，有種種跡象表明，odanacatib可能出現了問題。
近日，默沙東攜重磅數據歸來，odanacatib在關鍵III期LOFT研究中達到了主要終點。LOFT研究是在絕經後女性骨質疏鬆症群體中開展的迄今最大的預後研究，共招募16714例65歲及以上確診為骨質疏鬆症且絕經至少5年的患者。該項研究中，odanacatib在增加骨密度的同時，顯著降低了3種骨質疏鬆性骨折的更顯，同時降低了次要終點臨床椎體骨折的風險。
具體而言，與安慰劑組相比，odanacatib治療組：（1）新發和不斷惡化的形態學測定脊椎骨折相對風險降低54%（p＜0.001）；（2）臨床髖部骨折相對風險降低47%（p＜0.001）；（3）臨床非脊椎骨折相對風險降低23%（p＜0.001）；（4）臨床脊椎骨折相對風險降低72%（p＜0.0001）。此外，odanacatib治療組腰椎和髖骨骨礦物質密度（BMD）在治療5年內逐步增加。治療5年內，與安慰劑組相比，odanacatib治療組腰椎骨密度從基線變化11.2%（p＜0.001），全髖關節骨密度從基線的變化率為9.5%（p＜0.001）。
然而，該項研究中也出現了一些令人不安的副作用跡象。odanacatib治療組房顫風險略有升高，共109例發生房顫（佔1.4%），安慰劑組有89例發生房顫（佔1.1%）。心血管副作用也會引起監管部門的謹慎重視。odanacatib治療組出現5例硬斑樣皮損和非典型股骨骨折，安慰劑無一例無發生。
默沙東原本計劃在今年年底向FDA提交odanacatib的上市申請，但表示將推遲計劃，待收集更多數據後，將在明年向FDA提交odanacatib的監管申請。同時還計劃向歐洲藥品管理局（EMA）和日本勞動衛生福利部（MHLW）提交odanacatib的監管申請。
ISI分析師認為，默沙東公布的骨折數據已滿足臨床治療標準。然而，儘管odanacatib未顯著加重心血管事件，然而安慰劑在房顫、中風、MACE事件及死亡方面的良好表現，將會使FDA在審查odanacatib時仔細推敲。而且，即便odanacatib據此數據最終獲批，其上市銷售可能也會受到限制。ISI分析師預計，odanacatib的銷售潛力為3億美元，遠低於默沙東定義的成功標準。儘管如此，默沙東仍對odanacatib的前景保持樂觀，並認為現有的數據已支持odanacatib具有良好的療效/風險屬性，odanacatib在降低骨折風險方面的表現令人鼓舞。
去年，在宣布推遲odanacatib臨床開發及監管計劃時，默沙東一直不願意討論該藥的安全性。不過近日，其癌症管線中備受矚目的癌症免疫療法pembrolizumab獲得了FDA批准，是美國上市的首個PD-1抑制劑，同時業界也十分看好其處於後期階段的C肝項目。此時的默沙東，已經不需要像一年前一樣對odanacatib上市表現的如饑似渴。（生物谷Bioon.com）
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英文原文：Merck Announces Data from Pivotal Phase 3 Fracture Outcomes Study for Odanacatib, an Investigational Oral, Once-Weekly Treatment for Osteoporosis
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--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.