2014年5月8日讯 /生物谷BIOON/ --诺华（Novartis）5月5日公布了实验性药物Signifor LAR（pasireotide LAR；SOM230）关键性III期研究的积极数据。该项研究在当前标准疗法仍未充分控制病情的肢端肥大症（acromegaly）患者中开展。研究数据表明，与继续接受标准生长抑素类药物（奥曲肽LAR或兰瑞肽Autogel）治疗的患者组相比，接受帕瑞肽（pasireotide LAR）的患者组，取得了更显著的疾病控制。相关数据已提交至第16届欧洲内分泌大会（16th European Congress of Endocrinology）。
该项研究在即使接受最大剂量生长抑素类似物（SSAs）（如奥曲肽LAR或兰瑞肽Autogel）仍无法取得GH和IGF-1生化控制的肢端肥大症患者中开展，评估了帕瑞肽LAR 40mg剂量和60mg剂量和继续接受标准SSAs疗法的疗效。数据显示，帕瑞肽LAR 40mg剂量组和60mg剂量组有显著更多的患者实现了生化控制（分别为15.4%和20.0%），奥曲肽LAR或兰瑞肽Autogel治疗组为0%。该项研究在，不良事件发生率在各组相似。
Signifor（帕瑞肽）是一种多受体靶向生长抑素类似物，能够高亲和力结合5种促生长素抑制素受体亚型中的4种（sst1,2,3,5）。目前该药已获FDA批准用于不适合垂体手术或尚未治愈的库欣病（Cushing's disease）成人患者的治疗。同时，该药已获欧盟批准，用于不适合手术或手术失败的库欣病成人患者的治疗。Signifor每天2次皮下注射（SC）。目前，诺华正在评估Signifor LAR，这是一种长效释放（LAR）、每月一次肌肉注射（IM）剂型的Signifor。
英文原文：Novartis drug Signifor® LAR shows superior efficacy in acromegaly patients not controlled on first generation somatostatin analogues
Acromegaly, an endocrine disorder resulting from elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, is associated with high mortality[1,2]
Phase III data show patients on pasireotide LAR achieved greater biochemical control, as measured by both GH and IGF-1 levels, versus control group
These data, supported by a previously published Phase III study, are the basis for worldwide regulatory filings for pasireotide LAR in the treatment of acromegaly
Basel, May 5, 2014 - Novartis today presented results from a pivotal Phase III trial of investigational therapy Signifor® LAR (pasireotide LAR; SOM230) in patients with acromegaly for whom current standard of care provides inadequate disease control. The study findings showed that patients taking pasireotide long-acting release (LAR) achieved greater disease control when compared to continued treatment with the standard somatostatin analogue therapies, octreotide LAR or lanreotide Autogel*. These data were presented at the 16th European Congress of Endocrinology.
Acromegaly is caused by a benign (non-cancerous) tumor within the pituitary gland that secretes excess growth hormone (GH), leading to elevated levels of insulin-like growth factor-1 (IGF-1). This combined effect of elevated GH and IGF-1 levels causes the enlargement of body parts, including the hands, feet and facial features, along with serious morbidities such as cardiovascular, metabolic and respiratory diseases[1,4]. If exposed to long-term elevated levels of GH and IGF-1, acromegaly patients face a two- to three-fold increased risk of death[2,5]. Biochemical control of the disease, as measured by both GH and IGF-1 levels, is the primary goal of treatment. Other disease management objectives include tumor shrinkage and improvement in clinical signs and symptoms.
"Historically, we have evaluated somatostatin analogues for the treatment of acromegaly by the decrease in either growth hormone or insulin-like growth factor levels. With more sensitive assays and more stringent evaluation criteria, a recent meta-analysis indicates that up to 45% of patients can have either GH or IGF-I still elevated," said Dr. Monica Gadelha, professor, Federal University of Rio de Janeiro and study author. "As the health risks associated with acromegaly may persist until both GH and IGF-1 levels are normalized, this study further supports the importance of monitoring for and achieving full biochemical control."
This study evaluated pasireotide LAR 40 mg and 60 mg against continued therapy with octreotide LAR or lanreotide Autogel in patients who did not achieve GH and IGF-1 biochemical control despite receiving the maximum approved doses of these currently available somatostatin analogues (SSAs). In the trial, significantly more patients achieved biochemical control with each dose of pasireotide LAR compared to the octreotide LAR and lanreotide Autogel control arm. Specifically, 15.4% and 20.0% of those with inadequately controlled acromegaly taking pasireotide LAR 40 mg and 60 mg, respectively (95% confidence interval [CI], 7.6-26.5; P=0.0006; 95% CI, 11.1-31.8; P<0.0001), achieved biochemical control versus 0% achieving biochemical control on continued treatment with octreotide LAR or lanreotide Autogel (95% CI, 0-5.3). The incidence and severity of adverse events (AEs) was similar across all treatment groups, except for a higher frequency and degree of hyperglycemia in the pasireotide LAR arm.
"These results strengthen our understanding of this rare endocrine disorder and suggest pasireotide LAR may offer benefit for acromegaly patients whose disease is not fully controlled on their current therapy," said Alessandro Riva, president, Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "As part of our long-standing commitment to transforming the care of rare pituitary diseases, we are working to bring this potentially meaningful solution to the acromegaly community."
Worldwide regulatory filings for pasireotide LAR in acromegaly are currently underway based on these results and separate previously published robust Phase III data.
About the study
The multicenter Phase III study was a randomized, double-blind trial examining pasireotide LAR 40 mg or pasireotide LAR 60 mg versus continued open-label treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (the control group) for 24 weeks. The trial included 198 patients with inadequately controlled acromegaly on maximum approved doses of octreotide LAR or lanreotide Autogel for at least 6 months, regardless of prior surgical status. The primary endpoint of this study was the proportion of patients achieving biochemical control as measured by the mean GH levels of <2.5Mu g/L and normalized IGF-1 at 24 weeks.
The key secondary endpoint was the percentage of patients achieving normalized IGF-1; other secondary endpoints included the percentage of patients achieving normalized GH levels, tumor reduction and safety. Notably, in this study, IGF-1 normalization was achieved by 24.6% and 26.2% of patients taking pasireotide LAR 40 mg and 60 mg, respectively (95% CI, 14.8-36.9; P<0.001; 95% CI, 16.0-38.5; P<0.001) and was not achieved by any patients in the control arm (95% CI, 0-5.3). Additionally, 35.4% and 43.1% of patients in the pasireotide LAR 40 mg and 60 mg arms, respectively (95% CI, 23.9-48.2; 95% CI, 30.8-56.0) had mean GH levels of <2.5Mu g/L compared to 13.2% in the control arm (95% CI, 6.2-23.6).
Tumor size was also evaluated and the study found a greater proportion of patients receiving pasireotide LAR 40 mg and 60 mg achieved a greater than 25% decrease compared with those receiving octreotide LAR and lanreotide Autogel (18.5% [95% CI, 9.9-30.0] and 10.8% [95% CI, 4.4-20.9] versus 1.5% [95% CI, 0-7.9], respectively).
The most common AEs associated with pasireotide LAR 40 mg, 60 mg and the control arm were hyperglycemia (33.3%, 30.6% and 13.6%), diabetes mellitus (20.6%, 25.8% and 7.6%) and diarrhea (15.9%, 19.4% and 4.5%), respectively.