Olanzapine

Data show RDX-002 lowered postprandial triglycerides by 82% Exploratory analyses also confirmed significantly reduced weight gain in subjects treated with olanzapine FALLS CHURCH, Va.--(BUSINESS WIRE)-- Response Pharmaceuticals, Inc., a clinical stage company focused on weight management and metabolic health in high-risk populations, today announced positive topline results from its Phase 1b clinical trial evaluating the safety and efficacy of RDX-002, a first-in-class candidate treatment for the prevention of the rapid weight gain associated with the leading antipsychotic medications. Antipsychotic-induced weight gain (AIWG) is a drug-induced epidemic within the already vulnerable population of patients with severe mental illness, including schizophrenia, depression and bipolar disorder, with patients experiencing rapid increases in body weight, hyperlipidemia and hyperglycemia. “Antipsychotic medications are essential treatments that help millions of patients live better lives, but can be associated with rapid weight gain and obesity. This often leads to poor adherence to treatment and reduced quality of life, and contributes to long term cardiometabolic morbidities including decreased life expectancy” explained Joseph T. Coyle, MD, Emeritus Chair of Psychiatry and Neuroscience at Harvard Medical School. “The results of this trial suggest that RDX-002 may provide a unique therapeutic solution to address AIWG and the adverse metabolic changes that are associated with this weight gain.” In the 2-week open-label trial, 24 healthy, antipsychotic-naïve volunteers were initially treated for 1 week with olanzapine, a highly efficacious antipsychotic, usage of which is associated with AIWG. Subjects were randomized at the outset of the study to either add RDX-002 orally twice a day to OLAN, or continue on OLAN alone during week two. Subjects in the RDX-002 cohort met the primary endpoint for efficacy, lowering postprandial triglycerides (ppTGs). In an exploratory analysis of AIWG, subjects receiving OLAN alone saw significant weight gain during the first and second weeks of treatment whereas there was no significant weight change in the RDX-002 cohort in week 2. Subjects receiving olanzapine treatment showed a 54% increase in mean AUC postprandial triglycerides on Day 8 vs Day 1 (p=0.009) and remained elevated on Day 15. The olanzapine/RDX-002 cohort saw a decrease of 81.6% (p<0.001) in mean AUC ppTG on Day 15 vs Day 8. Overall RDX-002 was well-tolerated, with adverse events restricted to mostly mild to moderate GI effects, with no serious adverse events or treatment-related discontinuation during the study. In exploratory analyses, OLAN alone resulted in a mean increase in body weight of 1.6 kg (2.1%) (p<0.001 vs Day 1) in the first week of treatment and an additional 1.7 kg (2.2%) (p=0.016 vs Day 8) in the second week. Subjects receiving RDX-002 in the second week saw only a 0.4 kg increase (p=0.443 vs Day 8). Additionally, subjects in the OLAN-only group in the second week saw an increase in LDLc of 24.8% (p=0.016), while subjects receiving RDX-002 experienced and increase of 4.3% (p=NS). While exploratory, these findings support results seen in other trials where RDX-002 has demonstrated an impact on body weight, hyperlipidemia and hyperglycemia. “This study provides the first clinical evidence of increased post-prandial lipids with antipsychotic medications, suggesting upregulation in iMTP from antipsychotics may play a role in the rapid weight gain associated with these medications” said Response Pharmaceuticals Chief Science Officer and lead inventor of RDX-002 Dr. Paul Sweetnam. “Treatment with the iMTP-inhibitor RDX-002 significantly reduced ppTGs and blunted the weight gain in OLAN-treated subjects indicating a potential role in the treatment and prevention of AIWG. We expect to be presenting our detailed data set at an upcoming medical conference and in a scientific publication.” “This is very promising news for patients who have long fought to manage not only severe mental illness, but also the syndrome of AIWG and its associated morbidities. This early evidence feeds our drive to help patients around the world, including the approximately 58 million Americans suffering from mental illness according to the NIH,” said Response Pharmaceuticals CEO Eric Keller. “Response is actively engaged in preparing for next-stage clinical trials in AIWG, as well as development into other indications suited to the metabolic impact of the unique iMTP mechanism of action of RDX-002.” The planned Phase 2 clinical trial of RDX-002 will be a placebo-controlled 12-week study assessing weight gain and postprandial triglyceride changes in patients initiating olanzapine therapy for bipolar depression and schizophrenia. Response Pharmaceuticals is currently in the Series B funding stage. About Antipsychotic-Induced Weight Gain Antipsychotic-Induced Weight Gain affects millions of people worldwide. While current antipsychotic medications, such as olanzapine, quetiapine and clozapine, have been transformational for patients’ lives, a frequent side effect associated with these treatments is rapid, clinically meaningful weight gain, often occurring in the first few weeks of treatment and sometimes continuing for years. This results in high rates of medication discontinuation or a change to a less efficacious medication, and often leads to relapse and hospitalization. Along with clinically meaningful weight gain, atypical antipsychotics are known to cause other serious effects, including elevated serum triglycerides, increased LDL cholesterol, and blood sugar, each of which contribute to an increased risk of cardiovascular disease and diabetes, resulting in higher mortality rates and up to 17.5 years’ reduced life expectancy. About the Study The Phase 1B study was a single-center, open-label 15-day study in 24 healthy volunteers receiving OLAN. During the first week of treatment all subjects received OLAN alone and were randomized to either remain on OLAN alone or OLAN+RDX-002 during the second week of treatment. The primary endpoint was postprandial (pp)TG AUC measured on Day 1 (pre-OLAN), Day 8 and Day 15 after consumption of a meal standardized for total and fat calorie content. Secondary and exploratory endpoints included changes in fasting lipids and body weight as well as OLAN PK and safety. About RDX-002 RDX-002, Response Pharmaceuticals’ lead candidate, is a first-in-class, potent, selective, and gut-specific small molecule inhibitor of microsomal triglyceride transfer protein (MTP). The overall effect of MTP inhibition is a decrease in the amount of triglycerides and cholesterol delivered to the body after a meal. RDX-002 has been studied in multiple Phase 1 and Phase 2 clinical trials including 496 healthy subjects and patients dosed for up to 84 days. In these studies, RDX-002 lowered post-prandial triglyceride levels, circulating levels of low-density lipoprotein cholesterol (LDLc), and reduced weight. RDX-002 is being developed as an adjunctive therapy for patients taking atypical antipsychotic therapy, as well as a potential treatment in other settings in which clinically significant weight gain and/or adverse metabolic changes are prevalent. RDX-002 is being developed under an exclusive world-wide license from Sanofi S.A. About Response Pharmaceuticals Response Pharmaceuticals is a clinical-stage biotechnology company focused on developing treatments for weight management and metabolic health in high-need patient populations. The company is building its portfolio with an initial focus on helping those taking antipsychotic medications for disabling mental illnesses to combat weight gain and metabolic dysregulation associated with these treatments. For more information, please visit .

*仅供医学专业人士阅读参考随着全球人口的老龄化，痴呆症的发病率越来越高。据世界卫生组织估计，全球现有痴呆症患者超5000万，到2050年这一数字将达到1.5亿。冷漠、抑郁、攻击性、焦虑、易怒、谵妄和精神病等，是痴呆症患者的常见表现。因此，抗精神病药物是治疗痴呆症行为和心理症状的常用处方药。虽然已经有研究发现，抗精神病药物的使用，与痴呆症患者的脑血管疾病或死亡风险增加有关，但是此类药物在痴呆症患者群体中的安全性，目前的研究仍非常有限。近日，由曼彻斯特大学Pearl L H Mok领衔的研究团队，在顶级医学期刊《英国医学杂志》（BMJ）上发表了一项重要研究成果[1]。他们在分析近18万50岁以上成年人的数据之后发现，与不使用抗精神病药物的痴呆症患者相比，使用任何抗精神病药物都与至少七种疾病风险增加有关。尤其需要重视的是，在开具抗精神病药物处方后的90天与肺炎风险增加119%、急性肾损伤发生风险增加72%、静脉血栓栓塞风险增加62%、中风风险增加61%、骨折风险增加43%、心肌梗死风险增加28%和心力衰竭风险增加27%有关。基于以上结果，Mok团队认为，对于痴呆症患者而言，抗精神病药物的危害被低估了。这些药物的危害，比目前监管部门警示的范围宽泛的多，尤其是在开始治疗后的头三个月内。他们也建议，临床医生在给痴呆症患者开具相关处方的时候，需要考虑这些广泛的不良后果。论文首页截图Mok团队这项研究纳入了173910名在1998年1月1日至2018年5月31日期间确诊为痴呆症的成年人（≥50岁），女性占比63%。在所有痴呆症患者中，有35339名患者有抗精神病药物用药史。处方量最多的抗精神病药物是利培酮（占所有处方的29.8%）、喹硫平（28.7%）、氟哌啶醇（10.5%）和奥氮平（8.8%），这几种药物加在一起几乎占所有处方的80%。基于以上数据，Mok团队研究了抗精神病药物的使用与痴呆症患者患中风、静脉血栓栓塞、心肌梗死、心力衰竭、室性心律失常、骨折、肺炎和急性肾损伤等八种疾病之间的关系。总的来看，在开始使用抗精神病药物后的两年中，发生率最高的是肺炎、骨折和中风，而室性心律失常则很少见。除室性心律失常外，任何抗精神病药物的使用都会增加剩余7种疾病的风险，从肺炎的风险增加103%（HR=2.03）到心力衰竭的风险增加16%（HR=1.16）不等。如果将处方时间限制在过去的90天（当前使用），则与肺炎风险增加119%、急性肾损伤风险增加72%、静脉血栓栓塞风险增加62%和中风风险增加61%相关；近半年使用也与这些结果以及骨折风险的增加有关；但过去使用抗精神病药物与除肺炎以外的疾病风险的增加无关。抗精神病药物处方时间与八种疾病发生风险之间的关系Mok团队预计，在开始用抗精神病药物后的180天内，每9名痴呆症患者中，就可能有1名患者因使用抗精神病药物而患肺炎；每167名患者，就可能有1人出现心肌梗死。在用药两年后，风险有所下降，每15名接受治疗的患者可能会有1人患肺炎，每254名患者中会有1人发生心肌梗死。此外，Mok团队还分析了使用药物不同时间段的疾病累积发生率。在开始使用抗精神病药物后的90天内，抗精神病药物使用者的肺炎累积发病率为4.48%，而匹配的非使用群体的发病率为1.49%。一年后，抗精神病药物使用者的这一比例增至10.41%，而非使用者为5.63%。其他几种疾病的发生率见下面的表格。累积发生率总的来说，Mok团队的研究表明，在50岁及以上的痴呆症患者群体中，与不使用抗精神病药物相比，使用抗精神病药物会增加中风、静脉血栓栓塞、心肌梗死、心力衰竭、骨折、肺炎和急性肾损伤的风险。需要引起注意的是，在处方后的90天内，肺炎、急性肾损伤、中风和静脉血栓栓塞症的相对危险性最高，开始治疗后的第一周尤其需要注意。基于以上研究数据，研究人员认为，抗精神病药物对痴呆症患者的危害比以前公认的更大。参考文献：[1].Mok PLH, Carr MJ, Guthrie B, et al. Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study. BMJ. 2024;385:e076268. doi:10.1136/bmj-2023-076268本文作者丨BioTalker