Axsome Therapeutics Confirms Pivotal Status and Advancement of AXS-05 for the Treatment of Alzheimer’s Disease Agitation Based on Successful FDA Breakthrough Therapy Meeting

Axsome Therapeutics 基于成功的 FDA 突破性治疗会议,确定 AXS-05治疗老年痴呆症的枢轴状态和进展

2020-09-01 05:00:10 BioSpace

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    Previously completed positive, pivotal ADVANCE-1 trial sufficient with single additional Phase 3 efficacy trial for NDA in Alzheimer’s disease agitation Initiation of Phase 3, placebo-controlled, randomized-withdrawal efficacy trial on track for 4Q 2020 Initiation of long-term safety trial in patients with Alzheimer’s disease agitation expected in 4Q 2020 No treatments are currently approved for the treatment of Alzheimer’s disease agitation NEW YORK, Aug. 31, 2020 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, today announced confirmation of the pivotal development status and plan for AXS-05 in the treatment of Alzheimer’s disease (AD) agitation following a successful Breakthrough Therapy meeting with the U.S. Food and Drug Administration (FDA). AXS-05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist and sigma-1 receptor agonist. There is currently no approved treatment for AD agitation. Results of the meeting confirm the pivotal status of the previously completed positive ADVANCE-1 trial, and the establishment of the superiority of AXS-05 over its components (component contribution) in the treatment of AD agitation. Consequently, only one additional Phase 3 efficacy trial will be needed to support the filing of an NDA (New Drug Application) for approval of AXS-05 in this indication, and only a placebo control will be required for this trial. This additional Phase 3 efficacy trial will be conducted using a randomized-withdrawal design, in which all patients are first treated with open-label AXS-05, with the patients experiencing a treatment response being subsequently randomized in a double-blind fashion to continued treatment with AXS-05 or to switch to placebo. Axsome is on track to initiate this efficacy trial in the fourth quarter of 2020. Axsome also intends to initiate in the fourth quarter an open-label safety extension trial of AXS-05 in AD agitation patients to supplement the existing AXS-05 long-term safety database.   “Axsome is very pleased with the FDA feedback from our recent Breakthrough Therapy meeting, which confirms a streamlined path to NDA submission for AXS-05 in Alzheimer’s disease agitation, including the pivotal status of our completed ADVANCE-1 trial and the need for only one additional placebo-controlled efficacy trial,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “The randomized-withdrawal design of this additional Phase 3 trial may simultaneously improve signal detection and mitigate placebo response. We remain on track to initiate this trial before year end. Alzheimer’s disease agitation is very distressing to patients and their families, and is associated with earlier nursing home placement, accelerated progression to severe dementia, and increased risk of death. If successfully developed, AXS-05 has the potential to address this serious, prevalent, and debilitating condition, for which there is currently no approved treatment.” In June 2020, Axsome received Breakthrough Therapy designation from the FDA for AXS-05 for the treatment of AD agitation, the second Breakthrough Therapy designation received by Axsome for AXS-05. A Breakthrough Therapy designation is granted to potentially expedite development and review timelines for a promising investigational medicine when preliminary clinical evidence indicates it may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for a serious or life-threatening condition. The Breakthrough Therapy designation for AXS-05 in AD agitation was supported by the recent positive results from the pivotal Phase 2/3 ADVANCE-1 study, a randomized, double-blind, controlled, multicenter U.S. trial in which 366 Alzheimer’s disease patients were treated with AXS-05, bupropion, or placebo. In this trial, treatment with AXS-05 resulted in a rapid, substantial, and statistically significant improvement in agitation as compared to placebo. On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the Cohen Mansfield Agitation Inventory (CMAI) total score compared to placebo at Week 5, with mean reductions of 15.4 points for AXS-05 and 11.5 points for placebo (p=0.010). AXS-05 was also superior to bupropion on the CMAI total score (p<0.001), establishing component contribution. AXS-05 was well tolerated and not associated with cognitive impairment or sedation. The most commonly reported adverse events in the AXS-05 arm were somnolence (8.2% for AXS-05 versus 4.1% for bupropion and 3.2% for placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively). About FDA Breakthrough Therapy Designation Breakthrough Therapy designation is granted by the FDA in order to expedite the development and review of drugs for serious or life-threatening conditions. In order to receive Breakthrough Therapy designation, a drug must demonstrate preliminary clinical evidence that the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. Breakthrough Therapy designation provides an organizational commitment involving senior managers from the FDA, more intensive FDA guidance on an efficient drug development program, and greater access to and more frequent communication with the FDA throughout the entire drug development and review process. It also provides the opportunity to submit sections of a New Drug Application (NDA) on a rolling basis, where the FDA may review portions of the NDA as they are received instead of waiting for the entire NDA submission. In addition, Breakthrough Therapy designated products are eligible for Priority Review, where the FDA has a goal to take action on an application within six months, as opposed to ten months under standard review. Breakthrough Therapy designation does not change the standards for approval. About Alzheimer’s Disease (AD) Agitation Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological symptoms including agitation. AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050 [1]. Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition [2]. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality [2-4]. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD. About AXS-05 AXS-05 is a novel, oral, patent-protected, investigational NMDA receptor antagonist with multimodal activity under development for the treatment of Alzheimer’s disease agitation, major depressive disorder, and other central nervous system (CNS) disorders. AXS-05 consists of a proprietary formulation and dose of dextromethorphan and bupropion and utilizes Axsome’s metabolic inhibition technology. The dextromethorphan component of AXS-05 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, a sigma-1 receptor agonist, an inhibitor of the serotonin and norepinephrine transporters, a nicotinic acetylcholine receptor antagonist, and an inhibitor of microglial activation. The bupropion component of AXS-05 serves to increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist. AXS-05 is covered by more than 42 issued U.S. and international patents which provide protection out to 2034. AXS-05 has been granted U.S. Food and Drug Administration Breakthrough Therapy designation for major depressive disorder, Fast Track designation for treatment resistant depression, and Breakthrough Therapy and Fast Track designations for Alzheimer’s disease agitation. AXS-05 is not approved by the FDA. About Axsome Therapeutics, Inc. Axsome Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders for which there are limited treatment options. For the many people facing unsatisfactory treatments for CNS disorders, Axsome accelerates the invention and adoption of life-changing medicines. Axsome’s core CNS product candidate portfolio includes five clinical-stage candidates, AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14. AXS-05 is being developed for major depressive disorder (MDD), treatment resistant depression (TRD), Alzheimer’s disease (AD) agitation, and as treatment for smoking cessation. AXS-07 is being developed for the acute treatment of migraine. AXS-12 is being developed for the treatment of narcolepsy. AXS-14 is being developed for fibromyalgia. AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14 are investigational drug products not approved by the FDA. For more information, please visit the Company’s website at axsome.com. The Company may occasionally disseminate material, nonpublic information on the company website. References 1. Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2020;16(3):391+. 2. Tractenberg RE, Weiner MF, Thal LJ. Estimating the prevalence of agitation in community-dwelling persons with Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. 2002;14:11-18. 3. Porsteinsson AP, Antonsdottir IM. An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother. 2017;18:611-620. 4. Rabins PV, Schwartz S, Black BS, Corcoran C, Fauth E, Mielke M, Christensen J, Lyketsos C, Tschanz J. Predictors of progression to severe Alzheimer's disease in an incidence sample. Alzheimers Dement. 2013;9:204-207. Forward Looking Statements Certain matters discussed in this press release are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, the success, timing and cost of our ongoing clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials (including our ability to fully fund our disclosed clinical trials, which assumes no material changes to our currently projected expenses), futility analyses and receipt of interim results, which are not necessarily indicative of the final results of our ongoing clinical trials, and the number or type of studies or nature of results necessary to support the filing of a new drug application (“NDA”) for any of our current product candidates; our ability to fund additional clinical trials to continue the advancement of our product candidates; the timing of and our ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates (including, but not limited to, FDA’s agreement with the Company’s discontinuation of the bupropion treatment arm of the ADVANCE-1 study in accordance with the independent data monitoring committee’s recommendations); the potential for the MOMENTUM clinical trial to provide a basis for approval of AXS-07 for the acute treatment of migraine in adults with or without aura, pursuant to our special protocol assessment; the potential for the ASCEND clinical trial, combined with the GEMINI clinical trial results, to provide a basis for approval of AXS-05 for the treatment of major depressive disorder and accelerate its development timeline and commercial path to patients; the Company’s ability to successfully defend its intellectual property or obtain the necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s product candidates, if approved; the Company’s anticipated capital requirements, including the Company’s anticipated cash runway; unforeseen circumstances or other disruptions to normal business operations arising from or related to COVID-19; and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstance. Axsome Contact: Mark Jacobson Chief Operating Officer Axsome Therapeutics, Inc. 22 Cortlandt Street, 16th Floor New York, NY 10007 Tel: 212-332-3243 Email: mjacobson@axsome.com www.axsome.com
先前完成了积极的,关键的 ADVANC1试验,足以单独进行3期新药在阿尔茨海默病躁动中的疗效试验 启动第3期、安慰剂对照、随机抽取的疗效试验,追踪到2020年第4季度 2020年第4季度启动阿尔茨海默病躁动患者的长期安全性试验 目前还没有批准任何治疗老年痴呆症的方法 纽约,2020年8月31日( GLOBE NEWSWIRE )---- Axsome Therapeutics , Inc .( NASDAQ : AXSM ),一家生物制药公司,为中枢神经系统疾病的管理开发新的疗法,今天宣布了 AXS-05在与美国食品和药物管理局( FDA )的突破性治疗会议成功后的关键发展状态和治疗阿尔茨海默病( AD )的计划。AXS-05(右旋美沙芬/布丙酸调节释片)是一种新型的口服、研究 NMDA 受体拮抗剂和 sigma-1受体激动剂。目前还没有批准的治疗 AD 躁动。 会议结果证实了先前已完成的正 ADVANC1试验的关键地位,以及 AXS-05在治疗 AD 躁动方面的优越性(组分贡献)。因此,仅需要一个额外的第3期疗效试验来支持在本适应症中申请 AXS-05批准的 NDA (新药申请),并且本试验只需要安慰剂对照。本次额外的第3期疗效试验将采用随机抽取设计进行,其中所有患者首次使用开放标签 AXS-05进行治疗,经历治疗反应的患者随后以双盲方式随机接受 AXS-05的继续治疗或改用安慰剂。安盛有望在2020年第四季度启动这项疗效试验。Axsome 还计划在第四季度启动 AXS-05在 AD 躁动患者中的开放标签安全性扩展试验,以补充现有的 AXS-05长期安全性数据库。 “ Axsome 对 FDA 最近的突破性治疗会议的反馈非常满意,该会议证实了在阿兹海默症躁动中提交 AXS-05的简化途径,包括我们完成的 ADVANC1试验的关键地位,以及只需要一个额外的安慰剂对照疗效试验,” Herrios Tabuteau 医学博士说,安盛集团首席执行官.“这个额外的3期试验的随机撤回设计可以同时改善信号检测和减轻安慰剂反应。我们仍在努力在年底前开始这项试验。阿尔茨海默氏症的躁动对患者及其家人来说是非常痛苦的,并且与早期的护理家庭安置、加速发展为严重的痴呆症和增加死亡风险有关。如果开发成功, AXS-05有可能解决目前尚无批准治疗的严重、普遍和衰弱的状况。” 2020年6月,安讯士收到 FDA 颁发的 AXS-05治疗 AD 躁动的突破性治疗指定,这是安讯士为 AXS-05接受的第二个突破性治疗指定。当初步的临床证据表明一种或多种临床上有意义的终点与严重或危及生命的疾病的可用治疗方法相比有实质性改善时,批准了突破性治疗的指定,以可能加快有希望的研究药物的开发和审查时间表。AD 躁动中 AXS-05的突破性治疗指定得到了关键阶段2/3 ADVANC1研究的近期阳性结果的支持,该研究是一项随机、双盲、对照、多中心的美国试验,在该试验中,366名阿尔茨海默病患者接受了 AXS-05、益寿或安慰剂治疗。在本试验中,与安慰剂相比, AXS-05治疗导致了躁动的快速、实质性和统计学上的显著改善。在主要终点上, AXS-05与 Cohen Mansfield Agimization Inventory ( CMAI )总分中的基线相比有统计学意义的显著下降,与第5周的安慰剂相比, AXS-05平均下降15.4分,安慰剂平均下降11.5分( p =0.010)。AXS-05在 CMAI 总分上也优于 buproion ( p <0.001),建立了成分贡献。AXS-05耐受性良好,与认知障碍或镇静无关。AXS-05组最常见的不良反应为嗜睡( AXS-05组为8.2%,布丙酸组为4.1%,安慰剂组为3.2%),头晕(分别为6.3%、10.2%、3.2%),腹泻(分别为4.4%、6.1%、4.4%)。 关于 FDA 突破性治疗指定 FDA 批准了突破性治疗指定,以加快严重或危及生命的药物的开发和审查。为了获得突破性治疗的指定,药物必须证明初步的临床证据,该药物可能有实质性改善的至少一个临床上重要的终点比现有的治疗。突破性治疗指定提供了一个组织承诺,包括来自 FDA 的高级管理人员,更密集的 FDA 指导有效的药物开发计划,以及更多的机会和更频繁的沟通与 FDA 整个药物开发和审查过程。它还提供了在滚动的基础上提交新药申请( NDA )部分的机会, FDA 可以在收到新药申请时审查部分 NDA ,而不是等待整个 NDA 提交。此外, Breakthrough Therapy 指定的产品有资格获得优先审评, FDA 的目标是在六个月内对申请采取行动,而不是在标准审评中的十个月。突破性治疗指定不改变审批标准。 关于阿尔茨海默病( AD )发作 阿尔茨海默氏症( AD )是一种进行性神经退行性疾病,其特征是认知能力下降,行为和心理症状包括躁动。AD 是最常见的痴呆形式,在美国估计有600万人患有此病,预计到2050年这一数字将增加到约1400万。据报道,70%的 AD 患者出现了躁动,表现为情绪困扰、攻击性行为、破坏性易怒和抑制[2]。AD 患者的躁动与照顾者负担增加、功能下降、认知能力下降加速、早期护理家庭安置以及死亡率增加有关[2-4]。目前尚无 FDA 批准的用于治疗 AD 患者躁动的治疗方法。 关于 AXS-05 AXS-05是一种新型的、口服的、专利保护的、正在研究中的 NMDA 受体拮抗剂,用于治疗阿尔茨海默病、重度抑郁症和其他中枢神经系统( CNS )疾病。AXS-05由右旋美沙芬和丁丙酸的专有配方和剂量组成,利用 Axsome 的代谢抑制技术。AXS-05的右美沙芬成分是一种非竞争性 N-甲基-D -门冬氨酸( NMDA )受体拮抗剂,也称为谷氨酸受体调节剂、 sigma-1受体激动剂、血清素和去甲肾上腺素转运蛋白抑制剂、尼古丁乙酰胆碱受体拮抗剂和微神经胶质激活抑制剂。AXS-05的补骨素成分有助于提高右旋美沙芬的生物利用度,是去甲肾上腺素和多巴胺再摄取抑制剂,以及尼古丁乙酰胆碱受体拮抗剂。AXS-05涵盖了超过42个已发布的美国和国际专利,为2034年提供保护。AXS-05被授予美国食品药品监督管理局(Food and Drug Administration)重大抑郁症突破性治疗的称号,抗抑郁药快速通道的称号,以及突破性治疗和老年痴呆症快速通道的称号。AXS-05未经 FDA 批准。 关于 Axsom Therapeutics , Inc . Axsome Therapeutics , Inc .是一家临床阶段的生物制药公司,为治疗中枢神经系统( CNS )疾病开发新的治疗方案,治疗方案有限。对于许多面临 CNS 疾病治疗不满意的人来说, Axsome 加速了改变生命的药物的发明和应用。安盛的核心 CNS 产品候选组合包括5个临床阶段候选者, AXS-05、 AXS-07、 AXS-09、 AXS-12、 AXS-14。AXS-05正在被开发用于主要抑郁症( MDD )、抗治疗抑郁症( TRD )、阿尔茨海默病( AD )躁动以及戒烟治疗。AXS-07正在开发用于急性偏头痛治疗。AXS-12正在开发用于治疗嗜睡症。AXS-14正在开发用于纤维肌痛。AXS-05、 AXS-07、 AXS-09、 AXS-12、 AXS-14为未获 FDA 批准的在研药品产品。如需更多信息,请访问公司网站 axsome 。com 。公司可以偶尔在公司网站上发布材料、非公开信息。 参考文献 1。阿尔茨海默氏症协会.2020年老年痴呆症的事实和数字。Alzheimer Dement 2020;16(3):391+。 2。Trattenberg RE , Weiner MF , Thal LJ .估计社区居民中患有阿尔茨海默氏症的躁动的流行程度。神经精神病学.14:11-18。 3。波士顿森 AP ,安东斯多蒂 IM 。阿兹海默症躁动治疗的最新进展.药剂学专家.2017年;18:611-620。 4。Rabins PV ,施瓦茨 S , Black BS , Corcoran C , Faith E , Mielke M , Christensen J , Lyketssos C , Tschanz J . Predicators 进展为严重老年痴呆症的发病率样本。老年痴呆症患者.2013;9:204-207。 前瞻性陈述 本新闻稿中讨论的某些事项是“前瞻性陈述”。在某些情况下,我们可能会使用诸如“预测”、“相信”、“潜在”、“继续”、“估计”、“预计”、“预期”、“计划”、“可能”、“可能”、“可能”、“将”、“应该”等术语,或者其他表达未来事件或结果不确定性的词语来识别这些前瞻性陈述。特别是,公司关于趋势和未来潜在结果的陈述是此类前瞻性陈述的例子。前瞻性陈述包括风险和不确定性,包括但不限于我们正在进行的临床试验的成功、时间和成本,以及我们当前产品候选者的预期临床试验,包括关于启动时机的陈述。临床试验的注册和完成速度(包括我们完全有能力为已披露的临床试验提供资金,该试验假设我们目前预计的费用没有重大变化)、无效分析和收到中期结果,这不一定表明我们正在进行的临床试验的最终结果,以及支持为我们当前的任何产品候选者提交新药申请(“ NDA ”)所必需的研究数量或类型或结果的性质;我们为继续推进我们的产品候选者提供额外临床试验资金的能力;获得和维持美国食品药品监督管理局(Food and Drug Administration)(“ FDA ”)或其他监管机构对我们的产品候选者(包括但不限于FDA 同意公司根据独立的数据监测委员会的建议终止 ADVANC1研究的 buproion 治疗部门; MOMENTUM 临床试验的潜力,为 AXS-07在有或无先兆的成人中急性治疗偏头痛提供依据,根据我们的特殊协议评估; ASCEND 临床试验的潜力,结合 GEMINI 临床试验结果,为 AXS-05治疗重度抑郁症提供依据,并加快其发展时间表和通往患者的商业道路;公司能够成功捍卫其知识产权或以公司可接受的成本(如果有的话)获得必要的许可;公司研发计划和合作的成功实施;公司许可协议的成功;公司产品候选人的市场接受(如果获得批准);公司的预期资本要求;包括公司预期的现金跑道;因 COVID-19引起或与 COVID-19相关的意外情况或其他正常业务运营中断;以及不在公司控制范围内的其他因素,包括一般经济状况和监管发展。此处讨论的因素可能导致实际结果和发展与这些陈述所表达或暗示的结果和发展有重大差异。该等前瞻性陈述仅于本新闻稿刊发日期作出,本公司并无责任公开更新该等前瞻性陈述以反映其后事件或情况。 轴心接触: Mark Jacobson 首席运营官 Axsom Therapeutics , Inc . 22 Cortlandt 街16楼 纽约州纽约市10007 电话:212-332-3243 电子邮件: mjacobson @ axsome.com www.axsor.com

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