Clozapine

特约作者 | 张自然博士 责任编辑 | 郑瑶 一致性评价乌龙事件引起了大家对一致评价的关注。 本文就化学仿制药一致性评价的投入（费用、时间）、产出等做一分析。 01 耗资 一、过评费用 据国泰君安证券对已公布数据的162个药品的一致性评价费用分析发现： 100～500万元的占17%（27个品种），多为境内外共线品种。如华海的盐酸帕罗西汀片、复星的氯化钾颗粒、康恩贝的蒙脱石散等均在100～200万元之间。鲁抗的蒙脱石散，西南药业的对乙酰氨基酚片，复星的苯磺酸氨氯地平片，华海的厄贝沙坦片、氯沙坦钾片、利培酮片等都在200～300万元之间。 501～1000万元的占54%（87个品种）。 ＞1000万元的占30%（48个品种）。 二、奖励    1、奖励一致性评价 经作者长期跟踪发现，为鼓励一致性评价，各地先后出台了系列政策，绝大部分在2018年12月首批国采落地之前发布，有只给真金白银的，也有同时对因此新增设备设施给予奖励的。多则千万，少则50万。 经不完全统计，给予过评奖励最大方的是千年药都安徽亳州，2018年9月27日亳州市政府正式发文，“对符合奖励条件的仿制药一致性评价品种，给予单个品种1200-1500万元的财政奖励；单个品种年销售额首次突破5000 万元、1亿元、2亿元、5亿元的，每上一个台阶给予企业100万元的奖励”。当然，亳州是中药之都，对化药一致性评价如此豪横也兼有招商引资，配合当地由中药材向制剂升级之需。 同样是安徽，合肥市于2022年9月发文，“对通过仿制药质量和疗效一致性评价的固体制剂、注射剂，按品种分别给予最高500万元、100万元的奖补，在国内同品种前三家通过一致性评价的品种再给予最高100万元的奖励。单个企业每年最高1200万元”。 其次是安徽阜阳，湖南、深圳、苏州（前3家过评）等都给予500万元奖励； 江西赣南新区奖励450万元； 济南、温州洞头区前三家过评都奖励400万元； 北京、成都、甘肃、广西（前三家过评）、哈尔滨、内蒙古等都奖励300万元。 关于对过评奖励，各地文件行文比较复杂，除奖励现金外还涉及种类多样的其他奖项，现将其中可归类的数字部分整理如下图。     2、奖励集采中选 除奖励一致性评价过评外，还有少数区域对集采中标也给予奖励的。 如2021年8月，河北发布《关于支持医药产业发展若干措施的通知》，为“鼓励企业参与带量采购”，对进入国家集采的品种给予“不高于中标量销售额的10%”的专项资金支持。 2022年10月，杭州出台的《关于加快生物医药产业高质量发展的若干措施》明确，按国家、省级药械集中带量采购中标总价的 3%予以奖励，单个品种最高奖励不超过300万元。 02 耗时 据江苏华招网对截至2021年12月9日通过了一致性评价（以下简称“过评”）的1902个受理号（不含视同过评）分析发现，从一致性评价申请被CDE受理到通过一致性评价所需时间差异非常大，最短的不足2个月，最长的则超过了3年，平均约为15个月，且在9个月～1年半的最多，占了57%。具体如下图。 ＜半年的，占5%； 半年～1年的，占29%； 1年～1.5的，占38%；   1.5年～2年的，占18%； 2年～3年的，占9%； ＞3年的，占0.4%。 剂型不同，过评时长也有差异，口服常释剂型大多在1.5年之内过评，而注射剂则要2年甚至3年以上才能过评。 03 回本 第三批国采（2020年8月20日开标），共有125家企业的191个药品中选，其中，44个药品在其上市公司公告中披露了其一致性评价（含视同过评）费用，据医药魔方统计发现，若不考虑其既往收入和生产销售过程中产生的其他成本，只以第三批国采中选价格来看，这44个药品中有8个至少需要卖出1亿片（按主规格计）以上才能收回成本。其中， 需要卖＞4亿片的有1个，即氯氮平片（25mg），过评费用668万元，第三批国采中选价0.016元/片，需要卖4.23亿片才能收回成本； 需要卖＞3亿片的有1个，即卡托普利片(25mg)，过评费用900万元，中选价0.029元/片，需要卖3.1亿片才能回本； 需要卖＞2亿片的有1个，即盐酸二甲双胍片(0.5g)，过评费用721万元，中选价0.03元/片，需要卖2.4亿片才能回本； 需要卖1～2亿片的有5个，即卡托普利片（25mg,12.5mg）、氯氮平片(25mg)、盐酸二甲双胍缓释片（0.5g）、盐酸二甲双胍片(0.5g)、缬沙坦尿囊(80mg)，分别要卖1.76亿片、1.49亿片、1.28亿片、1.27亿片、1.04亿粒才能回本； 在上述统计的44个产品中，回本需要卖货最少的是盐酸达泊西汀片。 只需卖20多万片就能回本的有2个产品，即盐酸达泊西汀片(30mg），过评费用760万元，中选价33.69元/片，只需要卖23万片就能回本。左乙拉西坦口服溶液(30mg）过评费用1,982万元，中选价77元/片，只需要卖26万片就能回本。 需要卖100～300万片才能回本的有4个产品，即氨溴索西酞普兰片、来曲唑片、盐酸氟西汀胶囊，分别要卖135万片、144万片、247万片就能回本。 目前，不管是过评费用还是国采中选价都已发生了很大变化，且上述分析样本量尚少，还不足以反映国采全貌，故本文仅供参考。 仅从目前的数据来看，无论是耗资还是耗时，一致性评价都并不轻松，也需要给予信心。 注：文中已将涉及到的部分企业名称隐掉。 END 内容沟通：郑瑶（13810174402） 左下角「关注账号」，右下角「在看」，防止失联

MILAN, Italy & MORRISTOWN, New Jersey & SEOUL, Republic of Korea--( BUSINESS WIRE )--Newron Pharmaceuticals S.p.A. (“Newron”) (SIX: NWRN, XETRA: NP5), a biopharmaceutical company focused on the development of novel therapies for diseases of the central and peripheral nervous system, and Myung In Pharm Co. Ltd. (“Myung In Pharm”), South Korea’s leading CNS specialist pharmaceutical company, today announced that they have entered into a license agreement to develop, manufacture and commercialize Newron’s innovative modulator of the excessive release of glutamate, evenamide, an add-on therapy for treatment-resistant schizophrenia (TRS) and poorly responding patients with schizophrenia, in South Korea. Under the terms of the license agreement, Myung In Pharm will contribute 10% of the total patient population to be enrolled into Newron’s upcoming pivotal Phase III trial and cover the costs related to this population. Myung In Pharm’s involvement leverages its established clinical infrastructure and expertise in the central nervous system (CNS) field. Furthermore, the company will bear a percentage of eligible global development costs and will also be responsible for all regulatory, registration, marketing, and commercialization costs for evenamide in South Korea. In return, Newron will receive an upfront payment, milestone payments for development and regulatory achievements, and royalties on net sales. Further details were not disclosed by the parties. The Phase III randomized, double-blind, one-year trial is expected to begin in H1 2025 and will compare evenamide to placebo as an add-on treatment in at least 600 patients with TRS. It will be coordinated by Newron, who will oversee the trial design, execution, and data analysis. Myung In Pharm will be responsible for enrolling patients in South Korea through its extensive network of clinical sites, as well as providing support with monitoring and data collection. Newron continues to pursue further development opportunities for evenamide in other territories. On December 13, 2024, Newron and EA Pharma (a subsidiary of Eisai Co., Ltd.) announced a license agreement for evenamide in Japan and other Asian territories. “We are thrilled to partner with Myung In Pharm in this important clinical trial and to grant them the rights to develop, manufacture and commercialize evenamide in South Korea,” said Stefan Weber, CEO of Newron . “Their strong expertise in CNS therapies and their clinical infrastructure will be instrumental in advancing the development of evenamide. This collaboration underscores our shared commitment to transforming the treatment landscape for patients with unmet needs." Hang Myung LEE, Chairman of Myung In Pharm , commented: “Newron’s innovative approach aligns with our commitment to improving patient outcomes in the CNS area, and we believe our participation will make a significant contribution to the success of the study. Furthermore, we are honored to have received the license to commercialize evenamide in South Korea. This partnership presents a valuable opportunity for us to bring a new treatment option to patients in South Korea, a key market for Myung In Pharm. We look forward to working closely with the Newron team to bring this promising therapeutic to the forefront of clinical development and expand its impact in South Korea.” Jefferies International Limited (“Jefferies”) acted as the exclusive financial advisor to Newron. Orrick Herrington & Sutcliffe LLP advised as legal counsel to Newron. Cosmo Group Inc. of USA acted as the advisor to Myung In Pharm. About schizophrenia Approximately 25 million people worldwide are affected by schizophrenia, including more than 210,000 in South Korea as reported in 2022 by HIRA (Health Insurance Review & Assessment Service, Government agency). Despite more than 60 different types of atypical and typical antipsychotics used for schizophrenia globally, a considerable number of patients remain severely ill or resistant to treatment. Overall, 30-50% of patients do not respond to the available medications and are defined treatment resistant. In addition to the patients with treatment-resistant schizophrenia (TRS), another 20-30% are described as “poor responders to anti-psychotic medication,” even if not meeting the criteria for TRS. New findings indicate that patients with TRS have abnormalities in the glutamatergic system, but not in dopaminergic transmission, so there is a huge unmet medical need for a glutamatergic mechanism of action, efficacious both in TRS patients and in those who are poor responders to the current treatments. About evenamide Evenamide is the first new chemical entity that has demonstrated significant benefits in this difficult-to-treat patient population, as seen in the potentially pivotal Phase III study 008A trial, as an add-on treatment to second generation anti-psychotics including clozapine, in 291 poorly responding patients with chronic schizophrenia. The primary endpoint, the Positive and Negative Syndrome Scale (PANSS) 1 , and the key secondary endpoint, the Clinical Global Impressions Scale – Severity (CGI-S), were met and showed statistical significance compared to placebo. Importantly, evenamide treatment was associated with statistically significant increase in proportion of patients who experienced “clinically meaningful benefit” on the outcome variables. Evenamide was extremely well tolerated, without any of the usual side effects of available anti-psychotics. About Newron Pharmaceuticals Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central and peripheral nervous system. The Company is headquartered in Bresso near Milan, Italy. Xadago ® /safinamide has received marketing authorization for the treatment of Parkinson’s disease in the European Union, Switzerland, the UK, the USA, Australia, Canada, Latin America, Israel, the United Arab Emirates, Japan and South Korea, and is commercialized by Newron’s Partner Zambon. Supernus Pharmaceuticals holds the commercialization rights in the USA. Meiji Seika has the rights to develop and commercialize the compound in Japan and other key Asian territories. Newron is also developing evenamide as the potential first add-on therapy for the treatment of patients with symptoms of schizophrenia. For more information, please visit: www.newron.com About Myung In Pharm Myung In Pharm is a fully integrated pharmaceutical company established in 1985, based in Seoul, Republic of Korea. The company specializes in the manufacturing, processing, and distribution of pharmaceutical drugs, with a strong focus on central nervous system (CNS) therapies. Ranked number one in South Korea in the CNS field, Myung-In Pharm operates state-of-the-art manufacturing facilities that meet cGMP standards. With a robust network of over 1,200 neurologists and relationships with 98% of domestic neurology hospital departments, Myung In Pharm is dedicated to improving patient care and advancing the field of neuroscience. http://myunginph.co.kr/main/en/ Important Notices This document contains forward-looking statements, including (without limitation) about (1) Newron’s ability to develop and expand its business, successfully complete development of its current product candidates, the timing of commencement of various clinical trials and receipt of data and current and future collaborations for the development and commercialization of its product candidates, (2) the market for drugs to treat CNS diseases and pain conditions, (3) Newron’s financial resources, and (4) assumptions underlying any such statements. In some cases, these statements and assumptions can be identified by the fact that they use words such as “will”, “anticipate”, “estimate”, “expect”, “project”, “intend”, “plan”, “believe”, “target”, and other words and terms of similar meaning. All statements, other than historical facts, contained herein regarding Newron's strategy, goals, plans, future financial position, projected revenues and costs and prospects are forward-looking statements. By their very nature, such statements and assumptions involve inherent risks and uncertainties, both general and specific, and risks exist that predictions, forecasts, projections and other outcomes described, assumed or implied therein will not be achieved. Future events and actual results could differ materially from those set out in, contemplated by or underlying the forward-looking statements due to a number of important factors. These factors include (without limitation) (1) uncertainties in the discovery, development or marketing of products, including without limitation difficulties in enrolling clinical trials, negative results of clinical trials or research projects or unexpected side effects, (2) delay or inability in obtaining regulatory approvals or bringing products to market, (3) future market acceptance of products, (4) loss of or inability to obtain adequate protection for intellectual property rights, (5) inability to raise additional funds, (6) success of existing and entry into future collaborations and licensing agreements, (7) litigation, (8) loss of key executive or other employees, (9) adverse publicity and news coverage, and (10) competition, regulatory, legislative and judicial developments or changes in market and/or overall economic conditions. Newron may not actually achieve the plans, intentions or expectations disclosed in forward-looking statements and assumptions underlying any such statements may prove wrong. Investors should therefore not place undue reliance on them. There can be no assurance that actual results of Newron's research programs, development activities, commercialization plans, collaborations and operations will not differ materially from the expectations set out in such forward-looking statements or underlying assumptions. Newron does not undertake any obligation to publicly update or revise forward-looking statements except as may be required by applicable regulations of the SIX Swiss Exchange or the Dusseldorf Stock Exchange where the shares of Newron are listed. This document does not contain or constitute an offer or invitation to purchase or subscribe for any securities of Newron and no part of it shall form the basis of or be relied upon in connection with any contract or commitment whatsoever. 1 Positive and Negative Syndrome Scale (PANSS) is widely used in clinical trials of schizophrenia and is considered the “gold standard” for assessment of antipsychotic treatment efficacy (Innvo Clin Neurosci, 2017: https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/pmc/articles/PMC5788255/ )