OTO-825

这家Biotech公司2008年成立，2014年上市，2015年第一个独家产品获FDA批准上市。1个管线推进到临床III期，2个管线推进到II期，但是2022年11月14日，公司收到纳斯达克退市警告，2022年12月19日公司宣布解雇所有员工并计划解散公司。截至 2022年9月30日，公司从未盈利，累计亏损5.945亿美元。然而8年来，这家Biotech公司发生和经历了什么？为何要解散？14年走过的新药研发之路，对国内众多类似Biotech相关参与者和利益相关者，有哪些参考和启发？1公司意外中成立事情先从公司创始人Jay Lichter博士说起，在2008年Jay Lichter博士在开车途中，突如其来的一阵眩晕并伴有耳鸣，让他心中感到惊悚和疑惑，难道是没有休息好？事实并没有这么简单，而后经过多名医生的联合诊断，才确定 Jay Lichter博士患上了一种叫做“梅尼埃尔氏综合征”，也叫梅尼埃病。其典型临床症状为反复发作的旋转性眩晕、波动性听力下降、耳鸣和耳闷胀感等。更遗憾的是Jay Lichter博士被告知这种疾病在全球范围内皆无药可治。然而Jay Lichter博士作为生物医药投资领域的资深投资人，他不仅获得了伊利诺伊大学的生物化学学士学位和博士学位，还在耶鲁大学和杜邦默克制药公司完成了博士后研究。而且还是Avalon Venture投资机构的合伙人，在超过25年的职业生涯里，已经创立超过了25家不同的公司，参与的合作并购也已经超过了30亿美元。所以Jay Lichter博士决定向梅尼埃病发起挑战。他通过自身资源优势，迅速找到加州大学圣地亚哥分校耳鼻喉科/头颈外科主任Jeffrey Harris博士以及其他几位神经学专家，一起在圣地亚哥，成立了专注于开发和商业化内耳和中耳耳鸣治疗相关药物的生物技术公司，取名Otonomy。综合众多机缘Otonomy公司就这样在2008年成立了。2公司波折融资及顺利上市投行资深人士，专业医疗技术团队和巨大潜力市场等要素就这样组合在一起，然而公司一开始并不是很顺利，就像资本寒冬中的国内Biotech一样经历了一段极其困难的时光。不过寒冬总会过去，在2013年也就是公司成立的第5年，终于完成了第三轮募资，使得该项目总融资达到9400万美元。同时更多的投资者开始看好这一项目，其中就包括了大名鼎鼎的OrbiMed奥博资本。2014年4月，Otonomy又完成了4900万美元的第四轮融资。紧接着在上轮融资的4个月后，2014年8月13日在纳斯达克上市，又募集到1亿美元资金。对于国内当前很多Biotech公司，如果能顺利融资几轮后上市，大红背景下敲响的钟声，回应了多少人的期望，激荡出多少未来美好的畅想。但是对Otonomy公司来说，波折坎坷的发展道路才刚刚开始。3公司明星管线几近团灭2015年上市的产品OTIPRIO近年销量微乎其微；2018年OTIVIDEX （OTO-104）推进到III期失败；2022年OTO-313推进到II期失败；2022年OTO-413推进到II期失败；2023年临床前管线OTO-825 ，OTO-510和OTO-6XX计划出售。1OTIPRIOOtonomy在公司上市后一年多，2015年12月11日喜大普奔的宣布获得FDA批准其第一个产品OTIPRIO上市，这款产品是抗生素环丙沙星耳用混悬剂。也是美国第一个获得耳管手术适应症的抗生素，用于降低耳管手术失败的风险。据当时估计美国每年有超过100万的耳管放置手术再次复发耳部感染，其中85%发生在儿童。Otiprio希望能把父母从经常给孩子使用滴耳剂中解脱出来。公司上市不久就有大市场潜力的独家产品上市，对于Biotech来讲，这可是芝麻开花节节高的节奏，公司于2018年3月2日又宣布好消息， FDA批准其旗下的OTIPRIO（环丙沙星耳用混悬剂）第二个适应症，用于治疗年龄在6个月及以上的由于铜绿假单胞菌和/或金黄色葡萄球菌引起的急性外耳道炎（AOE）。OTIPRIO是FDA批准的首个用于治疗AOE的单剂量抗菌药物。当时公司首席执行官 Weber预测Otonomy 产品的全球市场规模会超过 10 亿美元，并将Otonomy定位为能够独立进行商业化的公司。然而这几年走过来，OTIPRIO销售情况如何呢？根据上市公司披露数据查询到，Otonomy公司2018年收入74.5万美元，2019年收入60.0万美元，2020年收入27.3万美元，2021年收入12.5万美元。现实的数据似乎有点过于残酷！为什么会这样？公司资料中描述的巨大的潜力市场，上百项酷炫专利，还拥有体温下能使液体转变为凝胶态的独特耳部药物给药技术，为什么在上市7年间的收入惨不忍睹？公司2015年底在Otiprio获批后，雄心勃勃的开始筹划自建队伍销售产品。2015年12月，40 名销售人员的招聘和培训完成。2016年通过向目标受众中约85%的2000名医生进行产品介绍，OTIPRIO 已获得处方批准或已被 360 多家机构购买，另外约 240 家医院正在进行审查。但是全年净销售额总70万美元的结果，立刻让公司聘请了资深的销售负责人David Kaplan，（Kaplan先生曾于2013年4月至2016年3月担任PaciraPharmaceuticals，Inc.的销售副总裁。在此期间，EXPAREL的年化销售额从不到5000万美元大幅增长到超过2.5亿美元。）他把销售人员的规模从40名销售代表减少到20名。2017年，重组后的销售队伍，仅完成了120万美元的销售额，公司宣布停止对 OTIPRIO 的促销支持，以大幅降低与该产品相关的运营费用。2018年，与Mission Pharmacal在急性外耳炎（AOE）方面建立共同推广伙伴关系。2019年，与Glenmark 建立了共同推广合作伙伴关系。2020年与ALK公司签订了一项联合推广协议。2021年 5月将与 OTIPRIO 相关的资产出售给 ALK，Upfront Payment为80万美元。从OTIPRIO历史过程中看到，在销售团队和销售模式调整后，市场难题都没有得到很好的解决，那么问题出在哪里了？或许是产品定位和市场的竞争格局。抗生素滴耳剂目前是 TTP 手术期间使用的主要治疗选择，而且多种滴耳液在美国获批准上市，其中就包括来自诺华的CIPRODEX (环丙沙星/地塞米松滴耳混悬液)。CIPRODEX每年销售额在4~5亿美元，而且在2003年就已经获FDA批准上市。面对如此强大的竞争对手，创业型公司的改良型新药，貌似没有绝对优势的产品，能有几分市场胜算？当然Otiprio以其预估的潜力成为Otonomy公司2014年完成的1亿美元IPO的主要动力。2OTIVIDEXOTIVIDEX（原先叫OTO-104）是一款地塞米松长效缓释注射液，适应症是治疗梅尼埃病。2017年8月，公司公布了在美国进行的AVERTS-1III期临床试验的阴性结果；该试验共招募了165名美尼尔氏病患者，OTIVIDEX患者报告第3个月眩晕频率较基线降低58%，而安慰剂患者为55%。2017年11月，公司宣布了在欧洲进行的OTIVIDEX的AVERTS-2III期临床试验的积极结果；根据对参与试验的所有174名美尼尔氏病患者的分析，OTIVIDEX组的眩晕频率降低了68%，而安慰剂组为40%。根据FDA的反馈，需要另外一项成功的关键试验来支持OTIVIDEX的获批。决定成败的关键III期临床试验在2021年2月宣布未达到主要终点。OTIVIDEX治疗的梅尼埃病，是一种原因并不明确的疾病，主要有免疫反应学说、内耳缺血学说、内淋巴管机械阻塞与内淋巴吸收障碍等学说，机制不明疾病的新药研发会不会像AD药物那样具有超高的失败率？对于可能发生的高安慰剂效应在临床试验中该如何考虑到更多影响因素和优化临床设计？3OTO-313在OTIVIDEX开发折戟后，Otonomy将精力放在了OTO-313上。OTO-313是一种强效和选择性的N-甲基-D-天冬氨酸(NMDA)受体拮抗剂加环利定（gacyclidine）的耳内局部注射制剂，用于治疗耳鸣。刚开始OTO-313的开发还算顺利。2019年4月，Otonomy启动了该产品的临床试验。2021年3月初步研究顺利达到主要终点，显示OTO-313可显著改善中度以上持续性耳鸣患者的耳鸣症状。然而到2022年8月，Otonomy宣布OTO-313的II期研究未达到显著改善患者耳鸣症状的主要终点，并将终止开发该产品，公司股价因此大跌近80%，从1.43美元/股跌至0.25美元/股。OTO-313II期研究表明，与安慰剂相比，在所有时间点的主要和次要终点方面没有临床意义的益处。随机、双盲、安慰剂对照的 II期试验招募了 153 名患有至少中度严重程度的持续性单侧耳鸣的患者。患者按 1:1 的比例随机分配至单次鼓室内注OTO-313 (n=77) 或安慰剂 (n=76) 并随访 4 个月。OTO-313与OTIVIDEX或许有着相似的原因？一种原因并不明确的疾病新药具有超高的失败率？对于可能发生的高安慰剂效应在临床试验中该如何考虑到更多影响因素和优化临床设计？4OTO-413在OTIVIDEX和OTO-313两款核心产品失败后，公司只能寄希望于治疗听力受损的OTO-413，从绝望中寻找希望。OTO-413是脑源性神经营养因子（BDNF）的缓释制剂，BDNF是一种天然存在的蛋白质，参与神经元的生长和修复。非临床研究表明，局部施用BDNF可修复因噪音创伤或接触耳毒性化学物质而受损的耳蜗内毛细胞和听觉神经纤维之间的连接。2022年4月，Otonomy宣布OTO-413治疗噪声性听力损失的IIa期研究成功，与安慰剂相比，单次鼓室内注射 0.3 mg OTO-413在多个语音输入中提供了具有临床意义的治疗益处，看似曙光就在眼前。但是2022年10月，OTO-413的高剂量队列研究结果出炉却是一个致命打击。对听力损失患者较高剂量（0.75mg和1.50mg）的超声检查显示，在多个噪声中言语（SIN）听力测试中，对患者使用较高剂量的临床评估表明，从基线到多个噪声中言语（SIN）听力测试的患者没有临床意义的改善。消息一出，Otonomy股价又跌去53%，从0.26美元/股跌至0.121美元/股。为什么OTO-413会这样？因为BDNF在一些临床前研究以及神经营养因子文献的研究中，预示着可能存在复杂的剂量反应关系，在较高剂量水平下观察到活性下降。Otonomy公司还要继续推进OTO-413的研究吗？貌似当前的境遇已无法支撑再走下去。至此，Otonomy的故事就快接近尾声，当然公司还有3款关于耳科疾病临床前产品，OTO-825，OTO-510和OTO-6XX，但是在当前已经很难扭转局势。— 小结 —新药研发失败不可避免，更重要的是如何与失败友好相处并创造更大价值！面对强大的竞争对手，创业型公司没有绝对优势的产品，能有几分市场胜算？面对机制不明的疾病，新药研发如何提高成功率？对于可能发生的高安慰剂效应在临床试验中该如何考虑到更多影响因素和优化临床设计？资本属性不错的公司，在科学性方面是否具有药物开发的硬实力？对于Otonomy失败的启示，作者也只能粗浅揣测，抛砖引玉。纸面上精妙的逻辑论述与账面上美妙的现金回款，实验室中精妙的科学技术与治疗室中美妙的临床价值；理论与现实，欲望与愿望间，什么才是避免失败真正的法则？愿有限的新药研发资源满足更多的健康需求！在抗体圈微信公众号回复“JPM23”可下载60 家药企PPT合集。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Evaluation of strategic options to realize value from pipeline is ongoingSAN DIEGO, Nov. 10, 2022 (GLOBE NEWSWIRE) -- Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today reported financial results for the quarter ended September 30, 2022 and provided an update on its product pipeline and corporate activities. Otonomy Program and Corporate Activity Updates In August 2022, Otonomy announced that OTO-313 demonstrated no clinically meaningful improvement versus placebo for primary and secondary endpoints in a Phase 2 clinical trial in tinnitus patients. Based on these results, Otonomy discontinued development of OTO-313 and implemented other measures to extend its cash runway. These included a reduction of its workforce by approximately 55%, with the majority of the reduction completed by the end of August. In October 2022, Otonomy announced that the clinical evaluation of higher doses for OTO-413 in patients with hearing loss demonstrated no clinically meaningful improvement for patients from baseline across multiple speech-in-noise hearing tests. Following these results, the company initiated an evaluation of strategic options to realize value from its pipeline including both OTO-413 and OTO-825. Strategic options could include a possible merger, business combination, sale of assets, wind-down, liquidation and dissolution or other strategic transaction. While those evaluations are ongoing, Otonomy has paused its product development activities and taken other steps to reduce costs in order to preserve its cash resources. Third Quarter Financial Highlights Cash Position: Cash and cash equivalents totaled $40.1 million as of September 30, 2022, compared to $77.4 million as of December 31, 2021. In October 2022, the term loan with Oxford Finance LLC was terminated in connection with the company’s payment of all amounts owed under the agreement totaling approximately $17.0 million. Operating Expenses: GAAP operating expenses were $11.8 million for the third quarter of 2022, compared to $12.5 million for the third quarter of 2021. Non-GAAP operating expenses, which exclude stock-based compensation, were $10.5 million for the third quarter of 2022, compared to $10.7 million for the third quarter of 2021. Research and Development Expenses: GAAP research and development (R&D) expenses for the third quarter of 2022 were $8.4 million, compared to $9.0 million for the third quarter of 2021. The decrease for the quarter was primarily due to lower third-party development costs for Otonomy’s product candidates. Selling, General and Administrative Expenses: GAAP selling, general and administrative (SG&A) expenses in the third quarter of 2022 were $3.4 million, compared to $3.5 million for the second quarter of 2021. Non-GAAP Operating Expenses In this press release, Otonomy’s operating expenses are provided in accordance with generally accepted accounting principles (GAAP) in the United States and also on a non-GAAP basis. Non-GAAP operating expenses exclude stock-based compensation. Non-GAAP operating expenses are provided as a complement to operating expenses provided in accordance with GAAP because management believes non-GAAP operating expenses help indicate underlying trends in the company’s business, are important in comparing current results with prior period results and provide additional information regarding the company’s financial position. Management also uses non-GAAP operating expenses to establish budgets and operational goals that are communicated internally and externally and to manage the company’s business and to evaluate its performance. The attached financial information includes a reconciliation of GAAP operating expenses to Non-GAAP operating expenses and a reconciliation of GAAP operating expense guidance to Non-GAAP operating expense guidance. About OtonomyOtonomy is a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology. The company pioneered the application of drug delivery technology to the ear in order to develop products that achieve sustained drug exposure from a single local administration. This approach is covered by a broad patent estate and has been utilized to develop products addressing important unmet medical needs with a current focus on hearing loss. For additional information please visit www.otonomy.com. Cautionary Note Regarding Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements generally relate to future events or the future financial or operating performance of Otonomy. Forward-looking statements in this press release include, but are not limited to, statements regarding Otonomy’s evaluation of strategic options to realize value from its pipeline including both OTO-413 and OTO-825. Otonomy’s expectations regarding these matters may not materialize, and actual results in future periods are subject to risks and uncertainties. Actual results may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to: Otonomy’s ability to successfully identify strategic options and consummate a strategic transaction to realize value from its pipeline; the risk of being delisted from Nasdaq for failure to meet Nasdaq’s continued listing requirements; Otonomy’s ability to obtain additional financing; Otonomy’s ability to implement measures to extend its cash runway and manage operating expenses; delays and disruption resulting from the COVID-19 pandemic and governmental responses to the pandemic, including current and future impacts to Otonomy’s operations; Otonomy’s ability to protect its intellectual property; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in Otonomy’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 10, 2022, and Otonomy’s future reports to be filed with the SEC. The forward-looking statements in this press release are based on information available to Otonomy as of the date hereof. Otonomy disclaims any obligation to update any forward-looking statements, except as required by law. Contacts: Investor InquiriesICR WestwickeRobert H. UhlManaging Director858.356.5932robert.uhl@westwicke.com Otonomy, Inc.Condensed Balance Sheet Data(in thousands) As of September 30, As of December 31, 2022 2021 (unaudited) Cash and cash equivalents$40,146 $77,412 Right-of-use assets 11,481 12,696 Total assets 57,527 95,637 Debt, current 16,130 - Long-term debt, net of current - 15,997 Leases, net of current 10,879 12,400 Total liabilities 36,130 40,730 Accumulated deficit (594,486) (555,805) Total stockholders' equity 21,397 54,907 Otonomy, Inc.Condensed Statements of Operations (in thousands, except share and per share data) Three Months Ended Nine Months Ended September 30, September 30, 2022 2021 2022 2021 (unaudited)Product sales, net$- $- $- $125 Costs and operating expenses: Cost of product sales - - - 370 Research and development 8,410 8,978 27,048 24,995 Selling, general and administrative 3,431 3,501 10,702 11,213 Total costs and operating expenses 11,841 12,479 37,750 36,578 Loss from operations (11,841) (12,479) (37,750) (36,453) Other expense, net (207) (401) (931) (1,149)Net loss$(12,048) $(12,880) $(38,681) $(37,602) Net loss per share, basic and diluted$(0.18) $(0.19) $(0.57) $(0.61) Weighted-average shares used to compute net loss per share, basic and diluted 68,128,113 67,792,425 68,008,741 61,969,780 Otonomy, Inc.Reconciliation of GAAP to Non-GAAP Operating Expenses(in thousands) Three Months Ended Nine Months Ended September 30, September 30, 2022 2021 2022 2021 (unaudited)GAAP operating expenses Research and development$8,410 $8,978 $27,048 $24,995 Selling, general and administrative 3,431 3,501 10,702 11,213 Total GAAP operating expenses 11,841 12,479 37,750 36,208 Non-GAAP adjustments R&D stock-based compensation expense (463) (823) (2,241) (2,443)SG&A stock-based compensation expense (905) (943) (2,815) (3,097)Total non-GAAP adjustments (1,368) (1,766) (5,056) (5,540)Non-GAAP operating expenses$10,473 $10,713 $32,694 $30,668