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Total FY'23 Revenues of $2.42 Billion (+15% Y/Y and +20% Y/Y at Constant Currency); GAAP Diluted Earnings per Share of $0.87 (+16% Y/Y) and Non-GAAP Diluted Earnings per Share of $2.08 (+36% Y/Y) VOXZOGO® Net Revenues of $146 Million in Q4'23 (+118% Q/Q) and $470 Million for FY'23 (+178% Y/Y) BioMarin's 2024 Financial Outlook Reflects Anticipated Double-digit Total Revenue Growth, Significant Non-GAAP Operating Margin Expansion, and Non-GAAP Earnings Per Share Growing Faster than Revenues Conference Call and Webcast Scheduled Today at 4:30 p.m. ET SAN RAFAEL, Calif., Feb. 22, 2024 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced financial results for the fourth quarter and full year ended December 31, 2023. "Strong financial results in 2023 were driven by global demand for VOXZOGO, the only approved treatment for children with achondroplasia, and contributions from our established enzyme products. VOXZOGO revenues grew 18% over the prior quarter and were positively impacted by an increase in prescriptions for children in the United States under the age of 5, following the Food and Drug Administration's (FDA) October approval of VOXZOGO for children of all ages with open growth plates," said Alexander Hardy, President and Chief Executive Officer of BioMarin. "Looking ahead in 2024, our full-year financial guidance reflects our focus on value creation through achievement of four strategic priorities outlined earlier this year. We intend to maximize the VOXZOGO opportunity, continue to build-out global access channels for ROCTAVIAN, judiciously prioritize the most potentially impactful R&D candidates, and drive operational excellence and cost optimization with the goal of delivering growth, efficiency and profitability." Financial Highlights: Total Revenues for the fourth quarter of 2023 were $646.2 million, an increase of 20% compared to the same period in 2022. The increase in Total Revenues was primarily attributed to higher VOXZOGO sales volume driven by new patients initiating therapy across all regions, which included a significant number of new patient starts in the U.S. for children under the age of 5 years. The increase was also due to higher VIMIZIM product revenues primarily driven by the timing of large government orders. This was partially offset by lower KUVAN product revenues attributed to continued generic competition as a result of the loss of market exclusivity. GAAP Net Income increased by $20.6 million to $20.4 million in the fourth quarter of 2023 compared to the same period in 2022. The increase was primarily due to higher gross profit driven by increased revenues and reduced severance costs associated with the company's organizational redesign announced in the fourth quarter of 2022. This was partially offset by higher spend in research and development (R&D) programs to support both early-stage research and clinical activities and higher selling, general and administrative (SG&A) expenses related to an asset impairment charge, corporate governance and leadership transition costs, costs to support the commercial launch of ROCTAVIAN as well as a decrease in income tax benefits and an investment loss. Non-GAAP Income increased by $31.8 million to $94.9 million in the fourth quarter of 2023 compared to the same period in 2022. The increased Non-GAAP Income was primarily due to higher gross profit driven by increased revenues, partially offset by higher R&D expenses for the same reasons noted above, higher SG&A expenses related to corporate governance and leadership transitions and ROCTAVIAN commercial launch costs as well as an increase in income tax expense. 2024 Strategic Priorities In January, BioMarin management outlined key priorities focused on value creation through accelerating growth, optimizing efficiencies and driving operational excellence. For 2024, the company plans to provide material updates across the business, both scientific and financial, according to these strategic priorities: Accelerate and maximize the VOXZOGO opportunity In the fourth quarter, the FDA approved VOXZOGO for children under 5 years of age. Approximately 70% of new U.S. treatment starts in the fourth quarter were from that age group following the age label expansion approval in October 2023. With VOXZOGO now approved for younger children in key large markets, product expansion is expected to accelerate across younger age groups throughout 2024. The number of children with achondroplasia being treated with VOXZOGO increased 128% in 2023 compared to the end of 2022. As of December 31, 2023, 2,613 children with achondroplasia were being treated with VOXZOGO across 41 active markets, compared to 1,150 children on therapy at the end of 2022. In the fourth quarter, BioMarin began the pivotal program with VOXZOGO for the treatment of children with hypochondroplasia. The 6-month run-in study will be followed by the 52-week randomized, double-blind, placebo-controlled phase of the 80-participant clinical trial, with the treatment study expected to begin mid-2024. BioMarin is engaging global health authorities in the first half of this year regarding development programs in idiopathic short stature and multiple genetic short stature pathway conditions, with plans to begin pivotal studies later this year. Establish ROCTAVIAN opportunity As an important new treatment option for those with severe hemophilia A, BioMarin expects continued progress increasing ROCTAVIAN access and patients treated in 2024. This year, BioMarin's commercial team will continue to focus on key elements critical to supporting the uptake of ROCTAVIAN including, clinical eligibility, site readiness and patient and physician education. In January, the Italian Medicines Agency approved reimbursement for ROCTAVIAN in severe hemophilia A. In 2023, three patients were treated with ROCTAVIAN, two in Germany and one in the U.S. Focus R&D on the most productive assets During the first quarter of 2024, BioMarin began a strategic portfolio review of all R&D programs to determine which meet the criteria for further investment and advancement. A complete update on prioritized R&D assets, those with the highest potential patient impact and highest potential value creation for shareholders, will be communicated at our Investor Day later in 2024. Accelerate EPS growth and expand margins BioMarin's 2024 financial outlook reflects anticipated year-over-year double-digit Total Revenue growth, reduced operating expenses as a percentage of revenue, acceleration of Non-GAAP Operating Margin expansion and Non-GAAP Earnings Per Share growing faster than revenue. 2024 Full-Year Financial Guidance BioMarin does not provide guidance for GAAP reported financial measures (other than revenue) or a reconciliation of forward-looking Non-GAAP financial measures to the most directly comparable GAAP reported financial measures because the company is unable to predict with reasonable certainty the financial impact of changes resulting from our strategic portfolio and business operating model reviews; potential future asset impairments; gains and losses on investments; and other unusual gains and losses without unreasonable effort. These items are uncertain, depend on various factors, and could have a material impact on GAAP reported results for the guidance period. As such, any reconciliations provided would imply a degree of precision that could be confusing or misleading to investors. BioMarin will host a conference call and webcast to discuss fourth quarter and full year 2023 financial results and full-year 2024 financial guidance today, Thursday, February 22, 2024, at 4:30 p.m. ET. This event can be accessed through this link or on the investor section of the BioMarin website at . About BioMarin Founded in 1997, BioMarin is a global biotechnology company dedicated to transforming lives through genetic discovery. The company develops and commercializes targeted therapies that address the root cause of genetic conditions. BioMarin's robust research and development capabilities have resulted in multiple innovative commercial therapies for patients with rare genetic disorders. The company's distinctive approach to drug discovery has produced a diverse pipeline of commercial, clinical, and pre-clinical candidates that address a significant unmet medical need, have well-understood biology, and provide an opportunity to be first-to-market or offer a substantial benefit over existing treatment options. For additional information, please visit . Forward-Looking Statements This press release and the associated conference call and webcast contain forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including, without limitation, statements about: the expectations of Total Revenues, Non-GAAP Operating Margin percentage, and Non-GAAP Diluted EPS for the full-year 2024; cash flows from operating activities; BioMarin's plans to reduce operating expenses and expand margins; BioMarin's focus on its strategic priorities and the anticipated benefits from the same; the timing of orders for commercial products; the timing of BioMarin's clinical development and commercial prospects, including announcements of data from clinical studies and trials; the clinical development and commercialization of BioMarin's product candidates and commercial products, including (i) the potential to leverage VOXZOGO in conditions beyond achondroplasia, such as hypochondroplasia as well as idiopathic short stature and other genetic short stature pathway conditions, and (ii) the product expansion opportunities for ROCTAVIAN, including results from any related clinical studies; the commercialization of BioMarin's products, including (i) the anticipated start and growth of commercial sales of VOXZOGO in additional countries, and (ii) the commercialization of ROCTAVIAN for the treatment of severe hemophilia A in the U.S. and Europe; the expected benefits and availability of BioMarin's product candidates; and potential growth opportunities and trends, including that BioMarin expects accelerated growth of VOXZOGO revenues as the product launch continues in future quarters and that BioMarin expects growth of ROCTAVIAN revenues as the product's access is expanded in Europe and the U.S. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: BioMarin's success in the commercialization of its commercial products, impacts of macroeconomic and other external factors on BioMarin's operations; results and timing of current and planned preclinical studies and clinical trials and the release of data from those trials; BioMarin's ability to successfully manufacture its commercial products and product candidates; the content and timing of decisions by the FDA, the European Commission and other regulatory authorities concerning each of the described products and product candidates; the market for each of these products; actual sales of BioMarin's commercial products; the introduction of generic versions of BioMarin's commercial products, in particular generic versions of KUVAN; and those factors detailed in BioMarin's filings with the Securities and Exchange Commission (SEC), including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 as such factors may be updated by any subsequent reports. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise. BioMarin®, BRINEURA®, KUVAN®, NAGLAZYME®, PALYNZIQ®, VIMIZIM® and VOXZOGO® are registered trademarks of BioMarin Pharmaceutical Inc., or its affiliates. ROCTAVIAN® is a trademark of BioMarin Pharmaceutical Inc., with registration in Europe and pending in the U.S. ALDURAZYME® is a registered trademark of BioMarin/Genzyme LLC. All other brand names and service marks, trademarks and other trade names appearing in this release are the property of their respective owners. Non-GAAP Information The results presented in this press release include both GAAP information and Non-GAAP information. Non-GAAP Income is defined by the company as GAAP Net Income (Loss) excluding amortization of intangible assets, stock-based compensation expense, contingent consideration expense, and, in certain periods, certain other specified items, as detailed below when applicable. Non-GAAP Operating Margin percentage is defined by the company as GAAP Income from Operations, excluding amortization of intangible assets, stock based compensation expense, contingent consideration expense, and, in certain periods, certain other specified items, divided by Total Revenues. The company also includes a Non-GAAP adjustment for the estimated tax impact of the reconciling items. Non-GAAP Diluted EPS is defined by the company as Non-GAAP Income divided by Non-GAAP diluted shares outstanding. The company's presentation of percentage changes in total revenues at constant currency rates, which is computed using current period local currency sales at the prior period's foreign exchange rates, is also a Non-GAAP financial measure. This measure provides information about growth (or declines) in the company's total revenue as if foreign currency exchange rates had not changed between the prior period and the current period. BioMarin regularly uses both GAAP and Non-GAAP results and expectations internally to assess its financial operating performance and evaluate key business decisions related to its principal business activities: the discovery, development, manufacture, marketing and sale of innovative biologic therapies. Because Non-GAAP Income, Non-GAAP Operating Margin percentage, Non-GAAP Diluted EPS, Non-GAAP Diluted Shares and constant currency are important internal measurements for BioMarin, the company believes that providing this information in conjunction with BioMarin's GAAP information enhances investors' and analysts' ability to meaningfully compare the company's results from period to period and to its forward-looking guidance, and to identify operating trends in the company's principal business. BioMarin also uses Non-GAAP Income internally to understand, manage and evaluate its business and to make operating decisions, and compensation of executives is based in part on this measure. Non-GAAP Income and its components are not meant to be considered in isolation or as a substitute for, or superior to comparable GAAP measures and should be read in conjunction with the consolidated financial information prepared in accordance with GAAP. Investors should note that the Non-GAAP information is not prepared under any comprehensive set of accounting rules or principles and does not reflect all of the amounts associated with the company's results of operations as determined in accordance with GAAP. Investors should also note that these Non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time to time in the future there may be other items that the company may exclude for purposes of its Non-GAAP financial measures; likewise, the company may in the future cease to exclude items that it has historically excluded for purposes of its Non-GAAP financial measures. Because of the non-standardized definitions, the Non-GAAP financial measure as used by BioMarin in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by other companies. The following tables present the reconciliation of GAAP reported to Non-GAAP adjusted financial information: SOURCE BioMarin Pharmaceutical Inc.

1「傲慢的笨蛋」与中国医药行业中「创业者即CEO」的常态不同，国际领域CEO通常以「打工人」的身份出现。Jean-Jacques BienaiméJean-Jacques Bienaimé，一位职业CEO。不谈BioMarin这家罕见病龙头公司时，几乎无法准确概括他的职业生涯。他并非生物技术专业出身，可以说彻头彻尾都是一位管理学精英。他是许多公司的董事会成员，也曾以CEO的身份让多家Biotech扭亏为盈，但在加入BioMarin后毁誉参半——他的贡献不容否认，错误决策在多年过去后却依然被外界指摘。2005年，Bienaimé加入BioMarin，当时公司股票价格约为每股5美元，现在股价约为每股84美元，市值从当时的4.5亿美元涨到近160亿美元。他在BioMarin工作了18年，本月月初（11月2日），BioMarin宣布Bienaimé将离开CEO岗位。社交媒体上有一些股票市场研究者对此新闻发表评论，说他「早该在drisapersen惨败后就出局」。70岁显然到了一个任众人评价的年纪。这本是一个「退位让贤」、「后浪推前浪」的故事，但我们发现，Bienaimé身上的精彩之处远不止如此。从商业角度来说，Bienaimé无疑是一位成功的价值收割者，在《福布斯》杂志最具创新力的美国CEO排名中排名第24位，在他之前有耐克、波士顿科学、麦当劳的领导者，在他之后有重返迪士尼担任CEO的Robert Allen，还有雅培的CEO Miles White。在Bienaimé的带领下，BioMarin被《福布斯》杂志评为全球十大最具创新精神的公司之一。全球药企CEO薪酬排行榜上，也能经常见到他的身影。Firece Pharma统计，2021年作为BioMarin CEO的Bienaimé排名第11，年薪酬1826万美元，仅次于阿斯利康CEO Pascal Soriot，高于Moderna、渤健、百济神州和默沙东的CEO。2020年，他的年薪也在1812万美元上下，超过众多Biopharma高管。这位商界精英，拥有宾夕法尼亚大学沃顿商学院的工商管理硕士学位和巴黎高等商学院（ESCP商学院）的经济学学位，在存在专业鄙视链的生物医药圈子里，并非一位生物科技出身的「专业人士」。因此，社交媒体上总有人或认真或戏谑地讨论他这一特质，「进入生物医药界需要是专业博士吗？」。但Bienaimé不以为然，他在采访中公开表示，「对科学的热爱，和对帮助他人的热爱」才是他从事生命科学的根本原因和前提条件。有时，这会是对外演讲时一句展开「故事」的开场白，但这并不能让众人理解他为什么在医药领域一直工作到70岁，更不能具象化他和BioMarin交错缠绕着的职业生涯。Bienaimé也做过错误决策，比如收购Prosensa以获得drisapersen，这一失败收购案直到今天仍被人们讨论。Endpoints在近期的离职新闻中，把他形容为活泼的、固执的，他的固执在drisapersen的决策错误中有很多体现——有时可以将外界对张艺谋的评价套用在他身上，「别人只肯走到五十步的错误，由于他的刻苦努力，能坚持错到百里之外」——但却并不总是如此。他从不在社交平台上回复争议与嘲笑，而是坦然承认，并在媒体采访中笑谈「是决策错了」、「错误工作是成功的关键」，他喜欢在分享职业生涯时提起拿破仑，认为他是「由连续的失败构成的成功」。关于活泼，除了常出现在CNBC等各家媒体上，另一面还是一种与基因治疗和罕见病领域气质不符的对于商业化的乐观主义。Bienaimé曾多次公开表示，「虽然药物昂贵，但预计不会出现重大的报销问题」，以此来肯定每位患者200万美元到300万美元的罕见病基因疗法的商业价值。但也有记者私下在社交媒体吐槽他是「傲慢的笨蛋」。不论如何，是他的加入让BioMarin成长为罕见病疗龙头公司。在Bienaimé的职业生涯中，BioMarin也是他的高光时刻，这是他们拔节成长、互相成就的18年。2「我想管理一家大公司」如果说Bienaimé是BioMarin的灵魂，那在他离职后，BioMarin按理说将经历一段不被看好的时间。事实是朝这一方向发展吗？11月1日，BioMarin在官网公告中详细阐明，70岁的Bienaime将在12月1日正式卸任CEO一职，由基因泰克CEO Alexander Hardy接替。在明年的年会之前，Bienaime将保留他的董事会席位，并继续担任公司顾问到2024年底。同时，自2015年以来一直担任首席独立董事的Richard Meier将接替Bienaime成为董事长。次日，BioMarin股价创下1年新低，该公司的交易价格低至78.02美元，最后一次交易价格为78.38美元。在此之后，BioMarin股票意外地持续上涨，11月7日，更是凭借9%的涨幅成为当天美股涨幅最大的公司之一。据路透社报道，美国历史最悠久的对冲基金之一Elliott Investment Management已入股BioMarin，股份上投资超过10亿美元，这时BioMarin估值约为160亿美元。消息传出后，公司股价上涨达12%，至85.36美元。业内人士看来，Biomarin获得著名基金大额投资这一事件在情理之中，但投资时机在意料之外。RBCCapital Markets分析师LucaIssi评论称，「鉴于Biomarin最近的业务执行情况，激进的对冲基金参与其中并不完全令人惊讶」，但「Biomarin上周刚宣布了新任CEO（就立马获得了大额投资），我们对这个时机感到有点惊讶，我们想知道他们是否意识到了这一点」。Elliott拒绝回应关于该笔投资的详细情况，BioMarin的企业代表也没有立即回应。事实上，Elliott可以从多个方向来释放BioMarin的价值，包括并购、削减研发、分拆、私有化、剥离基因疗法等。对BioMarin来说，CEO换人撞上公司获得大额投资可能是巧合。但从产品现状和财报情况来看，过往18年中，作为CEO的Bienaimé确实让BioMarin成长为一家有自我造血能力的基因治疗龙头公司。可以看到的是，暂且抛开价格争议、报销模式等不谈，至少BioMarin已拥有8款稳定带来收益的商业化产品和10余条在研管线。2023年第三季度财报显示，Biomarin总收入为5.813亿美元，与2022年同期相比增长15%。今年前三季度，这家公司总收入17.73亿美元，同比增长14%。BioMarin目前销售额最高的产品是Vimizim，是FDA批准的首个治疗黏多糖贮积症IVA型（MPS IVA）的特效药，该药物第三季度创造营收约1.59亿美元，前三季度营收约5.26亿美元，相较2022年同比增长3%。另一款潜力药物，用于治疗软骨发育不全症的Voxzogo前三季营收共3.24亿美元，同比增长217%。销量增长的原因在于，该药物最近扩大了用药患者年龄限制，现已在美国获批用于全年龄儿童，在欧洲已获批用于4个月及以上的儿童。2005年获批上市的、用于治疗罕见遗传代谢疾病粘多糖增多症VI（MPS VI）的Naglazyme疗法，在今年第三季度创造了1亿美元以上的营收。PKU疗法Palynziq和Kuvan合计也在一个季度内创造了1.2亿美元左右的营收。 其中，刚于6月底被FDA批准用于治疗成人严重血友病A的一次性基因疗法Roctavian，尚未来得及实现更高的销售额。在过去的几周里，BioMarin和德国国家法定健康保险基金协会（GKV）初步商定了Roctavian的最终价格（预计将在年底前公布），并完善了相关的保险报销步骤。同时，该公司为患者准备了治疗中心（HTC）站点。Bienaimé看来，这些发展使得BioMarin可能在2024年达到30亿美元的收入。 将要担任BioMarin CEO的Hardy，曾公开对Voxzogo和Roctavian的商业价值寄予厚望。现在的BioMarin，正如Bienaimé此前所总结的那样，「我曾说过想管理一家大公司，现在的BioMarin已经是了」。3讲故事的其实是真学霸BioMarin是一家存活了25年的Biotech，如今成为罕见病基因疗法龙头企业。2004年，也就是Bienaimé加入的前一年，这家公司年度总收入刚达到约1800万美元，股票价格约为每股5美元。 2005年5月，Bienaimé正式加入BioMarin，当时公司已经九个月没有CEO了，急需强有力的领导，Bienaimé的朋友们对此表示「不明白他为什么要接手这家公司」，媒体评价这家公司为「核心药物Aldurazyme已经上市两年，然而，BioMarin看起来似乎即将倒闭」。回头再看，这一时刻有些类似于外国版余国良接手中美冠科，只不过似乎「潜在机会更大」。BioMarin和Bienaimé的双向选择不无道理。首要的一点就是，Bienaimé与这家公司的核心团队成员一样，出身于Biotech界的「黄埔军校」——基因泰克。此外，在BioMarin的发展历程中，也能看出BioMarin和Bienaimé具有一部分类似的气质。BioMarin最初由Christopher Starr和Grant W. Denison在1997年创立，Grant是公司首位CEO，被创业合伙人认为是「富有商业头脑的」，他主导拍摄了公司第一部关于罕见病患者和投资者的视频，通过这一视频拿到了不少投资，据他所说「每次看这些视频时，我都会哭，投资者也被感动了，因此写下支票」。不用当下的理解来评判过往行为。总之，在创立初期，BioMarin顺利拿到了Glyko Biomedical提供的150万美元的初始投资。后来，BioMarin又成功地从私人投资者那里筹集到了1130万美元，开始名声渐响。定位于做罕见病基因疗法的公司，确实有不少感人故事可以讲，直到Bienaimé上任以后，讲故事传统都依然被完整保留下来。Youtube一直是BioMarin这家公司最活跃的社交账号之一——在过去6年中共发布过89条视频内容，其中一半以上是固定栏目「患者故事」，另一半则是罕见病科普和公司活动内容，观看量最高的一条科普视频发布于2年前，达到3.8万次观看。而Bienaimé，则在BioMarin成立20周年时（2017年），主导拍摄了关于BioMarin过往的微电影Finding Tommorrows，出版了A Rare Breed: how people and perseverance built BioMarin Pharmaceutical Inc. into one of the world's most innovative companies一书，讲述BioMarin初创团队如何从像旧军营一样、每逢下雨就生霉味的平房实验室中白手起家，又是如何一步步扩建场地和设施，最终成为一家3000人规模的大公司。2018年，艺术家Gordon Huether接受委托为BioMarin打造「生命之树」，这一雕塑目前被放置在BioMarin圣拉斐尔总部，树枝上挂置着许多心形锁，每一把锁上都镌刻了受粘多糖 （MPS）、苯丙酮尿症 （PKU）、Batten病或软骨发育不全影响的患者信息，以供获得捐赠。BioMarin官网展示的虚拟全景3D版生命之树雕塑 讲故事，并不代表只有故事。BioMarin的研发效率，对于投资者和后来选择加入的Bienaimé来说，都是极大的加分项。1997年12月，BioMarin就启动了第一个候选产品Aldurazyme的临床试验，次年，为推进该产品的全球开发和商业化，BioMarin和Genzyme果断决定合作成立BioMarin/Genzyme，但在合资合作过程中又遇到了双方制造转移等新的问题。好在5年后（2003年），该药物获得FDA和EC批准上市，成为首个被批准用于治疗MPS I的酶替代疗法。因为其快速的管线推进，BioMarin又拿到了1130万美元融资。说来容易，但内部成员回忆称，这是公司第一个生死攸关的节点「如果Aldurazyme没有获批，那公司基本上要关门了」。合作过程并非顺顺当当，但后来在另一款药物Orapred的商业化上，BioMarin再次选择采取类似的BD策略，由Alliant负责在北美地区的销售，而BioMarin将获得销售的里程碑式付款和版税。对于Biotech来说，这种BD模式在今天看来依然是明智之举。在Bienaimé加入之前，BioMarin还在1999年完成了纳斯达克上市，首次公开募股共筹集6730万美元。之后，该公司持续研究MPS和PKU，2000年时启动了针对MPS VI的药物Naglazyme（半乳糖苷酶替代疗法）的临床试验，5年之后（2005年），该药物顺利获FDA批准上市。另一方面，在2004年一年之间，BioMarin将用于PKU的Phenoptin推进到II期临床开发阶段，并且在美国和欧洲提交了Naglazyme的营销申请，该药物于2005年4月很快进入到临床III期，获得了FDA快速通道药物资格。 投资人看重研发效率，这是过往研发水平的证明，英文可称为「track record」。因为药物研发失败通意味着血本无归，投资人间的一个基本共识是，「如果你在看一个研发超过10年还未有一款药物上市的公司，一定要三思而后行」。因此，回过头来看当时的BioMarin，确实是潜力项目。这进一步验证了Bienaimé说的，「所有的朋友都认为我疯了」，「但我看到的是，有一些优秀的资产、人才和技术可以支撑公司。我认为我有很大的机会让BioMarin扭亏为盈」。 他确实做到了，光这么说未免有些轻描淡写，去年，BioMarin公司收入为已达到创纪录的21亿美元，现在市值近160亿美元，股价约为84美元。在他加入的18年间，他的角色像是一位家教，或是临时家长，把2005年时刚小学毕业的BioMarin一路送上名牌大学。4一家Biotech的青春期新高管的加入，很多都是临危受命，更何况是CEO。那么，媒体为什么形容2005年的BioMarin为「似乎即将倒闭」，这家刚「小学毕业」的Biotech，出现了什么问题？一个主要的问题是：2004年，BioMarin的管理层怀疑治疗罕见疾病药物的利润潜力，斥资1.75亿美元购买了一种类固醇泼尼松，据说这种泼尼松口感和味道更好，对孩子们来说接受性更高。然而，一家仿制药公司很快就找到了绕过专利的方法，因此该药物为BioMarin带来的年销售额仅有1900万美元。投资者被激怒了，开始了一场代理权之争。这样的故事对生物医药行业来说并不算稀奇。Biomarin最终给出的解决方案是重启CEO岗位，并邀请Bienaimé加入。Bienaimé是一位法国人，80年代后期开始在基因泰克做血栓破坏剂激活酶市场工作，担任过两家Biotech公司（SangStat和Genencor）的CEO，他曾将两家公司送上收并购市场，上述两家公司都曾以数亿美元的金额出售。 显然，投资者希望他将BioMarin也送上待售市场。但与预期相反，Bienaimé开始努力扭转局面。他解雇了1/3的员工（300人中的100人），这些人都是支持出售这种美味类固醇的一派。然后，他将Jim Collins的书《从优秀到卓越》（Good to Great）交给了剩下的高管团队，该书认为「领导者应该谦虚但专注，直接面对坏消息是建立强大公司的关键」。 人员调整是前期最关键的一步。在前任高管层中，Aldurazyme药物的开发者加州大学洛杉矶分校（UCLA）Emil Kakkis不仅需要负责他擅长的药物研发，还需要负责他不擅长的销售。「他更加理性，不擅长夸夸其谈」，Bienaimé让他专注于科学研究。和后来社交媒体上的形容词截然相反，Kakkis对Bienaimé的评价是「明智、稳定和可靠」。Bienaimé刚加入时，此前合作中埋下的隐忧开始凸显。BioMarin正在与Genzyme（已被赛诺菲收购）合作销售Aldurazyme，这笔交易使Genzyme收割了该药物一半的利润。与此同时，高管们又开始与Genzyme谈判另一项有关MPS药物的交易——这笔交易将赋予Genzyme药物Naglazyme的国际权利（如前文所述，这款药物今年第三季度销售额在BioMarin所有产品中名列第三，超1亿美元），而大多数（现在看来在85%以上）MPS VI患者居住在美国境外。 针对这项合作，Bienaimé的决策简短而迅速，「算了吧」。我们无法回头去看清Bienaimé每一次决策的具体细节，但能看到BioMarin后来的每一步。为了「做一家独立的公司」，放弃合作是一场疯狂的赌博。BioMarin必须从此时开始，从头建立一支国际销售队伍。在欧洲，BioMarin的第一批销售代表团队出自于网吧，意外地成功了。2005年获得批准后，Naglazyme的销售额不负众望，在2016年前后年销售额就已超过3亿美元。当时，一个典型患者每年要花费34万美元，剂量根据体重而定，所以实际花费更高。2012年，伯恩斯坦研究公司的分析师曾估计，对于成年患者来说，该药物每年的费用可能超过100万美元。在印度和中国以外的千余名MPS VI患者，几乎所有人都服用该药。这是一系列昂贵的、改变生命的药物的开端。2007年，BioMarin又一罕见病药物获批——Kuvan被批准用于治疗PKU，大多数人知道的是，这一疾病常以警告形式出现在可乐罐上。在发达国家，PKU约有50000名确诊患者；在欧洲，每10000名新生儿中约有1人患有这种疾病。目前全球约有万名左右患者在诊所接受PKU治疗，一名普通患者每年治疗费用约10万美元。但在Kuvan获批时，BioMarin资金非常紧张。曾带领公司三种药物通过FDA审批的Kakkis离开了公司，转而创办患者权益组织。Bienaimé聘请了基因泰克的老同事Fuchs接替他的工作。Fuchs加入后，第一个药物选择是另一种MPS疗法——Vimizim，这是BioMarin推出的迄今为止最为重磅的药物，今年第三季度创造营收约1.59亿美元。该药物于2014年推出，初年销售额就达到2.28亿美元。对于单个典型患者来说，花销约为38万美元，推出时，BioMarin认为全世界至少有3000名MPS IV 患者，而他们则确定了其中60%。此后，BioMarin的罕见病疗法版图不断扩大。2015年第一季度，BioMarin完成了对Prosensa的收购，主要目的是获得用于治疗杜氏肌营养不良症（DMD）的实验性药物drisapersen。该药物此前为GSK和Prosensa合作开发，后来一个186人参与的III期临床试验失败，GSK退出了与该药的合作，Bienaimé力排众议，最终说服了投资人，以6.85亿美元的高价收购了该产品。故事来到2016年前后，青春期的挫败以各种形式环绕BioMarin。1月份，drisapersen被FDA拒绝，近7亿美元基本覆没。这时BioMarin年销售额达到8.9亿美元，市值接近150亿美元，但投资者对BioMarin的声势浩大却毫无利润而逐渐不耐烦。Bienaimé听取了投资者的意见，采取了削减成本的措施，包括停止抗癌疗法方向的努力和另一个罕见病项目。再加上考虑到孕育中的血友病基因疗法，Bienaimé把drisapersen的失败暂时翻篇，「预计明年现金流转为正值」。 Flag立起来之后，BioMarin陷入了「明年复明年」的鬼打墙状态。不巧的是，两个坏消息比盈利来得更快——COVID-19和FDA拒绝血友病A基因疗法Roctavian的完整回复信。2021年，雪上加霜，FDA暂停了BioMarin的PKU基因治疗项目临床试验，此前有报道称小鼠患上了癌症，并且有证据表明用于提供基因治疗的病毒载体已经整合到基因组中。不过，对于Bienaimé个人来说，他在为BioMarin掌舵的第16个年头，获得了超1800万美元的薪酬待遇。时间不会等任何一个Biotech，但事物的发展常常是螺旋式上升。2022年，BioMarin再次向盈利目标冲刺。今年年初财报公布，BioMarin2022年总收入达到21亿美元，研发费用支出6.5亿美元，净利润1.42亿美元，扭亏为盈。Bienaimé在18年前立下的Flag实现了。5明日之后BioMarin是Bienaimé在职业CEO职业生涯中的光辉与荣耀，却并不是唯一的标签。Bienaimé还是Incyte、PhRMA基金会、Vital Therapies等多家公司机构的董事会成员。对于BioMarin来说，实现盈利是新的起点，Bienaimé虽然功成身退，但这家公司、甚至是罕见病领域的Biotech们，还有更长的路要走。在上文BioMarin的发展剧本中，我们刻意避开了一个重要话题，这家公司在基因治疗和罕见病双重Buff的加持下，开发如此昂贵的药物，谁来支付？在美国，这笔巨额治疗费用主要由保险公司支付，如果患者十分贫穷，则由医疗补助支付。在其他大多数国家，这笔药物费用将由政府支付。他们为什么愿意支付这么多钱？部分原因是，这些药物确实改善了患者的生存质量，尽管还尚不能治愈疾病。但在医药商业领域，并非能靠「善良」解决一切。这也许是一个奇迹，但却是由商业驱动的奇迹。由于病人很少，BioMarin会关注每一位病人，并确保治疗费用得到支付。使用Vimizim药物的患者Wise提供了一个线索，「我的保险不承担的费用，BioMarin 会承担，这样我就不用自掏腰包了」。与大多数罕见病公司一样，BioMarin也会向慈善机构捐款，在药物不能完全报销时帮助病人。由于这笔钱不是专门用于支付某种药物，因此不会触犯联邦反回扣法规。保险公司能接受这种制度吗？Bienaimé此前曾公开表示，「改变他们并不是当务之急」。另一面，美国药房福利管理机构Express Scripts的首席医疗官、高药价的批评者Steven Miller也表示，「在罕见病药物方面，制药公司摆出价格，保险公司也无能为力，我们都是价格接受者」。但定价压力确实已经到来。Bienaimé承认，考虑到价格压力的可能性，BioMarin治疗儿童软骨发育不全症的药物Voxzogo，价格会相对较低。受到罕见病药物昂贵药价冲击的，首先就是发展中国家的政府机构。 一个离我们最近的案例是，近几年，BioMarin的药物退出中国市场的新闻不断。2022年9月，BioMarin宣布药物Kuvan（用以治疗高苯丙氨酸血症）将退出中国市场，原因虽然是国外已有仿制药上市，带来了患者市场的大量流失，从企业整体考量，继续保留该产品线的价值不大。但价格也是整体考量中的一环。在中国，这款药物起初定价为9000元/瓶，后改至7480元/瓶，无慈善用药援助情况下，按推荐剂量使用一年的花费约27万元。该药物尚未进入国家版医保目录，但进入了部分省市地方的普惠保，比如北京普惠健康保和成都的惠蓉保，报销比例不一，以北京为例，最多可报销60%，报销限额为100万元。即使是报销后的价格，对许多中国家庭来说依然难以支付。去年Kuvan撤出中国市场之后，现实版「我不是药神」开始上演。仅时隔一年，鲁南制药山东新时代的仿制药就得以获批上市。但其他罕见病患者未必有同样的好运气。今年6月，BioMarin又宣布不再为Vimizim在中国的进口药品注册证（IDL）续期，目前该注册证将于2024年5月到期。而Vimizim，是目前世界上唯一获批用于治疗黏多糖贮积症IVA型（MPS IVA）的特效药。 发展中国家中，罕见病高值药可及性低的现状不会很快改变，药品定价和支付方的博弈不会停息，这是罕见病药物公司和市场端共同面临的、更长远的真实命题。参考资料：1.BioMarin官网2.Youtube网站3.BioMarin's longtime CEO Jean-Jacques Bienaimé hands the reins to Genentech's Alexander Hardy；Fierce Pharma4.Innovation, resilience and grit: Jean-Jacques ‘JJ’ Bienaimé；CEO Magazine5.Lead From the Heart – Jean Jacques Bienaime6.罕见病寡头BioMarin的25年，给国内biotech带来哪些启示？7.BioMarin: One of the world's most valuable biotechs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。