TD-1473

今年或是国产JAK抑制剂获批的元年，前有堵截后有追兵，JAK抑制剂市场竞争可能迅速趋向白热化。艾伯维的乌帕替尼和辉瑞的阿布昔替尼，两款用于治疗自身免疫性疾病的二代JAK选择性抑制剂，均在上月完成国谈后列入新版国家医保目录，此时距它们在中国上市不到一年时间。谈判价格虽未对外公布，但从医院渠道打听的消息是，在目录执行前二者都提前降价，患者实际支付的月治疗费用约为2000元，仅为上市初期的1/3。乌帕替尼和阿布昔替尼都选择以价换量，从侧面反映了JAK抑制剂竞品间的激烈厮杀，并可能大幅压缩后来者的获利空间。同时，由于JAK抑制剂难以彻底避免的毒性问题，更多研发资源开始转向开发更安全的新靶点自免疾病治疗产品。今年或是国产JAK抑制剂获批的元年，前有堵截后有追兵，JAK抑制剂市场竞争可能迅速趋向白热化。国产品种研发如PD-1般火热上世纪90年代，JAK相关靶点（JAK1、JAK2、JAK3和TYK2）被陆续发现。此后，该靶点被各大药企看好，2011年至今全球已有十款产品成功上市，获批适应症达数十个，多数与自免疾病相关，产品合计年销售额预估超百亿美元。在2022财报已对外公布的产品销售数据中，一代泛JAK抑制剂代表——Incyte与诺华合作销售的芦可替尼，全球销售额达39.70亿美元，辉瑞的托法替布也卖出了17.96亿美元；二代选择性JAK抑制剂乌帕替尼，表现出赶超上代产品的势头，年销售额25.22亿美元。JAK抑制剂可以覆盖的适应症和市场规模，以及国内自免疾病市场的不断扩容，都吸引了大量中国制药公司布局JAK抑制剂研发。据兴业证券发布的研究报告，中国自免市场整体规模将从2019年的24亿美元增至2030年的241亿美元，增速显著高于全球。根据企业公布的消息及相关临床试验登记数据，目前由国内公司主导研发的JAK抑制剂数量已超20个，其中泛JAK抑制剂较少，更多企业选择布局二代选择性JAK抑制剂，适应症主要围绕自免疾病展开。在这些国产品种中，研发进展领先的是泽璟制药的杰克替尼以及恒瑞医药子公司瑞石生物的艾玛昔替尼。杰克替尼是泛JAK抑制剂，于2022年10月向NMPA递交上市申请并获受理，适应症是中、高危骨髓纤维化；艾玛昔替尼是选择性JAK1抑制剂，2022年底宣布其用于特应性皮炎治疗的国际III期多中心研究抵达临床终点，正与药监部门沟通新药上市申请。这两款产品还有其他多项与自免疾病相关的III期研究正在进行。另外，信达生物、正大天晴、科伦制药、华东医药、石药集团等众多实力药企，研发管线里也有JAK抑制剂。这样的场景不免让人联想到近10年来，国内公司同样因产品覆盖面大、获利空间广泛而高密度布局PD-1抑制剂开发。其他靶点竞品不可忽视拥挤的赛道让PD-1抑制剂的价格降到极点，不少产品成为管线中的“鸡肋”，而JAK抑制剂的市场竞争激烈程度可能更胜一筹。PD-1抑制剂是肿瘤治疗的基石，竞品间的比拼更多停留在同靶点产品之间。而JAK抑制剂在自免疾病中的地位，无法与前者相提并论，将面临其他靶点药物的挑战。在Nature上发表的一篇题为Kinase inhibition in autoimmunity and inflammation的文章，罗列出与JAK激酶相关的数量众多的信号传导通路（见下图），这也对应了其广泛的适应症。但从图中亦可发现，不少信号通路的受体蛋白也被作为药物开发靶标，且有多款抗体类产品成功获批上市，其中不少是JAK抑制剂的市场劲敌。图片来源 | Nature例如，针对IL-4、IL-13等靶点的生物药，是JAK抑制剂多个自免适应症的重要竞争对手。这些竞品目前取得的市场业绩令人刮目相看，如：靶向IL-13受体的乌司奴单抗（ustekinumab），2022年全球销售额97.23亿美元；靶向IL-4的度普利尤单抗（dupilumab），2022年销售额也达到82.93亿欧元（约合86.81亿美元）。对比上述靶点产品上市后的销售额增长速度，JAK抑制剂反而略逊一筹。艾伯维期待通过乌帕替尼销售额增长弥补未来修美乐因仿制药竞争可能的损失，但从趋势看，乌帕替尼或许难有惊艳的表现。对比度普利尤单抗与乌帕替尼上市后的销售额，乌帕替尼的销售额增速最初三年与度普利尤单抗接近，但第四年（2022年）乌帕替尼增速明显放缓，不及同时期（2020年）的度普利尤单抗（见下表）。尽管JAK抑制剂在治疗效果和用药便捷性方面具备优势，在多项自免疾病临床研究中显示出比其他产品更好的长期疗效，但监管部门、临床医生及患者等各方，对JAK抑制剂的安全性始终存在担忧。FDA就相关产品给出多项黑框警告，包括恶性肿瘤、不良心血管事件和血栓形成发生率增加等，二代选择性JAK抑制剂同样未能避开这些不良反应困扰。临床医生在处方JAK抑制剂前，经常要先对患者开展心电图、肝肾功能等多项检查，这也提高了JAK抑制剂的用药门槛。安全性问题或缩短产品红利期安全性问题可能不止导致JAK抑制剂在当下竞争中处于不利位置，从远期看，企业可能投入更多资源参与替代产品研发，进而加快药品的更新迭代速度，这将间接缩短JAK抑制剂的市场红利期。随着二代选择性JAK抑制剂逐渐推广，部分一代泛JAK抑制剂如辉瑞的托法替布、礼来的巴瑞替尼，已显示出市场萎缩迹象。由下表可见，二者的全球年销售额均在2021年到达峰值后，于2022年明显下降，对比上年度分别下降27%和26%。巴瑞替尼2017年刚获批上市，2022年6月FDA还批准其增加了治疗成年人严重斑秃的适应症，这也是FDA批准的首个用于斑秃的全身疗法。但这一获批并未逆转销售额向下趋势。而与此形成对比的是，乌司奴单抗2009年获批至今，近年销售额仍在持续增长。JAK抑制剂市场未来还将面临其他小分子免疫制剂开发的影响。前述Nature文章提出，激酶正成为当下炎症和自免疾病药物开发的热门靶点，而JAK抑制剂仅是其中的一种，IRAK4，RIPKs，BTK，SYK和TPL2等激酶，都在成为新药开发的靶标。辉瑞最早开发JAK抑制剂用于自免疾病治疗，并就此靶点陆续布局多款产品。但从其去年公布的炎症免疫产品线看，研发重心可能向JAK以外安全性更好的靶点倾斜。其JAK1 抑制剂阿布昔替尼目前获批适应症仅有中重度特应性皮炎，产品线并未显示其有更多适应症开发计划。有临床证据显示，炎症性肠病患者可能从JAK1抑制剂治疗中获益。吉利德近期公布其JAK1抑制剂filgotinib在中重度活动性溃疡性结肠炎Ⅲ期临床中获得积极结果，瑞石的SHR0302也有同适应症临床研究正在开展，这是一项全球市场容量近百亿美元的适应症。但并未在clinicaltrials.gov上检索到阿布昔替尼有相关临床研究进行。从目前产品线看，辉瑞将拿下炎症性肠病大适应症的希望寄托在新一代S1P受体调节剂etrasimod，这也是一款口服小分子制剂。据公司信息发布，目前etrasimod与中重度溃疡性结肠炎相关的两项Ⅲ期临床研究，均已抵达全部主要终点和关键次要终点，etrasimod还显示出更好的心脏安全性，在首次用药时无需进行心脏监测。目前FDA和EMA已受理etrasimod用于溃疡性结肠炎治疗的新药上市申请，同时etrasimod还有用于斑秃、克罗恩病、特应性皮炎的临床研究正在进行，这些适应症均与JAK抑制剂有所重合。百时美施贵宝也有一款S1P受体调节剂奥扎莫德（ozanimod），已于去年底在欧盟获批中重度活动性溃疡性结肠炎适应症。S1P受体调节剂的触角也已伸入中国市场。奥扎莫德已在国内获批用于成人复发型多发性硬化。etrasimod的中国权益由云顶新耀获得，该公司计划在2023年上半年完成亚洲Ⅲ期临床研究的患者招募。而国内不少其他公司也在开展JAK靶点以外小分子自免疾病治疗产品的研发，信立泰近期公告其研发的SAL0119片获临床试验默示许可，新闻稿中着重强调该产品具有不同于JAK类的作用机制。另外，诺诚健华、劲方生物、安锐生物也有JAK靶点外自免疾病治疗药物进入临床阶段。综上所述，JAK抑制剂的市场获利空间，在当下及未来均面临多重挑战，短期内国产品种顺利获批上市，预期仍可瓜分一部分市场蛋糕，但研发进展较慢的品种，生存空间或被各路竞品严重挤压。差异化开发也是选择之一但差异化开发的JAK抑制剂如局部疗法等，市场仍对其抱有期待，这类产品全身影响小，从而降低不良反应发生概率。例如，Oncostellae 开发的OST-122，其选择性作用于肠道局部，正被开发用于炎症性肠病，但类似产品如Theravance与强生合作开发的TD-1473，同适应症临床研究在2021年曾公布过一项失败结果。更多的JAK局部疗法被研制为外用制剂，用于特应性皮炎等皮肤疾病。如瑞石的SHR0302同时也有外用软膏剂，目前处于Ⅲ期临床研究阶段；辉瑞处于Ⅰ期临床研究阶段的PF-07295324和PF-07259955，也是外用制剂；祐儿医药从Aclaris Therapeutics获得的JAK1/3抑制剂ATI-1777，同样使用外用液体溶液剂型。当前同类产品已有芦可替尼乳膏于2021年获FDA上市批准，根据Incyte2022发布的财报，产品销售额已从2021年的0.05亿美元升至2022年的1.29亿美元。编辑|姚嘉总第1818期访问研发客网站可浏览更多文章www.PharmaDJ.com

Reported another record quarter of YUPELRI® (revefenacin) net sales and profitability: $18.7 million Q3 2022 sales up 35% from Q3 2021 (TBPH implied 35% share)1 Presented ampreloxetine data in neurogenic orthostatic hypotension (nOH) at the 33rd International Symposium on the Autonomic Nervous System Continued to build the Company's intellectual property portfolio with patent covering YUPELRI until 2039 Closed transaction to sell TRELEGY ELLIPTA royalty interests to Royalty Pharma for approximately $1.1 billion in upfront cash, up to $250 million of potential milestones, outer year royalties and an investment in ampreloxetine Initiated a $250 million capital return program; purchased GSK's entire holdings at $9.75 per share; launched a Dutch auction tender offer for up to $95 million of its ordinary shares Eliminated debt and ended third quarter with $487 million of cash DUBLIN, Nov. 7, 2022 /PRNewswire/ -- Theravance Biopharma, Inc. ("Theravance Biopharma" or the "Company") (NASDAQ: TBPH) today reported financial results for the third quarter of 2022. "This quarter is a milestone in the Company's transformation and demonstrates the power of a team of people who are focused and stay true to the Company's purpose, delivering medicines that make a difference. I am proud and grateful for the team that has refocused the portfolio and monetized our interest in TRELEGY to reposition and reinvigorate the Company's business model. Theravance Biopharma today is debt free, and I believe we are well-positioned for value creation," said Rick E Winningham, Chief Executive Officer. Quarterly Highlights YUPELRI® (revefenacin) inhalation solution, the first and only once-daily, nebulized bronchodilator approved in the US for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), with net sales increasing by 35% year-over-year (Q3 2022 vs Q3 2021) – its strongest quarter to date and increased its share of the long-acting nebulized COPD market, increasing to 26.3% through August 2022, up from 25.6% in Q2 2022. Recently issued US Patent No. 11,484,531, covering methods of treating COPD using YUPELRI, is now listed in the U.S. Food and Drug Administration publication, Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. The patent provides for method of use until 2039. Ampreloxetine, an investigational, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic nOH in patients with multiple system atrophy (MSA). Phase 3 results (Study 0170) showed a benefit to MSA patients in the study that was observed in multiple endpoints. The Company held a Type C meeting with the FDA in June 2022 and agreed on a path to NDA filing with one new Phase 3 clinical study in MSA patients with symptomatic nOH which is planned to start in the first quarter of 2023. The registrational Phase 3 Study in MSA patients with nOH (Study 0197, CYPRESS) is expected to be a 12-week open-label; 8-week double-blind, placebo-controlled, randomized withdrawal study with a primary endpoint of change in Orthostatic Hypotension Symptom Assessment (OHSA) composite score. The Company reiterates it expects the $25 million investment from Royalty Pharma to fund the majority of the Phase 3 costs as a result of study size as well as insights and learnings from earlier studies. TRELEGY ELLIPTA (once-daily, single inhaler triple therapy for COPD and asthma) Sale of TRELEGY ELLIPTA Royalty Interest On July 20, 2022, Theravance Biopharma closed the sale of its units in Theravance Respiratory Company, LLC ("TRC, LLC") representing its 85% economic interest in the sales-based royalty rights on worldwide net sales of GSK's TRELEGY ELLIPTA ("TRELEGY") to Royalty Pharma (NASDAQ: RPRX) for over $1.5 billion in potential total value (the "TRELEGY Royalty Transaction"). The TRELEGY Royalty Transaction is intended to provide near-, mid- and long-term value to the Company with an upfront cash payment of approximately $1.1 billion, up to $250 million in additional milestone payments contingent on the achievement of certain TRELEGY net sales thresholds between 2023 and 2026 and outer year royalties to the Company. Global Net Sales and Milestones GSK posted third quarter 2022 global net sales of $552 million (up from $449 million, or 23%, from third quarter of 2021), and global net sales from the first nine months of 2022 have reached approximately $1.6 billion (up from $1.2 billion, or 34% from the first nine months of 2021). Theravance Biopharma is entitled to a milestone payment from Royalty Pharma of $50 million if TRELEGY global net sales are equal to or exceed $2.9 billion2 in 2023, the first of $250 million of potential milestones that can be achieved between 2023 – 2026. $250 Million Capital Return Program The Company purchased all of GSK's equity stake in Theravance Biopharma, consisting of approximately 9.6 million shares at $9.75 per share on September 20, 2022. The Company announced a Dutch auction tender offer (the "Offer") for up to $95 million of its ordinary shares on September 28, 2022. The Company plans to enter into an Open Market Share Repurchase Plan to facilitate the repurchase of approximately $60 million of its ordinary shares in open market purchases subsequent to the completion of the Offer, with a goal to complete this program by the end of 2023. Extension of the Offer The Company is extending the length of the Offer such that the Offer will expire at midnight, New York City time, at the end of the day on November 17, 2022, unless the Company extends the Offer for an additional period of time. Based on information provided by Computershare Trust Company, N.A., the depositary for the Offer, to date, approximately 95,487 shares have been validly tendered for purchase in the Offer. Shareholders who have validly tendered and not withdrawn their shares do not need to re-tender their shares or take any other action in response to the extension of the Offer. Third Quarter Financial Results Revenue: Total revenue for the third quarter of 2022 was $12.5 million, primarily comprised of $12.4 million in Viatris collaboration revenue. Total revenue for the third quarter represents a $0.7 million decrease over the same period in 2021 primarily driven by the completion of the recognition of non-cash Janssen collaboration revenue in 2021, resulting from the planned close-out of the izencitinib program. YUPELRI: The Viatris collaboration revenue of $12.4 million for the third quarter of 2022 represents amounts receivable from Viatris and is comprised of the Company's 35% share of net sales of YUPELRI as well as its proportionate amount of the total shared costs incurred by the two companies. The non-shared YUPELRI costs incurred by Theravance Biopharma are recorded within operating expenses. While Viatris records the total net sales of YUPELRI within its financial statements, Theravance Biopharma's implied 35% share of net sales of YUPELRI for the third quarter of 2022 was $18.7 million, up 9% from the second quarter of 2022. There was a 35% increase in year-over-year implied net sales for the third quarter, however, due to accounting guidelines, Viatris collaboration revenue increased by 20% due to lower costs incurred by Theravance Biopharma as a result of the corporate restructuring, which improves YUPELRI profitability but lowers Viatris collaboration revenue. Additionally, during the period there were higher costs incurred by Viatris , which also reduced our Viatris collaboration revenue. Research and Development (R&D) Expenses: R&D expenses for the third quarter of 2022 were $9.9 million, compared to $43.7 million in the same period in 2021. Third quarter R&D expenses included total non-cash share-based compensation of $2.6 million. Selling, General and Administrative (SG&A) Expenses: SG&A expenses for the third quarter of 2022 were $16.3 million, compared to $21.3 million in the same period in 2021. Third quarter SG&A expenses included total non-cash share-based compensation of $5.2 million. Loss on Extinguishment of Debt: Loss on extinguishment of debt of $3.0 million for the third quarter of 2022 was related to the paydown of our 2023 convertible senior notes. Income from Discontinued Operations (before income taxes): Income from discontinued operations (before income tax) of $1,115.0 million for the third quarter of 2022 was primarily related to the $1,141.1 million gain from the sale of our equity interests in TRC, LLC and was partially offset by a $24.0 million loss on the extinguishment of our non-recourse 2035 notes. Provision for Income Tax Expense (Discontinued Operations): Income tax expense from discontinued operations of $182.4 million for the third quarter of 2022 was primarily related to the tax liability arising from the gain from the sale of our equity interests in TRC, LLC. The Company estimates a current tax liability of approximately $120.6 million. Cash Position: Cash, cash equivalents and marketable securities totaled $486.8 million as of September 30, 2022. 2022 Financial Guidance Operating Expenses: The Company reiterates that it expects full year 2022 R&D expense of $45 million to $55 million and SG&A expense of $35 million to $45 million (in each case, excluding share-based compensation, one-time restructuring costs and one-time transaction related legal expenses). The Company continues to expect to approach breakeven cash flow from operations. Conference Call and Live Webcast Today at 5:00 pm ET Theravance Biopharma will hold a conference call and live webcast accompanied by slides today at 5:00 pm ET / 2:00 pm PT / 10:00 pm GMT. To participate in the live call by telephone, please register here. Those interested in listening to the conference call live via the internet may do so by visiting Theravance Biopharma's website at , under the Investors section, Presentations and Events. A replay of the webcast will be available on Theravance Biopharma's website for 30 days through December 7, 2022. About Theravance Biopharma Theravance Biopharma, Inc.'s focus is to deliver Medicines that Make a Difference® in people's lives. In pursuit of its purpose, Theravance Biopharma leverages decades of expertise, which has led to the development of FDA-approved YUPELRI® (revefenacin) inhalation solution indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Its pipeline of internally discovered programs is targeted to address significant unmet patient needs. For more information, please visit . THERAVANCE BIOPHARMA®, THERAVANCE®, and the Cross/Star logo are registered trademarks of the Theravance Biopharma group of companies (in the U.S. and certain other countries). YUPELRI® is a registered trademark of Mylan Specialty L.P., a Viatris Company. Trademarks, trade names or service marks of other companies appearing on this press release are the property of their respective owners. Forward-Looking Statements This press release and the conference call will contain certain "forward-looking" statements as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans, objectives, expectations and future events. Theravance Biopharma intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. Examples of such statements include statements relating to: contingent payments due to the Company from the sale of the Company's TRELEGY ELLIPTA royalty interests to Royalty Pharma, the Company's goals, designs, strategies, plans and objectives, the ability to provide value to shareholders, the Company's regulatory strategies and timing of clinical studies (including the data therefrom), the potential characteristics, benefits and mechanisms of action of the Company's product and product candidates, including potential points of differentiation, the market for products being commercialized and product candidates, product sales or profit share revenue and the Company's expectations for its future financial performance and expectations as to future cash flows, the effectiveness of the Company's intellectual property portfolio, the timing of the Offer, including the settlement thereof and the satisfaction of conditions to the Offer, and the Company's repurchase of its ordinary shares by way of an open market share repurchase plan. These statements are based on the current estimates and assumptions of the management of Theravance Biopharma as of the date of this press release and the conference call and are subject to risks, uncertainties, changes in circumstances, assumptions and other factors that may cause the actual results of Theravance Biopharma to be materially different from those reflected in the forward-looking statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements include, among others, risks related to: whether the milestone thresholds can be achieved, delays or difficulties in commencing, enrolling or completing clinical studies, the potential that results from clinical or non-clinical studies indicate the Company's product candidates or product are unsafe, ineffective or not differentiated, risks of decisions from regulatory authorities that are unfavorable to the Company, dependence on third parties to conduct clinical studies, delays or failure to achieve and maintain regulatory approvals for product candidates, risks of collaborating with or relying on third parties to discover, develop, manufacture and commercialize products, and risks associated with establishing and maintaining sales, marketing and distribution capabilities with appropriate technical expertise and supporting infrastructure, ability to retain key personnel, the impact of the Company's restructuring actions on its employees, partners and others, the ability of the Company to protect and to enforce its intellectual property rights, the satisfaction of the conditions to the Offer, volatility and fluctuations in the trading price and volume of the Shares, and general economic and market conditions. Other risks affecting Theravance Biopharma are in the Company's Form 10-Q filed with the SEC on August 8, 2022, and other periodic reports filed with the SEC. In addition to the risks described above and in Theravance Biopharma's filings with the SEC, other unknown or unpredictable factors also could affect Theravance Biopharma's results. No forward-looking statements can be guaranteed, and actual results may differ materially from such statements. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Theravance Biopharma assumes no obligation to update its forward-looking statements on account of new information, future events or otherwise, except as required by law. Important Information Regarding the Tender Offer This press release is for informational purposes only and is neither an offer to buy nor the solicitation of an offer to sell any of the Company's ordinary shares, par value $0.00001 per share (the "Shares"). A Dutch auction tender offer (the "Offer") to purchase up to $95 million of the Shares is being made solely by the Company's Offer to Purchase, dated September 28, 2022, the related Letter of Transmittal and other related materials, as they may be amended or supplemented. Holders of Shares should read the Company's offer statement on Schedule TO filed with the SEC in connection with the Offer, which includes as exhibits the Offer to Purchase, the Letter of Transmittal and related materials, as well as any amendments or supplements to the Schedule TO when they become available, because they will contain important information. Each of these documents has been, or will be, filed with the SEC, and, when available, holders may obtain them for free from the SEC at its website () or from the information agent in connection with the Offer. This press release does not set forth all of the terms and conditions of the Offer. Shareholders should carefully read the Offer to Purchase, the Letter of Transmittal and related materials, for a complete description of all terms and conditions before making any decision with respect to the Offer. None of the Company, its management, its board of directors, its officers, the dealer manager, the depositary, or the information agent, or any of their respective affiliates, makes any recommendation that holders tender or refrain from tendering all or any portion of their Shares, and no one has been authorized by any of them to make such a recommendation. Holders must make their own decision as to whether to tender their Shares and, if so, the amount of Shares to tender and the purchase price or prices at which to tender. Contact: Andrew Hindman Chief Financial Officer [email protected] 650-808-4045 1 While Viatris, Inc. ("Viatris") records the total YUPELRI net sales, the Company is entitled to a 35% share of the profits and losses pursuant to a co-promotion agreement with Viatris. 2 The first milestone payment of $50.0 million, will be triggered if Royalty Pharma receives $240.0 million or more in royalty payments from GSK with respect to 2023 TRELEGY global net sales, which we would expect to occur in the event TRELEGY global net sales reach approximately $2.863 billion. Royalties payable from GSK to Royalty Pharma are upward tiering from 6.5% to 10%. SOURCE Theravance Biopharma, Inc.