Etanercept

2024年2月1日，默沙东公布2023年业绩，其当家花旦Keytruda（帕博利珠单抗，俗称K药）迎来历史性高光时刻，全年营收250.11亿美元，荣登2023年“药王”宝座。不过默沙东并非高枕无忧。一方面，诺和诺德的司美格鲁肽2023年销售额已达212亿美元，且增长势头强劲，未来极有可能超越K药成为新药王。另一方面，K药的一些关键专利将在2028年到期，目前其生物类似药来势汹汹，布局厂家不乏安进、山德士等巨头。内忧外患下，K药有可能成为史上“最短命药王”。那么，默沙东为保卫K药做了哪些尝试？虎视眈眈的生物类似药据不完全统计，目前已有近10家药企的K药生物类似药进入临床试验阶段，最快的已进入III期临床。今年3月15日，安进在Clinicaltrials.gov网站上注册了K药生物类似药ABP 234的III期临床试验。该研究计划入组927例晚期或转移性非鳞状非小细胞肺癌（NSCLC）患者，预计2027年10月完成。无独有偶，去年12月1日，仿制药巨头山德士登记了一项K药生物类似药GME751与K药的头对头临床试验，将在需要K药辅助治疗的已切除晚期黑色素瘤患者中对GME751与K药进行比较。同年12月7日，山德士再次登记了一项GME751的III期头对头试验，该试验旨在比较GME751和K药在未经治疗的转移性非鳞状NSCLC患者中的有效性、安全性和免疫原性。试验计划入组720例患者，按1:1的比例随机接受GME751或K药联合化药治疗。以上两项试验均预计将于2026年完成。另外，三星Bioepis也加入了K药生物类似药的竞争行列。三星Bioepis原由三星生物与渤健公司共同成立，后渤健公司将三星Bioepis股权出售给三星生物。三星Bioepis主要聚焦于生物类似药研发，目前产品已经覆盖依那西普、英夫利西单抗、阿达木单抗、曲妥珠单抗、贝伐珠单抗、雷珠单抗等6大品类。今年2月21日，三星Bioepis宣布启动K药生物类似药SB27的I期临床试验，旨在比较SB27与K药在完全切除和辅助铂类化疗后的II-IIIA期NSCLC患者中的药代动力学、疗效、安全性等。视线回到国内，今年2月底，百奥泰在Clinicaltrials.gov网站上注册了K药生物类似药BAT3306一线治疗非鳞状NSCLC的III期临床试验，计划入组676例NSCLC患者，试验主要终点包括药代动力学、临床等效性等，预计将于2027年初步完成该试验。去年12月，齐鲁制药也在Clinicaltrials.gov网站上注册了其K药生物类似药QL2107的I期临床试验，该试验计划入组168例健康志愿者，预计2024年6月完成。除此之外，复宏汉霖也申报了K药类似药HLX17的临床试验。目前无论是海外还是国内，盯着K药生物类似药的企业都不在少数。倘若未来几年生物类似药产品顺利上市，K药的市场份额将很快被蚕食，K药保卫战迫在眉睫。那么为保药王之位，默沙东做了哪些尝试？拓展适应症事实上，自2014年K药首次获FDA批准以来，默沙东一直不曾停下拓展其适应症的脚步。截至目前，K药已在美国获批约40项适应症，覆盖黑色素瘤、肺癌、肝癌、头颈癌等多个瘤种，在中国也获批十余项适应症。K药在国内获批的适应症来源：公开资料打造K药基石属性，探索联合治疗模式在拓展适应症过程中，联合疗法是重要维度。据悉，默沙东在高达1600多项临床试验中研究K药联合各种治疗方案在不同瘤种中的作用，包括与溶瘤病毒、ADC、mRNA肿瘤疫苗等的联合使用。2020年7月，默沙东与溶瘤病毒领域明星公司Oncorus开展临床试验合作，以评估Oncorus的ONCR-177联合K药治疗晚期和/或难治性皮肤、皮下或转移性淋巴结实体瘤患者的效果。不过该联用疗法的I期临床试验结果并不尽如人意，随后该管线被砍。在与ADC联合方面，K药联合安斯泰来的靶向Nectin-4 ADC产品维恩妥尤单抗（Padcev），在一线治疗尿路上皮癌中降低53%的死亡风险，佐证了K药与ADC联合的效果。目前，该联合方案用于一线治疗局部晚期或转移性尿路上皮癌（la/mUC）的补充生物制品许可申请（sBLA）获FDA优先审评，PDUFA日期为2024年5月9日。由于ADC联用可成为K药的强力辅助，因此默沙东将重金砸向ADC领域。于是就有了默沙东与科伦博泰的3次牵手，以及与第一三共220亿美元的合作。围绕ADC，默沙东共达成了8项交易。日前，默沙东在Clinicaltrials.gov网站上注册了两项MK-2870的全球III期临床试验，分别用来评估MK-2870单药或联用K药在特定类型乳腺癌和NSCLC患者中的疗效。MK-2870是科伦博泰研发的一款靶向Trop2的ADC 产品，由靶向Trop2的人源化单克隆抗体、可酶促裂解的连接子和新型拓扑异构酶I抑制剂组合而成。此次注册的两项临床试验分别是将MK-2870与K药联用头对头对比K药，用于辅助治疗既往接受新辅助K药与含铂双药化疗且手术后未达到病理完全缓解的NSCLC患者（可切除的II期-IIIB期），计划入组780例患者，预计2034年2月初步完成。另一项研究则是评估MK-2870单药或联合K药治疗局部晚期或转移性HR+/HER2-乳腺癌的全球Ⅲ期临床试验，计划入组1200例患者，预计在2027年7月初步完成。除了上述两项联用疗法外，K药还与吉利德的Trop2 ADC Trodelvy联用开展一线治疗三阴性乳腺癌（TNBC）和NSCLC的临床试验。2022年，K药又再次联手阿斯利康/第一三共的Trop2 ADC DS-1062（Dato-DXd），冲击PD-L1低表达NSCLC。值得一提的是，这些研究的对照组均为K药单药。未来K药将与ADC擦出什么样的火花，值得期待。在与mRNA肿瘤疫苗联用方面，2023年12月，默沙东宣布启动III期INTerpath-002研究，该研究旨在评估Moderna的肿瘤mRNA疫苗mRNA-4157联合K药辅助治疗完全切除的II、IIIA或IIIB期NSCLC患者的有效性与安全性。mRNA独有的优势在肿瘤领域极具想象空间，与K药联合，或许可成为下一个癌症治疗范式。除此之外，肿瘤电场、TIL（肿瘤浸润淋巴细胞疗法）、微生物、CAR-M（嵌合抗原受体巨噬细胞）等前沿疗法也出现在K药联用方案中。向疾病早期迈进，加注辅助治疗赛道2023年10月，默沙东发布了K药在早期NSCLC治疗的III期临床数据。在这项名为KEYNOTE-671的III期临床试验中，K药用于可切除的II期、IIIA 期或IIIB期NSCLC围手术期治疗达到了主要终点OS。基于此项研究，FDA批准了K药与含铂化疗联用作为术前新辅助治疗，并在术后单药作为辅助治疗，用于治疗可切除NSCLC患者。此外，默沙东还在黑色素瘤、肾细胞癌、TNBC等领域进一步探索K药早期治疗的潜力。K药迈入疾病早期阶段，预示着其适应症范围进一步扩大。如今看来，默沙东已把持续拓宽K药联用疗法，作为K药破局的“利器”。最终能在多大程度上延长K药的生命周期，仍待观察。总之，K药的卫冕之路仍任重道远。参考来源1.clinicaltrials.gov2.医麦客《默沙东K药的“药王保卫战”：物尽其用、联合百搭》3.FDA grants priority review to Merck’s application for Keytruda plus Padcev (enfortumab vedotin-ejfv) for the first-line treatment of patients with locally advanced or Metastatic Urothelial Cancer.4.新康界《准药王”突围战：默沙东“K药”推进早期肺癌治疗》

– ARCALYST® (rilonacept) Q1 2024 net product revenue of $78.9 million, representing 85% year-over-year growth – – ARCALYST 2024 expected net product revenue increased to $370 - $390 million – – Abiprubart Phase 2b trial in Sjögren’s Disease planned to initiate in 2H 2024 – – Current operating plan expected to remain cash flow positive on an annual basis – – Conference call and webcast scheduled for 8:30 am ET today – HAMILTON, Bermuda, April 23, 2024 (GLOBE NEWSWIRE) -- Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) (Kiniksa), a commercial-stage biopharmaceutical company with a pipeline of immune-modulating assets designed to target a spectrum of cardiovascular and autoimmune diseases, today reported first quarter 2024 financial results and recent portfolio execution. “One of the drivers of strong ARCALYST growth is an expanding utilization of ARCALYST as a steroid-sparing therapy for patients suffering from recurrent pericarditis. In addition, with continued frequent prescriber engagement and high physician and patient satisfaction, we now expect 2024 ARCALYST net sales to increase from our previous guidance of between $360 and $380 million to $370 and $390 million,” said Sanj K. Patel, Chairman and Chief Executive Officer of Kiniksa. “Additionally, we believe abiprubart has the potential to provide meaningful benefit through convenient subcutaneous dosing, and we plan to initiate a Phase 2b trial in Sjögren’s Disease in the second half of 2024. This continued commercial execution and pipeline advancement is included in our current operating plan, which we expect to remain cash flow positive on an annual basis.” Portfolio Execution ARCALYST (IL-1α and IL-1β cytokine trap) ARCALYST net product revenue was $78.9 million for the first quarter of 2024. Since launch in April 2021, approximately 2,000 prescribers have written ARCALYST prescriptions for recurrent pericarditis. As of the end of the first quarter of 2024, average total duration of ARCALYST therapy in recurrent pericarditis was approximately 23 months. Data from the RESONANCE patient registry were presented at the American College of Cardiology Scientific Session (ACC.24). The data highlight a shift in recurrent pericarditis management by pericarditis-focused cardiologists at 21 academic sites across the US and demonstrate increasing proportional ARCALYST use compared to and in advance of corticosteroids since ARCALYST commercial availability for recurrent pericarditis in 2021. Abiprubart (anti-CD40 monoclonal antibody inhibitor of CD40-CD154 interaction) Kiniksa expects to initiate a Phase 2b trial designed to evaluate the efficacy of biweekly and monthly abiprubart administered subcutaneously in patients with Sjögren’s Disease in the second half of 2024. Mavrilimumab (monoclonal antibody inhibitor targeting GM-CSFRα) Kiniksa is evaluating potential partnership opportunities to advance development of mavrilimumab, which has generated positive data in mid-stage clinical trials across multiple indications. Financial Results Total revenue for the first quarter of 2024 was $79.9 million, compared to $48.3 million for the first quarter of 2023. Total revenue for the first quarter of 2024 included $1.0 million in license and collaboration revenue, compared to $5.7 million for the first quarter of 2023. Total operating expenses for the first quarter of 2024 were $96.4 million, compared to $59.5 million for the first quarter of 2023. Total operating expenses for the first quarter of 2024 included $20.8 million in collaboration expenses, which are driven by ARCALYST collaboration profitability, compared to $8.3 million for the first quarter of 2023. Total operating expenses for the first quarter of 2024, included $7.2 million in non-cash, share-based compensation expense, compared to $6.1 million for the first quarter of 2023. Net loss for the first quarter of 2024 was $17.7 million, compared to a net loss of $12.3 million for the first quarter of 2023. As of March 31, 2024, Kiniksa had $213.6 million of cash, cash equivalents, and short-term investments and no debt. Financial Guidance Kiniksa expects 2024 ARCALYST net product revenue of between $370 million and $390 million, compared to prior guidance of between $360 million and $380 million. Kiniksa expects its current operating plan to remain cash flow positive on an annual basis. Conference Call Information Kiniksa will host a conference call and webcast at 8:30 a.m. Eastern Time on Tuesday, April 23, 2024, to discuss first quarter 2024 financial results and recent portfolio execution. Individuals interested in participating in the call via telephone may register here. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. To access the webcast, please visit the Investors and Media section of Kiniksa’s website. A replay of the event will also be available on Kiniksa’s website within approximately 48 hours after the event. About Kiniksa Kiniksa is a commercial-stage biopharmaceutical company focused on discovering, acquiring, developing, and commercializing therapeutic medicines for patients suffering from debilitating diseases with significant unmet medical need. Kiniksa’s immune-modulating assets, ARCALYST, abiprubart, and mavrilimumab, are based on strong biologic rationale or validated mechanisms, target a spectrum of underserved cardiovascular and autoimmune conditions, and offer the potential for differentiation. For more information, please visit . About ARCALYST ARCALYST is a weekly, subcutaneously injected recombinant dimeric fusion protein that blocks interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) signaling. ARCALYST was discovered by Regeneron Pharmaceuticals, Inc. (Regeneron) and is approved by the U.S. Food and Drug Administration (FDA) for recurrent pericarditis, cryopyrin-associated periodic syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome, and deficiency of IL-1 receptor antagonist (DIRA). The FDA granted Breakthrough Therapy designation to ARCALYST for the treatment of recurrent pericarditis in 2019 and Orphan Drug exclusivity to ARCALYST in 2021 for the treatment of recurrent pericarditis and reduction in risk of recurrence in adults and pediatric patients 12 years and older. The European Commission granted Orphan Drug Designation to ARCALYST for the treatment of idiopathic pericarditis in 2021. IMPORTANT SAFETY INFORMATION ABOUT ARCALYST ARCALYST may affect your immune system and can lower the ability of your immune system to fight infections. Serious infections, including life-threatening infections and death, have happened in patients taking ARCALYST. If you have any signs of an infection, call your doctor right away. Treatment with ARCALYST should be stopped if you get a serious infection. You should not begin treatment with ARCALYST if you have an infection or have infections that keep coming back (chronic infection). While taking ARCALYST, do not take other medicines that block interleukin-1, such as Kineret® (anakinra), or medicines that block tumor necrosis factor, such as Enbrel® (etanercept), Humira® (adalimumab), or Remicade® (infliximab), as this may increase your risk of getting a serious infection. Talk with your doctor about your vaccine history. Ask your doctor whether you should receive any vaccines before you begin treatment with ARCALYST. Medicines that affect the immune system may increase the risk of getting cancer. Stop taking ARCALYST and call your doctor or get emergency care right away if you have any symptoms of an allergic reaction. Your doctor will do blood tests to check for changes in your blood cholesterol and triglycerides. Common side effects include injection-site reactions (which may include pain, redness, swelling, itching, bruising, lumps, inflammation, skin rash, blisters, warmth, and bleeding at the injection site), upper respiratory tract infections, joint and muscle aches, rash, ear infection, sore throat, and runny nose. For more information about ARCALYST, talk to your doctor and see the Product Information. About Abiprubart Abiprubart is an investigational humanized monoclonal antibody that binds to CD40 and is designed to inhibit the CD40-CD154 (CD40 ligand) interaction, a key T-cell co-stimulatory signal critical for B-cell maturation and immunoglobulin class switching and Type 1 immune responses. Kiniksa believes disrupting the CD40-CD154 co-stimulatory interaction is an attractive approach to addressing multiple autoimmune disease pathologies. About Mavrilimumab Mavrilimumab is an investigational fully human monoclonal antibody that blocks activity of GM-CSF by specifically binding to the alpha subunit of the GM-CSF receptor (GM-CSFRα). Phase 2 clinical trials of mavrilimumab in rheumatoid arthritis and giant cell arteritis achieved their primary and secondary endpoints with statistical significance. Kiniksa is evaluating potential partnership opportunities for mavrilimumab. Forward-Looking Statements This press release contains forward-looking statements. In some cases, you can identify forward looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions, although not all forward-looking statements contain these identifying words. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation, statements regarding: our expectation that ARCALYST 2024 net product revenue will be between $370 million and $390 million; our plan to initiate a Phase 2b clinical trial of abiprubart in Sjögren’s Disease in the second half of 2024; our expectation to remain cash flow positive on an annual basis within our current operating plan; future clinical trial design, including the design of our planned Phase 2b trial of abiprubart in Sjögren’s Disease; our beliefs about the mechanisms of our product candidates and potential impact of their approach, including that using abiprubart to disrupt the CD40-CD154 co-stimulatory interaction is an attractive approach to address multiple autoimmune disease pathologies; and our belief that all of our product candidates offer the potential for differentiation. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including without limitation, the following: risks arising from the planned redomiciliation of our principal holding company from Bermuda to the United Kingdom; delays or difficulty in enrollment of patients in, and activation or continuation of sites for, our clinical trials; delays or difficulty in completing our clinical trials as originally designed; potential for changes between final data and any preliminary, interim, top-line or other data from clinical trials; our inability to replicate results from our earlier clinical trials or studies; impact of additional data from us or other companies, including the potential for our data to produce negative, inconclusive or commercially uncompetitive results; potential undesirable side effects caused by our products and product candidates; our inability to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities; potential for applicable regulatory authorities to not accept our filings, delay or deny approval of any of our product candidates or require additional data or trials to support approval; our reliance on third parties as the sole source of supply of the drug substance and drug product used in our product candidates; raw material, important ancillary product and drug substance and/or drug product shortages; our reliance on third parties to conduct research, clinical trials, and/or certain regulatory activities for our product candidates; complications in coordinating requirements, regulations and guidelines of regulatory authorities across jurisdictions for our clinical trials; changes in our operating plan, business development strategy or funding requirements; and existing or new competition. These and other important factors discussed in our filings with the U.S. Securities and Exchange Commission, including under the caption “Risk Factors” contained therein, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. Except as required by law, we disclaim any intention or obligation to update or revise any forward-looking statements. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Every Second Counts! ® Kiniksa Investor and Media Contact Rachel Frank (339) 970-9437 rfrank@kiniksa.com KINIKSA PHARMACEUTICALS, LTD. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except share and per share amounts) (Unaudited) Three Months Ended March 31, 2024 2023 Revenue: Product revenue, net $ 78,885 $ 42,659 License and collaboration revenue 973 5,686 Total revenue 79,858 48,345 Operating expenses: Cost of goods sold 10,583 7,036 Collaboration expenses 20,801 8,288 Research and development 26,334 15,172 Selling, general and administrative 38,682 29,045 Total operating expenses 96,400 59,541 Loss from operations (16,542 ) (11,196 ) Other income 2,266 1,832 Loss before income taxes (14,276 ) (9,364 ) Provision for income taxes (3,428 ) (2,906 ) Net loss $ (17,704 ) $ (12,270 ) Net loss per share attributable to common shareholders —basic and diluted $ (0.25 ) $ (0.18 ) Weighted average common shares outstanding—basic and diluted 70,633,023 69,751,697 KINIKSA PHARMACEUTICALS, LTD. SELECTED CONSOLIDATED BALANCE SHEET DATA (In thousands) (Unaudited) As of March 31, December 31, 2024 2023 Cash, cash equivalents, and short-term investments $ 213,552 $ 206,371 Working capital 206,379 212,631 Total assets 519,673 526,322 Accumulated deficit (495,654 ) (477,950 ) Total shareholders' equity 431,895 438,839