美印合作乳癌Herceptin(R)生技學名藥 (MYL-1401O; Mylan & Biocon) 14個新興市場上市仍需 Genentech/ Roche 點頭(授權)

學名藥30年好日子已成過去式！ 2017/09/20 出處：財訊雙週刊 第 537 期 作者：夏彌新 美國專利制度對於藥物創新扮演十分重要的角色，讓新藥公司藉由市場的排他性以訂定高藥價，來獲取高回收以彌補研發投入的龐大成本；只是，相對的消費者往往要付出高昂費用。學名藥（小分子）是指原廠藥的專利過期後，其他藥廠可以用同樣成分與製程進行生產，其用途、劑型、安全性、效力、給藥途徑、藥效特性等，都能與原廠藥完全相同或具有生物等效性。

榮景》政府支持＋專利到期 帶動學名藥30年成長 學名藥的開發相較新藥研發費用少，且相關的試驗風險亦較低。依照美國食品藥物管理局（FDA）規定，學名藥廠可引用美國FDA先前核准上市的原廠藥所揭露的安全性與療效等資訊，不須再一一進行各種複雜且花費高的臨床實驗，加速學名藥上市的時程。學名藥產業的長線發展，需要國家政策支持，以及法規單位加速審核的配合。英國Visiongain研究所的調查報告指出，已有部分政府硬性規定，凡是民眾普遍使用的藥品，一旦有了學名藥上市後，就不能再使用專利品牌原廠藥，日本政府也積極提高學名藥使用。美國政府為了讓人民選擇等效又便宜的學名藥，1984年通過《藥物競價及專利權恢復法案》；這項俗稱的Hatch-Waxman法案，也使得美國於1999至2008年間節省高達7341億美元的醫藥成本，並帶動美國學名藥產業的發展。另一個讓學名藥加速成長的原因，是原廠面臨專利到期，就是我們常稱的「專利懸崖」（Patent Cliff）。根據EvaluatePharma預估，一一至一六年全球最暢銷藥物因專利到期所流失的銷售達2550億美元，其中不乏年銷百億美元的巨磅藥，如輝瑞降膽固醇Lipitor、必治妥施貴寶抗凝血Plavix、禮來治療精神疾病的Zyprexa，以及日本武田治療糖尿病的Actos。一旦專利到期，學名藥廠就會以一到三折的價格湧入市場；專利到期後6個月內，八成以上的原廠處方藥會被學名藥取代。不過，原廠也不是省油的燈，為了不讓營收巨幅流失，品牌大廠透過不同策略，希望把勢力延伸進學名藥市場。 取損人不利己降價的撒手鐗，以及品牌原廠自己授權學名藥（AG）的販售。當然這些漸漸被養大的學名藥廠有營收、有現金，為了力抗原廠的入侵學名藥市場，就不斷透過併購，將學名藥的上中下游包括原料藥廠、製造、行銷與配送，進行垂直整合和擴展營運版圖，甚至享有某些藥物的獨占市場，不斷提高藥價，享有高達三○%的營業利益率。 根據美國學名藥學會的估計，學名藥30年來為美國節省數兆美元的醫療支出，而且美國小分子學名藥市占率已達86%。政府大力支持以及原廠專利到期，使學名藥廠在過去30年享有平穩成長，平均年增率為9.6%，而近年增長更達10到15%。原本是學名藥發展天堂的美國，現在看起來也遇到了發展瓶頸，因為不但政府打壓藥價，藥品大批發商和零售商也結盟要求藥廠調降藥價。美國最大的藥品零售商包括沃爾瑪（Wal-Mart）和Walgreens正形成更大的聯盟，希望可以強迫學名藥廠再降價；加上FDA新頭頭Scott Gottlieb也公開表示，讓學名藥市場競爭加速是他首要任務，使學名藥廠的利潤再度受擠壓。其實，零售商聯盟自一三年就在進行。一三年Walgreens和全球最大學名藥採購批發商AmerisourceBergen結盟；今年北美最大藥品管理採購Express Scripts和美國藥品零售商CVS Health和Cardinal Health，以及Wal-Mart和藥品批發商McKesson都分別進行合作。在這樣的聯盟下，對學名藥採購議價能力愈來愈強。這些超級買家首先砍價的對象是葛蘭素的氣喘吸入型藥物，以及賽諾菲和Novo Nordisk的胰島素，接著就是下手砍殺學名藥廠藥價。8月初，美國最大的醫療服務公司Cardinal Health和AmerisourceBergen，以及全球最大學名藥廠TEVA都示警，學名藥價將再調降7至9%，導致當天學名藥相關公司股價大跌，包括TEVA跌24%、Mylan跌6%、AmerisourceBergen批發商跌10%、Perrigo藥廠和Endo藥廠分別下跌5%和6%，而Cardinal Health也下跌10%。

利空》市場供過於求 劣質印度學名藥品大舉入侵 全球最大學名藥廠TEVA最近法說會也說明，美國超過八成的藥品採購集中在前四大採購單位（GPO），TEVA受Wal-Mart和McKesson聯盟的影響很大，價格將往下調，當然聯盟的貨架庫存減少，也導致TEVA出貨量減少；第二季降價幅度約6%，可以預見下半年的價格調整將更嚴苛。美國學名藥廠Mylan法說會中也強調，未來調降藥價壓力仍在。這還不是最糟的，美國學名藥廠最大利空就是印度的學名藥雖有品質問題，但仍大舉入侵美國市場。市場分析師認為，現在學名藥廠面臨供過於求，且藥廠聯盟對藥價的態度又很強勢，所以學名藥降價趨勢不變，營收和獲利持續受壓縮。學名藥過去受惠政府法案以及原廠專利到期的利多加持，30年來享盡好處，但不斷靠併購來成長有其極限，尤其遇到整個醫藥環境大改變，現在可說是最艱困的時候；而正當紅的生物相似藥是否有機會帶動學名藥廠下一個成長？美國政府一○年簽署通過《生物製劑價格競爭與創新法案》（BPCIA），提供生物相似藥簡易上市的審核流程，因為生物相似藥相較原廠生物製劑的開發時程較短、投資金額較少、成功機率較高，也吸引不少學名藥廠進入搶食市場。市調研究報告指出，二○年生物相似藥市場將達250至350億美元，其中美國會是最大的單一市場，預估一六至二○年，生物相似藥將為美國和歐洲5國節省500億到1100億美元的市場。誰都想搶生物相似藥的市場，不過學名藥進入生物相似藥可以再造過去學名藥的榮景？恐怕這次遇到的競爭者都是一級強手。原廠如生技大哥Amgen為了捍衛市場，也加入生物相似藥的戰場；另一個後起之秀三星集團更搶市攪局，Samsung Biologics打出38萬公升代工產能，加上Samsung Bioepis連拿歐、美五張生物相似藥的藥證。三星拿的都是價值6、70億美元起跳的市場，最近又與美國生技大廠Biogen取得市場規模160億美元的Humira生物相似藥。因為原廠強勢捍衛市場，所以學名藥大廠TEVA和Mylan進入生物相似藥市場的態度是積極帶保守，採取合縱連橫試水溫。TEVA與南韓的Celltrion獨家合作除了羅氏Herceptin生物相似藥CT-P6，還有治療非何杰金氏淋巴瘤Rituxin生物相似藥CT-P10。7月31日，TEVA與合作夥伴Celltrion宣布向FDA遞送羅氏治療乳癌Herceptin的生物相似藥CT-P6申請，藥物有效性與安全性的臨床數據可是來自全球22個國家、共500位病患，來勢洶洶。Mylan和印度的Biocon合作開發6項生物相似藥，其中治療乳癌生物相似藥MYL-1401O已在14個新興市場銷售，並已送件歐洲與美國FDA，是否能成功打進美國市場，12月3日揭曉。

考驗》搶入生物相似藥 一線大廠加入戰況愈形激烈 其實，TEVA或是Mylan等一級大學名藥廠，要取得FDA核准生物相似藥已是氣喘吁吁，上市後還要面臨行銷問題。學名藥藥廠因法案的關係，可讓藥師決定是否幫病患替換原廠藥，所以學名藥廠不必建立人數眾多的行銷團隊，只要與批發通路保持良好關係，後面推銷至醫院藥局或大型醫院集團，學名藥藥廠都不須擔憂。不過，不像小分子學名藥可以自由替換，生物相似藥的銷售困難度就高多了。歐盟的法規相對寬鬆，所以競爭更激烈；美國的法規較嚴，加以FDA的態度不清，到4月底只有5個生物相似藥通過核准。 學名藥的發展是否如台灣生技天王趙宇天所說的已是過去式？還需要觀察，因為學名藥在美國市占率仍有86%，也許經過下半年來嚴苛的價格調整後，一八年學名藥公司的基本面有機會反彈。至於，受惠於另一個「專利懸崖」的生物相似藥，會不會是學名藥廠下一個成長的動力，恐怕就要承受考驗了！（作者任職於財信數位）

Mylan Announces Global Settlement And License Agreements With Genentech And Roche On Herceptin®  Hertfordshire, England and Pittsburgh, PA /PRNewswire/ -- Mylan N.V. (NASDAQ, TASE: MYL) today announced that Mylan has agreed to the terms of a global settlement with Genentech, Inc. and F. Hoffmann-La Roche Ltd. in relation to patents for Herceptin® (trastuzumab), which provides Mylan with global licenses for its trastuzumab product. The global license will provide a clear pathway for Mylan to commercialize its trastuzumab product in various markets around the world, commencing on the license effective dates, which are confidential. The licenses pertain to all countries except Japan, Brazil and Mexico. In addition to eliminating any legal uncertainty over the launch of Mylan's trastuzumab, the settlement eliminates further patent litigation expenses associated with Genentech and Roche. Mylan has agreed to withdraw its pending Inter Partes Review (IPR) challenges against two U.S. Genentech patents (patent numbers 6,407,213 and 6,331,415) as part of the settlement. Following this settlement and the recent acceptance of Mylan's application for its proposed biosimilar trastuzumab with the U.S. Food and Drug Administration (FDA), Mylan anticipates potentially being the first company to launch a biosimilar to Herceptin in the U.S. All other terms and conditions of the settlement and license agreement are confidential. Mylan CEO Heather Bresch commented, "There is an unmet need for access to more affordable versions of biologic products such as trastuzumab. We look forward to enhancing access to this important treatment option, which complements our comprehensive cancer care offerings, in the U.S. and around the world. With 16 biosimilar products in development, we believe Mylan has one of the industry's broadest portfolios of biosimilars and that we will be a leader in bringing high-quality biosimilar products to market given our ability not only to develop and manufacture such complex products, but also to navigate the intricate regulatory and legal environment and successfully commercialize these products on a global basis." Mylan's proposed biosimilar trastuzumab is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar trastuzumab in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world. In the U.S., Mylan's Biologics License Application (BLA) for proposed biosimilar trastuzumab is currently under review by FDA. The anticipated FDA goal date set under the Biosimilar User Fee Act (BsUFA) is Sept. 3, 2017. Mylan currently markets its trastuzumab products in 14 emerging markets and has submissions pending in the European Union and several additional emerging markets, in addition to the U.S.

FDA Approves First Biosimilar for Cancer Treatment  Jason Harris Published Online: Thursday, Sep 14, 2017 ABP-215 (bevacizumab-awwb; Mvasi), a biosimilar for bevacizumab (Avastin) developed by Amgen and Allergan, is indicated for the treatment of colorectal, lung, brain, kidney, and cervical cancers in adult patients. A biosimilar is a biological product that is demonstrated to be highly similar to an already-approved biological product, and that has no clinically meaningful differences in terms of safety, purity and potency from the reference product. "Bringing new biosimilars to patients, especially for diseases where the cost of existing treatments can be high, is an important way to help spur competition that can lower healthcare costs and increase access to important therapies," FDA Commissioner Scott Gottlieb, MD, said in a press release. "We'll continue to work hard to ensure that biosimilar medications are brought to the market quickly, through a process that makes certain that these new medicines meet the FDA's rigorous gold standard for safety and effectiveness."

ABP-215 is approved for: • First- or second-line treatment of metastatic colorectal cancer, in combination with 5-fluorouracil-based chemotherapy • Second-line treatment of metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for patients who progressed on first-line bevacizumab • First-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous non–small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel • Glioblastoma, as a single agent for patients with progressive disease following prior therapy • Metastatic renal cell carcinoma, in combination with interferon alfa • Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan

There are several pending applications for biosimilars to treat cancer awaiting FDA consideration, including one for MYL-1401O, a biosimilar for trastuzumab (Herceptin). The FDA is expected to rule on a biologics license application for MYL-1401O to treat HER-positive breast cancer, HER2-positive gastric cancer, and gastroesophageal junction cancer by the end of this year. In July, the FDA's Oncologic Drugs Advisory Committee voted 17-0 to recommend approval of ABP-215. Some committee members were concerned at the time about recommending approval for all 6 indications because all the data presented came from patients with advanced/metastatic NSCLC. They eventually determined that the pharmacokinetic (PK) data and method of action were consistent enough to warrant their support. ODAC reviewed data from a pair of studies, the 3-arm, single-dose PK study 20110216 that compared ABP-215 with US- and EU-approved bevacizumab, and a comparative clinical study, 210120265. The second study compared ABP-215 and EU-approved bevacizumab in patients with advanced/metastatic NSCLC to support the demonstration of no clinically meaningful differences in terms of response, safety, purity, and potency. In the PK study, 68 patients were assigned to ABP-215 and 67 each were assigned to the bevacizumab groups. All healthy male participants (N = 202) received an infusion of 3 mg/kg. Investigators concluded that the 90% confidence interval (CI) for the ratios of geometric mean of AUC0-∞, AUC0-t, and CMAX demonstrated PK similarity between ABP-215 and US- and EU-approved bevacizumab. CMAX was 98.1 (90% CI, 93.7-102.8) between ABP-215 and US-approved bevacizumab, 102.9 (90% CI, 98.2-107.8) between ABP-215 and EU-approved bevacizumab, and 104.9 (100.1-109.9) between US-approved bevacizumab and EU-approved bevacizumab. Study 20120265 was a randomized, double-blind study comparing ABP-215 (n = 328) and EU-approved bevacizumab (n = 314) in patients with advanced NSCLC. All patients received an infusion of 15 mg/kg every three weeks in combination with 6 AUC carboplatin and 200 mg/m2 paclitaxel for 6 cycles. Overall response rate was 39% in the ABP-215 arm compared with 41.7% for EU-bevacizumab (risk ratio, 0.93; 90% CI, 0.8-1.09). There were 2 complete responses in each group, and 38.4% of the ABP-215 group had partial responses versus 41.1% in the bevacizumab group. Duration of response was 5.8 months for ABP-215 (95% CI, 4.9-7.7) compared with 5.6 months with bevacizumab (95% CI, 5.1-6.3). Forty percent of patients in both groups experienced progression-free survival (PFS) events (HR, 1.03; 95% CI, 0.8-1.34). Median PFS was 6.6 months for ABP-215 (95% CI, 6.3-7.9) versus 7.0 months in the bevacizumab arm (95% CI, 6.6-8.2). Trough serum concentrations (Ctrough) were collected on cycle 1 through cycle 4, and cycle 6 pre-dose to describe the PK of ABP-215 and EU-approved bevacizumab. The study was not intended to evaluate PK similarity between the 2 arms, but investigators observed comparable Ctrough and inter-subject variability. Investigators said safety outcomes were similar to the known toxicity profile of US-approved bevacizumab, and there were no meaningful differences in adverse events (AEs), serious AEs, deaths up to 30 days after last treatment dose, or treatment discontinuations. Reported grade 3/4 AEs were 42% in the ABP-215 arm and 44% in the bevacizumab arm. No grade 3/4 AE exceeded a 2% incidence rate. In a press release, the FDA reported that, as with bevacizumab, ABP-215's label includes a boxed warning regarding an increased risk gastrointestinal perforations, surgery and wound healing complications, and severe or fatal pulmonary, gastrointestinal, central nervous system and vaginal hemorrhage.