(糖尿病藥or癌藥 ??) Metformin二甲雙胍: 延緩肺癌患者靶向藥耐藥時間&逆轉肺纖維化 !!!!!

一片不到一塊錢的糖尿病藥物，竟把肺癌總生存期延長了10個月！ 原創： 覓健肺癌康復圈"聽說二甲雙胍能延緩肺癌患者靶向藥耐藥時間？請問這是真的嗎？"這是一位患者在"肺凡力量"講座上對上海長征醫院腫瘤科臧遠勝教授提出的疑惑。臧遠勝教授："二甲雙胍確實是個'神藥'，最近兩年的學術報告上都有相關的研究，大家可以關注一下。"臧遠勝教授並沒有具體回答，但卻肯定了二甲雙胍的神奇。那麼這個價格很便宜、應用很廣泛的糖尿病傳統用藥究竟能不能延緩靶向藥耐藥時間呢？它在治療肺癌過程中還有哪些神奇的作用呢？小編深度解析了關於二甲雙胍在今年美國臨床腫瘤學會議（ASCO）上的報告以及近日在《Nature Medicine》上發表的一項科學研究，得出了結論——它可以輔助治療肺癌，不僅能提高患者使用靶向藥的時間及療效，還可以逆轉肺纖維化。

二甲雙胍有抗癌作用，還可提高患者對靶向藥的敏感度 二甲雙胍，是世界上使用最廣泛的糖尿病治療藥物，至今已經有50多年的歷史了。意外的是，在最近的研究中，這個用於治療糖尿病患者的藥物搖身一變變成了抗癌新藥。在上個月的ASCO大會上，醫學家Oscar Arrieta發佈了一項研究：對於擁有EGFR突變的非小細胞肺癌患者，二甲雙胍聯合一代、二代的EGFR-TKI能顯著提高EGFR-TKI單獨使用的療效。

研究資料解析：在非小細胞肺癌患者中，LKB1是一種抑癌基因，它的失活常常是癌症發生的原因之一；並且這類腫瘤侵襲性還比較高。而二甲雙胍正是可以通過各種機制來影響抑癌基因LBK1，以達到抗癌的作用。對於肺癌患者，二甲雙胍還可以增加非小細胞肺癌對於TKI的敏感度。

什麼是EGFR-TKI ？很多覓友可能會疑惑，到底什麼是EGFR-TKI呢？EGFR-TKI是一種表皮長因數受體酪氨酸激酶抑制劑的統稱（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）。也就是大家常說的針對EGFR位點突變的靶向藥物。一代的TKI藥物主要有厄洛替尼、埃克替尼、吉非替尼，它們在臨床上有效率能達到70%以上。第二代靶向藥主要有阿法替尼，是靶向EGFR（HER1）及HER2的雙靶點抑制劑。其中，超過一半的患者是因為發生了T790M（就是第790氨基酸由"T"蘇氨酸變成了"M"甲硫氨酸）的二次突變，而發生一代TKI藥物耐藥，針對於此的第三代EGFR-TKI抑制劑奧希替尼也因此誕生。奧希替尼不僅對T790M突變有良好的應對之策，還能透過血腦屏障，可以一定程度上緩解患者腦轉移的症狀。但是在此次的研究中，研究人員只是採取二甲雙胍和一代或者二代的EGFR-TKI聯合來對比研究的，對三代TKI聯合二甲雙胍的研究還沒有展開。這是一項雙盲、隨機且對照安慰劑的二期臨床試驗（NCT03071705），試驗納入了1116名有EGFR突變的晚期非小細胞肺癌患者。他們被分成兩組，一組只接受EGFR-TKI治療，另一組患者接受二甲雙胍+EGFR-TKI的治療。

結果振奮人心——接受二甲雙胍聯合治療的患者較單藥治療的患者中位無進展生存期超出了4個月（14.0月vs 10.0月）！不僅如此，總生存週期延長了接近10個月！對於腫瘤的緩解程度也大大提高，客觀緩解率達到67.4% vs. 47.5%。與單獨使用EGFR-TKI的總反應率為54.3%相比，二甲雙胍和EGFR-TKI聯合使用的總反應率顯著較高，達到了71%。這些資料非常明顯地告訴我們，二甲雙胍是具有一定的抗癌作用的。因為對於有EGFR突變的非小細胞肺癌患者，在使用EGFR靶向藥物中加入二甲雙胍可以明顯提高患者的PFS（無進展生存期）、OS（總生存期）和ORR（客觀緩解率）。雖然，一代TKI聯合使用二甲雙胍的研究資料優勝于單藥，但是使用同時要密切觀察藥物的安全性。還要特別注意的是，研究中未納入第三代EGFR-TKI藥奧希替尼。2

二甲雙胍可逆轉肺纖維化 二甲雙胍不僅僅是在抗癌的方面有一定的作用，經過科學家的研究，它還有助於逆轉已經形成的肺纖維化。肺癌患者的肺部本就脆弱，尤其是經過放療的患者，很可能會發生肺纖維化，也就是說大量的成纖維細胞增殖聚集在肺部，這樣可能造成原有的肺泡組織損傷或者在肺部形成疤痕。就像我們皮膚表皮被割傷後，再怎麼癒合都難以和以前一模一樣了，這些難看的疤痕在我們的手上胳膊上可能只是看起來難看，並不影響功能。但是在肺部，如果肺纖維化範圍較大，會影響人體呼吸功能，表現為乾咳、進行性呼吸困難（自覺氣不夠用）等症狀，這對於肺癌患者簡直就是雪上加霜。近日在《Nature Medicine》上發表了一項科學研究：美國阿拉巴馬大學伯明罕分校(University of Alabama at Birmingham， UAB)的研究人員發現二甲雙胍居然可以逆轉已經產生的肺纖維化(pulmonary fibrosis)。研究中，研究人員先使用化療藥物讓小鼠產生肺纖維化，在服用化療藥物三周之後小鼠肺部已經產生了嚴重的纖維化。這時，研究人員讓小鼠服用二甲雙胍。奇跡出現在服用二甲雙胍 5周之後，研究者們發現二甲雙胍竟然可以加快已經產生的纖維化組織的消融速度。經過這個研究，在概念上已經證明了使用二甲雙胍或其它藥物啟動AMPK能夠啟動促進纖維化組織消融的信號通路，從而最終加快肺纖維化部分的消融速度。二甲雙胍也可能因此成為治療進行性纖維化疾病的新秀！但目前，這項研究僅停留在動物試驗階段，到真正的人體臨床使用還有一段距離。但無論如何，對於肺癌的患者，可能在將來，會不用太再懼怕放化療引起的肺纖維化和由此造成的肺部損傷了！

編後：二甲雙胍確實是神藥，在內分泌領域既便宜又好用，目前在腫瘤領域它也顯示了神奇的功效。但大家一定不要盲從，因為這兩項臨床試驗只是在一定程度上探索了二甲雙胍的藥理作用，且不說是否覆蓋了亞洲人群，只是肺纖維化的試驗還尚且停留在動物試驗階段。廣大的覓友興奮之余一定要保持理智，因為所有腫瘤用藥都要在醫生的指導下使用，切不可擅自購買二甲雙胍聯合使用。在不遠的未來，相信醫學家會把二甲雙胍研究得更加透徹，在保證了安全性和有效性的基礎下應用，才是我們應對肺癌的正確選擇。

オリザ油化ではツバメの巣エキスについて、タイトジャンクション形成促進作用を有する旨の特許を取得したことを発表した（特許番号6358692号）

( エーブィエ バイオファーム)2018/7/13タイトジャンクション（TJ）とは、隣り合う細胞同士の隙間を接着させ、細胞と細胞の隙間を水やイオンが自由に行き来しないようにする役割を持つ構造のこと。表皮TJ は体内の水分が過剰に漏れださないよう、また体外からの異物を入り込ませないようバリア機能を果たしている。TJ 構成タンパクであるクローディンやオクルディンは細胞膜上に存在し、隣り合う細胞と細胞の間をジッパーで閉じ合わせるように細胞間の隙間をシールしている。そのため、TJの形成を促進することにより、皮膚の弾力等の改善効果が期待できる。同社では、ツバメの巣エキスを使ってタイトジャンクション形成促進作用を調べた。正常ケラチノサイトを培養し、TJ構成タンパクのなかでも特に皮膚バリア機能に関与すると考えられるクローディン１・クローディン４の遺伝子・タンパク発現を見たところ、ツバメの巣エキス0.1％以上の添加で各遺伝子・タンパクともに発現を増強させることを確認した。また正常ケラチノサイトのクローディン4 タンパクを蛍光色素で染色し、ツバメの巣エキスによる影響を蛍光顕微鏡で観察した結果、無添加と比較して0.1％添加では細胞間をシールするようにクローディン4 の発現が確認された。以上の結果により同社はツバメの巣エキスにおけるタイトジャンクション形成促進作用を有することを見出し、特許取得に至った。ツバメの巣エキスは主として美肌向上素材として上市されたもの。広範な細胞の分化や増殖に影響を与える上皮細胞増殖因子（Epidermal Growth Factor；EGF）を含有し、美肌作りに欠かせない皮膚細胞（ケラチノサイト、線維芽細胞）の増殖効果を有し、創傷治癒効果を有することを自社データで見出している。これにより、日本のみならず世界で数々の採用実績を持っている。今回のタイトジャンクション形成促進作用における特許の取得により、皮膚バリア機能を有する素材として期待することができ、国内外の更なるグローバルな拡販も期待されている。

《Journal of Clinical Oncology》日本Eisai發表 Halaven治療晚期脂肪肉瘤 (天然軟海綿素B合成類似物)

總生存期翻倍！衛材抗腫瘤新藥3期結果優異 原創： 更多資訊 藥明康得 日本衛材藥業（Eisai）今天公佈了一項關鍵3期臨床研究的亞組分析結果，研究比較了甲磺酸艾瑞布林（eribulin mesylate）（Halaven注射劑）與達卡巴嗪（dacarbazine）在之前接受過治療的晚期脂肪肉瘤（LPS）和平滑肌肉瘤（LMS）患者中的療效。這項發表在《Journal of Clinical Oncology》的研究309亞組分析，支持了FDA批准的Halaven治療晚期脂肪肉瘤患者。軟組織肉瘤（STS）是從骨或軟骨以外的身體結締組織細胞，如脂肪，肌肉，神經，纖維組織和血管發育而來的癌症。每年大約有12000例新的軟組織肉瘤病例被診斷出來。脂肪肉瘤指由脂肪細胞或其前體產生的腫瘤，可出現在身體的任何地方。脂肪肉瘤約占軟組織肉瘤總數的17％。患有包括脂肪肉瘤在內的許多STS患者可以完全手術切除，但對於不能通過手術治癒或腫瘤細胞轉移擴散至體內其他部位的患者預後較差，局部或遠處轉移的患者5年相對生存率分別只有54％和16％。Eisai發現和開發的艾瑞布林是從Halichondria okadai海綿中提取的天然產物軟海綿素B的一種合成類似物。這種微管動力學抑制劑，主要通過微管蛋白的機制作用，導致長時間的和不可逆的有絲分裂阻塞，最終使細胞凋亡。研究309是一項隨機、開放標籤、多中心、主動對照的3期臨床試驗，在21天療程的第1天和第8天對患者靜脈注射1.4毫克/平方米的Halaven，或在第1天靜脈注射850至1200毫克/平方米達卡巴嗪（n = 452）。這些患者患有無法切除的局部晚期或轉移性平滑肌肉瘤或脂肪肉瘤，接受過至少兩種全身性化療（其中一種為包括蒽環類藥物），並且接受最新化療方案6個月後疾病發生進展。在這項研究中，接受Halaven與接受達卡巴嗪的患者相比總生存期（OS）提高，所有接受Halaven治療的患者中位OS為13.5個月，接受達卡巴嗪的患者為11.3個月（HR 0.75; 95％CI：0.61-0.94; P = 0.011）。Halaven和達卡巴嗪組的無進展生存期（PFS）均為2.6個月 （HR 0.86; 95％CI：0.69-1.06）。根據對預先計畫的探索性亞組分析，Halaven的治療效果僅限於脂肪肉瘤患者。Halaven對晚期或轉移性平滑肌肉瘤患者沒有療效。對脂肪肉瘤患者進行組織學亞組分析顯示，與達卡巴嗪相比，Halaven組的中位OS有所改善（HR：0.511; 95％CI：0.35 - 0.75; P <0.001）。接受Halaven治療的患者中位OS為15.6個月（95％CI：10.2 - 18.6個月）（n = 71），而接受達卡巴嗪的患者為8.4個月（95％CI：5.2 - 10.1個月）（n = 72）。接受Halaven治療的脂肪肉瘤患者中位無進展生存期與接受達卡巴嗪的患者相比更長（2.9個月相比1.7個月; HR：0.52; 95％CI：0.35 -0.78; p = 0.0015）。在研究309的亞組分析中觀察到的不良事件與已知的Halaven概況一致。哈佛大學醫學院教授，丹娜·法伯癌症研究所（Dana-Farber Cancer Research Institute）肉瘤和骨腫瘤中心主任George Demetri博士表示："這一亞組分析的結果進一步證實，艾瑞布林是這些侵襲性難治性脂肪肉瘤患者的有效治療選擇。軟組織肉瘤，如脂肪肉瘤，通過其他療法治療病情出現進展和轉移後非常有挑戰性。艾瑞布林是第一個在晚期脂肪肉瘤的3期臨床試驗中，顯著改善總生存期的單藥。"衛材腫瘤業務部門的首席臨床官和首席醫務官Alton Kremer博士說："該亞組分析結果顯示，接受艾瑞布林的晚期脂肪肉瘤患者與接受達卡巴嗪的患者相比，總體生存期較長，這表明了艾瑞布林作為這些患者治療選擇的重要性。"我們期待這款新藥能夠為更多晚期脂肪肉瘤患者延長生命，改善生活品質。

參考資料：[1] Eribulin Mesylate Nearly Doubles Overall Survival in Previously Treated Patients with Advanced Liposarcoma in Subanalysis  Published in the Journal of Clinical Oncology[2] 衛材官網

(Cell Reports) 癌細胞逃脫PD-L1/PD-1 治療 新發現: 自我中和PD-L1/PD-1 (無靶)

Biologists discover process that neutralizes tumors July 10, 2018, University of California - San Diego The molecular "brake" known as PD-1 can bind and neutralize the same tumor cell, instead of an opposing tumor cell. Credit: Hui Lab, UC San Diego Researchers from the University of California San Diego have identified an unexpected mechanism that could help determine whether a cancer patient will respond to immunotherapy. Ideally, the immune system identifies tumors as threatening elements and deploys immune cells (T cells) to find and kill them. However, tumor cells have evolved to employ a protein called PD-L1 to blind T cells from carrying out their functions and evade immune defenses. PD-L1 protects tumor cells by activating a "molecular brake" known as PD-1 to stop T cells. In important therapeutic progress, antibodies developed to block PD-L1/PD-1 have been clinically proven to benefit certain cancer patients. Yet why some patients don't respond to such therapy has remained a mystery. Now, UC San Diego's Yunlong Zhao, Enfu Hui and their colleagues at the University of Chicago and the Nanjing Medical School in China have uncovered some clues. As described July 10 in the journal Cell Reports, the researchers discovered an unexpected twist in the tumor versus T cell battle. Some tumor cells display not only their PD-L1 weapon, but also the PD-1 "brake." This simultaneous expression leads PD-1 to bind and neutralize PD-L1 on the same tumor cell. Thus, the PD-L1 on these tumor cells can no longer engage the PD-1 brake on T cells."It's a very exciting finding," said Hui. "Our study uncovered an unexpected role of PD-1 and another dimension of PD-1 regulation with important therapeutic implications."This study suggests that patients with high levels of PD-1 on tumor cells may not respond well to the blocking antibodies because the PD-1 pathway is self-canceled. In these patients, mechanisms other than PD-L1/PD-1 are likely employed by the tumors to escape from immune destruction. Looking to extend the immunotherapy potential of the finding, Hui and his colleagues are now seeking to determine additional mechanisms of "self-cancellation" at the interface of the tumor and immune cells."We think that our finding is the tip of the iceberg," said Hui, recently named a Pew Biomedical Scholar and Searle Scholar. "We speculate that self-cancellation is a general mechanism to regulate immune cell function. Understanding these processes more clearly will help develop better immunotherapy strategies and more reliably predict whether a patient will respond or not."

大鵬薬品3億美金 拿下AB928亞洲權力 (中國除外): Antagonist adenosine 2a and 2b receptors 瞄準免疫抗體藥合併使用 !!!

大鵬薬品　新たながん免疫療法の開発に参入 Arcus Bioscience社のアデノシン受容体阻害剤をアジアで独占的に開

Arcus Biosciences Announces That Taiho Pharmaceutical Has Exercised Its Option to Develop and Commercialize AB928 in Its Territories July 12, 2018  HAYWARD, Calif.--(BUSINESS WIRE)--Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, today announced that Taiho Pharmaceutical Co., Ltd. (Taiho) exercised its option under the Option and License Agreement entered into in September 2017 (Taiho Agreement) to obtain an exclusive development and commercialization license to the Company's adenosine receptor antagonist program, which includes AB928 and back-up compounds, in Japan and certain other territories in Asia (excluding China). In addition to an option exercise payment, Arcus is eligible to receive clinical and regulatory milestones totaling up to $130 million as well as commercialization milestones and royalties on net sales for this program."Our collaboration with Arcus is an important relationship for Taiho, as we expand our oncology franchise in Japan and other important territories in Asia" "We are pleased that Taiho has decided to exercise their option just as we are initiating our Phase 1/1b program for AB928 in the U.S. and Australia," said Terry Rosen, Ph.D., CEO at Arcus. "We believe that Taiho's decision to exercise their option to this program at this early stage reflects their recognition that AB928, the first adenosine 2 receptor antagonist in clinical development to be specifically designed for the oncology setting, has significant potential to treat a broad array of tumor types. We are confident that Taiho's expertise and capabilities in oncology, as well as their experience co-promoting Keytruda® in Japan, make them the ideal partner to bring AB928 to cancer patients as quickly as possible in their territories.""Our collaboration with Arcus is an important relationship for Taiho, as we expand our oncology franchise in Japan and other important territories in Asia," said Masayuki Kobayashi, President and Representative Director at Taiho. "We have been impressed by Arcus's small molecule drug discovery capabilities, the quality of their clinical candidates and the scientific rigor of their candidate selection process. AB928 appears to have the ideal properties to block the immuno-suppressive effects of adenosine in the tumor microenvironment. We look forward to working with Arcus on the development of this important new immuno-oncology mechanism for the treatment of multiple tumor types."

About the Taiho Agreement Arcus and Taiho entered into an option and license agreement in September 2017. Taiho will provide $35.0 million of cash payments to Arcus during the first three years of the agreement in exchange for an exclusive option, over a five-year period, to in-license the development and commercialization rights to clinical stage product candidates from Arcus's portfolio for Japan and certain other territories in Asia (excluding China). Taiho is obligated to pay an option exercise payment for each option exercise of between $3.0 million to $15.0 million, with the amount dependent on the development stage of the applicable Arcus program for which the option is exercised. In addition, Taiho is obligated to pay to Arcus clinical, regulatory and commercialization milestones up to $275.0 million per program as well as royalties ranging from high single digits to mid-teens on net sales in Taiho's territories.

About AB928 AB928 is an orally bioavailable, highly potent antagonist of the adenosine 2a and 2b receptors. The activation of these receptors by adenosine interferes with the activity of key populations of immune cells and inhibits an optimal anti-tumor immune response. By blocking these receptors, AB928 has the potential to reverse adenosine-induced immune suppression within the tumor microenvironment. AB928 was designed specifically for the oncology setting, with a profile that includes potent activity in the presence of high concentrations of adenosine and a minimal shift in potency due to non-specific protein binding, both essential properties for efficacy in the tumor microenvironment. AB928 has other attractive features, including high penetration of tumor tissue and low penetration through the healthy blood-brain barrier. In a Phase 1 trial in healthy volunteers, AB928 has been shown to be safe and well tolerated and to have pharmacokinetic and pharmacodynamic profiles consistent with a once-daily dosing regimen.

About Arcus Biosciences Arcus Biosciences is a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies. Arcus has several programs targeting important immuno-oncology pathways, including a dual adenosine receptor antagonist AB928, which will be evaluated in combination with other agents in multiple tumor types in a Phase 1/1b program, and an anti-PD-1 antibody, which is being evaluated in a Phase 1 trial and will be tested in combination with Arcus's other product candidates. Arcus's other programs include a small molecule inhibitor of CD73 and an anti-TIGIT antibody, both of which are in IND-enabling studies. Arcus has extensive in-house expertise in medicinal chemistry, immunology, biochemistry, pharmacology and structural biology. For more information about Arcus Biosciences, please visit www.arcusbio.com.

 ( エーブィエ バイオファーム)・販売する権利を取得 大鵬薬品工業株式会社 (本社：東京都千代田区、代表取締役社長：小林将之、以下「大鵬薬品」)は、革新的ながん免疫療法の創薬・開発に注力している米国のArcus Biosciences社 (以下、｢Arcus社｣) が開発中のアデノシン受容体阻害剤AB928とそのバックアップ化合物を、アジア (中国除く) で独占的に開発・販売する権利を取得したことをお知らせいたします。これは、2017年9月に両社が締結したオプション契約に基づき、大鵬薬品がオプション権を行使したものです。AB928は、がん微小環境における免疫抑制メカニズムに関与すると考えられているアデノシン受容体のサブタイプA2aおよびA2bを選択的に阻害する低分子化合物です。アデノシン受容体阻害剤がさまざまな疾患で開発されている中で、AB928はがんをターゲットに設計されたアデノシン受容体阻害剤であり、経口剤としてArcus社が開発を進めています。アデノシン受容体阻害剤は、今後がん免疫療法における新たな治療法になる可能性があるとして期待されています。Arcus社はAB928に関して、健常人における第I相臨床試験を既に実施しており、AB928の安全性、忍容性および薬物動態が確認されています。また、AB928と化学療法やPD-1抗体などさまざまな併用療法を複数のがん種において検討する第I相臨床試験を本年開始しました。Arcus社は本試験を通して、AB928の安全性等をさらに検討する予定です。大鵬薬品は今後Arcus社とともに最適な治療法をできるだけ早期に確立、提供することを目指しています。大鵬薬品は、今後もがん治療において、患者さんや医療関係者により一層貢献できるよう努めてまいります。

Arcus receives FDA approval for Phase l/lb trial of AB928 combination，12 JUNE 2018  Arcus Biosciences has received approval from the US Food and Drug Administration (FDA) validating its two new product candidates, AB928 and AB122. The approval is based on the investigational new drug (IND) applications submitted by Arcus and has enabled the company to conduct its proposed Phase l/lb trial of AB928 in combination with other agents, including AB122 and chemotherapy. The trial aims to examine the safety, tolerability and preliminary efficacy of the AB928 combination for the treatment of patients with breast and gynaecologic malignancies. It will include a dose-escalation phase to determine the optimal dose of AB928 to be combined with fixed doses of AB122 and with each of the three different immunogenic cell death (ICD) inducing chemotherapy regimens. After selecting the recommended dose of AB928 for each combination, the trial will enrol expansion cohorts to investigate AB928 in combination with AB122 or chemotherapy to begin three tumour-specific trials for breast, gynaecologic and gastrointestinal malignancies, as well as lung cancer and renal cell carcinoma (RCC). “If approved, the company will start trials of AB928 combinations in gastrointestinal malignancies, non-small cell lung cancer (NSCLC) and RCC.” Each of the trials will allow Arcus to add new AB928 combination arms in the future. In the dose-escalation portion of the trials, the company will evaluate the evidence of immune engagement to enable a mechanistic understanding of early clinical responses and others. Results from the dose-escalation portion of the Phase l/lb trial are scheduled to be available in the first half of next year. In addition, Arcus plans to submit two additional IND applications this month. If approved, the company will start trials of AB928 combinations in gastrointestinal malignancies, non-small cell lung cancer (NSCLC) and RCC.Arcus has also been completing the regulatory process to investigate the combination of AB928 and AB122 in patients in Australia and expects to dose its first patient with this combination soon.

浩鼎300萬美金購 OBI-3424 (TH-3424,Threshold)開花待果：未含中/日/印/新/馬/泰/土

Threshold Pharma completes sale of TH-3424 to OBI Pharma for $3M，Jun. 22, 2017 Threshold Pharmaceuticals (NASDAQ:THLD) finalizes the sale certain rights to cancer candidate TH-3424, a small molecule prodrug, to Taiwan's OBI Pharma for total consideration of $3M.

Eighteen months after being poleaxed by the failure of its lead drug, Threshold Pharma's recovery efforts—including a planned merger—are looking brighter thanks to a licensing deal with Taiwan biotech OBI Pharma. OBI is buying rights to TH-3424—billed by Threshold as a first-in-class drug targeting cancers that overexpress the enzyme aldo-keto reductase 1c3 (AKR1C3)—for an undisclosed, one-off payment. The Taiwan firm gets rights to the drug in all world markets, but excluding several Asian countries including China, Japan and India. The drug, which will be renamed OBI-3424, is a prodrug that releases a tumor cell-killing alkylating agent in the presence of AKR1C3, seen in a number of hard-to-treat cancers, including liver and prostate cancer as well as T-cell acute lymphoblastic leukemia. OBI says it plans to file for approval to start trials in the U.S. early next year. In December 2015, Threshold was hit by the failure of its lead cancer drug evofosfamide (TH-302)—formerly partnered with Merck KGaA—in two phase 3 trials, and the following year a second candidate called tarloxotinib flunked a phase 2 proof-of-concept study in skin cancer and was dropped. Threshold still hasn't wholly given up on the drug, as it maintains it saw an improvement in overall survival among a subset of Asian patients in Merck's MAESTRO study. Discussions with the Japanese authorities about the possibility of a marketing application based on the data came to naught, however, and the company has been informed it has to carry out another trial. For now, its focus on evofosfamide is on a clinical trial looking at the drug in combination with Bristol-Myers Squibb's checkpoint inhibitor Yervoy—which is being carried out in collaboration with MD Anderson Cancer Centre—and on investigator-led trials of the drug alongside angiogenesis inhibitor drugs. In a recent SEC filing, Threshold said it had resources on hand for another 12 months or so of operations and was looking at partnering TH-3424 and possibly another early-stage candidate—PET imaging agent HX4—to help fund future development of evofosfamide. The embattled biotech called in strategic advisers in the wake of the phase 3 failure to work out which way to turn, and in March agreed a merger with Molecular Templates, pooling their respective cancer pipelines with a $20 million venture cash injection pledge from Longitude Capital. That deal hasn't yet gone through, but if it comes to fruition will see the two companies operate under the Molecular Templates banner, adding the latter's lead candidate MT-3724, an anti-CD20 drug in a phase 1 trial that has shown activity in heavily pre-treated non-Hodgkin lymphoma (NHL) patients, to their joint pipeline. With the OBI licensing deal in hand, Threshold's appeal to its would-be merger partner looks likely to have gone up.

Threshold Pharmaceuticals and National Cancer Institute to Collaborate on Drug Candidate TH-3424 December 19, 2016 08:02 ET | Source: Threshold Pharmaceuticals, Inc.-- Preclinical studies will explore the effects of TH-3424 against T-cell acute lymphoblastic leukemia cancer cell lines with high AKR1C3 expression --SOUTH SAN FRANCISCO, Calif., Dec. 19, 2016 (GLOBE NEWSWIRE) -- Threshold Pharmaceuticals, Inc. (NASDAQ:THLD), a clinical-stage biopharmaceutical company developing novel therapies for cancer, today announced that it has entered into a collaboration with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to study TH-3424, the company's new drug candidate for the treatment of cancer. The collaboration will explore the effects of TH-3424 against T-cell acute lymphoblastic leukemia (T-ALL) xenograft cell lines with high AKR1C3 expression. The studies will be conducted through the NCI-funded Pediatric Preclinical Testing Consortium (PPTC). Under this collaboration, Threshold will supply TH-3424, and the NCI will fund the studies that will be conducted at the PPTC leukemia research program led by Professor Richard Lock of Children's Cancer Institute (Sydney, Australia). TH-3424 is a novel, small-molecule compound invented at Threshold with potentially broad anticancer properties. TH-3424 is activated by the enzyme AKR1C3, which is over-expressed in a number of different cancers, to release a cytotoxic agent directly to the tumor. Preclinical results showed that TH-3424 is effective in a variety of human xenograft models of cancer, as initially presented at the American Association for Cancer Research Annual Meeting in April 2016."TH-3424 is designed to be activated by AKR1C3 inside tumor cells and spare healthy tissue," said Barry Selick, Ph.D., CEO of Threshold Pharmaceuticals. "Evaluating this compound in collaboration with the NCI enables us to expand the scope of our investigations to better inform our strategy for potential future clinical studies for this molecule."

About TH-3424 TH-3424 is a small-molecule drug candidate being evaluated for the potential treatment of hepatocellular cancer (HCC), castrate resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemias (T-ALL), and other cancers expressing high levels of aldo-keto reductase family 1 member C3 (AKR1C3). Tumors overexpressing AKR1C3 can be resistant to radiation therapy and chemotherapy and immunotherapy. TH-3424 is a prodrug that selectively releases a potent DNA cross-linking agent in the presence of AKR1C3. Investigational New Drug (IND)-enabling toxicology studies are being done in collaboration with Ascenta Pharmaceuticals, Ltd.

OBI-3424(TH-3424) 為一化療前驅型新藥，它會選擇性地在AKR1C3酵素作用下，釋出強效DNA烷基化劑；這種選擇性的啟動機制﹐OBI-3424與傳統烷基化藥物，如cyclophosphamide 與ifosfamide有很大區別。根據雙方合約，Threshold將會移轉OBI-3424所有權。及臨床前和製造相關數據予浩鼎；浩鼎將支付Threshold一次性款項，未來則不需要另行支付Threshold任何款項或權利金。這項轉讓除了亞洲區部份國家（不包括大陸、香港、澳門、台灣、日、韓、新加坡、馬來西亞、泰國、土耳其及印度）外，浩鼎將取得OBI-3424的全球智慧財產及其商務、開發與生產權利。根據文獻，AKR1C3在多種抗藥性及難治癌症的腫瘤細胞中均有過度表現，舉例來說﹐大多數肝細胞癌病人即有AKR1C3高度表現。

延伸一窺: 深圳艾衡昊医药(仙瞳资本)+台灣浩鼎: 癌藥AST-3424（OBI-3424）: FDA准進臨床I/II期 !

(Orion Pharma) 挺進 三期運用: 肌萎縮 脊髓側索硬化症（Amyotrophic lateral sclerosis，縮寫為ALS）呼吸治療臨床: Simdax (levosimendan心衰竭藥)

Orion takes repurposed heart failure drug into phase 3 for ALS by Phil Taylor | Jul 6, 2018 Finnish drugmaker Orion Pharma is pressing ahead with a pivotal trial for its amyotrophic lateral sclerosis drug ODM-109, despite mixed results in a phase 2 trial. The first patients have now been recruited into its phase 3 trial of ODM-109—an oral formulation of Orion's heart failure drug Simdax (levosimendan)—in the hope of showing that it can help support breathing function in patients with the devastating neurodegenerative disease. Orion said it plans to enroll 450 subjects in the placebo-controlled trial at sites in Europe, North America and Australia, with patients taking the drug for a year to see if it can slow down the respiratory difficulties that are the usual cause of death in ALS. In a phase 2 trial involving 66 ALS patients, ODM-109 missed its primary endpoint of an improvement in sitting slow vital capacity (SVC)—a measure of lung function—but was able to improve SVC when patients were lying on their backs."If the results of the [phase 3] trial are positive, the aim is to file for marketing authorization in the U.S. and Europe," according to Orion. Results from the study are due in 2020.For years, ALS only had one FDA-approved therapy—Sanofi's Rilutek (riluzole)—which has limited efficacy, with most patients still dying three to five years after diagnosis. In 2017, Mitsubishi Tanabe got FDA approval for free radical scavenger Radicava (edaravone), after filing the drug at the agency's request, based on a six-month study that showed a slower decline in physical function compared to placebo. Not all are convinced by the data for Radicava just yet, however, and it's widely recognized that other new therapies are desperately needed that can definitively slow down the loss of function in ALS. Prospects for a new therapy for ALS took a big knock last year after the high-profile failure in phase 3 of Cytokinetics' tirasemtiv, despite major tweaks to the trial protocol, but the company is hoping a clutch of new drugs, along with ODM-019, could end the drought. Another European biotech, France's AB Science, had a marketing application for its masitinib drug for ALS provisionally turned down in Europe in April, with regulators saying a phase 2/3 trial that showed efficacy at the highest dose used wasn't sufficient to support approval. The company has filed additional information to the EMA and is planning a confirmatory trial that it hopes will also support a U.S. filing. Meanwhile, some of the other players in the field include Biogen and Ionis, which have a SOD1-targeting antisense drug called BIIB067 in phase 1/2 trials, Amylyx with AMX0035 (sodium phenylbutyrate and tauroursodeoxycholic acid) in phase 2 with results due later this year, and new startup QurAlis.

Levosimendan(治療慢性心衰竭) 藉由增加細胞內鈣離子與心肌的troponin C結合之敏感度而導致心臟收縮，因此，不會損害心室放鬆。此外，Levosimendan 打開位於血管平滑肌上對ATP敏感的鉀離子管道，藉此誘導全身、冠狀動脈及全身靜脈血管的擴張。體外試驗證實 Levosimendan為具選擇性的 phosphodiesterase III 抑制劑，但並不清楚其在治療濃度下的相關性。對於患有心衰竭的患者，Levosimendan之心收縮力增強及血管放鬆作用，可導致收縮力的增加，並且降低前負荷與後負荷，而不會對舒張期功能有不良的效應。在PTCA或血栓溶解之後，Levosimendan會活化患者之心肌。 Simdax輸注可增加心臟手術後病人的冠狀動脈血流量和改善心衰竭病人的心肌灌注量，但不會增加心肌的氧氣消耗量。使用Simdax輸注治療，會明顯的降低鬱血性心衰竭病人循環系統中之 endothelin-1濃度。在建議的輸注速率下，則不會增加血漿中catecholamine的濃度。

肺癌 免疫治療如何精準治療: PD-L1 高低不重要？！癌突變壓力(Tumor mutation burden) 成關鍵？

CheckMate 227 trial in advanced lung cancer by Dr. Borghaei.

Tumor mutation burden matters than PD-L1: 

1, regardless of the level of PD-L1 expression or histology, patients who had this biomarker of a high tumor mutational burden above a certain threshold had a better outcome compared to patients with a relatively low tumor mutational burden, in terms of PFS and response rate, with the combination of ipilimumab plus nivolumab compared to chemotherapy alone.

2, even in this population of PD-L1–negative patients, a high tumor mutational burden was associated with better PFS and better duration of response with ipilimumab plus nivolumab than either chemotherapy alone or nivolumab plus chemotherapy.

3, patients have PD-L1–negative tumors and a low tumor mutational burden, the addition of nivolumab to chemo or ipilimumab to nivolumab didn’t really provide additional benefit over chemotherapy alone.

Side effects: add nivolumab to chemotherapy there are more side effects compared to chemotherapy alone. But interestingly, in this analysis, the group of patients that got ipilimumab plus nivolumab had a lower percentage of the grade 3 and 4 severe side effects. In the chemotherapy-plus-nivolumab group, the grade 3 and 4 toxicities were close to 50%—but only 25% and 35% of patients in the ipilimumab-plus-nivolumab group and chemotherapy-alone group experienced these toxicities.

*Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

* Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs. This results in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and and plays a key role in in tumor evasion from host immunity. 

Glutathione peroxidase can dramatically reduce risk of cardiovascular disease

Published on June 16, 2012University of Minnesota Medical School researchers have collaborated with the School of Public Health and discovered an enzyme that, when found at high levels and alongside low levels of HDL (good cholesterol), can dramatically reduce the risk of cardiovascular disease.The enzyme - glutathione peroxidase, or GPx3 - is a natural antioxidant that helps protect organisms from oxidant injury and helps the body naturally repair itself. Researchers have found that patients with high levels of good cholesterol, the GPx3 enzyme does not make a significant difference. However, those patients with low levels of good cholesterol, the GPx3 enzyme could potentially be a big benefit. The enzyme's link to cardiovascular disease may also help determine cardiovascular risk in patients with low levels of good cholesterol and low levels of the protective GPx3.The new research, published today by PLoS One, supports the view that natural antioxidants may offer the human body profound benefits."In our study, we found that people with high levels of the GPx3 enzyme and low levels of good cholesterol were six times less likely to develop cardiovascular disease than people with low levels of both," said lead author Jordan L. Holtzman, M.D., Ph.D., professor of pharmacology and medicine within the University of Minnesota Medical School. "This GPx3 enzyme gives us a good reason to believe that natural antioxidants like GPx3 are good for heart health."The combination of low HDL and low GPx3 affects an estimated 50 million people - one in four adults - in the U.S. This condition can lead to fatal heart attacks and strokes. Researchers continue to look for new ways to better predict who is at risk for these diseases and how patients can limit the impact of the disease once it's diagnosed.