2015-4-1国内、国际新药信息汇总 - 药群论坛

国家食药监总局（CFDA）网站4月1日信息显示，海正药业（600267.SH）重磅新药“安佰诺”（注射用重组人II型肿瘤坏死因子受体-抗体融合蛋白）申报状态变更为“在审批”，这意味着该药品已递交CFDA签字，进入审批最后的流程环节，有望在1-2月内获批。

　　值得一提的是，此前海正药业内部人士曾向大智慧通讯社（DZH_NEWS）表示，从安佰诺本身来说，已经没有什么问题，公司对拿到最后的批文抱有信心。

　　安佰诺是海正药业首个单抗药物，该药物于2011年完成III 期临床，并于2013年7月12日申报生产。2014年4月，公司向药监局递交补充资料，并于9月同时进入产品注册现场检查和生产车间GMP认证。

　　公开资料显示，安佰诺的原研药是辉瑞公司旗下的恩利(商品名)，后者是全球首个全人源化的、第一个用于治疗类风湿关节炎和强直性脊柱炎的可溶性肿瘤坏死因子拮抗剂，全球市场年销售金额超80亿美元。

　　海正药业主营抗生素、抗肿瘤药物原料药，正谋划从单一的原料药向高端制剂转型，基因药物和大分子药物则是公司转型中的一个重要板块。

Actelion制药公司肺动脉高压药物Opsumit（macitentan）近日在监管方面收获第3个重大里程碑，该药近期获日本批准，作为一种每日一次的口服药物，用于肺动脉高压（PAH）的治疗，以延缓病情进展。此前，Opsumit已于2013年底接连获批在美国和欧盟2大主要市场上市。

Opsumit是Actelion公司另一款PAH口服药物Tracleer的继任者，后者是该公司最畅销的产品，2012年销售额高达15亿瑞士法郎。然而，Tracleer将于2015年面临专利悬崖，该公司正指望Opsumit来弥补Tracleer专利到期所致的销售损失，该药将与市面上的其他PAH药物竞争，包括吉利德的Letairis、拜耳的Adempas（riociguat）、辉瑞的万艾可（Vigra，即伟哥）、礼来的希爱力（Cialis）及相关仿制药。

Opsumit是一种双效内皮素受体拮抗剂（ERA），能够松弛肺动脉并降低血压，该药与同类其他药物一样都具有一个黑框警示，禁止用于孕妇，因为这类药物可能对胎儿造成伤害。Opsumit的安全性和疗效已在迄今规模最大、开展时间最长的PAH临床试验SERAPHIN中得到证实，有近40个国家151个中心参与了研究。数据显示，与安慰剂相比，10mg剂量Opsumit使发病/死亡风险显著降低45%，同时使PAH相关住院或死亡风险显著降低50%。

肺动脉高压（PAH）是一种罕见病，全球发病率仅为百万分之十五至五十，特征是肺动脉血压异常升高，该病是一种慢性、极度严重、致死性疾病。尽管PAH罕见，但在高危群体中发病率显著升高，如HIV感染者中发病率约为0.5%，镰状细胞病患者中发病率约2-3.75%，而系统性硬化症患者中的发病率高达7-12%。

Actelion Ltd(OTCMKTS:ALIOF)’s pulmonary arterial hypertension drug, Opsumit, has won finalapproval from the Japanese Ministry of Health, Labor and Welfare. The decision,announced on Thursday, means the drug, also known by its chemical namemacitentan can be launched immediately onto the local market.

Pulmonary arterialhypertension is one of a broad group of disorders jointly described as pulmonaryhypertension (PH). PAH causes very high blood pressure in the arteriesextending between the heart and lungs. It is a chronic, lethal disorder withsymptoms such as tiredness and loss of breath and heart failure. It is moreprevalent in non-Hispanic blacks, women, and people aged 75 and over.

PAH is a raredisease affecting only 15-50 people per million around the world. However, theincidence rate is higher in high-risk patients would be individuals infectedwith HIV, who suffer a 0.5% occurrence rate; patients with systemic sclerosishave a prevalence of 7-12%, while the disease affects around 2-3.75% patientswith sickle cell disease..

Opsumit, works as adual endothelin receptor antagonist (ERA). It’s safety and efficacy of the drugwas established by SERAPHIN, the largest, longest PAH final-stage trial study.151 centers in almost 40 countries were used to undertake the study, which wasconcluded 2012.

The trial primarilytested mortality and morbidity rate in 287 PAH patients treated with either a 3mg or 10 mg once-daily drug, Opsumit or a placebo pill. The results indicatedthat the 10 mg dose of Opsumit reduced combined mortality-morbidity rate by 45%as compared to the placebo. The trial results further reported at least 3% moreadverse effects in Opsumit-treated patients than the placebo group. The commonadverse effects included headache, nasopharyngitis, anemia, urinary tractinfection, bronchitis, influenza and pharyngitis.

The SERAPHINprovided the basis of the Japanese approval for Opsumit. This was furtherbacked by positive results from a local study of the drug. In both studies, PAHaffected volunteer patients exhibited pulmonary vascular resistanceimprovements, a 6 min walk distance (6MWD), and WHO functional class.

The oral drugOpsumit becomes the third major drug in Actelion’s PAH drug portfolio alongsideEpoprostenol "ACT" and Tracleer. The intravenous treatment option forPAH, Epoprostenol “ACT” was granted approval in Japan back in February 2013.The drug is marketed in US under the brand name Veletri. The oral endothelinreceptor antagonist Tracleer has been approved in Japan since 2005.

Opsumit, however,has prominence over the other two PAH drugs under Actelion’s umbrella. Tracleerhas been known to cause abnormal enzyme elevations in the liver, so thatpatients are required to endure liver monitoring every month. Epoprostenol“ACT” has to be injected which makes it a more stable but inconvenient PAHtreatment option.

Satoshi Tanaka,President of Actelion Japan, described Opsumit’s improvement over Actelion’sprevious PAH treatments, "Opsumit represents a major step forward for themanagement of PAH as the first and only approved PAH treatment with provenlong-term outcome efficacy.”

in October 2013Opsumit received approval from the US Food and Drug Administration, whilstEuropean approval arrived in December 2013. and was given the go-ahead in Europeby. The drug is currently being launched in the Australia, Canada, the EUSwitzerland and the US.

最近，默沙东公司宣布将和位于美国麻省沃尔瑟姆的小型生物医药公司Syndax进行合作开发肿瘤联合疗法。能被制药巨头默沙东选为合作伙伴，Syndax公司可并不是浪得虚名。事实上，Syndax公司是FDA自2013年开始进行突破性药物认证以来第一批获此殊荣的公司。公司开发的entinostat是一种脱乙酰化酶抑制剂药物，目前正处于治疗抗药性绝经期妇女乳腺癌相关的临床三期研究。

FDA此前已经表示如果entinostat能够在无进展生存期方面实现突破，FDA将对其采取有限审批的措施。这也可见FDA对entinostat的期望之深。

此次默沙东希望结合公司新近上市的PD-1药物Keytruda和entinostat联合治疗非细小细胞肺癌和黑色素瘤。这一协议也被认为是公司大力推广Keytruda计划的一部分。

随着肿瘤免疫疗法市场的持续火爆，PD-1药物领域的研究更加趋于白热化。默沙东、百时美施贵宝、阿斯利康、罗氏均在推进各自的临床项目，同时广泛合作深度挖掘各自免疫疗法的临床潜力。

就在近日，百时美与Bavarian Nordic签署高达10亿美元协议，合作开发癌症免疫鸡尾酒。就在不久之前，默沙东还与日本药企卫材（Eisai）宣布了一项战略合作开展多个临床试验，评估其PD-1免疫疗法Keytruda（pembrolizumab）与卫材肿瘤学药物Lenvima（lenvatinib）和Halaven（eribulin）组合疗法的疗效和安全性。双方已计划开展的研究包括：一项Ib/II研究将调查Keytruda+Lenvima组合疗法用于特定实体瘤；一项Ib/II研究评估Keytruda+Halaven用于三阴乳腺癌（TNBC）。

Are twobreakthrough cancer drugs better than one? Pharma giant Merck ($MRK) andWaltham, MA-basedSyndax plan to find out in a Phase Ib/II study matching thetiny biotech's entinostat with Keytruda, Merck's big anti-PD-1 therapy, foreither non-small cell lung cancer or melanoma. Investigators plan to startrecruiting for the study in the second half of this year.

Syndax was one ofthe chosen few among the little biotechs to gain a breakthrough drugdesignation for a cancer drug, joining the first wave of BTDs back in 2013 foran experimental histone deacetylase (HDAC) inhibitor now in Phase III testingin treatment-resistant postmenopausal women with metastatic ER-positive breastcancer. The FDA issued the designation--which offers a potentially shorter pathto an approval--after reviewing promising progression-free survival and overallsurvival data racked up in Phase II.

This latestimmuno-oncology collaboration follows a lengthy string of pacts inked by Merck,which sees its PD-1 drug as a natural combo for a wide range of targeted drugs.Keytruda works by dismantling a natural cloaking device cancer cells use tostay hidden from the immune system. And Merck has been close behindBristol-Myers, the leader in the field with Opdivo, an IO drug recently approvedto treat lung cancer.

Syndax tried tocapitalize on its BTD win at the FDA with an IPO last year, but later threw inthe towel on the offering and inked a $100 million licensing deal with KyowaHakko Kirin in January, which included a $25 million upfront payment for rightsto the Japanese and Korean markets. Syndax CEO Arlene Morris toldXconomy's BenFiedler a few weeks ago that the biotech decided to steer clear of the IPOmarket for now after determining the drug's potential in an immuno-oncology combo,hinting about the Merck deal then in the works.

Syndax is a 2007Fierce 15 company. The biotech has been financed by Domain Associates, whichbrought in their Russian partners at RusnanoMedInvest on a syndicate that alsoincludes MPM Capital and Forward Ventures. Domain founded the company withtechnology developed at the Salk Institute

"The broadbase of clinical data involving our anti-PD-1 therapy, Keytruda, continues toprovide a strong foundation for advancing the study of different novelcombination regimens," said Dr. Eric Rubin, vice president and therapeuticarea head, oncology early-stage development, Merck Research Laboratories.

本周，以色列著名制药巨头梯瓦公司宣布以32亿美元的价格将罕见病药物研发公司Auspex收入囊中。这一协议距Auspex公司公布其治疗亨廷顿氏症药物临床三期积极研究数据过了仅仅不到三个月。

根据协议，梯瓦公司将以每股42%的溢价收购Auspex公司的股价。这也意味着梯瓦公司将获得Auspex公司负责开发的一系列中枢神经系统相关罕见病药物。分析人士认为，此次梯瓦公司获得的最大好处就是Auspex公司在研的SD-809，这种药物是一种胺转运体（VMAT2）的小分子抑制。Auspex公司认为SD-809能够调控患者大脑中多巴胺的含量以治疗亨廷顿症等罕见疾病。而市场对于这一药物也是充满期待，分析人士认为SD-809上市后其销售峰值将达到2亿-3亿美元之间。此外，Auspex公司还有用于治疗特发性肺纤维化药物SD-560处于临床研究阶段。无论从哪方面将，Auspex公司都可算得上是难得的优良资产，这也难怪众多分析人士都认为32亿美元的价格对于梯瓦公司来说真是物有所值。

最近一段时间，梯瓦公司可谓是内忧外患。公司的摇钱树--治疗多发性硬化症药物copaxone即将面临仿制药市场的强力挑战，同时公司近年来一系列研发活动也未能取得太大成就。在这一背景下，梯瓦公司收购Auspex就显得格外引人注目。梯瓦公司这家久未有大动作的生物医药巨头或许将借此展开一系列雄心勃勃的大计划。有了Auspex的强力加盟，梯瓦公司将可以在中枢神经系统疾病领域开展更深入的研究。

Three months afterAuspex Pharmaceuticals ($ASPX) excited the market with news that its Phase IIIstudy of a new drug for controlling the involuntary movements triggered byHuntington's disease had succeeded, Teva ($TEVA) has swooped in to buy thecompany in a deal that values the biotech at $3.2 billion.

Teva is paying $101a share to get its hands on SD-809, a drug that cleared late-stage testing byproviding evidence that the drug clearly improved patients' Total MaximalChorea (TMC) scores compared to placebo. That study included about 90 patients.The therapy--deutetrabenazine--is a small molecule inhibitor of vesicularmonoamine 2 transporter, or VMAT2, which is designed to regulate the levels ofdopamine in the brain.

Simply put, SD-809is a deuterated version of tetrabenazine--Xenazine, already in use forHuntington's--that is designed to break down more slowly in the body, allowingphysicians to give it less often in lower doses for maximum efficacy. ConcertPharmaceuticals, which recently completed its own IPO, has been one of thebiotech leaders in the deuterium R&D field.

Teva is paying a42% premium on Auspex's Friday close. Its 52-week low is $14.75, providinganother example of the big premiums being paid these days for biotech assets aswell as the upside for some of the investors who have been pouring into thesector over the past two years. Auspex went public about a year ago at $12 ashare.

Auspex has beenworking on drugs based on its deuterium R&D platform, a method that's usedto improve the efficacy and safety profiles of new drugs. The La Jolla,CA-based biotech is expected to post further Phase III data on tardivedyskinesia for its lead drug this summer. The drug is also in the clinic forTourette syndrome. Auspex has also been adding to its pipeline. SD-560(deuterated pirfenidone) is in development for idiopathic pulmonary fibrosis.

Bernstein's RonnyGal looked at the deal today, flagging concerns that Teva is angling to tacklea drug that is about to go generic with a new drug that may be hard to sell toU.S. payers. "Auspex was acquired in an auction (per comment on call) andSD-809 is essentially a second generation product for a $200-$300M drug,"Gal adds in a note to investors. "The $3.2B is a fair price (includingM&S synergies) for this initial drug/indication. The value created in thisdeal is basically in what Teva would do with the pipeline. Teva mentionedadditional compounds for Huntington, MS, IPF, migraine and pain. For us, thisis the major driver here. Teva essentially now has a library of 'NTE-like'molecules in neurology to follow."

Over at SterneAgee, meanwhile, Shibani Malhotra notes that the buyout highlights Teva'sintent to ink a string of new deals. " We remain buyers as we believefurther and potentially transformational deals are likely to provide a catalystfor TEVA shares as management continues to execute on it's strategy toreinvigorate Teva's growth trajectory and enhance shareholder value."

The buyout putsTeva right wher it needs to be: Prepping for a new drug application for a CNStherapy. Teva has struggle mightily in recent years to advance new drugs as itfaces major league competition to its big franchise for the MS drug copaxone.

"We lookforward to accelerating the development and commercialization of the Auspexportfolio based on our infrastructure, capabilities and strong commercial andR&D position in CNS. As we have outlined recently, one of our keypriorities for 2015 is to support Teva's mid to long-term growth and createvalue for our shareholders with business development opportunities that areclosely aligned with our core therapeutic areas. This transaction represents afirst major step with regards to that commitment and we expect to continue thisfocus in the future," said Erez Vigodman, the CEO of Teva.

安进（Amgen）抗癌药Kyprolis（carfilzomib）近日在美国监管方面收获利好消息，FDA已授予Kyprolis补充新药申请（sNDA）优先审查资格。此次申请，安进意在将Kyprolis的加速批准转为完全批准，并扩大Kyprolis适应症，由三线治疗扩大为二线治疗。FDA将于2015年7月26日作出审查决定。如果获批，Kyprolis令人垂涎的二线治疗将为安进带来更庞大的患者群体，同时将显著提升Kyprolis当前不甚理想的销售状况。

目前，业界正密切关注Kyprolis的表现，尤其考虑到安进在2013年耗资高达104亿美元收购Onyx制药公司后，才将Kyprolis收入囊中，而该药2014年销售额仅区区3.31亿美元。对于安进而言，此次也是该公司继续奋力追赶竞争对手新基（Celgene）抗癌药Pomalyst的绝佳机会。Pomalyst于2013年2月获FDA批准，时间方面Kyprolis领先Pomalyst 8个月上市，但Pomalyst在销售方面却遥遥领先于Kyprolis。

Kyprolis此次sNDA的提交，是基于国际III期ASPIRE研究及其他相关数据。ASPIRE研究在既往接受1-3种方案治疗失败的多发性骨髓瘤（MM）患者中开展。数据显示，与Revlimid（lenalidomide，来那度胺）及低剂量地塞米松（dexamethasone）联合疗法（Rd）相比，Kyprolis与来那度胺及低剂量地塞米松的联合疗法（KRd）显著推迟了病情的恶化（PFS：26.3个月 vs 17.6个月），并提高了总缓解率（87% vs 67%）。

除ASPIRE研究外，安进进一步公布了更多的数据，支持Kyprolis用于二线治疗和一线治疗。今年3月初，在首个头对头III期研究中，Kyprolis不负众望一举击败多发性骨髓瘤（MM）临床首选药物——武田万珂（Velcade），Kyprolis联合低剂量地塞米松将病情恶化显著推迟一倍时间（PFS：18.7个月 vs 9.4个月）。Velcade是过去11年中唯一一种被证明能够延长初诊和复发性多发性骨髓瘤（MM）生存期的药物，已用作临床首选药物在该病的临床治疗中发挥了重要作用，该药在2013年的全球销售额近30亿美元。

多发性骨髓瘤（Multiple myeloma，MM）是第二种最常见的血液癌症，是骨髓内浆细胞异常增生的一种恶性肿瘤。安进抗癌药Kyprolis于2012年7获FDA加速批准，用于既往至少2种治疗方案失败的多发性骨髓瘤（MM）患者，包括硼替佐米（bortezomib）和一种免疫调节剂（IMiD），Kyprolis的获批是基于缓解率数据。

Amgen's ($AMGN)hoping its blood cancer med Kyprolis can win an FDA bump-up from third-linetreatment to second-line, and it won't have to wait long to find out whetherits hopes pay off.

The agencyfast-tracked Amgen's application for the new use, which should give Amgen ananswer by July 26, the company said. If Kyprolis passes muster, the second-linenod will open up a larger patient population that stays on treatment for alonger period of time. Read: bolstered sales.

That's somethingthe California biotech could definitely use as Kyprolis continues to trailbehind Celgene's ($CELG) rival drug Pomalyst. Despite Kyprolis' 8-month-headstart, Pomalyst has been trouncing the Amgen drug in the sales department.Kyprolis' performance has raised more than a couple of eyebrows amongindustry-watchers, especially considering the $10.4 billion Amgen paid toacquire its maker, onyx Pharmaceuticals, in 2013.

Whether Kyproliscan win that coveted second-line status depends on how regulators view itsPhase III ASPIRE data. In that trial, adding Kyprolis to a combo of Celgene'sRevlimid and the standard chemotherapy dexamethasone extended progression-freesurvival to 26.3 months from 17.6 months. The three-drug combo also took the overallresponse rate to 87%, from 67% among patients using Revlimid and dexamethasone.Three times as many patients showed a complete response to the three-drugcocktail, Amgen said last December, and the regimen also hit secondaryendpoints in duration of response and health-related quality of life.

Since then, Amgenhas come up with more data that could support second-line use--and eventuallyhelp it make a case for first-line treatment. Earlier this month, Amgen saidthat patients with relapsed multiple myeloma who received Kyprolis anddexamethasone chemotherapy lived for a median 18.7 months without their diseaseworsening, compared with Takeda's Velcade, which kept disease progression atbay for a median of 9.4 months.

浙江海正药业（SH:600267）的 3.1 类新药伊沙匹隆（原料药及注射剂）于 2015 年 3 月 24 日由 CDE 承办，进入审评中心。目前办理状态为「在审评」，涉及受理号为：CXHL1402215、CXHL1402216、CXHL1402217。

伊沙匹隆（Ixabepilone）是一种半合成的埃博霉素内酰胺类似物，它是全球第一个埃博霉素类抗肿瘤药物。与紫杉醇药物相比，两者结构不一样，但作用机制类似，都是通过干预癌症细胞的分裂使肿瘤细胞凋亡。

伊沙匹隆原研企业为百时美施贵宝，最早于 2007 年 10 月获 FDA 批准，用于单药或联合卡培他滨治疗蒽环类、紫杉烷衍生物和卡培他滨治疗无效的转移性或局部进展的晚期乳腺癌。

海正药业此次申报是国内第一个 3.1 类伊沙匹隆申请，这款药物在国内的进口临床申请已两次获批，目前还未提交申请上市。因此浙江海正有望抢仿伊沙匹隆，或者成为国内首仿企业。

其中， 6 类申报中包括了与伊沙匹隆联用治疗乳腺癌的卡培他滨，卡培他滨片于 2015 年 3 月 28 日提交上市申请。如此可见海正药业在抗肿瘤领域的精心布局，并且将持续发力。