1. Roche：T-DM1+帕妥珠单抗vs曲妥珠单抗+紫杉醇/多西他赛（MARIANNE试验）

MARIANNE试验（NCT01120184）是Roche开展的一项关键III期临床研究，对比T-DM1（商品名Kadcyla）+帕妥珠单抗（Perjeta）与曲妥珠单抗（商品名Herceptin）+紫杉醇/多西他赛两种方案治疗HER阳性乳腺癌的疗效。如果该试验成功，Herceptin将被从标准疗法中替换出来，这样Roche就成功限制了Herceptin生物仿制药的市场。

2. Vertex Pharma：lumacaftor+ivacaftor（TRAFFIC试验、TRANSPORT试验）

TRAFFIC试验（NCT01807923）、TRANSPORT试验（NCT01807949）是Vertex Pharma开展的III期临床研究，评价lumacaftor (VX-809) +ivacaftor（商品名Kalydeco）治疗CFTR F508del纯合子突变型囊肿性纤维化。ivacaftor 于2012年经FDA批准上市，用于G551D突变型囊肿性纤维化，2013年上半年销售额为1.61亿美元，EvaluatePharma预测2018年销售额为26.6亿美元。美国48%的患者为双拷贝F508del突变，40%的患者为单拷贝F508del突变，4%的患者为单拷贝G551D突变。如果该试验结果支持lumacaftor+ivacaftor上市，分析师预测年销售额峰值在60亿美元。

3. AbbVie：ABT-450/r+ABT-267+ABT-333

2013年12月，Gilead Sciences的sofosbuvir在美国上市，标志纯口服抗丙肝时代降临，但战争还远没有结束，sofosbuvir对于GT1型HCV感染仍然需要与干扰素联用，组合抗丙肝疗法则有望解决这个问题。FDA认定了4个突破性组合抗丙肝疗法，分别是Gilead的sofosbuvir+ledipasvir二联、Merck的MK-5172+MK-8742二联、AbbVie的ABT-450/r+ABT-267+ABT-333三联、Bristol-Myers Squibb的daclatasvir+asunaprevir+BMS-791325三联，AbbVie的抗丙肝三联临床推进最快，部分临床数据显示SVR12应答率达到99%。AbbVie分别于2013年11月、12月公布了SAPPHIRE-I试验、SAPPHIRE-II试验的结果，其他临床研究如TURQUOISE-II试验（NCT01704755）、PEARL试验也将在2014年公布。

4. Eli Lilly：dulaglutide vs liraglutide（AWARD-6试验）

AWARD-6试验（NCT01624259）是Eli Lilly开展的dulaglutide vs liraglutide（商品名Victoza）对比试验，这两个药都是GLP-1类似物，liraglutide是一天注射一次的，而dulaglutide则是一周注射一次的，该试验结果可能会影响未来GLP-1市场走向。另外Eli Lilly的SGLT-2抑制剂empagliflozin也在进行III期临床试验，希望能拿到与DPP-4抑制剂linagliptin联用的数据。

5. Bristol-Myers Squibb：nivolumab

Bristol-Myers Squibb是癌症免疫疗法的老大，ASCO2013年会报道了nivolumab治疗黑素瘤的效果，现在我们将目光转向一个更大的适应症——非小细胞肺癌。目前Bristol-Myers Squibb正开展一系列nivolumab治疗非小细胞肺癌的临床研究，包括两种癌症免疫疗法nivolumab+ipilimumab（商品名Yervoy）联用，ASCO2014年会肯定少不了nivolumab。

6. Merck：MK-3475

在癌症免疫疗法的竞争中，Merck可谓不惜血本，为了后来居上超越Bristol-Myers Squibb，I期临床就入组了1000例患者，吓到一堆分析师、投资人。1月13日，Merck宣称将在2014上半年完成MK-3475的上市申请，试图上市第一个anti-PD-1单抗。目前MK-3475治疗晚期黑素瘤的Ib期试验（PN 001）、II期试验（PN 002）已完成入组，III期临床试验则对比MK-3475、ipilimumab（商品名Yervoy）的疗效，这些数据都值得期待。

7. Novartis/Pfizer：CDK4/6抑制剂

在Pfizer紧锣密鼓地研究CDK4/6抑制剂palbociclib时，Novartis的同类药物LEE011也追赶上来，2013年12月宣布启动LEE011+letrozole治疗乳腺癌的III期临床研究。Pfizer将在2014第一季度拿到palbociclib的II期临床总生存期数据，分析师仍在争论Pfizer是否会用II数据直接递交上市申请。

8. Novartis：LCZ696 vs enalapril（PARADIGM-HF试验）

LCZ696是Novartis开发的血管紧张素II受体、脑啡肽酶双靶点抑制剂，2009年底启动III期临床研究PARADIGM-HF试验（NCT01035255），对比LCZ696与依那普利对慢性心衰患者发病率和死亡率的改善，Novartis预计该药年销售额为50亿美元。

9. Roche：onartuzumab

Onartuzumab (MetMAb)是Genentech开发的anti-Met单抗，2011年公布的II期临床数据显示，对于Met阳性非小细胞肺癌，厄洛替尼、MetMAb+厄洛替尼组的无进展生存期分别为1.5个月、2.9个月，总生存期分别为3.8个月、12.6个月。2014年，Genentech将公布MetMAb治疗Met阳性非小细胞肺癌的第一项III期临床数据，以及治疗结直肠癌、胃食管癌的II期临床数据。MetMAb会是Genentech开发的又一个重磅抗癌单抗吗？

10. Amgen：carfilzomib（FOCUS试验）

Amgen在2013年以104亿美元收购Onyx Pharma，其中一个重磅产品就是2012年上市的carfilzomib（商品名Kyprolis），当时是基于应答率数据加速批准上市，2014年可以拿到总生存期数据了。一些分析师担心该药在总生存期上逊色于Celgene的Pomalyst，而且Amgen需要用该试验的数据去打消该药心脏毒性的疑虑。

11. Novartis/Eli Lilly/AstraZeneca/Amgen：anti-IL-17单抗

Novartis的secukizumab是一种全人源anti-IL-17A单抗，II期临床显示对斑块状银屑病、类风湿性关节炎、强直性脊柱炎、牛皮癣性关节炎等免疫性疾病有效，并且能在相对较快的2-4周内缓解症状。2014年，Novartis将公布secukizumab的III期临床结果，Eli Lilly的ixekizumab、AstraZeneca/Amgen的brodalumab也有望拿到III期试验数据。

 The drug trial results that will shape 2014

Following on from last week's highly popular FirstWord Lists article – FirstWord Lists – The drugs that will shape 2014 - this week's article takes a look at the key products among large cap pharma and biotech players for which significant clinical data are due to be released over the next 12 months.

There is some overlap between the two lists – the PD-1 inhibitors being developed by Bristol-Myers Squibb and Merck & Co. for example are certain to be key drugs in 2014 irrespective of the rules of assessment.

Products not assessed below, but worthy of mention, include Johnson & Johnson's haematological cancer therapy Imbruvica, the PCSK-9 inhibitors being developed by Amgen and Sanofi/Regeneron Pharmaceuticals, and Medivation and Astellas's Xtandi. Key data releases for each of these products are anticipated shortly but in the most part have been 'top-lined' already.

Analysts at Bloomberg Industries conclude that AbbVie, Bristol-Myers Squibb, Merck & Co. and Roche are likely to have the most "revolutionary" R&D assets reporting data in 2014, pointing in particularly to PD-1 inhibitors and AbbVie's hepatitis C regimen. Bloomberg analyst Asthika Goonewardene also highlighted to FirstWord the emergence of the IL-17 antibodies in psoriasis and Pfizer's palbociclib as important assets to watch over the next 12 months.

Roche - Kadcyla/Perjeta (breast cancer)

Data from the Phase III MARIANNE study are due to read out in the second half of 2014. Expectation has continued to grow for positive results that would provide strong rationale for Roche's Perjeta and Kadcyla franchises to be used in combination in first-line HER2-positive breast cancer patients. This could displace Roche's Herceptin as the gold standard therapy, deliver obvious commercial benefit and limit the opportunity for biosimilar trastuzumab products.

Vertex Pharmaceuticals – Kalydeco/VX-809 (cystic fibrosis)

Positive data from the Phase III TRAFFIC and TRANSPORT studies – expected mid-year – would facilitate approval of Vertex Pharmaceuticals' cystic fibrosis treatment Kalydeco (in combination with VX-809) in the approximate 26,000 patients with the F508del homozygous mutation. Launched in 2012, Kalydeco is already used to treat around 2000 patients with the G551D gene mutation. Positive data from TRAFFIC and TRANSPORT could open up a market with peak sales of approximately $6 billion, suggest analysts.

AbbVie – Hepatitis C combo

Although Gilead Sciences – via its Sovaldi franchise – is widely expected to emerge as the dominant player in the oral, interferon-free, short-duration hepatitis C market, AbbVie is also expected to file for approval of its own cocktail of direct-acting antiviral products in 2014 for the treatment of genotype 1 patients. Positive data were released for the combination in November and December, but will continue to read out over the next few months. Subsequent data will shape the clinical and commercial profile of AbbVie's product, argue analysts. Data from the TURQUOISE-II study in cirrhotic patients and the PEARL study (demonstrating strength of regimen without ribavirin) will be particularly important, they add.

Eli Lilly – dulaglutide/empagliflozin (diabetes)

After a notable leave of absence, Eli Lilly anticipates a flurry of FDA approvals in 2014 with a notable emphasis on diabetes. Both the GLP-1 agonist dulaglutide and the SGLT-2 inhibitor empagliflozin are expected to secure approval, but Eli Lilly will also report key data that will shape the commercial profiles of both products.

For dulaglutide, forthcoming data from the AWARD-6 trial – a head-to-head study versus Novo Nordisk's market leading Victoza – will be important in determining both relative efficacy and weight loss profile, while in the case of empagliflozin, Eli Lilly is expected to report Phase III data in combination with its DPP-4 inhibitor Tradjenta. Analysts anticipate that this combination could reach the market at least a year ahead of competitors and act as a key growth driver.

Bristol-Myers Squibb – nivolumab (NSCLC)

With the rapid pace of immuno-oncology development matched by the breadth of clinical evaluation, a host of clinical data for the PD-1/PD-L1 inhibitors will be keenly devoured by analysts, investors and oncologists over the course of 2014. A key focal point will naturally be the annual ASCO meeting in May/June, already previewed by one analyst as being a "treasure trove" of data.

Key results will include that from Bristol-Myers Squibb's Phase II study of nivolumab in third-line squamous non-small-cell lung cancer (NSCLC), which is expected to be used to file nivolumab in this indication. Significant attention is also focused on a Phase I combination study of nivolumab and Yervoy in treatment-naive NSCLC patients, data from which will likely be presented at ASCO. Key to success of this study will be whether incremental efficacy can offset any tolerability concerns with the regimen - ViewPoints: Bristol-Myers Squibb looks for biomarker benchmark in immunotherapy race

Merck & Co. – MK-3475 (melanoma)

An unusually large (1000 patient) Phase I study for Merck & Co.'s own PD-1 antibody MK-3475 across multiple tumour types has prompted some intrigue among analysts and investors. Bernstein's Tim Anderson talked up the opportunity for Merck to deliver an earlier-than-expected approval on the back of the study and earlier this month the company confirmed that it has initiated a rolling submission for MK-3475 in Yervoy-refractory melanoma patients.

This could speed up the route to market by six to 12 months, say analysts and therefore potentially facilitate MK-3475's status as the first PD-1 inhibitor to gain regulatory approval. Whilst not in the most lucrative indication, such an achievement would provide a boost to Merck's credibility in the immuno-oncology race. Therefore, data from a Phase I cohort expansion in melanoma (expected in mid-2014) and from a larger 500-patient Phase II study in Yervoy-refractory melanoma patients (possibly by end of year) are keenly anticipated. There is also a possibility that preliminary Phase III results in a head-to-head study of MK-3475 versus Yervoy in treatment-naive melanoma patients could read out in late 2014.

Novartis/Pfizer – LEE011/palbociclib (breast cancer)

The Swiss drugmaker caught analysts and investors by surprise last year when it announced that LEE011 – a CDK4/6 inhibitor – had progressed into Phase III studies in breast cancer. Given this rapid progression, any mid-stage data made available in 2014 will be heavily scrutinised. LEE011 is of particular interest to Pfizer, given that it will compete directly with its own compound palbociclib, which is also in pivotal-stage studies. Overall survival data from Phase II studies of palbociclib could also be made available in Q1; analysts are still debating whether Pfizer will be able to submit for approval based on the mid-stage study results.

Novartis – LCZ696 (chronic heart failure)

Novartis has high expectations for the first-in-class dual inhibitor of angiotensin II receptor and neural endopeptidase, neprilysin – currently known as LCZ696 (which comprises the angiotensin receptor blocker Diovan and the neprilysin inhibitor pro-drug AHU377). Phase III data from the PARADIGM-HF outcomes study in chronic heart failure (CHF) are due in the second quarter of 2014. Strong results would drive upside to consensus forecasts; for its part Novartis believes a combined opportunity in CHF and acute heart failure could be worth up to $5 billion a year.

Roche – MetMAb (NSCLC)

Roche's focus on personalised cancer therapies will fall under the spotlight again in 2014 when the company releases data for MetMAb. Previously released Phase II data in second- and third-line NSCLC patients demonstrated a tripling in overall survival versus Tarceva in c-met (mesenchymal-epithelia transition factor)-positive patients. Roche estimates that around 50 percent of metastatic NSCLC patients carry c-met mutations that could cause c-met amplification. The first Phase III data in the second/third-line setting could be available towards the end of 2014. Initial results from Phase II studies in colorectal and gastroesophageal cancer could also potentially be released in 2014.

Amgen – Kyprolis (myeloma)

The biggest M&A activity in 2013 – Amgen's $10.4-billion purchase of Onyx Pharmaceuticals – was essentially focused on the integration of the latter's multiple myeloma therapy Kyprolis into Amgen's portfolio. FDA approval of Kyprolis was based on patient response rates, and data from the FOCUS study – due to read out at some stage during the first half of 2014 – is designed to demonstrate its survival benefit. Some analysts are concerned that Kyprolis will fail to match the overall survival benefit of five months demonstrated by Celgene's competing product Pomalyst. Furthermore, Amgen needs the data from FOCUS to help dispel concerns over cardiac toxicities.

Various – IL-17 antibodies (psoriasis)

Novartis' secukizumab is a fully-human monoclonal antibody against interleukin-17A (IL-17A), a key-inflammatory cytokine that is associated with a number of immune-mediated diseases, such as psoriasis. Phase II studies in moderate-to-severe plaque psoriasis, rheumatoid arthritis (RA), ankylosing spondylitis and psoriatic arthritis sufferers have indicated that secukizumab could provide a potential new treatment strategy for immune-mediated diseases. The drug has a relatively rapid onset of action with symptom relief as early as two to four weeks. Novartis is likely to have the first compound approved in this category (for psoriasis, possibly by the end of the year) and is due to publish Phase III data in RA, ankylosing spondylitis and psoriatic arthritis during 2014. Eli Lilly and AstraZeneca/Amgen are also looking to commercialise IL-17 antibodies with Eli Lilly's ixekizumab (plaque psoriasis) and AstraZeneca/Amgen's Brodalumab (psoriasis) both also expected to report Phase III data in 2014.

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