日本批准首款Lantus生物类似物

By Ian Haydock / 

【摘要】礼来公司和勃林格殷格翰公司都已经证实，作为赛诺菲公司来得时Lantus（甘精胰岛素）的首款生物类似物，其旗下的甘精胰岛素产品已获得日本监管机构的批准，这也是基础胰岛素类似物首次在日本遭遇竞争。

礼来制药公司与勃林格殷格翰制药公司刚刚联合披露，其联合开发的甘精胰岛素产品已于12月获得日本厚生劳动省的批准，之后该产品将提交给日本生物类似物监管途径进行复审。

虽然礼来日本分公司称赞此次获批是一项意义非凡的成就，而勃林格殷格翰日本分公司在接受《亚洲制药资讯》（PharmAsia News）采访时却指出，虽该产品获得价格补偿或上市还没有时间表，但正式上市指日可待。

在日本，估计约有六百万2型糖尿病患者，此外，还有近一千一百万日本人属糖尿病预备军。

该型代号为LY2963016长效胰岛素类似物由礼来公司开发并将在日本生产和上市，德国勃林格殷格翰将联合推广。

2013年7月，两公司联合开发的这款产品已在欧洲提出上市申请，并于2014年9月获批。而在美国，这款产品于2013年12月通过505（b）途径提出上市申请，而不是作为一款生物类似物申请上市，原因是能够更加灵活地调整产品剂型和其他特性。

虽然这款胰岛素已于去年8月在美国获得暂时批准，但由于赛诺菲公司提出专利侵权行为起诉，FDA在30个月内暂停该胰岛素的上市审批工作. 除非礼来公司能够打赢这场官司，否则2016年中旬之前这款胰岛素很难在美国上市。

礼来和勃林格公布了一系列关于这款胰岛素的临床和其他研究数据，包括之前报道的两项多国Ⅲ期试验、ELEMENT 1和2、以及多项Ⅰ期临床试验研究，这些研究的结果都显示，这款胰岛素的临床疗效与甘精胰岛素相似。

日本对生物类似物的监管政策与欧盟相似，即制造工艺必须与已在日本获批上市的原研药高度一致，生物类似物应具有原产药的所有特征，而且剂量和给药途径也必须与原产药一样。

目前已有多种其他类型的生物类似物通过这一过程，并已在日本获批上市。

但在日本生物类似物监管下，这款胰岛素不允许有自己的品牌名称，只能被称为“甘精胰岛素BS（生物类似物）”

与日本不同的是，这款胰岛素在欧洲是以提议品牌名Abasria上市，在美国上市申请中拟用的品牌名为Basaglar。礼来公司称将考虑对这些品牌名进行修改，提出一个全球通用名称。

日益激烈的市场竞争

这款胰岛素的获批将会进一步危及赛诺菲日本分公司市场。目前，赛诺菲日本分公司已有多款产品面临这种竞争，包括Allegra（非索非那定）和Myslee （唑吡坦）。此外，其顶级产品波立维（氯吡格雷）在未来数年期间也将面对首款竞争者。

赛诺菲日本分公司拒绝透露近来年来得时在日本销量，但是，依据IMS发表的数据，2012年期间以医保支付价计算，其在日本共收到了183亿日元（约合1亿5600万美元）。

其他基础胰岛素中，诺和诺德公司的德谷胰岛素目前已在日本获批上市。过去数年期间，日本糖尿病市场最显著的特点是DPP–4抑制剂使用量快速增长，以及多种SGLT2抑制剂相继获批上市。

Datamonitor公司预测，由于全球范围内DPP-4抑制剂、SGLT2抑制剂、以及其他类型降糖药物（例如GLP-1受体激动剂）的使用快速增长，有可能会导致基础胰岛素使用出现轻度下滑，包括来得时；而且这些药物还具有使用方便，可以口服给药；并能降低来得时引起的体重增加风险等优点。

在此期间，赛诺菲公司也在通过不断引入新的适应症，以巩固来得时的市场地位，目前日本已批准基础胰岛素与多种新药联合治疗，包括首款在日本上市的GLP-1受体激动剂Lyxumia（lixisenatide）和SGLT2抑制剂Apleway （托格列净）。

此外，赛诺菲公司也在积极研发浓度更高、作用持续时间更久的甘精胰岛素剂型——Toujeo (U300)，以求战胜当地生物类似物带来的冲击，并有助于来得时直接面对德谷胰岛素的竞争。Toujeo 已在日本提出上市申请，并于2014年07月获得批准。因此，虽然稍落后于来得时生物类似物，但Toujeo 有望在今年某个时候上市。

但是，目前礼来仍在日本糖尿病和胰岛素领域占有很重要地位，勃林格也在通过旗下的SGLT2抑制剂 Jardiance（艾帕列净）建立其在糖尿病领域的地位，该药已于去年12月获批上市。

Eli Lilly & Co. and Boehringer Ingelheim GMBH have just jointly disclosed that the co-developed product was approved in late December by the ministry of health, labor and welfare, after it was submitted for review under Japan's defined regulatory pathway for biosimilars.

While Lilly's Japanese subsidiary hailed the clearance as a "very meaningful achievement," Nippon Boehringer Ingelheim told PharmAsia News that it could not say at present when the product was likely to receive a reimbursement price or be launched, but that this would be announced at the time.

Roughly six million people in Japan are estimated to be living with type 2 diabetes, and around 11 million to have some form of the disease.

The long-acting insulin analog, coded LY2963016, was developed by Lilly, which will manufacture and market it in Japan, with co-promotion to be carried out together with the German firm.

The Lilly/BI product was also filed as a biosimilar in July 2013 in Europe, where it was approved last September. In the U.S. however, it was filed in December 2013 through the 505(b) (2) pathway for modified NDAs rather than as a biosimilar, which provides flexibility to "tweak" product formulations and other characteristics.

Although it received a tentative FDA approval last August, a final approval decision has been put on hold due to a patent infringement action brought by Sanofi and a related 30-month stay of approval, meaning a clearance is not possible before mid-2016 unless Lilly wins the case.

Lilly and BI have generated a suite of clinical and other data for their product including two previously reported international Phase III trials, ELEMENT 1 and 2, and several Phase I studies, which have showed similar clinical results to Lantus.

Japan's regulatory framework for biosimilars is comparable to the approach adopted in the EU, with the manufacturing process having to be highly consistent, the biosimilar fully characterized, and dosage and administration route the same as the reference product, which also must be approved in Japan.

Several other types of biosimilars have already passed through the process and been approved in the country.

The Lilly/BI product has been approved in Japan as a cartridge and for use with the Lilly Miriopen delivery system, but under local regulations has no brand name, being referred to only as "insulin glargine BS [biosimilar]".

This is different to the provisional Abasria name in Europe and the proposed Basaglar brand in the U.S., although Lilly has said that it is looking at revising these names to come up with a standard global name.

Rising Competition

For Sanofi in Japan, the approval presents a further genericization risk to its business, which is already contending with such competition to several products including Allegra (fexofenadine) and Myslee (zolpidem). The subsidiary's top product Plavix (clopidogrel) is also set to face its first local generic challengers within the next few years.

Sanofi in Japan declined to disclose recent Japanese sales of Lantus, but according to published figures from IMS, these were JPY18.3 billion ($156 million) at reimbursement prices in calendar 2012.

Among other basal insulins, Novo Nordisk AS's Tresiba (insulin degludec) is already marketed in Japan, while the broader diabetes sector in the country has been marked by the rapid rise of DPP-4 inhibitors and approvals for a clutch of SGLT2 inhibitors over the past few years.

Datamonitor expects the rise of these and other new therapies such as GLP-1 agonists (of which several have also been launched in Japan) to "lead to a slight reduction in the use of basal insulins, including Lantus" on a global basis, by merit of convenient oral dosing and fewer of the weight gain risks associated with Lantus.

Sanofi has in the meantime been strengthening its own portfolio through new introductions including the first GLP-1 agonist launched in Japan, Lyxumia (lixisenatide) - approved for use in combination with basal insulin therapy - and the SGLT2 inhibitor Apleway (tofogliflozin; licensed from Chugai Pharmaceutical Co. Ltd. ).

It is also looking to its more concentrated and longer lasting glargine formulation, Toujeo (U300), to help weather the local biosimilar challenge to Lantus, and to more directly compete with Tresiba. The product was filed for Japanese approval in July 2014 and so could be approved sometime this year, albeit after the biosimilar Lantus.

While Lilly already has a strong presence in diabetes and the insulin sector in Japan, BI is building up its presence through the SGLT2 inhibitor Jardiance (empogliflozin), which was approved in December ("Latest Japan Approvals Include World Firsts" — PharmAsia News, Dec. 29, 2014 5:22 AM GMT).