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OI388GT终止试验后,诺和诺德再次部署口服胰岛素,计划三年内进入人体临床

医药魔方 医药魔方 来源:医药魔方
2019-02-11
口服胰岛素 诺和诺德
原文

胰岛素是制药史上最重要的药物之一。自加拿大医生班廷(Frederick Grant Banting)从动物体内分离出有活性的胰岛素以来,距今已有近百年,依然一直被不断升级以满足治疗糖尿病的需求。


时至今日,胰岛素疗法依旧是治疗糖尿病的最有效方法,同时将注射胰岛素改成口服制剂一直被视为是临床热点需求之一,市场规模预计会超过100亿美元。


1、从乌龟身上获得的灵感


近日,据《科学》(Science)报道,麻省理工学院、布莱根妇女医院及诺和诺德的研究人员提出了一种叫做“口服胰岛素丸”的产品。这是一种蓝莓大小的口服胶囊,携带着一只由胰岛素构成的小探针,与一个由糖片压住的弹簧装置相连。



当胶囊进入胃部之后,它能够调整自身的取向,保证它与胃壁组织接触,胃酸溶解糖片之后,弹簧将胰岛素构成的小探针射入到胃壁中,达到递送胰岛素的效果。


科学家表示这一设计灵感来自豹龟(leopard tortoise)。目前该产品在大鼠和猪身上的动物实验表明,其血糖降低水平与注射胰岛素相似。


2、口服胰岛素研究路漫漫


对于一些糖尿病患者来说,每日注射是个沉重的负担,注射胰岛素所用的针头犹如饮用水的水龙头般重要。为此,制药界自发现胰岛素第一天起就尝试非注射胰岛素的开发,但近百年来进展非常有限。


事实上,作为糖尿病领域的霸主,这不是诺和诺德第一次布局口服胰岛素了。诺和诺德于2012年宣布将投资近40亿美元研发口服胰岛素,并预计在8~10年内上市。


2016年上半年,诺和诺德完成了口服胰岛素项目OI338GT的IIa期临床试验,并在2017ADA(美国糖尿病协会科学年会)及EASD(欧洲糖尿病研究学会年会)公布了详尽的IIa临床试验数据,OI388GT在控制血糖水平方面与Sanofi注射Lantus一样有效。


遗憾的是,诺和诺德早于2016年10月就宣布终止OI338GT的研究,官方给出的理由是“出于对前期高昂投入商业运作的考虑”。但业内认为,其终止的原因是OI338GT胶囊对胰岛素原料产能有较高要求,产能压力不小,出于成本考虑,终止了该项目。

 

诺和诺德首席科学官Mads Krogsgaard Thomsen博士在一篇博客文章中说,公司仍然相信口服胰岛素的潜力。此次与麻省理工学院等机构的合作,可见其在该领域的不死之心。


诺和诺德并不是唯一在“口服胰岛素”领域的布局者。2017年,赛诺菲与Enteris BioPharma达成了一项研究协议,将利用后者的口服给药平台进行2型糖尿病治疗。


以色列Oramed的口服胰岛素胶囊ORMD-0801已经处于II期临床试验。2018年11月13日,Oramed宣布已成功随机分配超过50%的预期285名患者进行ORMD-0801的90天剂量范围的Pivotal 2b期临床研究,旨在为疗效和安全性终点产生有意义的数据。


3、能否重振诺和诺德长期高增长?


大概在十多年前,吸入式胰岛素曾是一个热门方向。只是由于肺安全问题,药物吸收稳定性等问题,吸入式胰岛素产品并不被市场所看好。


其中一开始最被看好的是辉瑞率先上市的Exubera,该产品曾被预测峰值销售能到30亿,但第一年只卖了1200万、而后黯然退市。


在业内人士看来,Exubera的部分失败原因与该装置过于笨拙相关。可惜的是,Mannkind随后上市了更为精巧的吸入式胰岛素Afrezza,不过市场吸收依旧十分缓慢。


由于糖尿病市场竞争加剧和价格压力,驱使了诺和诺德不得不尽早摆脱对传统注射胰岛素产品的依赖。就在前几天,诺和诺德公布了2018年财报(见:诺和诺德2018财报:利拉鲁肽中国收入激增73%,口服索马鲁肽2019Q1申请上市)显示,在全球胰岛素中的市场份额占到近半壁江山的胰岛素同比增加仅0.5个百分点。


为此,诺和诺德-麻省理工学院的科学家们正在努力优化这款产品的制造工艺,同时通过进一步研究以确定每日胃注射引起的长期影响。诺和诺德计划在三年内进行该产品的人体临床试验。


该研究的共同资深作者Robert Langer教授在一份声明中表示:“我们坚信,这种新型胶囊有朝一日可以帮助目前只能通过注射或输液给药接受治疗的糖尿病患者。”


科学家表示,这一给药平台不仅可以递送胰岛素,还可以递送传统上必须注射的更广泛的生物制剂,包括肽和核酸,如DNA疗法和RNA疗法。


这个来自乌龟灵感的口服胰岛素胶囊,能否帮助诺和诺德重回长期高增长时代?由于其尚未进入临床试验,没有充足的人体数据来验证其效果,我们也只能拭目以待了。


机器翻译

Insulin is one of the most important drugs in pharmaceutical history.Since Frederick Grant Banting isolated active insulin from animals, nearly a hundred years ago, it has been escalated to meet the needs of diabetes treatment.

1.Inspiration from the Turtle.Researchers at Brigham and Women's Hospital and Novo Nordisk have come up with a product called an oral insulin pill.It is a blueberry size capsule for oral administration, carrying a small probe made of insulin, connected to a spring device held down by sugar tablets.

Scientists say the design was inspired by leopard tortoise.Current animal studies in rats and pigs have shown that the blood sugar level is similar to that of injected insulin.

2.Oral insulin has a long way to go.For this reason, the pharmaceutical industry has tried the development of non-injectable insulin since the first day of insulin discovery, but the progress in the last 100 years has been very limited.

In fact, this is not the first time that Novo Nordisk has laid out oral insulin as a leader in the diabetes field.Novo Nordisk announced in 2012 that it will invest nearly $4 billion in the development of oral insulin and expects to launch it in 8 to 10 years.

In the first half of 2016, Novo Nordisk completed the phase IIa clinical trial of the oral insulin program OI338GT, and published detailed clinical trial data of IIa in 2017ADA (American Diabetes Association Scientific Annual Meeting) and EASD (European Association for the Study of Diabetes Annual Meeting). OI388GT is as effective as Sanofi injection of Lantus in controlling blood glucose levels.

Regrettably, Novo Nordisk announced the termination of the OI338GT study as early as October 2016, and the official reason was "due to the consideration for the high commercial operation in the early stage".However, the industry believes that the reason for its termination is that OI338GT capsules have higher requirements for insulin raw material capacity, capacity pressure is not small, for cost considerations, terminated the project.

Dr. Mads Krogsgaard Thomsen, Chief Scientific Officer at Novo Nordisk, said in a blog post that the company still believes in the potential of oral insulin.This cooperation with MIT and other institutions, it can be seen in the field of undead heart.

Novo Nordisk is not the only one in the field of "oral insulin".In 2017, Sanofi entered into a research agreement with Enteris BioPharma to use the latter's oral dosing platform for the treatment of type 2 diabetes.

Oral Insulin Capsules ORMD-0801 from Oramed, Israel is already in Phase II clinical trial.On 13 November 2018, Oramed announced that it had successfully randomized more than 50% of the expected 285 patients to the 90-day dose-ranging Pivotal Phase 2b clinical study of ORMD-0801 to generate meaningful data for efficacy and safety endpoints.

3.Can it revive Novo Nordisk's high long-term growth?

Probably more than a decade ago, inhaled insulin was a popular direction.Only because of lung safety issues, drug absorption stability and other issues, inhaled insulin products are not the market.

One of the most promising in the beginning was Pfizer's pioneering Exubera, which had been forecast to peak at $3 billion but sold only $12 million in the first year.And then it's out of the market.

In the eyes of the industry, some of Exubera's failures are related to the device's awkwardness.Sadly, Mannkind later launched Afrezza, a more sophisticated inhaled insulin, but its absorption is still slow.

Due to the intensification of competition in the diabetes market and price pressures, Novo Nordisk has to get rid of its dependence on traditional insulin injection products as soon as possible.Just a few days ago, Novo Nordisk announced its 2018 earnings report (see Novo Nordisk 2018 earnings report: liraglutide revenue surged 73% in China, oral semaglutide 2019Q1 application for listing) showed that the global market share of insulin accounted for nearly half of the increase in insulin only 0. 5%.5 percentage points.

For this reason, scientists at Novo Nordisk MIT are working to optimize the manufacturing process of this product, and through further studies to determine the long-term effects caused by daily gastric injections.Novo Nordisk plans to conduct human clinical trials of the product within three years.Professor Robert Langer, co-senior author of the study, said in a statement: "We firmly believe that this new capsule will one day help people with diabetes who are currently treated only with injections or infusions.Scientists say the platform can deliver not only insulin but also a wider range of biological agents that traditionally have to be injected, including peptides and nucleic acids, such as DNA and RNA therapies.

This turtle-inspired oral insulin capsule can help Novo Nordisk return to a long-term era of high growth?Because it has not yet entered clinical trials, there is not enough human data to verify its effectiveness, and we can only wait and see.

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