Innovation / October 2013

Insulin in a tablet - why is it so difficult?

Many companies have tried, and failed, to develop insulin in tablet form. So what makes Novo Nordisk think it can do any better?

Many people ask why insulin and GLP-1 products such as Victoza® (liraglutide) are not made in tablet form. The short answer is that it is really difficult. Insulin and GLP-1 are amazing protein molecules, but if taken orally they would ordinarily be attacked by digestive enzymes in the gastrointestinal tract whose job it is to break down proteins, which is useful for food uptake but detrimental if the protein is a drug that needs to stay intact. And even if they were to somehow survive in the stomach, these large molecules would then have difficulty passing through the wall of the intestine and entering the bloodstream.

Oral insulin and GLP-1 – that is insulin and GLP-1 in tablet form – therefore have to be designed and engineered to overcome these challenges. But even if these barriers can be overcome, further challenges lie ahead as these proteins have to be absorbed by the body in the right quantities and stay in the blood for the right length of time – regardless of whether the patient has an empty stomach, has just eaten or is suffering from diarrhoea. “We have been working on oral insulin and GLP-1 for about five years. I can tell you that when we started, I thought this was nearly impossible – and it is!” says Dr Peter Kurtzhals, senior vice president and head of Diabetes Research at Novo Nordisk. “But I’ve been positively surprised and encouraged by the progress we’ve made. Many other companies have tried to develop oral insulin but none have been able to show proof of concept – but we are getting very close to this stage. I would say we are the leaders in this field at this point.”

Convenience leads to better outcomes

Currently, when people are diagnosed with type 2 diabetes they are often given a tablet-based medication, for example metformin. What these medications have in common is that their active substance is a small molecule – a chemical – which is not broken down by enzymes in the gastrointestinal tract. However, for many people with type 2 diabetes the disease eventually progresses to a stage where insulin therapy is necessary to control the blood sugar. But insulin injections are daunting for many, and patients must be educated by healthcare professionals in order to administer insulin effectively and safely. Progression to insulin injections is therefore often delayed, with potential serious consequences for health in the long term.

Insulin in a tablet would enable patients to begin insulin therapy earlier and treat themselves more easily. “The simplicity and convenience of oral insulin would be amazing. While it takes time to learn how to inject insulin with a pen, everyone knows how to swallow a pill. This in turn could support greater compliance and lead to much better treatment outcomes to the benefit of patients, healthcare providers and society,” highlights Peter Kurtzhals. He emphasises that insulin in tablets will probably not be able to replace injections entirely because it is likely to be used only in patients whose bodies can still produce some insulin.

Expert knowledge

For a company that is committedto changing diabetes, it is therefore understandable that Novo Nordisk is investing so much time and money in developing oral insulin and GLP-1. And Peter Kurtzhals believes the company has the best people working on this task: “The research and development team is built on our 90 years of experience with the insulin molecule and 20 years of experience with GLP-1. The scientists involved have been experts in the field for decades. This is a clear strength for engineering and designing the molecules for the oral route and is a major advantage over our competitors.”

While Novo Nordisk is an expert in protein research, these oral preparations also require formulations that will enable the active ingredients to reach their targets in the body. Novo Nordisk has over the last five years built substantial oral formulation expertise and has entered into licensing and collaboration agreements with companies having technologies to facilitate oral absorption. “It has been a learning curve for Novo Nordisk to establish technologies, animal models and exploratory clinical trials to support the development of oral insulin and GLP-1 formulations,” says Peter Kurtzhals, “and the company currently has two oral insulin and three oral GLP-1 formulations in phase 1 clinical trials.”

The journey ahead will not be easy. “We’re up against major barriers and we still don’t know whether they can be overcome,” reports Peter Kurtzhals. “But if we look at the ideas we’ve got and the progress we’ve made I’m optimistic that Novo Nordisk will be the first to turn oral insulin and GLP-1 into a reality. We are currently in phase 1 development so it is not unrealistic to think that if studies are successful, oral insulin and oral GLP-1 could be available in about 10 years. In the world of pharmaceutical research and development that’s pretty close.”

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