Therapeutic focus - Oral insulin emerging as biggest hope to replace injections

Novo Nordisk has placed another bet on oral insulin, signing a deal with Emisphere Technologies to develop pill formulations of its insulins. That the world’s largest maker of drugs for diabetics has decided to pursue the oral route over any other in the search for alternatives to injections is an indication that this is an area worth watching.

A look at the pipeline of new insulins reveals that there are almost as many oral formulations in development as injected products (see tables). MannKind’s Afrezza remains the sole inhaled version, on which the FDA is due to deliver its verdict any day now. Behind this, however, the pipeline is early stage, meaning should Afrezza fail to reach the market, injected insulin is likely to remain the only treatment option for some time.

Count of insulin products in development 
Routes of Administration No of products in clinical development
Injection 9
Oral 7
Inhalation 1
Intranasal 1
Suppository 1
Transdermal 1

This is the second deal Novo has signed with Emisphere – the first was over oral formulations of GLP-1 agonists, another big diabetes therapy area (Novel delivery of GLP-1s a challenge but alternatives lining up, January 13, 2010).

The Danish firm is paying $5m upfront and may pay another $52.5m in development and sales milestones, plus royalties. The companies will work to develop the oral insulins using Emisphere’s Eligen platform technology. This creates carriers from synthetic chemical compounds, which allows therapeutic molecules to be delivered without altering its chemical form or biological integrity.

Novo hopes to have a compound in the clinic next year under this deal. It already has NN1952 in phase I trials, a compound developed under a deal with Merrion Pharmaceuticals. A phase I/II trial of NN1952 in type 1 and 2 diabetes patients completed in June, and data should be revealed in the first half of next year.

Novo clearly believes it is worth having a couple of shots at developing an oral product, and has in the past expressly dismissed pursuing other delivery routes (EP Vantage Interview - Novo Nordisk hoping for fireworks to finish 2009, December 8, 2009).

Interestingly, apart from Novo's programmes, the remaining pipeline of alternative insulins is unpartnered.

Ahead

The challenge for oral insulins is adapting the molecule to life in the digestive tract. A few companies have come up with seemingly viable techniques, and have made it a bit further in the clinic.

The most promising appears to be Oramed Pharmaceuticals’ oral ORMD 0801, which released positive phase IIb safety data a month ago. The company uses adjuvant carriers with a history of successful pharmaceutical use that it says protects the active insulin peptide as it is carried through the gastrointestinal tract, promotes absorption across the intestinal wall, and protects the peptide in circulating blood. These carriers are selected for their highly specific interactions with the peptide.

Studies are ongoing, and the company is also developing a novel rectal suppository insulin formulation, ORMD 0802, geared more towards paediatric use.

Of the other agents, Diasome Pharmaceuticals' Oral HDV-Insulin completed a phase II/III study in October last year, although no word has been released on its future development.

Meanwhile NOD Pharmaceuticals appears to only be working in China. Nodlin is formulated using NOD technology - a bioadhesive nanoparticle-based system which, NOD says, allows for more efficient drug delivery.

Earlier stage

Alongside Novo at earlier stages in development a few more delivery routes are being tested, although it looks unlikely whether any will progress much further. 

Optinose has said little about its intranasally-delivered insulin since announcing positive phase I data in March 2008. The company, which has developed a nasal device that “enables administration of drugs deep in the nasal cavity”, recently raised $48.5m in private equity funding to progress its pipeline, although its main focus appears to be rhinosinusitis, so it seems unlikely this product will progress very far unless a partner is found.

Ossulin is being developed by Puredel, a joint venture between CM&D and US-based Natreon. It uses a delivery system based on a naturally-occurring product, which enables insulin to be taken orally. Phase I data was presented in 2009, but little news has been released since.

Altea Therapeutics meanwhile is developing a skin patch, with human clinical trials “well underway” according to the company’s website. However since reporting encouraging results from a phase I trial in 2007, the company does not appear to have released any further news on the project.

While much attention has been paid to Biodel’s injectable insulin Linjeta, recently given an FDA complete response letter (Biodel could be sent back to square one with FDA ruling, November 1, 2010), little mention has been made on developments with its orally-delivered insulin VIAtab although the programme is still listed as active.

Alternatives

Another company not on this list because the its product is technically already approved is Generex Biotechnology with Oral-lyn, insulin delivered via a spray to the mouth. Approvals have been won in several minor territories including Ecuador and Lebanon, but applications have yet to be made in the major markets of Europe or the US.

A worldwide phase III study that will support a filing in the US is due to complete this month, comparing the product’s efficacy in type 1 diabetics against standard regular human insulin therapy.

Earlier this month, Generex appointed former Eli Lilly Medical Director Dr James H Anderson Jr to its advisory board, who played a central role in the early development of Oral-Lyn, which was previously partnered with Lilly in late 2000. The pharma giant walked away from the deal two and a half years later, and few equity analysts are forecasting sales for the product.

A couple of years ago, this analysis would probably have looked a lot different, with inhaled products dominating. The failure of Pfizer's Exubera prompted many companies to abandon the inhaled avenue, but should MannKind be successful with Afressa some could be tempted to dust off their projects.

However serious doubts exist over whether the US will allow Afrezza on the market (Event - MannKind holds its breath as FDA decision approaches, December 1, 2010). Should the products in the table below move through the clinic successfully, oral insulin could well emerge as the only viable alternative to injections.

Alternatives to injected insulin in development 
Product Company Originator Routes of Admin.
Filed Afrezza MannKind MannKind/Emisphere Technologies Inhalation
Phase II ORMD 0801 Oramed Pharmaceuticals Oramed Pharmaceuticals Oral
Nodlin NOD Pharmaceuticals NOD Pharmaceuticals Oral
Capsulin Diabetology Diabetology/Proxima Concepts Oral
Oral HDV-Insulin Diasome Pharmaceuticals Diasome Pharmaceuticals Oral
Phase I NN1952 Novo Nordisk Novo Nordisk/Merrion Pharmaceuticals Oral
ORMD 0802 Oramed Pharmaceuticals Oramed Pharmaceuticals Suppository
VIAtab Biodel Biodel Oral
AT1391 Altea Therapeutics Altea Therapeutics Transdermal
Ossulin CM&D Pharma CM&D Pharma Oral
Intranasal Insulin OptiNose Optinose Intranasal

Share This Article