Therapeutic focus – Alternative GLP-1 delivery slowly approaching


From a modest entry less than a decade ago, glucagon-like peptide-1 (GLP-1) agonists have slowly carved a significant space in non-insulin diabetes care. The next step for the class is its conversion to non-injectable formulations, an event that could happen in the next five years.

Eli Lilly, which may be on the verge of re-entering the GLP-1 space courtesy of its injectable dulaglutide, yesterday acknowledged the attractiveness of oral delivery, a comment that suggests it could be on the hunt for a new candidate or a technology partner. However, it will be difficult to catch up to Victoza owner Novo Nordisk, which has advanced the pill form of its weekly GLP-1 semaglutide into mid-stage trials, with data due by year end (see table).

No needle, no damage done

GLP-1s are now recognised as a potent weapon in the fight to keep diabetics’ blood sugar under control, providing another option prior to progressing to insulin. But being delivered by subcutaneous injection puts them at a competitive disadvantage against other non-insulin antidiabetic classes like the DPP-IVs. That is likely one reason for the higher sales forecasts for the DPP-IV class, $12.6bn in 2020 to $7.2bn for the GLP-1s, according to EvaluatePharma data.

The hunt for alternative delivery routes has been on for some time. Novo had partnered with Emisphere Technologies to develop an oral GLP-1even before Victoza had launched, while Eli Lilly had been involved with transdermal and intranasal delivery routes for Byetta, the very first GLP-1, before it surrendered rights to the molecule in 2011. That work is reported to have been continued by AstraZeneca, which now owns the exenatide franchise that includes Byetta and Bydureon, although little news has been reported on it.

The most advanced development has been made by privately held Intarcia Therapeutics, which raised $210m to advance its matchstick-sized yearlong exenatide implant into phase III (VC dollars rain onto Intarcia on diabetes implant hopes, November 19, 2012). Its first major study, in 450 patients taking a backbone of oral antidiabetics, is due to report sometime this year. A larger cardiovascular outcomes trial is recruiting and will not report until 2018.

Given that transdermal exenatide was deemed to be unworthy of advancing either on clinical or commercial grounds, the ITCA 650 trial results should be interesting to watch.

The quest for a pill

Oral delivery is complicated by digestive action and potential limitations on crossing from the gut into the bloodstream because of the size of the molecule. This may help explain why the pipeline is so small, although the fact that two compounds have entered phase II is a sign that some drugmakers have mastered at least the pharmacokinetics.

Novo has given up on its first GLP-1 pill, NN9925, but is now hard at work on a daily oral form of semaglutide, its weekly follow-on to once-daily Victoza. A phase II dose-ranging trial is underway, testing eight different strengths alone or with metformin over 26 weeks in 600 patients. Inclusion of a placebo arm in the trial should give some early signs of efficacy.

Given that injectable semaglutide is in massive phase III trials in preparation for an expected 2017 launch, Novo’s oral strategy is difficult to predict. However, should it be able to launch the first oral GLP-1 it might be considered a nice problem to have.

Outside of Intarcia and Novo, an oral exenatide is being advanced by Israel-based Oramed, based on a proprietary technology. Its focus at the American Diabetes Association’s scientific sessions has been on oral insulin ORMD 0801, not on the GLP-1 ORMD 0901. Meanwhile, Midatech is seeking to combine GLP-1s with its nanoparticle technology, but the candidate remains in early stage.

If a GLP-1 pill is to make it to the market in the current decade, the odds are it will be owned by Novo Nordisk. Intarcia, meanwhile, has an interesting looking approach, although much needs to be proven. And if Lilly is serious about following through on the oral GLP-1 opportunity, it needs to kick its business develoment activities up a notch.

Non-injected GLP-1 agonists in development 
Phase  Product Routes of Admin. Company Clinical trials
Phase III ITCA 650 (exenatide synthetic) Implant Intarcia Therapeutics NCT01455896;
Phase II OG217SC (semaglutide oral) Oral Novo Nordisk
(Emisphere Technologies)
Pre-clinical ORMD 0901 (exenatide synthetic) Oral Oramed Pharmaceuticals  -
Pre-clinical GLP-1 Research Project Oral Midatech  -
Abandoned in Phase I in 2011 NN9925 Oral Novo Nordisk
(Merrion Pharmaceuticals)
Abandoned in Phase I in 2011 Transdermal Exenatide Transdermal Eli Lilly/Amylin   -

To contact the writers of this story email Jonathan Gardner or Amy Brown in London at or follow @JonEPVantage or @AmyEPVantage on Twitter

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