Novel delivery of GLP-1s a challenge but alternatives lining up

News that the first clinical trial is underway to test an oral version of a glucagon-like peptide-1 (GLP-1) agonist, a major class of drug to treat diabetes, throws the spotlight on companies working on novel delivery formulations of GLP-1s; all marketed and advanced pipeline candidates administered by subcutaneous injection.

Novo Nordisk’s oral candidate, developed using Emisphere Technologies’ delivery technology, is now the most advanced pill formulation with four more still in pre-clinical studies. However, it is intriguing to note that Amylin Pharmaceuticals and Eli Lilly, the developers of the only marketed GLP-1 so far, Byetta, have shunned the oral route and instead enlisted the help of MDRNA and Altea Therapeutics to develop intranasal and transdermal versions, respectively (see table below).

Delivery challenges

All GLP-1 products, like Byetta and Novo’s own Victoza which is awaiting a crucial approval decision from the FDA, are large molecule compounds which essentially copy the GLP-1 hormone or protein that occurs naturally to stimulate the secretion of insulin from the pancreas, thereby controlling blood glucose levels.

The main challenges therefore to developing an oral version of GLP-1 are in preventing the compound from being broken down by enzymes in the gut before it enters the intestinal system and its large molecular size, which makes crossing into the bloodstream problematic.

Novo and Emisphere struck a partnership in June 2008 to develop an oral version of one of Novo’s follow-on GLP-1 products, distinct from Victoza. The companies are naturally hopeful that their novel, once-daily oral pill could reach the market first, providing a significant dosing advantage to all other GLP-1s on the market or in late stage development which need to be injected twice-daily, once-daily or once-weekly.

In addition to the clear dosing advantage, there is some hope that an oral pill may help to reduce the sometimes severe vomiting side effects that have so far hampered the use of Byetta and are expected to blight all further GLP-1s to some extent.

However, at this stage the main rationale for developing an oral version is convenience. Peter Kurtzhals, Novo’s head of diabetes research, told EP Vantagethat any side-effect benefit would simply be a bonus.

Alternative routes

Behind Novo’s oral version four candidates are in pre-clinical studies, with Oramed Pharmaceuticals’ ORMD 0901 the most advanced having received regulatory clearance last September to start clinical trials.

The most advanced alternative delivery formulations of GLP-1s have also not progressed any further than phase I.

Of the two novel formulations of Byetta, Altea’s transdermal patch appears to be the most advanced, having completed phase I trials in April 2009 at which point Lilly and Amylin converted the original research collaboration into a formal development and commercialisation deal.

Meanwhile, MDRNA, formerly Nastech Pharmaceutical, signed a deal with Amylin in 2006 to develop a nasal spray formulation of Byetta and a year ago Amylin signalled its commitment to further development by paying MDRNA an accelerated $1m milestone.