Diabetes would not have been much of a concern a century ago, but it would be interesting to hear Sigmund Freud's reaction to the news from Novo Nordisk this week, who announced that they are planning to invest as much as $3.7 billion in developing six diabetes pills, among which will be oral versions of existing injectable insulin and GLP-1 receptor agonist therapies. No doubt Freud would claim that Novo Nordisk's motivation for the pursuit of oral therapies lies deep in the human psyche, but the reality is far different and far more lucrative.
Novo Nordisk is not the first company to pursue the development of oral versions of GLP-1 receptor agonists or oral insulin formulations. The Israeli biotech Oramed has initiated Phase II trials of the oral insulin ORMD-0801 and the oral GLP-1 receptor agonist ORMD-0901; while an oral insulin/GLP-1 receptor agonist fixed-dose combination tablet of these two agents is in pre-clinical development (for a greater discussion of Oramed's oral insulin formulation, see our previous blog entry).
It is well documented that the acidic environment of the digestive tract can impact on the bioavailability of orally-administered drugs, as can simpler factors such as dietary habits. Therefore it may appear counterintuitive to pursue oral versions of insulin in particular, which requires a predictable pharmacokinetic response. The level of investment promised by Novo Nordisk for oral therapies suggests an oral fixation that even Freud might struggle to explain. However, there are significant grounds for optimism.
Novo Nordisk has partnered with two firms that offer the ability to administer injectable therapies orally. Firstly, Novo Nordisk has partnered with Emisphere to develop oral versions of both insulins and GLP-1 receptor agonists using their proprietary Eligen® technology that ?uses passive transcellular transport to enable drug molecules of all sizes to cross cell membranes? without affecting the drugs pharmacological properties (full details on the Eligen® technology are available here). Novo Nordisk has also entered a partnership agreement with Merrion Pharmaceutical to utilize their GIPET® (GastroIntestinal Permeation Enhancement Technology) platform. By partnering with both Emisphere and Merrion so early in the development of these agents, Novo Nordisk has been able to gain access to two delivery platforms for a relatively small investment (the Emisphere ?Insulin Agreement? includes $57.5 m in potential payments for an initial $5 m downpayment; the Merrion agreement promises up to $58 m in payments for the first oral insulin to reach the market), doubling Novo Nordisk's chances of bringing an oral formulation to market for a fraction of a drug's potential sales.
Further grounds for optimism lie in the scale of the development of the oral agents prior to the promised investment of $3.7 billion to advance their development. Having analyzed Novo Nordisk's pipeline, we have identified six potential therapies that we believe are those candidates that Novo Nordisk plan to develop (detailed in the table below). Five of the six agents have completed Phase I testing, while the other candidate, a sustained-release oral version of the GLP-1 receptor agonist semaglutide (NN-9928), is currently undergoing Phase I testing in as many as 160 subjects. The breadth of Phase I development in these agents again increases the chances of Novo Nordisk successfully bringing these agents to market.