Novo Nordisk initiates phase 1 trials for oral insulin candidate NN1952 – December 14, 2009

Novo Nordisk announced the initiation last week of the first phase 1 trial for the company’s oral insulin candidate, NN1952. According to clinicaltrials.gov (NCT01028404), this is a two-part trial that is expected to enroll 84 individuals, including healthy volunteers and insulin-treated type 1 and type 2 diabetes patients. This trial will consist of two substudies (one in healthy volunteers and one in type 1 and type 2 patients) that will compare the effects of NN1952 to an active comparator, insulin aspart (Novo Nordisk’s NovoLog), and placebo. In part one, escalating doses of NN1952 will be given to healthy volunteers. In part two, barring any unforeseen safety issues in healthy subjects, single doses of NN1952 will be given to type 1 and type 2 diabetes patients with or without a meal (presumably to test how the insulin works to cover carbs and to correct high blood glucose). The primary outcome of the study is the number and severity of adverse events after three visits for part one and six visits for part two. Secondary outcome measures are the 12-hour area under the serum insulin concentration-time curve after a single dose and the 12-hour area under the glucose infusion rate-time curve after a single dose. The study’s estimated completion date is May 2010. As expected, Novo Nordisk will use this study to also investigate the pharmacokinetic and pharmacodynamic profiles of NN1952. At the Reuters Health Summit in November, Novo Nordisk CEO Lars Sorensen said the drug could be on the market within six years. Although this phase 1 trial should shed light on basic safety concerns, we are also very interested in bioavailability and other pharmacological properties, especially in relation to the active comparator, insulin aspart. We are also interested in learning more about absorption, “time in zone” (although presumably monitors won’t be used at this early stage), ease of use and the perceived hassle factor by patients and healthcare providers.

Novo Nordisk paid a $2 million milestone payment to Merrion Pharmaceuticals on its initiation of phase 1 trials for NN1952; the two companies established a licensing and development agreement one year ago. As a reminder, Merrion is focused on developing oral formulations of drugs that have poor absorption and are generally administered via injections. The partnership strikes us as one similar to the partnership Novo Nordisk established with Aradigm in 2001 to explore the company’s interest in an inhaled insulin formulation. While that program was terminated in May of 2008 after the commercial failure of Pfizer’s Exubera, Novo Nordisk is clearly taking a more aggressive approach with this oral insulin development program and a more pioneering (rather than potential “fast follower”) role – the enthusiasm it is directly toward oral insulin has taken us a bit by surprise; for example, the company is building a center of excellence for oral protein development (see Closer Look ) and we take Sorensen’s proposed timeline of six years to mean the company will be interested in committing serious resources to this project as the development program progresses.

• Nearly one year ago, Novo Nordisk and Merrion Pharmaceuticals entered into a license and development agreement, in which Merrion holds responsibility for early development of the oral formulations and Novo Nordisk responsible for development expenses and commercialization. According to the agreement, Merrion could receive up to $58 million for the first oral candidate to complete the phases of development as well as obtain regulatory approval. We see this as a particularly positive agreement for Novo Nordisk; the downside, given its intent, is that it seems on the low side given the apparent upside with which they view the market (Novo Nordisk paid $55 million in cash for Aradigm’s inhaled insulin program in 2004).
• Merrion’s gastrointestinal permeation technology (GIPET) enhances the intestinal delivery of compounds by releasing them in the duodenum along with an ‘absorption enhancer’. The technology relies on enteric-coated tablets that target the duodenum by co-releasing this absorption enhancer with the drug. The presence of both compounds improves the absorption and transport of the drug across the duodenal cell membrane, resulting in increased bioavailability. It’s not yet clear if this method of delivery will affect the efficacy or tolerability of Novo Nordisk’s insulins; however, we look for phase 1 studies to shed more light.
• Aside from safety issues, we are very interested in the bioavailability, absorption and general pharmacological profile of NN1952, especially compared to Novolog. Initially, NN1952 will be designed as a prandial compound for type 2 patients, however, the compound is also being tested in type 1 patients in as early as the first phase 1 study. At the recent Reuters Health Summit, CEO Lars Sorensen noted the drug could be on the market within six years. One major challenge in developing an oral insulin is to achieve a high level of bioavailability and therefore minimize the cost of goods sold (COGS). According to conversations with those familiar with the technology, the company has demonstrated clinically acceptable bioavailability in animal models that it believes will ultimately lead to commercial viability. Currently, we know of at least three companies with oral insulin candidates in clinical trials: Biocon’s IN-105 (currently in phase 3), OraMed’s ORMD-0801 (currently in phase 2b), and Diabetology’s Capsulin (currently in phase 2b).

-- by Sanjay Trehan, Jessica Swienckowski, and Kelly Close