First-time data for the investigational oral formulation of Novo Nordisk’s semaglutide were presented at the annual meeting of the Endocrine Society. Billed as one of the company’s brightest pipeline prospects, it has sailed through a phase II trial.
Currently, GLP-1 receptor agonists are available only as injectables, either once daily or once weekly. Semaglutide is a long-acting GLP-1 receptor agonist that is also being developed as a once-weekly injectable. An oral semaglutide version leading to higher solubility and protection from enzymatic degradation is also being developed.
If the data is approved for marketing, this version of semaglutide would be the first-ever GLP-1 receptor agonist available in daily pill form.
In the phase 2 dose-finding study, HbA1C and weight reduction were of similar magnitude to that seen with the injectable GLP-1 receptor agonist formulations, and there were no red flags in terms of safety.
However, there may be issues relating to how food and other medications might affect the drug’s absorption and activity, and whether people with delayed gastric emptying or achlorhydria might respond differently to the drug. Also, that the higher doses required for efficacy compared with the injectable form might be costlier to produce.
The phase 2 study enrolled 632 adults with type 2 diabetes of 6 to 7 years’ duration, managed with lifestyle with or without metformin, and HbA1C 7.0% to 9.5% (mean, 7.9%). They were randomized to oral semaglutide in doses of 2.5, 5, 10, 20, or 40 mg once daily, or to placebo, or to open-label injected once-weekly 1.0-mg semaglutide. Patients started at 2.5 mg or 5 mg once daily and the higher-dose groups were titrated up at 4-week intervals.
Because food can interfere with the absorption of oral semaglutide, all the patients in the oral groups, including the blinded placebo arm, were instructed to take the pill fasting in the morning and to wait 30 minutes after taking the pill before eating breakfast. The primary endpoint was change in HbA1C from baseline to week 26.
At 26 weeks, mean HbA1C decreased dose-dependently with oral semaglutide, with drops ranging from 0.7% with 2.5 mg to 1.9% with 40 mg. Subcutaneous once-weekly semaglutide also produced a 1.9% drop in HbA1C, while the placebo group experienced a decrease of only 0.3% (P = .07 for 2.5 mg vs placebo, P < .0001 for other doses).
For all the groups taking 5-mg oral semaglutide or higher doses, more than 80% of the patients achieved HbA1C values less than 7%, and the groups treated with 10-mg dose or more achieved mean HbA1C less than 6.5%.
Fasting plasma glucose also dropped significantly, from a baseline of 170 mg/dL, with reductions ranging from 17 mg/dL with 2.5 mg to 51 mg/dL for the other oral doses (P = .08 for 2.5 mg, P < .0001 for other doses) and a reduction of 56 mg/dL with 1.0-mg subcutaneous semaglutide vs 1 mg/dL with placebo.
The proportion of patients achieving 5% or more weight loss was 21% to 71% in the oral group and 66% in subcutaneous group, compared with 13% in the placebo group.
None of the adverse events were considered serious and all were reported as mild to moderate in severity. Increases in lipase levels were greater in the oral and subcutaneous semaglutide groups, compared with placebo.
It was noted two separate arms of the study explored slow vs fast dose titration (8 weeks vs 2 weeks) and showed greater tolerability when titration was done more slowly. Also, the gastrointestinal effects were mostly mild to moderate and tended to diminish over time. Pancreatitis was confirmed in three patients (one with subcutaneous semaglutide and two with oral semaglutide 20 and 40 mg).
Based on these data, oral semaglutide is now being studied in a large phase 3 trial.
There’s a number of concerns that include the oral delivery of peptide drugs — food can interfere with drug absorption, which is why patients in the phase 2 trial were instructed not to eat for 30 minutes. In the real world, patients may not follow this instruction perfectly. It will be important to understand whether imperfect compliance will cause significant variability in drug response.
Also, it was noted that pH can affect solubility and bioavailability of oral semaglutide, and it will be important to study interactions with proton-pump inhibitors or concomitant conditions such as achlorhydria or disorders such as gastroparesis. Plus it was pointed out that the large dosing difference between the oral and injectable versions might mean higher cost for the oral version.
It is noted that doses of 10 to 40 mg of oral drug were required to achieve similar efficacy as 1 mg of subcutaneous semaglutide, presumably because oral bioavailability is substantially less than 100%. The larger dose will likely be associated with higher manufacturing costs for the oral formulation.
- The most common adverse events were nausea and vomiting.
- Once-daily oral semaglutide improved glycemic control and body weight in type 2 diabetes.
- Oral semaglutide had no new safety or tolerability findings compared with subcutaneous semaglutide.
Researched and prepared by Steve Freed, BPHarm, Diabetes Educator, Publisher and reviewed by Dave Joffe, BSPharm, CDE
ENDO 2016; Boston, Massachusetts; April 2, 2016. Abstract OR15-3
Phase III trials begin for new oral type 2 diabetes drug semaglutide. http://www.diabetes.co.uk/news/2015/aug/phase-iii-trials-begin-for-new-oral-type-2-diabetes-drug-semaglutide-96135914.html
Novo Nordisk’s game-changing oral diabetes drug clears Phase II. http://www.fiercebiotech.com/r-d/novo-nordisk-s-game-changing-oral-diabetes-drug-clears-phase-ii
GLP-1 Analog Semaglutide – Oral Formulation starts Phase 3a Development. http://diabetesnewsjournal.com/2015/08/27/glp1-analog-semaglutide/
Novo Nordisk’s oral GLP-1 analogue looks set for phase III. http://www.pmlive.com/pharma_news/novo_nordisks_oral_glp-1_analogue_looks_set_for_phase_iii_659823