Novo Nordisk is developing an oral formulation of their glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide to treat type 2 diabetes (T2D). Emisphere Technologies’ Eligen technology is being used to deliver and ensure the bioavailability of oral semaglutide across the gastrointestinal (GI) tract. In August 2015, Novo Nordisk announced the decision to progress oral semaglutide through Phase III trials, following positive results from Phase II trials. The Phase III PIONEER program for oral semaglutide comprises of seven trials (including a cardiovascular outcomes trial [CVOT]) involving approximately 9,000 patients; all trials were initiated in 2016.
The PIONEER 1 trial achieved its primary objective by demonstrating significant and superior improvements in glycated hemoglobin (HbA1c) for all three doses of oral semaglutide (3mg, 7mg, and 14mg) compared with placebo. Oral semaglutide appeared to be safe and well tolerated in this global 26-week trial of over 700 people with T2D.1 People treated with 3mg, 7mg and 14mg oral semaglutide achieved reductions in HbA1c of 0.8%, 1.3% and 1.5%, respectively, compared with a reduction of 0.1% in people treated with placebo; the mean baseline HbA1c was 8.0%. Furthermore, the 14mg dose of oral semaglutide demonstrated significant and superior weight loss versus placebo. Weight loss was observed for the 7mg and 3mg doses but did not reach statistical significance.
PIONEER 2 is comparing semaglutide with sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin. This trial achieved its primary goal by demonstrating a statistically significant and superior improvement in HbA1c with oral semaglutide compared with empagliflozin at 26 weeks. However, the difference in weight loss between oral semaglutide and empagliflozin was not statistically significant.2
PIONEER 3 trial too achieved its primary objective by demonstrating statistically significant and superior reductions in HbA1c with oral semaglutide 7mg and 14mg, compared with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin at week 26. In addition, people treated with oral semaglutide 7mg and 14mg achieved statistically significant and superior reductions in body weight compared to sitagliptin at week 26.3
PIONEER 4 (NCT02863419) is a head-to-head with Novo Nordisk’s own liraglutide rather than a less-efficacious GLP-1 receptor agonist. PIONEER 5 (NCT02827708) is investigating the efficacy and safety of oral semaglutide versus placebo in subjects with T2D and moderate renal impairment while the aim of the PIONEER 6 trial (NCT02692716) is to investigate the cardiovascular safety of oral semaglutide in subjects with T2D.
The highest oral semaglutide dose assessed (40 mg) in the Phase II trial had comparable efficacy to once-weekly injectable semaglutide (1 mg) but with considerably more adverse events (AEs)4. Consequently, lower doses (2.5 mg, 5 mg, 10 mg, 20 mg) are being assessed in the Phase III program, although the lower doses come at the risk of reduced efficacy compared with injectable semaglutide. The PIONEER 7 trial appears designed to overcome this problem by using a flexible dosing strategy in a head-to-head trial with sitagliptin.
The results thus far from the PIONEER program are overall positive for oral semaglutide. The fact that the first of these PIONEER trials compare oral semaglutide with sitagliptin and empagliflozin, suggests that Novo Nordisk views oral semaglutide as a direct competitor to the DPP-IV and SGLT-2 inhibitors. Should oral semaglutide remain superior to sitagliptin while minimizing GI AEs through flexible dosing in the PIONEER 7 trial, it will boost the efficacy and tolerability profile of oral semaglutide as an alternative to DPP-IV inhibitors. Positive results in PIONEER 4 may also encourage physicians to switch patients from liraglutide to oral semaglutide prior to liraglutide’s patent expiration in 2022.
Acknowledging that the GLP-1 receptor agonist drug class is one of the most efficacious therapeutic options available for the treatment of T2D, an oral formulation will increase both patient and payer willingness to use these therapies earlier in the treatment algorithm. However, questions remain if the oral formulation will deliver the same efficacy as injectable formulations due to the difficulties in preserving the bioavailability of the drug when delivered orally. Another obstacle to the development of oral semaglutide will be the incidence of GI-related AEs. GI AEs are among the most commonly cited with the use of injectable formulations of GLP-1 receptor agonists. Given the increased incidences of GI AEs reported in Phase II and Phase III trials, the concern is that an oral administration of semaglutide may exacerbate these AEs. However, it is important to note that the increase in GI effects may be a result of the higher dose being administered orally rather than the oral formulation itself. Needless to say, physicians and payers alike are eagerly awaiting further results from the PIONEER program given that the injectable delivery of the GLP-1 receptor agonists (aside from cost) is their major drawback. Considering the weight loss and glucose-lowering efficacy of the class, a safe and well tolerated oral GLP-1 receptor agonist will be a highly desirable therapeutic option for T2D.
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1 Novo Nordisk, press release, February 22, 2018. https://www.novonordisk.com/content/Denmark/HQ/www-novonordisk-com/en_gb/home/media/news-details.2170941.html
2 Novo Nordisk press release, May 29, 2018. https://www.novonordisk.com/content/Denmark/HQ/www-novonordisk-com/en_gb/home/media/news-details.2195846.html
3 Novo Nordisk press release, June 28, 2018. https://www.novonordisk.com/content/Denmark/HQ/www-novonordisk-com/en_gb/home/media/news-details.2201779.html
4 Davies M, et al. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2017;318(15):1460-1470.
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Jihan Khan, Ph.D., is a director in the oncology team at DRG. Dr. Khan manages a team of analysts who conduct extensive primary and secondary market research on several oncology indications across the major pharmaceutical markets. She also provides sales and client support across DRG oncology products.
Previously, Dr. Khan was a principal analyst on the cardiometabolic team at DRG. Her specialties were the type 2 diabetes and renal disorders markets. Dr. Khan provided forecasts of these pharmaceutical markets by evaluating the agents in development and the changing clinical behaviors and conducting primary research with payers and physicians. Prior to joining DRG, she worked as a knowledge specialist in a company where she conducted in-depth research on products and processes for commercialization. She obtained her Ph.D. in organic chemistry from Brandeis University and was a postdoctoral fellow at Brigham and Women’s Hospital and Harvard Medical School.