Oral GLP-1 Agonist Promising in Phase 2 in Type 2 Diabetes

Miriam E Tucker

April 03, 2016

BOSTON — A novel oral formulation of a glucagonlike peptide-1 (GLP-1) receptor agonist has shown "robust" dose-dependent glucose lowering and weight reductions in patients with early type 2 diabetes in a phase 2 study.

First-time data for the investigational oral formulation of Novo Nordisk's semaglutide were presented here at the annual meeting of the Endocrine Society, ENDO 2016, by Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center at Medical City and clinical professor of medicine, University of Texas Southwestern Medical Center.

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. The oral version is coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC, Eligen Technology), which causes a localized increase in pH, leading to higher solubility and protection from enzymatic degradation, Dr Rosenstock explained.

If the data pan out and it 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.

"For the first time, we're able to give a peptide by mouth and have an effect. The effects are very robust in terms of HbA1c reduction and weight loss," Dr Rosenstock told Medscape Medical News.

Asked to comment, Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, said: "Many companies have worked for years to develop orally bioavailable peptide diabetes drugs. It is incredibly impressive that oral semaglutide has achieved remarkable efficacy comparable to that of once-a-week injectable semaglutide."

However, he cautioned that 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, he pointed out that the higher doses required for efficacy compared with the injectable form might be costlier to produce.

Dose-Dependent Effects; Phase 3 Trial Ongoing

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 end point 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%, Dr Rosenstock added.

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.

Body weight also dropped dose-dependently from a baseline of 92 kg, by 2 to 7 kg with oral semaglutide and 6 kg with subcutaneous semaglutide, vs 1 kg with placebo. The reductions were statistically significant vs placebo at oral semaglutide doses of 10 mg and above (P < .0001).

The proportion of patients achieving a 5% or greater weight loss was higher for both oral (21%–71%) and subcutaneous (66%) semaglutide vs placebo (13%).

Side effects were also dose-dependent and reported by 63% to 86% patients on oral semaglutide, 81% on subcutaneous semaglutide, and 68% on placebo.

Mild/moderate gastrointestinal adverse events were the most commonly occurring in the semaglutide groups, with nausea occurring in 13% to 34%, vomiting in 6% to 22%, and diarrhea in 7% to 23%.

Discontinuation due to adverse events occurred in 6% to 9% at the lower doses of semaglutide and up to 27% with the higher doses, mostly due to gastrointestinal events.

However, Dr Rosenstock 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, Dr Rosenstock said.

Development Plan Needs to Address Number of Issues

However, "a number of challenges…will need to be addressed in the development plan" for semaglutide, Dr Taylor told Medscape Medical News.

These 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," he explained.

In addition, Dr Taylor noted that because pH can affect solubility and bioavailability of oral semaglutide, "it will be important to study interactions with proton-pump inhibitors or concomitant conditions such as achlorhydria or disorders such as gastroparesis."

And, he pointed out, the large dosing difference between the oral and injectable versions might mean higher cost for the oral version.

"It is noteworthy 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."

If the result is significantly higher cost, Dr Taylor added, "It will be interesting to see whether payers assign value to the convenience of oral administration, especially when compared with once-weekly administration of a ready-to-use formulation of an injectable drug. In any case, it is exciting to see that patients are offered an increasingly attractive set of therapeutic options."

Dr Rosenstock is a consultant to, advisory group member of, or researcher for Janssen Pharmaceuticals, Daiichi Sankyo, Merck, Sanofi, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Lexicon Pharmaceuticals, Intarcia, Hanmi, GlaxoSmithKline, Takeda, AstraZeneca, and Novartis Pharmaceuticals . Disclosures for the coauthors are listed in the abstract. Dr Taylor was previously a vice president at Bristol-Myers Squibb (2002–2013) and a scientific advisor at Calibrium (2014–2015), which was sold to Novo Nordisk in 2015. He has no continued relationship with Novo Nordisk. He currently owns stock in Bristol-Myers Squibb and is a consultant at Aegerion and at Ionis Pharmaceuticals. He has no current disclosures related to GLP-1 receptor agonists.

ENDO 2016; Boston, Massachusetts; April 2, 2016. Abstract OR15-3

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