Bagsvaerd, Denmark-based Novo Nordisk A/S' chief medical officer, Todd Hobbs, told BioWorld it "won't be too much longer" – probably a week or so – before the firm sets pricing of oral once-daily Rybelsus (semaglutide) in type 2 diabetes, approved Friday thanks to a priority review voucher that guaranteed a greased path for the first non-injected glucagon-like peptide (GLP-1) receptor protein therapy.

Rybelsus won U.S. regulators' nod at 7-mg and 14-mg doses to improve control of blood sugar in adults with proper diet and exercise. The approval hardly surprised Wall Street.

In October 2017, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee gave its blessing with a 16-0 vote and one abstention to recommend the marketing go-ahead. Panelists deliberated over findings from five phase III studies and a cardiovascular outcomes trial with semaglutide, the longer-acting version of Victoza (liraglutide) from Novo. (See BioWorld, Oct. 19, 2017.)

Jefferies analyst Peter Welford wrote in a report Friday that the oral symposium on Rybelsus at the European Association for the Study of Diabetes meeting in Barcelona, Spain, "was standing-room only, with subsequent numerous presentations also well attended, despite limited significant new data. The symposium panel and presenters mused whether [the drug] could increase acceptance of GLP-1s amongst physicians and patients, and change GLP-1 prescribing habits, particularly amongst primary care physicians, and potentially also make GLP-1 use more frequent and bringing it earlier in the treatment paradigm." He estimated $7.2 billion in worldwide peak sales. Novo's injectable version of semaglutide was approved as Ozempic in late 2017.

Non-insulin therapies for type 2 diabetes, GLP-1 drugs restore a normal body hormone that's often found in levels too low in type 2 diabetes patients. Rybelsus – investigated in a wide-ranging clinical program called Pioneer – slows digestion, blocks sugar production in the liver and boosts insulin output by the pancreas. Two experiments testing the candidate were placebo-controlled and several compared Novo's bid to GLP-1 injected drugs. Rybelsus was studied as a monotherapy and when paired with other diabetes treatments, including metformin, sulfonylureas (insulin secretagogues), sodium-glucose co-transporter-2 (SGLT2) inhibitors, insulins and thiazolidinediones. "We went up against the leaders in those other classes, Jardiance [empagliflozin, Boehringer Ingelheim GmbH/Eli Lilly and Co.] as well as the DPP4 inhibitors, and our own Victoza," Hobbs noted. He said a "remarkable number of primary care physicians in particular" are not getting the benefits of GLP-1s for their patients because of the injection route – disliked by patients as well as doctors, he said, noting that the pill should bring better compliance. Jardiance an SGLT2 inhibitor.

Word on two more NDAs to come

The Pioneer effort, which yielded positive findings on blood sugar and weight, included 10 clinical experiments enrolling 9,543 participants. Standalone treatment with Rybelsus in placebo-controlled studies turned up a significant reduction in hemoglobin A1c (HbA1c) vs. the inactive treatment. Specifically, after 26 weeks, 69% of those taking 7 mg once daily and 77% of those taking 14 mg once daily of Rybelsus decreased their HbA1c to lower than 7%, compared with 31% of patients on placebo.

The FDA's go-ahead comes with a boxed warning about the potential increased risk of thyroid c-cell tumors, pointing out that Rybelsus is not recommended as the first choice of medicine for treating diabetes. Patients who have ever had medullary thyroid carcinoma (MTC) or who have a family member who has ever had MTC are advised to stay away from the compound. Those who have ever had multiple endocrine neoplasia syndrome type 2 are steered from the new drug as well. Rybelsus is not for use in patients with type 1 diabetes and people with diabetic ketoacidosis.

More cautionary language about Rybelsus cites the possibility of pancreatitis, diabetic retinopathy, hypoglycemia, acute kidney injury and hypersensitivity reactions. Physicians are reminded it's not known whether the treatment can be used by patients who already have had pancreatitis, and the risk of hypoglycemia increased when Rybelsus was paired with sulfonylureas or insulin. Rybelsus' most common side effects are nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation. "The good news is there's nothing new," Hobbs said. "These [risks] are all fairly standard class labeling for GLP-1-class agents."

Three factors influence the launch date. "One is that we have enough of the product in the pharmacies," Hobbs said. "That's a pretty significant challenge. We've been ramping up production in our Denmark plant of the active ingredient. In a year or so, we'll shift back to our North Carolina plant." Also, the field force needs to be trained. The third and most important piece involves securing access on the formularies. "With all that said, the full launch will be the first part of 2020," he predicted, though limited sales likely will start in the next month or so.

Novo submitted the NDA for Rybelsus in March. A second NDA for the oral semaglutide seeks approval for an indication to reduce the risk of major adverse cardiovascular events (MACE) such as heart attack, stroke, or death in adults with type 2 diabetes and established cardiovascular disease (CVD).

Novo also filed a supplemental NDA for its once-weekly Ozempic injection 0.5 mg or 1 mg. The company is pursuing an indication to reduce the risk of MACE such as heart attack, stroke, or death in adults with type 2 diabetes and established CVD. "We're asking for similar language in both labels," Hobbs said. Rybelsus deploys Roseland, N.J.-based Emisphere Technologies Inc.'s Eligen SNAC Carrier Technology.

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