Novo Anticipates Q4 Soft Launch For Closely Watched Oral GLP-1 Agent Rybelsus In The US
Executive Summary
US CMO Todd Hobbs told Scrip the full launch will be in early 2020 as sales, manufacturing and reimbursement preparations for oral semaglutide continue based on the now-approved FDA label in type 2 diabetes.
Fourteen years after the first approval of an injectable glucagon-like peptide-1 (GLP-1) agonist for the treatment of type 2 diabetes, Novo Nordisk AS won US Food and Drug Administration for the first oral GLP-1 agent – Rybelsus (semaglutide) – on 20 September.
Novo Nordisk US chief medical officer Todd Hobbs told Scrip in an interview that the company anticipates a soft initial launch in the fourth quarter of this year while sales teams are trained to market Rybelsus according to its label, as manufacturing is ramped up to meet commercial demand and while reimbursement negotiations with US payers to secure patient access continues. The company believes that more diabetes patients will be offered treatment with a GLP-1 agent now that physicians, particularly primary care doctors, have an oral drug to prescribe.
The US FDA approved Rybelsus 7mg and 14mg tablets as a once-daily therapy in combination with diet and exercise to reduce blood glucose in adults with type 2 diabetes, based on results from the PIONEER clinical trial program, which enrolled 9,543 patients in 10 studies and included head-to-head trials against Merck & Co. Inc.'s oral dipeptidyl peptidase-4 (DPP-4) inhibitor Januvia (sitagliptin), Eli Lilly & Co./Boehringer Ingelheim International GmbH's oral sodium-glucose co-transporter 2 (SGLT2) inhibitor Jardiance (empagliflozin) and Novo's once-daily injectable GLP-1 agent Victoza (liraglutide).
Making The GLP-1 Class More Accessible
The first GLP-1 agonist – AstraZeneca PLC's Byetta (exenatide), originally developed by Amylin Pharmaceuticals Inc. – was approved in the US in 2005 and Victoza has been on the market since 2010. However, Hobbs noted that while GLP-1 drugs have been able to safely lower blood glucose and reduce weight in diabetes patients – and have shown a reduction in cardiovascular risk – uptake has been limited by the fact that they are injectable therapies, despite inclusion in treatment guidelines from the American Diabetes Association (ADA) and other medical groups.
"In particular, if you look at the most recent treatment guidelines from ADA – and even at the [European Society of Cardiology (ESC)] meeting recently – and all of the cardiovascular associations, they basically favor SGLT2 inhibitors and GLP-1 agonists early and even right with metformin or first-line after metformin," Hobbs said. "That's where we really think that oral semaglutide is going to be able to move the use of GLP-1 earlier up into that area of the diabetes treatment cascade." (Also see "Novo Nordisk Touts First-Line Potential For Oral Semaglutide" - Scrip, 27 Jun, 2018.)
Data from the Phase III PIONEER 6 trial presented at the ADA meeting in June showed a 21% reduction in major adverse cardiovascular events (MACE) with Rybelsus, although the result versus placebo was not statistically significant. Nevertheless, the study showed that the oral drug appears to be safe for diabetes patients at high risk of cardiovascular events.
Novo Nordisk is running a larger cardiovascular outcomes trial for Rybelsus, but it already has filed supplemental applications with the US FDA seeking label claims that semaglutide and the company's once-weekly injectable GLP-1 agonist Ozempic (semaglutide) – first approved in December 2017 – reduce the risk of MACE. (Also see "Novo Nordisk Plans Value-based Contracts For GLP-1 Agonist Ozempic" - Scrip, 6 Dec, 2017.) Decisions on those applications are expected in the first quarter of 2020.
Hobbs noted that an FDA-approved label claim regarding MACE reduction would make doctors more comfortable prescribing Rybelsus, help payers give the product more favorable placement on their formularies, and boost the drug's status in treatment guidelines.
"The data has been published and ADA and other guidelines have looked upon semaglutide favorably, but we clearly think it's important to have it in the label and get the FDA's blessing on the data and the benefit," he said. "We are also conducting several outcomes studies, one of which is a cardiovascular outcomes trial with oral semaglutide, so if for some reason we don't get the indication with this application, we're going to generate further data to explore it in greater detail in the future."
Applications seeking approval for Rybelsus to treat adults with diabetes are under review in Europe, Japan and other ex-US markets.
US Launch Will Have A Slow Start
Hobbs noted that there are a lot of moving pieces involved in the US launch of Rybelsus, including manufacturing adequate supplies of the product, reimbursement negotiations with payers, and training that ensures sales representatives are prepared to market the drug in line with its label and the data generated in the PIONEER studies.
Because those efforts are ongoing, he said there will be a "soft, limited launch within a month or so" and a full launch in the first quarter of 2020.
Initial supplies of Rybelsus will come from Novo's manufacturing facilities in Denmark, but the company is bringing a manufacturing site online in Clayton, NC, and it acquired a tableting and packaging facility in Durham, NC earlier this year to supply the US market.
While the company still is negotiating reimbursement from US payers, Novo already has established a savings card program for patients with commercial insurance to reduce their out-of-pocket costs for Rybelsus to as little as $10 per month.
The drug's list price will be revealed within the next few business days, but Hobbs said it will be competitive with other GLP-1 agonists.
Novo's first- and second-generation GLP-1 drugs Victoza and Ozempic garnered a 53% share of new GLP-1 agent prescriptions in the US as of the second quarter of this year. Ozempic's sales exceeded analyst expectations at $349m in the second quarter – a needed boost as the company experienced a decline in sales for its blockbuster Victoza, which will face generic competitors in 2023.
"We continue to believe the company faces a fine balancing act in pricing [Rybelsus] to enable broad access, whilst minimizing market disruption and impact on its existing highly profitable injectable franchise," Deutsche Bank analyst Richard Parkes said in a 20 September note.
"It makes most sense to us to price Rybelsus close to injectable GLP-1s and gradually increase rebating to expand market access," Parkes added. "However, it remains possible that payers will be reluctant to provide broad access to an oral drug without meaningful rebates versus injectable drugs that naturally address a more limited patient population due to patient reluctance to initiate injectables."
The Deutsche Bank analysis viewed other investment banks' Rybelsus sales projections as close to best-case scenarios. Indeed, Jefferies analyst Peter Welford acknowledged in a 20 September note that its peak sales estimate of $7.2bn is above consensus forecasts.
Welford said he anticipates a Rybelsus list price closer to injectable GLP-1 agents with a pre-rebate cost of more than $700 per month versus pricing of about $770 for Ozempic and $920 for Victoza.
Dosing Requirements Also A Challenge
In addition to pricing, Rybelsus uptake also could be challenged by strict requirements for when and how patients take the drug – with no more than 4oz of water at least 30 minutes before eating or drinking anything or taking another oral medication.
Hobbs said he was worried about that issue when Novo first kicked off clinical trials for Rybelsus, but noted that the pill's efficacy in those studies wiped out any fears he had that patients wouldn't be able to take Rybelsus as directed and therefore wouldn't benefit from treatment. In fact, in pricing and reimbursement negotiations, payers have responded to the potential for improved adherence to GLP-1 therapy with an oral drug.
Jefferies analyst Welford also noted that prescribers are interested in an oral option as evidenced by standing room-only attendance at Rybelsus data presentations during the recent European Association for the Study of Diabetes (EASD) meeting in Barcelona.
"The symposium panel and presenters mused whether oral semaglutide 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," Welford wrote.
However, the Rybelsus label has a boxed warning about a potentially increased risk of thyroid C-cell tumors and it notes that the drug is not recommended as a first-line treatment for type 2 diabetes.
Rybelsus should not be prescribed to patients who previously have had medullary thyroid carcinoma (MTC) or have a family history of MTC. It also shouldn't be prescribed to patients who have ever been diagnosed with multiple endocrine neoplasia syndrome type 2 (MEN 2). Other safety warnings include pancreatitis, diabetic retinopathy, hypoglycemia, acute kidney injury and hypersensitivity reactions.
The most common side effects in clinical trials were nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation.