As the race for oral glucagon-like peptide-1 receptor agonists (GLP-1RA) intensifies, physicians hope that their small molecule format will make obesity treatments more accessible for patients.
Both Novo Nordisk and Eli Lilly have announced Phase III data from their respective drugs, semaglutide and orforglipron, with their eyes set on approval from the US Food and Drug Administration (FDA).
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In Novo Nordisk’s OASIS4 trial (NCT05035095), oral semaglutide at a 25mg dose demonstrated 13.6% weight loss compared to 2.2% in the placebo cohort after a 64-weeks of treatment. Meanwhile, Lilly’s Phase III ATTAIN-1 trial (NCT05869903), demonstrated that all three doses of once-daily orforglipron delivered statistically and clinically meaningful weight loss of up to 12.4% in the high dose cohort (36mg) after 72 weeks.
Lilly later announced that orforglipron outperformed oral semaglutide in a head-to-head study in type 2 diabetes, also showing higher weight loss. In the ACHIEVE-3 trial (NCT06045221), which compared the GLP-1RAs in 1,698 patients with type 2 diabetes, orforglipron met all the primary and secondary endpoints, delivering greater improvements in A1C and weight loss. Patients receiving orforglipron lost 6.7% body weight in the low dose and 9.2% on the high dose compared with 3.7% and 5.3% in low and high dose oral semaglutide, representing a 73.6% greater relative weight loss at the highest dose comparison.
While manufacturing capacity for injectable GLP-1RAs has struggled to keep pace with demand, Eli Lilly has stockpiled nearly $550m worth of pre-launch inventory for its weight-loss pill orforglipron, positioning itself well ahead of regulatory approval.
Novo Nordisk’s oral semaglutide is already available to patients with type 2 diabetes, marketed as Rybelsus. The Danish company has invested $4.1bn in a manufacturing facility in Clayton, North Carolina, along with a new site near Durham, showing it is preparing for increased demand of the oral formulation.
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By GlobalDataThe GLP-1RA class has revolutionised the diabetes and obesity treatment space, with GlobalData analysis predicting drug sales in obesity will surpass $126bn by 2030, dominated by Eli Lilly and Novo Nordisk.
According to GlobalData’s GLP-1R Agonists Label Expansions/Repurposing: Market Overview report, beyond obesity and type 2 diabetes, the potential of this drug class stands on its anti-inflammatory and insulin-sensitising properties.
GlobalData is the parent company of Clinical Trials Arena.
Dr Katherine Saunders, an obesity specialist and co-founder of FlyteHealth, a company focused on scaling and democratising access to comprehensive medical obesity care, tells Pharmaceutical Technology that while oral GLP-1RAs are likely to have a major impact, her primary hope is that lower costs will make them more accessible than injectable treatments.
Editor’s note: This interview has been edited for length and clarity.
Abigail Beaney (AB) We’re already seeing front-runners in Eli Lilly and Novo Nordisk, who are both set to put in their applications for their oral GLP-1RAs in obesity. How will oral GLP-1RAs impact the weight loss space?
Dr Katherine Saunders (KS): This is a very exciting time for the field of obesity medicine. For years, we had limited options, and we’ve done our best to help our patients in as personalised a way as possible. Obesity is such a heterogeneous disease where it’s not a one-size-fits-all approach, and not everybody responds to the same kinds of treatment. Therefore, the more options that we have, the better we can really treat people in a personalised, effective, and tolerable way. We have a few that are looking promising, and many more in the pipeline. The GLP-1RA class of medication has already been wonderful for the field, so to be able to have it in an oral form is a huge asset.
AB: Do you think that Eli Lilly and Novo Nordisk will continue to be the front-runners, or are you foreseeing any other players that may potentially have a real impact on their market dominance?
KS: Eli Lilly and Novo Nordisk absolutely have the first player advantage, and their names are so recognisable in the space, and they have oral agents that are very good agents, but others will definitely emerge as strong competitors. It really all comes down to efficacy, tolerability, ease of administration, half-life, coverage, and more. There are so many different factors, so until Phase III trials are done, and medications are FDA-approved, it’s hard to know where everything will stand
AB: While taking a tablet is much easier than a subcutaneous injection, it is daily, whereas subcutaneous is less frequent. Do you think that patients will prefer an oral daily, or do you think there’ll be some patients that will just prefer the less frequent subcutaneous application?
KS: All the patients I see have at least one other weight-related health complication – obesity is associated with over 200 weight-related health complications. The average patient we see is on at least a few medications that may change as they lose weight and their health complications improve with weight loss, but because people are already taking daily pills, adding another pill is usually not such a huge problem, whereas when somebody you know is taking a weekly injectable, it can be very easy to forget something that it is weekly, unless they have something else in their life that’s weekly that they’re attaching that to.
AB: Regarding transitioning patients, do physicians know how to properly transition patients if they do want to have an oral GLP-1RA, as opposed to injectable?
KS: That’s a good question. When we switch among different GLP-1RAs, there isn’t an exact equivalent dose. We, as experts in the field and providers who’ve been doing this for a long time, do not have much of an issue with this, but for newer providers, it can be a little bit tricky.
Again, with obesity, there’s so much heterogeneity in terms of the disease itself, and there’s so much variability in terms of people’s responses to any different treatment.
The way I usually do it, because we make these changes very thoughtfully, we include the patient in our decision-making. If we want to be conservative, we can potentially underdo it, and if we want to be aggressive, we can potentially overdo it. I talk about what that means and let the patient decide, depending on their characteristics, and if there are other risks involved – it’s not just like an easy ‘let’s switch you over’, we do everything in a very thoughtful way with a lot of education and support.
AB: Do you think oral GLP-1RAs are potentially going to be more cost-effective?
I’m hoping that will be the case, but I don’t know for sure that the orals will be less expensive than the injectables. If you think about just the injection apparatus itself, that’s very expensive, and that’s been one of the limiting factors in terms of producing enough of the medications. As a result, I’m hoping with oral that the price comes down, because that’s been such a big barrier to access to care. One thing we do know for sure is that small molecules are easier to produce than peptides.
AB: Do you think that having an oral option will make even more patients consider these kinds of therapies?
KS: Having been in this field for a long time, it’s fascinating to see the evolution. When I was first practising a decade ago, it was a crazy idea for people to treat obesity – people weren’t even talking about obesity. The idea of needing to take a medication long-term, or even an injectable medication to treat obesity, was just not as accepted.
I think we’re just getting started. If you look at the numbers, under 10% of people who are eligible for obesity medications are taking them. The ability to take a pill instead of an injection, at a hopefully lower price, improved coverage, and more providers being educated about obesity and how to treat it will change what we see, and I think that we still have a way to go.
