Novo Nordisk’s recent growth renaissance has arrived thanks in no small part to semaglutide—the GLP-1 molecule behind the company’s leading marketed trio of Ozempic, Rybelsus and Wegovy.
These days, much of the semaglutide hype surrounds Ozempic’s domination in diabetes, plus Wegovy’s potential to stir the slumbering giant that is the global obesity market. But even as the molecule’s metabolic empire prospers, Novo Nordisk isn’t letting its GLP-1 stay in its comfort zone. Novo is also pitting the drug against a pair of elusive targets: nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease.
And while CEO Lars Fruergaard Jørgensen is quick to admit the company’s ambitions in these new diseases are among Novo’s “most risky” R&D endeavors, the payoff for patients could be “tremendous,” he said during a recent interview at Novo Nordisk’s headquarters in Plainsboro, New Jersey.
Novo throws down the NASH gauntlet
NASH is about as hyped as it has been perilous to drugmakers' development engines—a fact Novo Nordisk’s CEO didn’t shy away from.
In fact, semaglutide has already come up short in NASH once. In June, Novo revealed the GLP-1 failed to match placebo in a phase 2 study. Among 71 patients in the trial, just 10.6% of those on semaglutide experienced an improvement in liver fibrosis without their disease getting worse. That compared with 29.2% of patients on placebo, according to data presented at the 2022 annual meeting of the European Association for Study of the Liver.
Nevertheless, the company stands behind its GLP-1 contender. As Jørgensen sees it, semaglutide’s impressive “weight-lowering potential” could help the med make inroads in NASH, where it has a “relatively good chance of working” in the disease’s early stages but “not the fibrotic stage,” the helmsman said.
“Based on the weight-management profile, if we can show that [semaglutide] can halt progression of the early stages, I think that’s attractive,” Jørgensen explained.
The helmsman’s comments suggest semaglutide may be cruising for a bruising in a separate phase 3 trial targeting NASH patients who’ve already advanced beyond the disease’s non-fibrotic stages.
Novo kicked off that late-stage research study, called ESSENCE, back in April 2021. That trial, which is expected to wrap up by late May of 2028, according to ClinicalTrials.gov, is looking at NASH patients with histological evidence of stage 2 or stage 3 fibrosis.
Much like in cancer, Jørgensen figures it will take combinations of “complementary mechanisms” to make a major dent in late-stage disease. For its part, Novo is weighing possible combo regimens in late-stage NASH, the CEO added.
Apart from the late-stage ESSENCE study—where semaglutide is on its own—investigators are testing a combo with Gilead Sciences’ cilofexor and firsocostat in a phase 2 trial. That study is assessing the triple combination prospect in NASH patients with cirrhosis, the next stage of disease after fibrosis, according to the online resource NASHFacts.com.
That study is expected to conclude by March 2024, and it’s testing both oral and under-the-skin injectable versions of semaglutide. The phase 2’s primary endpoint is the percentage of patients who hit a certain improvement in fibrosis according to NASH Clinical Research Network measures, without their disease getting worse.
Still, “NASH is not an easy place to go,” Jørgensen acknowledged. “Honestly, not a lot of it has come out positive,” the helmsman said of other efforts across the industry.
Sema's Alzheimer’s obligation
As difficult a goal as NASH is, it’s nothing compared to semaglutide’s uphill climb in Alzheimer’s.
Novo's decision to kick off late-stage oral semaglutide development in the confounding neurodegenerative disease was inspired by “GLP-1 data from preclinical models, real-world evidence studies, post-hoc analysis of data from large cardiovascular outcomes trials, as well as discussions with regulatory authorities," the company said in December 2020.
Jørgensen admitted Alzheimer’s is a distant target, though his company does see “some potential” for GLP-1s in the disease. That said, “it will take quite some years before we have the data,” Jørgensen pointed out. Novo’s Alzheimer’s work makes for “probably the most risky phase 3 program we have ever conducted,” he added.
Novo’s been evaluating semaglutide in Alzheimer’s for about a year and a half now. The company kicked things off at the end of 2020 by unveiling a research study evaluating a 14-mg oral dose of the GLP-1.
The late-stage trial officially started in May 2021. Novo expects to complete the main leg of the study by August 2024, with the goal to wrap things up for good in April 2026, according to ClinicalTrials.gov.
Novo is measuring its molecule’s effect on patients’ clinical dementia ratings, which measure the toll that cognitive declines take on functioning across areas such as memory, judgment and problem solving. The ratings also look at so-called function domains, which include involvement in community affairs, home and hobbies and personal care.
Secondary outcomes being watched in the study include a patient’s time to advance to dementia plus patients’ scores on various metrics used to evaluate Alzheimer’s progress.
Novo feels a certain obligation to run trials in Alzheimer’s on the chance its drug holds promise.
“If [semaglutide] could turn out to directly benefit patients living with cognitive disorder, we ought to generate those data,” Jørgensen said.
With that in mind, Jørgensen acknowledged Novo will have to wait and see how commercially successful an Alzheimer’s nod could be. Given the time it would take to generate data for a potential green light, semaglutide would likely be closing in on a patent expiration. In turn, the med could enjoy some “good years” in Alzheimer’s—if approved—Jørgensen said. The silver lining for patients, meanwhile, could come in the form of cheaper Alzheimer’s generics, which Jørgensen said would constitute a “major contribution to society.”
Saxenda holds the line
Jørgensen’s comments came shortly after the company reported a stellar showing in 2022’s second quarter. For the entire first half of the year, Ozempic grew sales 73%, the CEO pointed out. Over that same stretch, Novo recorded net revenues of 83.29 billion Danish kroner (about $11.36 billion), an increase of 25%. For the rest of the year, Novo now expects to grow sales 12% to 16% at constant currencies. The company previously forecast sales growth between 10% and 14%.
In weight loss specifically, Novo’s sales climbed a staggering 83% for the quarter. However, Wegovy sales were down sequentially, slipping to 1.18 billion Danish kroner ($161 million) versus the 1.4 billion Danish kroner (about $188 million) it generated in the first three months of the year. Holding the line was Wegovy’s weight-loss predecessor Saxenda, which charted 29% growth to 2.5 billion Danish kroner ($336 million).
Saxenda’s second wind comes as Wegovy recovers from a supply squeeze unveiled last winter. With that Wegovy hurdle in place, Novo’s earlier weight loss med reached “new highs” in 2022’s second quarter, the company’s North American head Doug Langa said in a separate interview with Fierce.
Outside the U.S.—where 1.7-mg and 2.4-mg doses of Wegovy are back on tap and Novo expects to have all dose strengths available again by year-end—Saxenda grew 57% internationally and 55% specifically in Europe, Asia and the Middle East, Langa pointed out.
That sales resurrection seems to suggest Novo’s efforts to jump-start the obesity market are paying off.
As Novo’s CEO sees it, Saxenda’s sales revival speaks to the fact that “the underlying obesity market is changing,” which Jørgensen credited, in part, to “the efficacy of Wegovy.” He said the med has “opened people’s minds” to obesity as a disease that can be tackled with a therapeutic.
Meanwhile, the company is making sure it doesn’t run into supply issues on Wegovy again.
“We are scaling up manufacturing significantly,” Jørgensen said, adding that Novo is supplying “more and more products into the market” each week to cater to demand.
“You could say with the contract manufacturer, I regret that we didn’t forecast this uptake,” Jørgensen said, referencing the popularity of Wegovy in the wake of its approval last summer.
Intense demand meant the company “depleted inventory” early on. Novo would have been able to counter its contract manufacturer’s production glitch with additional supply had early demand not been so intense, Jørgensen explained. Drugmakers are typically equipped to weather temporary production hiccups, but “if you start by emptying all your inventory, then suddenly you’re really vulnerable,” the CEO said.
Nevertheless, Novo is looking at the situation long-term and feels “quite confident that we’ll get back strongly,” Jørgensen said.
Further, Novo is adding four more production lines for Wegovy, one of which will be in-house, while the other three will be leveraged for contract manufacturing.
From sea to shining A1C
Lastly, as a diabetes company, Novo isn’t leaving insulins by the wayside. It is plowing ahead on a final study of its once-weekly insulin icodec. That trial is expected to read out later this year, with Novo aiming for a regulatory submission sometime in 2023.
When it comes to insulin icodec’s potential uptake, Novo thinks history could repeat in its favor this time. Jørgensen likened the product’s potential rollout to that of Eli Lilly’s once-a-week GLP-1 injection Trulicity, which subsequently dethroned Novo’s once-daily Victoza on the diabetes scene.
Even though Victoza actually trumped Trulicity in a head-to-head trial, Jørgensen figures the rival med’s once-a-week dosing edge caused Victoza to lose market share.
The company hasn’t decided on how to price insulin icodec yet. Meanwhile, Jørgensen says the current insulin pricing paradigm is tough because the market is oversaturated and suffers from a lack of innovation. Insulin icodec, however, “is going to be differentiated, and you can price it in slightly different ways and also protect yourself from continued price erosion” given that players wouldn’t have the same insulin “switching opportunity” that they do today, Jørgensen said.