Lilly Data Show Zepbound Reduces Type 2 Diabetes Risk Long Term

Eli Lilly and Company continues to roll out data supporting use of its obesity blockbuster tirzepatide with an extension study showing that long-term treatment of prediabetics dramatically lowered the risk of progressing to type 2 diabetes. The company is discussing options with regulators and a claim would be a significant addition to the Zepbound label, but the evidence could help with reimbursement hurdles as well.

The Indianapolis pharma reported three-year data from the extension portion of its pivotal SURMOUNT-1 trial on 20 August, showing that tirzepatide weekly injection maintained a statistically significant decrease in body weight compared to placebo and also lowered the risk of progressing to type 2 diabetes by 94% in prediabetic patients who were obese or overweight at baseline.

The readout followed 72-week data that Lilly reported in 2022 from the SURMOUNT-1 study which provided the backing for tirzepatide’s second US Food and Drug Administration approval for management of obesity. (Also see "Tirzepatide’s Glowing Obesity Data Steal Show On Lilly’s Earnings Call" - Scrip, 28 Apr, 2022.) The GLP-1/GIP receptor agonist was approved as Mounjaro to treat type 2 diabetes in May 2022 and then added a label indication for obesity as Zepbound last November. (Also see "Lilly Plans ‘Big, Bold’ Launch For Zepbound" - Scrip, 8 Nov, 2023.)

Lilly noted that after publishing 72-week data for the primary endpoint of weight loss from baseline in non-diabetic patients who are overweight or obese, it enrolled 1,032 overweight/obese prediabetic patients for a 176-week treatment extension period, followed by a 17-week off-treatment follow-up. The company likely will use the data from the extension to continue building a case for long-term therapy with tirzepatide in several patient populations.

In a same-day note, Leerink Partners analyst David Risinger praised the data, saying they “support the utility of tirzepatide in providing transformational health benefits beyond weight loss alone, in our view.” However, Risinger questioned whether the data could form the basis for a label claim of type 2 diabetes prevention, even though Lilly followed American Diabetes Association guidelines in designing and enrolling the trial extension.

“Lilly plans to discuss the data with regulators, but it is unclear if the company can file for approval for T2D prevention,” Risinger said. “We currently assume that the data is simply added to tirzepatide’s label; if Lilly is able to secure a formal indication, it would represent material upside, in our view.”

“We are continuing to evaluate the results of the 176-week data from the SURMOUNT-1 study. Regulatory authorities throughout the world have different evidence requirements to obtain an indication for risk reduction of type 2 diabetes. We recognize the importance of these data and will assess our options based on discussions with regulators,” the firm told Scrip.

The SURMOUNT-1 extension data should also be useful to Lilly in discussing the drugs’ benefits with payers. While the brands are growing significantly, there are still challenges with coverage. Lilly reported more than $4.3bn in combined Mounjaro and Zepbound sales during the second quarter. (Also see "Lilly, With Tirzepatide Supply Issues Addressed, Raises Guidance By $3bn" - Scrip, 8 Aug, 2024.) The nearly $3.1bn in Mounjaro sales accounted for a more than 300% year-over-year increase, while Zepbound’s $1.2bn more than doubled the $517m tallied during Q1, its first full quarter on the market.

Lilly shareholders responded positively to the data, with the company’s share price finishing trading on 20 August up 3% to $949.97.

Two Key Secondary Endpoints Met

In the SURMOUNT-1 extension, tirzepatide met a key secondary endpoint by posting a significant reduction in risk for prediabetic patients who are overweight or obese to progress to type 2 diabetes, with a 94% risk reduction seen at week 176 (p<0.0001), Lilly said. This was from pooled data of patients receiving either a 5mg, 10mg or 15mg weekly injection of the drug.

On another key secondary endpoint, patients receiving the 10mg or 15mg dose of tirzepatide achieved statistical significance for weight loss from baseline at week 176 (p<0.001). The 10mg dose yielded a 19.9% reduction in body weight and the 15mg dose produced a 22.9% reduction in body weight, compared with 2.1% for placebo. The 5mg dose showed a numerical difference from placebo with a 15.4% reduction in weight.

Lilly also noted that the off-treatment follow-up period showed both that patients regained some weight and saw some increase in their risk for progression to type 2 diabetes. At week 193, after 17 weeks off tirzepatide therapy, patients still had an 88% risk reduction for type 2 diabetes (p<0.0001), the firm reported.

While the 20 August readout was topline data from the SURMOUNT-1 extension, Lilly said it will report detailed results at ObesityWeek 2024 in November and submit the data to a peer-reviewed medical journal.

Data The Latest Salvo In Battle With Novo Nordisk

Lilly is in a wide-ranging competition with Novo Nordisk A/S for supremacy in both the type 2 diabetes and obesity markets, with the Danish’s firm’s GLP-1 agonist Ozempic/Rybelsus/Wegovy (semaglutide) positioned directly against Lilly’s Mounjaro/Zepbound in both spaces. (Also see "Lilly And Novo Nordisk Shape Up For Obesity Treatment Battle Of The Heavyweights" - Scrip, 6 Apr, 2023.)

Novo Nordisk has data from its trials showing semaglutide’s benefits in prediabetic patients as well, demonstrating in the SELECT-1 trial and some of the STEP trials in obesity that fewer patients with baseline prediabetes progressed to type 2 diabetes.

That battle is being extended to other fronts; Novo Nordisk obtained an FDA indication for reduced risk for major cardiovascular events in Wegovy’s label in March, while Lilly has tirzepatide under FDA review for the treatment of obstructive sleep apnea with a 21 December action date. (Also see "Lilly Can Rest Easy As Tirzepatide Scores Phase III Sleep Apnea Win" - Scrip, 17 Apr, 2024.) Lilly has tirzepatide in Phase III for chronic heart failure with preserved ejection fraction and in Phase II for non-alcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis, chronic kidney disease and diabetic nephropathy as well. (Also see "Lilly’s Tirzepatide Shows Benefit In Heart Failure, Including Outcomes" - Scrip, 1 Aug, 2024.)

Meanwhile, Novo Nordisk recently pulled an FDA filing seeking approval of semaglutide for heart failure with a plan to refile in 2025 with outcomes data. (Also see "Novo Pulls Wegovy Heart Failure Application, Will Resubmit To Get ‘Hard Endpoints’ In Label" - Pink Sheet, 7 Aug, 2024.) Meanwhile, the company has semaglutide under FDA review for treatment of diabetic nephropathy with a decision expected next January, and in Phase III for NASH/MASH, diabetic retinopathy, peripheral arterial disease and other indications. Prevention of type 2 diabetes is not one of the sought indications at present, however.

Leerink’s Risinger said the next major inflection point in the Lilly/Novo Nordisk competition may come before the end of the year, with topline data expected from the SURMOUNT-5 head-to-head study of tirzepatide versus semaglutide, which has a primary completion date of 6 November. (Also see "Lilly Offloads Baqsimi To Amphastar While Investing In Mounjaro Head-To-Head Trial" - Scrip, 24 Apr, 2023.) “We expect tirzepatide to drive significantly greater weight loss than semaglutide,” the analyst predicted.