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In May, MedPage Today reported on the FDA approval of the first-in-class tirzepatide (Mounjaro) for type 2 diabetes. In this report, we follow up on what's happened since this approval and what's next.

The FDA green-lit tirzepatide (Mounjaro), a once-weekly injectable glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GLP-1/GIP) agonist, in three dose levels (5 mg, 10 mg, and 15 mg), as adjunct to diet and exercise for type 2 diabetes.

Underpinning the approval of tirzepatide were multiple trials in the SURPASS program, which showed that the agent was better for HbA1c reduction, either alone or as an add-on therapy, versus long-acting insulin degludec or insulin glargine, the GLP-1 receptor agonist semaglutide (Ozempic), or placebo.

But just a week prior to tirzepatide's approval for diabetes, developer Eli Lilly released topline data from its 72-week, phase III SURMOUNT-1 clinical trial. People with overweight or obesity taking 15 mg of the once-weekly injectable lost on average 22.5% of body weight, representing a mean loss of 52 lb (24 kg).

Both of the lower doses were also effective for weight loss: Those taking 5 mg saw an average weight reduction of 16.0% (35 lb/16 kg) and those taking 10 mg saw a loss of 21.4% (49 lb/22 kg) from the average baseline body weight of 231 lb (105 kg).

The trial included 2,539 adults with overweight or obesity who had at least one other comorbidity -- hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease -- but were free of type 2 diabetes. Tirzepatide was added to a reduced-calorie diet and increased physical activity regimen.

A few weeks later in June, full trial data were presented at the 2022 American Diabetes Association (ADA) meeting, where trial co-author Ania M. Jastreboff, MD, PhD, of the Yale University School of Medicine in New Haven, called this "a new era for obesity treatment."

"There were first-generation medicines, second-generation medicines, which were about 2010 to 2020. Starting last year with semaglutide [Wegovy] and now tirzepatide, this is a new era for obesity treatment," she said during an ADA press conference.

"Those medications are much more highly effective than any other medications we've had for the treatment of obesity right now. They are clearly exceeding the greater than or equal to 5% weight reduction target," Jastreboff pointed out. "What we really need to focus on is [that] this is a new era for our patients; this is a new era for physicians caring for patients with obesity -- which is all of us -- and we now have the tools, and will have more tools going forward, to be able to treat our patients with obesity."

FDA Fast Track

Shift forward a few months to October, and Eli Lilly announced the FDA granted fast track designation for tirzepatide for the treatment of adults with obesity, or overweight with weight-related comorbidities. The designation was largely because of SURMOUNT-1 trial findings, but also hinged on the ongoing showing positive findings. This second installment of SURMOUNT, which is expected to wrap up by the end of April 2023, includes participants with overweight or obesity with comorbid type 2 diabetes.

The drug developer announced at the same time that it planned to initiate a rolling submission of a new drug application, and plans to complete the submission "shortly after SURMOUNT-2 data is available."

Lilly also has a couple other installments to the SURMOUNT program with results expected next year. The , which will finish up by mid-May 2023, will see how tirzepatide can maintain body weight or bolster weight loss after an intensive lifestyle modification program in people with overweight or obesity without diabetes. is slated to follow on SURMOUNT-3's heels, providing insights into the benefit of staying on tirzepatide treatment after a lead-in phase versus switching to placebo.

'Kink in the U.S. Supply Chain'

If approved, tirzepatide will join the growing ranks of diabetes-turned-obesity treatments, currently driven by the tremendous success of semaglutide 2.4 mg (Wegovy) from Novo Nordisk.

With its "game-changing" approval in June 2021, the GLP-1 receptor agonist Wegovy gained indications for chronic weight management in adults with obesity (BMI of 30 or greater) or for adults with overweight (BMI 27 or greater) plus at least one weight-related condition, such as hypertension, type 2 diabetes, or high cholesterol, used in conjunction with a reduced calorie diet and an exercise regimen.

Wegovy was the first drug approved for this indication since 2014.

Novo Nordisk released phase IIIa pediatric data at the 2022 ObesityWeek annual meeting that showed the drug's efficacy in adolescents with obesity. At 68 weeks, the mean change in BMI from baseline was a 16.1% reduction with the glucagon-like peptide-1 (GLP-1) receptor agonist and a 0.6% increase with placebo.

"The degree of body weight reduction is unprecedented," study author Daniel Weghuber, MD, of Paracelsus Medical University in Salzburg, Austria, told MedPage Today at the meeting. "After years of frustration, all of a sudden patients were actually losing weight. They'd never seen that before."

Because of supply-chain issues, and overwhelming demand for a new obesity agent -- Wegovy became Hollywood's new "it" drug -- there were nationwide shortages. In late December 2021, Novo Nordisk released a statement: "As a consequence, Novo Nordisk does not expect to be able to meet demand in the U.S. in the first half of 2022 and few new patients are expected to be able to initiate treatment...this kink in the U.S. supply chain also isn't expected to be fully resolved until the second half of 2022."

These shortages even led to bootleg semaglutide, with compounded formulations of the drug popping up online and in some clinics.

Wegovy's supply shortage continued, but in early November it was "on track to make all dose strengths of Wegovy available in the U.S. towards the end of the year."

"It will then take a few weeks for product to be broadly available at retail pharmacies across the country," according to the company statement.

Wegovy supply issues put tirzepatide in a position to potentially take over the obesity market should it gain FDA approval in 2023. Eli Lilly faced its own setback in mid-December when the FDA added Mounjaro and dulaglutide (Trulicity) to . The agency noted that while the 2.5-mg, 7.5-mg, 10-mg, 12.5-mg, and 15-mg doses of tirzepatide are currently available, the 5-mg dose may experience "intermittent periods of backorder" persisting into early 2023.

According to , Lilly plans to double its manufacturing capacity for Mounjaro and Trulicity by the end of 2023.

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