dm+d

Unassigned

New Medicines

Mounjaro Type 2 diabetes mellitus - combination therapy

Information

Mounjaro
New molecular entity
Eli Lilly
Eli Lilly

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Approved (Licensed)
May 22Approved in US as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro will be available in six doses (2.5mg, 5mg, 7.5mg, 10mg, 12.5mg and 15 mg) [31].
Jan 22Tirzepatide is considered by analysts to have blockbuster potential [28].
Dec 21Is also pre-registration in US [30].
Nov 21Filed in EU via centralised procedure [27].
May 21Lilly plan to file by end of 2021 [20].
Oct 18Analysts predict global launch in 2022, with 20% chance of success [13].
Oct 18The safety and efficacy of GIP/GLP-1 RA are being studied further in a large phase 3 clinical program (SURPASS) which is expected to begin in early 2019 and complete in late 2021.[3]

Category

Dual glucose-dependent insulinotropic peptide (GIP) and GLP-1 receptor agonist (first in class)
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [6].
Type 2 diabetes mellitus - combination therapy
Subcutaneous injection

Further information

Yes

Trial or other data

Feb 22PIII SURPASS-5 RCT (NCT04039503; n=475) found, in patients with poor glycaemic control, addition of tirzepatide to insulin glargine therapy significantly reduced HbA1c vs placebo (-1.24%, -1.53% & -1.47% for 5mg, 10mg & 15mg doses respectively, all p<0.001). Diarrhoea and nausea were common adverse effects [29].
Oct 21Results from the randomised, parallel, open-label, PIII SURPASS-4 trial (NCT03730662) showed consistent activity in maintaining A1C and weight control in 2000 adults with type 2 diabetes (mean duration 11.8 yrs) inadequately controlled with 1-3 oral antihyperglycemic medicines who have increased cardiovascular (CV) risk. Mean baseline weight was 90.3kg and mean HbA1c was 8.52%. Pts received tirzepatide 5 mg, 10 mg or 15 mg or insulin glargine. At 2 yrs, SURPASS-4 hit all primary endpoints vs. insulin glargine. Mean HbA1C at 52 (n=1750) weeks were: 6.3% (5 mg), 6.1% (10 mg), 6.0% (15 mg), 7.1% (insulin glargine). Mean HbA1c at 104 (n=199) weeks were 6.4% (5 mg), 6.1% (10 mg), 6.1% (15 mg), 7.5% (insulin glargine). Weight change at 52 weeks (n=1,755)were; -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin glargine). At 104 weeks (N=202), weight changes were: -5.8 kg (-8.6%, 5 mg), -10.4 kg (-10.8%, 10 mg), -11.1 kg (-12.8%, 15 mg), +2.3 kg (+2.3%, insulin glargine). Hypoglycemia (< 54 mg/dL) was observed in 8.8%, 6.1%, and 8% of pts receiving 5 mg, 10 mg, and 15 mg of tirzepatide vs. 19.1% with insulin glargine. Adverse events were mostly GI-related, dose related and generally mild to moderate in severity, including nausea (12% to 23%), diarrhea (13-22%) and vomiting (5-9%). [26]
Sep 21The PIII SURPASS-3 trial study showed tirzepatide (5 mg, 10 mg, 15 mg) led to greater reductions in liver fat content compared to insulin. All three tirzepatide dose levels led to more time in the tight glucose target range, improved glycaemic variability and numerically less time in hypoglycaemia compared to titrated degludec. [25]
Aug 21Results of PIII SURPASS-3 reported in The Lancet [24].
Jul 21Results of PIII SURPASS-1 study report in The Lancet [23].
Jul 21Results of PIII SURPASS-2 study reported in NEJM [22].
Jun 21Lilly presented data from PIII SURPASS-1 trial which showed tirzepatide reduced A1C by up to 2.07% and body weight by up to 20.9 pounds, about 11% vs placebo. 54.2% of the pts were treatment-naïve, with a baseline A1C of 7.9% and a baseline weight of 189 pounds. Up to 52% of trial pts achieved an A1C of less than 5.7%. At 15 mg dose of tirzepatide, there was a reduction in total cholesterol, triglycerides, LDL, VLDL and HDL. 5mg dose led to A1C and body weight reductions of 1.87% and 15 pounds. The use of tirzepatide also led to improvements in the change in fasting serum glucose from baseline and improvements in the change in two-hour post-meal glucose values from baseline. The overall safety profile of tirzepatide was similar to other GLP-1 agonists. Results are published in the Lancet. [21]
May 21Lilly announce positive data from SURPASS-4. After 52 weeks, the proportion of patients across the three tirzepatide arms with A1C of 5.7% or less, the threshold for normal blood sugar, ranged from 23% to 43%, compared to 3% in the insulin glargine cohort. Weight reduction from baseline in the tirzepatide cohorts spanned 8% to 13%, while the insulin glargine group gained 2% over the course of the study [20].
Mar 21 SURPASS-CVOT is a cardiovascular outcome trial. Results are anticipated in 2024 [19].
Mar 21 SURPASS-2 (n=1,879) met its primary endpoint. Across three doses, tirzepatide reduced HbA1c from 2.09% to 2.46% vs. a drop of 1.86% with semaglutide 1mg. Whilst tirzepatide has also been linked to significant reductions in weight, semaglutide offers the advantage of better tolerability (3.8% drop out vs. 5.1-7.9% drop out with tirzepatide) [18].
Feb 21Analysts suggest trial data on efficacy of the lowest dose of tirzepatide (5mg) may be of most interest, since these data indicate the drug appears to offer better efficacy at this dose than lower doses of semaglutide [17]
Feb 21Lilly announces positive results from two further PIII trials. In SURPASS-3 (n=1444), after 52 weeks patients randomised to tirzepatide 15mg experienced a 2.37% drop in A1Cf blood sugar vs. 1.34% in control group. At the end of the study almost 50% of patients had an A1C of <5.7%. In SURPASS-5 (n=475) at week 40 A1C dropped as much as 2.59% in the treatment group vs. 0.93% in the control group and almost two thirds of patients on tirzepatide had A1C levels of 10% of patients on the highest dose of 15mg discontinuing treatement[16].
Dec 20Topline data from Phase III SURPASS-1 trial show that a 40-week treatment with either once-daily tirzepatide 5 mg, 10 mg or 15 mg or placebo led to significant reductions in HbA1c and body weight in adults with inadequately controlled type 2 diabetes. tirzepatide led to HbA1c reductions of 2.07% from baseline reductions in body weight by 11% from baseline. Treatment discontinuation rates due to adverse events were less than 7 percent in each tirzepatide treatment arm.[15]
May 20Estimated primary completion dates of trials are: NCT03954834 - Nov 20, NCT03882970 and NCT03882970 - Jan 21, NCT03861039 and NCT03987919 - Mar 21, NCT03861052 - Apr 21, NCT03730662 - Jun 21 and NCT04093752 - Mar 22 [14].
Nov 19PIII study NCT04093752 (SURPASS-AP-Combo) of tirzepatide in patients with T2D on metformin with or without sulfonylurea (SURPASS-AP-Combo) begins [12].
Aug 19PIII study NCT04039503 (SURPASS-5) of tirzepatide vs placebo in patients with T2D inadequately controlled on insulin glargine with or without metformin begins [11].
Jul 19PIII study NCT03987919 (SURPASS-2) of tirzepatide vs semaglutide once weekly as add-on metformin therapy in patients with T2D begins [10].
Jun 19PIII NCT03954834 study (SURPASS-1) of tirzepatide in patients with T2D not controlled with diet and exercise alone (SURPASS-1) begins [9].
Apr 19PIII NCT03882970 (SURPASS-3) study of tirzepatide vs insulin degludec in patients with T2D begins [8].
Nov 18PIII SURPASS-4 study to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in 1,878 participants with type 2 diabetes and increased cardiovascular risk starts (NCT03730662). The study will last about 108 weeks and may include up to 30 visits. Patients will be recruited from countries around the world including the US & EU (not UK). Primary outcome is change from baseline in HbA1c at 52 weeks; collection of these data is due to complete May 21 [5].
Oct 18Results from PIIb study (NCT03131687, n=300) published in the lancet. In this double-blind, randomised, 26 week study, pts with type 2 diabetes were randomly assigned to receive once-weekly s.c. LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1·5 mg), or placebo. At 6 months, average HbA1c reductions of up to 2.4% and average weight reduction of up to 11.3kg (12.7%) were seen. All GIP/GLP-1 RA doses and dulaglutide showed significant reduction in HbA1c from baseline in a dose dependant manner [GIP/GLP-1 RA: -1.6% (5 mg), -2.0% (10 mg), and -2.4% (15 mg); dulaglutide -1.1% (1.5 mg)] vs. placebo (+0.1%). Pts taking GIP/GLP-1 RA achieved significant weight loss [-4.8 kg (5 mg), -8.7 kg (10 mg) and -11.3 kg (15 mg)], as with dulaglutide [-2.7 kg (1.5mg)] vs. placebo (-0.4 kg). The safety profile of GIP/GLP-1 RA was similar to the GLP-1 RA class. Common side effects included nausea, diarrhoea and vomiting which were mild to moderate and generally temporary. No pts in any of the treatment groups experienced severe hypoglycemia.[3,4]
Apr 18Completion of double-blind, placebo-controlled PII study (n=111, NCT03311724) which evaluated the efficacy of LY3298176, in pts with type 2 diabetes. Change from baseline in HbA1c level was the primary endpoint of the trial.[2]
Mar 17PII study initiated to evaluate the safety and efficacy of LY3298176 vs. placebo and dulaglutide in pts with type-2 diabetes mellitus (NCT03131687). Enrolment of ~300 pts initiated in the US, Mexico and Slovakia wiht plans to expand to other countries.[2]

Evidence based evaluations

Information

Licence extension / variation
Eli Lilly
Eli Lilly

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

Dual glucose-dependent insulinotropic peptide (GIP) and GLP-1 receptor agonist (first in class)
From 2012 figures, 24% of men and 25% of women are obese. A further 42% of men and 32% of women were overweight. This means most adults in England are overweight or obese [1]. The Health Survey for England 2019 found that the percentage of people who are obese had increased to around 27% of men and 29% of women [3].
Obesity or overweight in adults with weight related comorbidities, with or without type 2 diabetes
Subcutaneous injection