Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Steglatro®, Steglujan, Segluromet™
Compound: ertugliflozin monotherapy, ertugliflozin and Januvia® (sitagliptin), fixed-dose combination of ertugliflozin and metformin.
Therapeutic area: Metabolic diseases
Action mechanism: SGLT2 inhibitor.
Company: Merck&Co (USA - NJ) Pfizer (USA - NY)
Disease: type 2 diabetes
- • On January 25, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Segluromet®, intended for the treatment of type 2 diabetes. The drug will be available as film-coated tablets (containing 2.5 mg ertugliflozin/1000 mg metformin; 2.5 mg/850 mg; 7.5 mg/1000 mg; and 7.5 mg/850 mg). The benefit with Segluromet is its ability to lower blood glucose. The most common side effects are vulvovaginal mycotic infection and other female genital mycotic infections as well as gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal pain and loss of appetite). Serious diabetic ketoacidosis occurs rarely.
The full indication is:
“Segluromet is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
- - in patients not adequately controlled on their maximally tolerated dose of metformin alone;
- - in patients on their maximally tolerated doses of metformin in addition to other medicinal products for the treatment of diabetes;
- - in patients already being treated with the combination of ertugliflozin and metformin as separate tablets.
- • On December 22, 2017, Merck&Co and Pfizer announced that the FDA has approved Steglatro® (ertugliflozin) tablets, an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the fixed-dose combination Steglujan® (ertugliflozin and sitagliptin) tablets. Steglatro® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Steglujan® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate.
- These FDA approvals are supported by seven Phase 3 studies of approximately 4,800 patients. Steglatro® was studied as monotherapy and in combination with metformin and/or sitagliptin, as well as with insulin and a sulfonylurea, in adults with type 2 diabetes and moderate renal impairment.
- One of the studies supporting the FDA approvals was VERTIS SITA2, a 26-week double-blind, placebo-controlled study. VERTIS SITA2 evaluated Steglatro® (ertugliflozin) compared to placebo in 463 patients with type 2 diabetes inadequately controlled (baseline A1C of 7.0-10.5%) on background metformin (?1,500 mg/day) and sitagliptin (100 mg/day). Patients were randomized to Steglatro® 5 mg, Steglatro® 15 mg or placebo administered once daily, in addition to continuation of background metformin and sitagliptin therapy. In the study, Steglatro® provided significant additional A1C reductions on top of metformin plus sitagliptin of 0.7 percent and 0.8 percent, respectively, for the 5 and 15 mg doses, compared with 0.2 percent for placebo (p<0.001, for both comparisons), which was the study’s primary endpoint.
- In this study, Steglatro® significantly reduced body weight by 6.6 pounds with the 5 mg dose and 6.2 pounds with the 15 mg dose, on top of metformin plus sitagliptin, compared with 2.2 pounds with placebo. Baseline body weight was 193.1 pounds, 190.9 pounds and 190.6 pounds for the 5 mg, 15 mg and placebo groups, respectively. The difference from placebo was -4.2 pounds for Steglatro® 5 mg (95% CI: -5.7, -2.9) and -4.0 pounds for Steglatro® 15 mg (95% CI: -5.3, -2.6). Steglatro® 5 mg and 15 mg were also associated with significant reductions in fasting plasma glucose (25.7 mg/dL and 32.1 mg/dL, respectively, vs. 6.5 mg/dL for placebo; p<0.001, for both comparisons). Baseline fasting plasma glucose levels were 167.7 mg/dL, 171.7 mg/dL and 169.6 mg/dL for the 5 mg, 15 mg and placebo groups, respectively. Significant reductions in systolic blood pressure were also observed for Steglatro® (3.8 mmHg for 5 mg and 4.5 mmHg for 15 mg, vs. 0.2 mmHg for placebo). Baseline systolic blood pressure values were 132.1 mmHg, 131.6 mmHg and 130.2 mmHg for the 5 mg, 15 mg and placebo groups, respectively. For systolic blood pressure, the difference from placebo was -3.7 mmHg for Steglatro® 5 mg (95% CI: -6.1, -1.2) and -4.3 mmHg for Steglatro® 15 mg (95% CI: -6.7, -1.9). Steglatro® is not indicated for weight loss or hypertension.Steglatro® causes intravascular volume contraction. Symptomatic hypotension may occur after initiating Steglatro®, particularly in patients with impaired renal function (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2), elderly patients (?65 years), patients with low systolic blood pressure or patients on diuretics. Before initiating Steglatro®, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms after initiating therapy.
In addition to Steglatro® and Steglujan® (ertugliflozin and sitagliptin), the only fixed-dose combination of an SGLT2 inhibitor and the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin, the FDA also approved the fixed-dose combination Segluromet™ (ertugliflozin and metformin hydrochloride). Segluromet™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin. Segluromet™ is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. The labeling for Segluromet™ contains a boxed warning for lactic acidosis. Segluromet™ is contraindicated in patients with severe renal impairment, end-stage renal disease or on dialysis, acute or chronic metabolic acidosis, including diabetic ketoacidosis, or a history of a serious hypersensitivity reaction to Segluromet™, ertugliflozin or metformin hydrochloride.
- Steglatro® is available in 5 mg and 15 mg tablets. Steglujan® combines 5 mg or 15 mg of ertugliflozin with 100 mg of sitagliptin. Segluromet™ combines 2.5 mg or 7.5 mg of ertugliflozin with 500 mg or 1,000 mg of metformin hydrochloride.
- • On March 6, 2017, Merck&Co and Pfizer announced that the FDA has accepted for review three New Drug Applications (NDAs) for medicines containing ertugliflozin, an investigational SGLT2 inhibitor in development to help improve glycemic control in adults with type 2 diabetes: one for monotherapy, one for the fixed-dose combination of ertugliflozin and Januvia® (sitagliptin), and one for the fixed-dose combination of ertugliflozin and metformin.
- The Prescription Drug User Fee Act (PDUFA) action date from the FDA is in December 2017 for the three NDAs. Additionally, the European Medicines Agency (EMA) has validated for review three Marketing Authorization Applications (MAAs) for ertugliflozin monotherapy and the two fixed-dose combination products
- The marketing applications are supported by studies in the VERTIS clinical development program of ertugliflozin, including VERTIS MONO, VERTIS FACTORIAL, and VERTIS SITA2, which were first presented at medical congresses in 2016. The full VERTIS clinical development program is comprised of nine Phase 3 trials in approximately 12,600 adults with type 2 diabetes.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-12-22
Favourable opinion UE: 2018-01-25
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: