On 20 March 2014, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Jardiance, 10 mg and 25 mg film-coated tablets, intended for the treatment of type 2 diabetes mellitus.
The applicant for this medicinal product is Boehringer Ingelheim International GmbH. They may request a re-examination of any CHMP opinion, provided they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion.
The active substance of Jardiance is empagliflozin, a blood glucose lowering agent, ATC code: A10BX12. Empagliflozin works by blocking a protein in the kidney called the human sodium-glucose co-transporter-2 (SGLT2). This reduces glucose re-absorption in the kidney leading to glucose excretion in the urine, thereby lowering levels of glucose in the blood of patients with type 2 diabetes.
The benefits with Jardiance are its ability to improve glycaemic control. The most common side effects are hypoglycaemia (when used with sulphonylurea or insulin), genital and urinary tract infections, pruritus and increased urination.
A pharmacovigilance plan for Jardiance will be implemented as part of the marketing authorisation.
The approved indication is:
“Treatment of type 2 diabetes mellitus to improve glycaemic control in adults as:
Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.
1 Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion.
Jardiance
EMA/CHMP/157961/2014 Page 2/2
Add-on combination therapy
In combination with other glucose–lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations)."
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Jardiance and therefore recommends the granting of the marketing authorisation.
(*) The correction concerns the deletion of the following sentence “It is proposed that Jardiance be prescribed by physicians experienced in the treatment of type 2 diabetes”.
Information
Generic Name:
empagliflozin
Trade Name:
Jardiance
Synonym:
BI 10773, BI10773
Entry Type:
New molecular entity
Developmental Status
UK:
Approved (Licensed)
EU:
Approved (Licensed)
US:
Not approved
UK launch Plans:
Available only to registered users
Actual UK launch date:
Comments
May 14: EU approval for treatment of type 2 diabetes. [23] 27/05/2014 09:25:40
Mar 14: EU positive opinion for empagliflozin for treatment of type 2 diabetes mellitus to improve glycaemic control in adults as monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance, and as as add-on combination therapy in combination with other glucose–lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control [20]. 21/03/2014 14:05:26
Mar 14: In its complete response letter, the FDA has not asked Boehringer Ingelheim to complete any new clinical trials to support approval of the application [19]. 06/03/2014 09:56:55
Mar 14: The FDA rejects empagliflozin because of deficiencies at one of Boehringer Ingelheim´s manufacturing facilities [19]. 06/03/2014 09:54:14
Mar 13: Filed in the EU for treatment of T2DM in adults [15]. 05/04/2013 09:49:59
Mar 13: Filed for marketing approval in the US [14] 26/03/2013 09:16:36
Launch anticipated 2014 [7] 09/05/2011 15:44:18
PIII study to start Aug 10 [1]. 30/05/2010 22:43:07
Trial or other data
Sep 13: EMPA-REG MONO trial published in the Lancet Diabetes & Endocrinology. 228 pts were randomised to placebo, 224 to empagliflozin 10 mg, 224 to empagliflozin 25 mg, and 223 to sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were −0·74% (95% CI −0·88 to −0·59; p<0·0001) for empagliflozin 10 mg, −0·85% (—0·99 to −0·71; p<0·0001) for empagliflozin 25 mg, and −0·73% (—0·88 to −0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events, as did 123 (55%) patients in the empagliflozin 10 mg group, 135 (60%) patients in the empagliflozin 25 mg group, and 119 (53%) patients in the sitagliptin group [18]. 10/09/2013 08:45:37
Aug 13: EMPA-REG METSU Trial (n=666) published in Diabetes Care. Pts inadequately controlled on metformin & sulfonylurea (HbA1c ≥7 to ≤10%) were randomised and treated with once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo for 24 weeks. At week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.17% (0.05) for placebo vs. −0.82% (0.05) & −0.77% (0.05) for empagliflozin 10 & 25 mg, respectively (both p<0.001). Empagliflozin significantly reduced MDG, weight, & systolic (but not diastolic) blood pressure vs placebo. Adverse events were reported in 62.7, 67.9 & 64.1% of pts on placebo & empagliflozin 10 & 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3 & 8.3% of pts on placebo & empagliflozin 10 & 25 mg, respectively (females: 13.3, 18.0 & 17.5%, respectively; males: 2.7, 2.7 & 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7 & 2.3% of pts on placebo & empagliflozin 10 & 25 mg, respectively (females: 0.9, 4.5 & 3.9%, respectively; males: 0.9% in each group) [17]. 22/08/2013 10:38:21
Jun 13: Results of a 78-week phase III clinical trial of empagliflozin as add-on to basal insulin in adults with T2DM presented at the ADA. Placebo-adjusted reductions in HbA1c for empagliflozin 10 mg and 25 mg were 0.6% and 0.7% (p<0.001), respectively, at week 18, and 0.5% and 0.6%, respectively, at week 78 (p<0.001). The study included an 18-week fixed insulin dose period, after which the dose was adjusted at investigator discretion. At week 78, the placebo-adjusted change in required daily insulin dose was decreased by 6.7 International Units (IU) and 6.0 IU for empagliflozin 10mg (p=0.002) and 25 mg (p=0.009), respectively. Drug-related AEs were reported by 39% and 44% of patients, respectively, and by 31% of patients on placebo. Hypoglycemia was reported in 36% of patients on empagliflozin and 35% on placebo. Two patients on empagliflozin 25 mg required assistance to treat the hypoglycemic event [16]. 25/06/2013 16:13:17
A fixed dose combination of empagliflozin + metformin is in development. 09/05/2013 16:28:31
Jan 13: Top-line results for four completed Phase III clinical trials for empagliflozin. In all four studies, the primary efficacy endpoint, defined as significant change in HbA1c from baseline compared to placebo, was met with empagliflozin (10 and 25 mg) taken once daily. Study 1245.20 (n=986) eva luated 10 mg and 25 mg doses of empagliflozin as monotherapy versus placebo for 24 weeks. Study 1245.23 (n=1,504) compared 10 mg and 25 mg doses of empagliflozin as an add-on to metformin and metformin plus sulfonylurea versus placebo for 24 weeks. Study 1245.19 (n=499) assessed 10 mg and 25 mg doses of empagliflozin as an add-on to pioglitazone and pioglitazone plus metformin versus placebo for 24 weeks. Study 1245.36 (n=741) eva luated 25 mg dose of empagliflozin in patients with type 2 diabetes with mild, moderate or severe renal impairment, and 10 mg dose in those with mild renal impairment versus placebo for 52 weeks. Incidence of adverse events was similar for placebo, empagliflozin 10mg and 25mg. Genital infections occurred more often with empagliflozin (both dosages) compared with placebo. This safety information is consistent with findings reported in the Phase II study results for empagliflozin. [13] 08/01/2013 13:45:07
NCT01719003 A 24-week PIII randomized, double-blind study to eva luate the efficacy and safety of twice daily oral administration of empagliflozin + metformin vs the individual components of empagliflozin or metformin in 1424 drug naive patients with T2DM. The primary endpoint is change from baseline in HbA1c. The study started Oct 12 and is due to complete Aug 14 [12] 08/11/2012 16:18:06
Oct 12: Data from a pooled analysis of two PIIb trials announced at the 48th European Association for the Study of Diabetes (EASD) Annual Meeting in Berlin, inlcuding two double-blind, placebo-controlled RCTs with treatment durations of 12 weeks (poster #770), assessing the safety and efficacy of empagliflozin alone (n=408) or as add-on to metformin (n=495) in adult pts with T2D. Pts were treated with either empagliflozin 10 mg or 25 mg. At week 12, reductions in mean SBP of 3.8 mmHg and 4.5 mmHg were observed with empagliflozin 10 mg and 25 mg, respectively, versus 1.2 mmHg for placebo. Mean SBP at baseline of 131.3 mmHg and 132.5 mmHg were observed with empagliflozin 10 mg and 25 mg, respectively, versus 134.3 mmHg with placebo. For both dosages, this reduction in SBP was statistically significant compared to placebo. In patients with higher SBP at baseline (>140 mmHg), mean reductions of 17.0 mmHg and 13.4 mmHg were observed with empagliflozin 10 mg and 25 mg, respectively, and 10.4 mmHg with placebo. Reductions in diastolic blood pressure (DBP) were numerically greater with both empagliflozin doses compared to placebo, but the differences did not reach statistical significance. For the entire cohort, the reductions in DBP were 2.3 mmHg and 2.7 mmHg for empagliflozin 10mg and 25mg, respectively, and 1.8 mmHg for placebo. For pts with high DBP (>85 mmHg), reductions were 8.1 mmHg and 7.6 mmHg for empagliflozin 10mg and 25mg, respectively, and 6.1 mmHg for placebo. Overall, changes in SBP and DBP did not correlate with changes in pulse rate or A1C. The Pearson correlation coefficients between weight and SBP changes were 0.10 and 0.04 for empagliflozin 10 mg and 25 mg, respectively, and 0.12 for placebo. Between A1C and SBP changes, the coefficients were -0.09 and -0.02 for empagliflozin 10 mg and 25 mg, respectively, and 0.11 for placebo. None of these correlations reached statistical significance. Adverse events (AEs) at week 12 were experienced by 34.2% and 31.6% of pts who received empagliflozin 10 mg and 25 mg, respectively, and by 34.6% who received placebo.1 The most commonly observed AEs included urinary tract and genital infections, generally categorized as mild, as seen in all clinical trials to date.[11] 03/10/2012 10:42:11
Jun 12: Jun 12: Results from a PIIb open-label extension study were presented at the American Diabetes Association Sessions. Patients treated with 10 or 25 mg of empagliflozin (monotherapy or + metformin), metformin alone, or sitagliptin + metformin in one of two 12-week trials continued on the same treatment for an additional 78 weeks. Patients who had received 1, 5 or 50 mg of empagliflozin or placebo were randomized to 78 weeks of treatment with either 10mg or 25mg of empagliflozin. At week 90, decreases in average A1C levels (%), FPG levels (mg/dL), and body weight (kg) were observed with empagliflozin 10mg alone (-0.34; -30.4; -2.24, respectively) and 25mg alone (-0.47; -27.8; -2.61, respectively), vs metformin (-0.56; -26.0; -1.28, respectively). In combination with metformin, empagliflozin 10mg, 25 mg and sitagliptin reduced A1C levels by -0.34; -0.63; and -0.40; FPG levels by -21.3; -31.8 and -15.6; and body weight by -3.14; -4.03; and -0.41 [10] 12/06/2012 14:30:34
Jun 11: NCT01370005 is a PIII 12 week RCT of BI 10773 (10 or 25 mg daily) in 816 hypertensive patients with T2DM. The primary endpoints are change of HbA1c and change of mean 24-hour systolic blood pressure from baseline. The study started Jun 11 and is due to complete Jun 12 [8]. 27/06/2011 15:38:10
Mar 11: NCT01306214 is a 1 year PIII, randomized, double-blind, placebo-controlled, parallel group study of BI 10773 (10mg and 25mg once daily) 555 in patients with T2DM and insufficient glycaemic control on insulin alone or with metformin. Primary outcome is change from baseline in HbA1c after 18 weeks of treatment. The study started Feb 11 and is due to complete Aug 12 [6]. 08/03/2011 11:32:09
Jan 11: Eli Lilly and Boehringer Ingelheim have agreed to collaborate on the research and commercialization of four diabetes drugs: linagliptin, BI10773, LY2605541 and LY2963016 [5]. 13/01/2011 14:12:39
Oct 10: NCT01210001 is a PIII randomised, double-blind, placebo-controlled study of BI 10773 (10 and 25mg once daily) over 24 weeks in 468 patients with T2DM who are not controlled on a background of pioglitazone alone or in combination with metformin. The study starts Sep 10 and is due to complete Mar 12; the primary outcome is change from baseline in HbA1c at 24 weeks [4] 01/10/2010 18:02:20
Jul 10: NCT01164501 is a PIII, randomised, double-blind, placebo-controlled, parallel group, efficacy and safety study of BI 10773 (10 mg and 25 mg once daily) as add on to pre-existing antidiabetic therapy over 52 weeks in 682 patients with T2DM, renal impairment and insufficient glycaemic control. The primary outcome is change from baseline in HbA1c at 24 weeks. The study will start Jul 10 and complete Jun 12 [3]. 19/07/2010 17:15:19
Jul 10: NCT01159600: is a PIII randomised, double-blind, placebo-controlled study of low or high dose BI 10773 in 1390 patients with T2DM as add-on to metformin or metformin + sulphonylurea. The primary outcome is the change from baseline in HbA1c after 24 weeks. The study is due to start this month and complete Nov 11 [2]. 11/07/2010 21:54:55
Starting Aug 10, NCT01131676 is a randomized, double-blind PIII study eva luating BI 10773 as add-on to Usual Care vs Usual Care alone in 4000 patients with Type 2 diabetes mellitus at high cardiovascular risk. Patients may be drug naive or pre treated with any background hypoglycaemic therapy. The primary endpoint is time to the first occurrence of any of the following adjudicated components of the primary composite endpoint: cardiovascular death (including fatal stroke and fatal MI, non-fatal MI and non-fatal stroke over 4 years. Patients will receive BI 10773 at low or high dose, once daily, or placebo. The study is due to complete Aug 14 [1]. 30/05/2010 22:49:15
Sodium glucose co-transporter type 2 (SGLT-2) inhibitor
Epidemiology:
Over 5% of men & 4% of women in England have diagnosed diabetes, & it has been estimated that 3.1% of men & 1.5% of women aged 35 and over have undiagnosed diabetes (85% type 2) [9].
Boehringer Ingelheim. (3/21/14). "Press Release: Type 2 Diabetes – CHMP Recommends Empagliflozin for Approval [For Non-US and Non-UK Media]". Ingelheim & Indianapolis, IN.
For Non-US and Non-UK Media
Positive opinion for investigational SGLT2 inhibitor empagliflozin for the treatment of T2D in adults
Boehringer Ingelheim and Eli Lilly and Company are pleased to announce a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), recommending approval of the investigational sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin* (if approved to be marketed under the name Jardiance®) for the treatment of adults with Type 2 Diabetes (T2D).
Empagliflozin is an investigational compound that belongs to the SGLT2 inhibitor class of drugs that targets glucose directly and works independently of ß-cell function and insulin resistance.1, 2 Following the CHMP positive opinion, the European Commission generally follows the recommendation and usually issues its final decision for marketing authorisation within two months.3
"The CHMP positive opinion brings us a step closer to having a potential new treatment option in Europe for people with Type 2 Diabetes," said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "If approved, empagliflozin would be the third product approved in Europe as part of the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance."
An estimated 382 million people worldwide have Type 1 or Type 2 Diabetes.4 T2D is the most common type, accounting for 85-95 percent of diabetes cases in high-income countries.4 Although a range of treatments exist to manage the condition, 50 percent of people do not achieve their glycaemic targets.5
About Boehringer Ingelheim and Eli Lilly and Company
In January 2011, Boehringer Ingelheim and Eli Lilly and Company entered into an alliance in diabetes that centers on compounds representing several of the largest diabetes treatment classes. The alliance leverages the strengths of two of the world's leading pharmaceutical companies. By joining forces, the companies demonstrate commitment in the care of patients with diabetes and stand together to focus on patient needs. Find more information about the alliance at www.boehringer-ingelheim.com or www.lilly.com
About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.
Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavours.
In 2012, Boehringer Ingelheim achieved net sales of about €14.7 billion. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.
For more information please visit www.boehringer-ingelheim.com
About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and http://newsroom.lilly.com/social-channels.
About Lilly Diabetes
Lilly has been a global leader in diabetes care since 1923, when we introduced the world's first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research and collaboration, a broad and growing product portfolio and a continued determination to provide real solutions-from medicines to support programs and more-we strive to make life better for all those affected by diabetes around the world. For more information, visit www.lillydiabetes.com.
This press release contains forward-looking statements about empagliflozin for the treatment of type 2 diabetes. It reflects Lilly's current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in the process of drug development and commercialization. There is no guarantee that future study results and patient experience will be consistent with study findings to date or that empagliflozin will prove to be commercially successful. For further discussion of these and other risks and uncertainties, please see Lilly's latest Forms 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.
* Empagliflozin is an investigational compound. Its safety and efficacy have not yet been fully established
References:
1 Ferrannini E, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508.
2 DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5-14.
3 EMA. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/q_and_a/q_and_a_detail_000114.jsp (accessed: 17 February).
4 International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation; 2013.
5 Teoh H, Home P, Leiter LA. Should A1C targets be individualized for all people with diabetes? Arguments for and against. Diabetes Care. 2011;34 Suppl 2:S191-6.
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