• Early combination treatment strategy with vildagliptin (Galvus®) and metformin was superior to standard of care in newly diagnosed type 2 diabetes patients[1],[2]
     
  • The landmark VERIFY study is the first to investigate the long-term clinical benefits of this early combination strategy in type 2 diabetes (T2DM)[1]
     
  • Novartis is committed to optimizing patient management of T2DM to achieve better glycemic control and favorable long-term clinical outcomes 

Basel, September 18, 2019 — Novartis today announced the key results from the Phase IV clinical study VERIFY evaluating the long-term efficacy and safety of early combination treatment strategy with metformin plus vildagliptin (dipeptidyl peptidase-4 [DPP-4] inhibitor) compared to the traditional stepwise approach with metformin as initial therapy followed by vildagliptin, added at the time of metformin failure[1],[2]. The key study findings were presented today at the European Association for the Study of Diabetes (EASD) Annual Meeting and published simultaneously in The Lancet.

VERIFY is a unique study designed to determine durability, over a pre-specified five-year follow-up of early use of combination therapy strategy with vildagliptin-metformin. The study was conducted across 254 centers in 34 countries and involved 2001 treatment-naïve diverse individuals recently diagnosed with T2DM (HbA1c between 6.5–7.5% [48–58 mmol/mol])[1],[2].

In the randomized, double-blind Phase IV study (ClinicalTrials.gov Identifier: NCT01528254), early combination therapy of vildagliptin (50 mg, twice daily) and metformin (individually, 1000–2000 mg, daily) met the primary endpoint with a statistically significant 49% reduction in the relative risk for time to initial treatment failure (HbA1c >= 7.0% twice, consecutively, 13 weeks apart), versus metformin alone (HR: 0.51, 95% CI [0.45, 0.58]; P<0·0001)[1],[2].

The combination treatment strategy also showed a lower frequency of secondary failure when all patients were receiving combination therapy (HR: 0.74, 95% CI [0.63, 0.86]; P<0.0001). Furthermore, patients treated with early combination had consecutively lower HbA1c levels (below 6.0%, 6.5% or 7.0%) for 5 years versus those receiving combination therapy only after metformin monotherapy failure[1].

“The initial findings from the VERIFY study uniquely demonstrate that early intervention with a combination therapy strategy provides greater and durable long-term benefits for patients. The currently recommended initial monotherapy approach with later treatment intensification in type 2 diabetes management is now shown to be an inferior strategy,” said Professor David Matthews, EASD President and Emeritus Professor of Diabetic Medicine, University of Oxford, UK.

The overall safety and tolerability profile was similar between the treatment approaches, with no unexpected or new safety findings reported[1].

“Despite type 2 diabetes having become an epidemic with growing mortality and morbidity rates, there is a distinct lack of optimized management strategies at diagnosis that can induce durability and slow down disease progression,” said Marcia Kayath, Global Head Medical Affairs and Chief Medical Officer, Novartis Pharmaceuticals. “These promising results from the VERIFY study have the potential to improve patient outcomes and the way in which we treat type 2 diabetes in the future”.

Additional pre-defined secondary analyses of the VERIFY study results are ongoing and data will be disclosed over the coming months at international and local medical congresses and in scientific journals.

About vildagliptin/metformin combination (Eucreas® /Galvusmet®)
The combination of these two anti-diabetic agents with complementary mechanisms of action provides superior efficacy and allows patients to reach glycemic targets without increasing the risk of hypoglycemia, weight gain and other CV risk factors[3]. Vildagliptin-metformin combination was the first single-pill dual therapy of a DPP-4 inhibitor with metformin approved in Japan and Europe[4]. The vildagliptin and metformin dual therapy is used when the patient’s T2DM is insufficiently controlled by metformin monotherapy[5].

About vildagliptin (Galvus®)
Vildagliptin is approved as an oral treatment for adults with T2DM in more than 120 countries, including the EU, Japan, Latin America and Asia-Pacific. Vildagliptin is approved for use as monotherapy, dual therapy in combination with metformin, sulfonylurea (SU) or a thiazolidinedione, as a triple oral therapy in combination with a SU and metformin or as an add-on to insulin (with or without metformin)[4],[5],[6].

Vildagliptin is a selective and potent DPP-4 inhibitor that acts by preventing the usually rapid degradation of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which in turn, enhances the alpha- and ß-cell sensitivity to glucose and inhibits glucagon secretion, thereby improving glycemic control in T2DM[7],[8],[9],[10]. Vildagliptin has been widely studied in randomized clinical trials but it also has an extensive pool of evidence in real world settings within diverse patient populations across the disease continuum[11].

About metformin
Metformin hydrochloride is widely-used and is the recommended first-line therapy in patients with newly-diagnosed T2DM either immediately after diagnosis, or in those not able to achieve glycemic targets despite diet and other lifestyle interventions[12].

Despite its discovery already in 1922, the exact mode of action for metformin is not yet known. However, its effect in management of diabetes is through reduction of glucose output in the liver and secondarily, through increase of glucose uptake in the peripheral tissues. However, recent data suggests that some clinical activity may also arise from the synthesis and stimulation of intestinal release of incretin hormones[12],[13].

About VERIFY study[1],[2]
The VERIFY study is a five-year, multi-center, randomized, double-blind Phase IV trial designed to assess the durability of glycemic control of a combination regimen strategy with vildagliptin and metformin compared with standard-of-care monotherapy approach with metformin initiated in treatment-naïve, diverse patients with recently diagnosed T2DM (HbA1c between 6.5-7.5% [48–58 mmol/mol]).

The study involved 2001 patients prescribed with stable dose of metformin (1000–2000 mg daily) 4 weeks prior to or during the trial and randomized (1:1) to receive additional vildagliptin 50 mg twice daily or placebo. Dose adjustment of metformin in both treatment arms was permitted during the first 4 weeks in the trial, to allow adjustment to a dose of up to 2000 mg/day or the maximum tolerable dose of at least 1000 mg/day post-randomization. If the initial treatment strategy failed to maintain an HbA1c level <7.0%, participants in the metformin monotherapy group were administered vildagliptin 50 mg twice daily in place of the placebo.

The primary endpoint was time to confirmed initial treatment failure, defined as HbA1c >=7% at two consecutive scheduled visits, 13 weeks apart. Secondary endpoints included rate of loss of glycemic control, HbA1c development over time, rate of loss in glycemic control in fasting plasma glucose, rate of loss of beta cell function from baseline to end of study, rate of change in insulin sensitivity from baseline to end of study, and rate of adverse events. Exploratory endpoints include adjudication of cardiovascular events and changes in glucose homeostasis (HOMA).

About T2DM
Diabetes mellitus is a condition characterized by increasing hyperglycemia due to defects in both insulin production and insulin sensitivity[14]. The prevalence of diabetes has quadrupled in the past three decades with approximately 1 in 11 adults now having the disease worldwide, of these approximately 90% have T2DM[15]. Additionally, factors such as glucose intolerance (pre-diabetes), underdiagnosed and/or delayed diagnosis of T2DM are causing a rapid increase in disease burden. This is especially seen in developing countries, which contributes to the continuously growing burden of diabetes. The International Diabetes Federation estimates that there is a new diagnosis every 6 seconds somewhere in the world[16].

After diagnosis, the majority of patients are unable to achieve and maintain the recommended glycemic control targets as defined by the guidelines[17].  This universal lack of achievement of glycemic control is partly attributed to the current treatment paradigm involving sequential monotherapy, frequent early treatment failure and delayed therapy intensification leading to prolonged periods of sustained hyperglycemia. Combatting inertia in treatment intensification could also include a strategy of earlier and more comprehensive introduction combination therapy approach[11],[18].

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach more than 750 million people globally and we are finding innovative ways to expand access to our latest treatments. About 108,000 people of more than 140 nationalities work at Novartis around the world. Find out more at www.novartis.com.

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References
      [1]    Novartis. Data on file.
      [2]    NIH: ClinicalTrials.gov. VERIFY: A Study to Compare Combination Regimen With Vildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus. Available at: https://clinicaltrials.gov/ct2/show/NCT01528254. Accessed August 2019.
      [3]    Halimi S, et al. Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet. Vasc Health Risk Manag 2008: 4(3): 481-492.
      [4]    Novartis. Corporate Factsheet: Innovative Medicines. Available at: https://www.novartis.com/news/novartis-corporate-fact-sheet/innovative-medicines-en. Accessed August 2019.
      [5]    EMA Galvus SmpC. Available at: https://www.ema.europa.eu/en/documents/product-information/galvus-epar-product-information_en.pdf. Accessed August 2019.
      [6]    Profit L, et al. Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus. Core Evid 2008: 3(1): 13-30.
      [7]    Pan CY & Wang XL. Profile of vildagliptin in type 2 diabetes: efficacy, safety, and patient acceptability. Ther Clin Risk Manag 2013: 9: 247-257.
      [8]    Garber AJ & Sharma MD. Update: vildagliptin for the treatment of Type 2 diabetes. Expert Opin Investig Drugs 2008: 17(1): 105-113.
      [9]    Stamataros G & Schneider SH. Vildagliptin in the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother 2011: 12(12):1967-1973.
      [10]  Villhauer EB, et al. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:  A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties. J Med Chem 2003; 46(13): 2774-2789.
      [11]  Strain WD & Paldánius PM. Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes. Eur Endocrinol 2017: 13(2): 62-67.
      [12]  Sanchez-Rangel E & Inzugghi SE. Metformin: clinical use in type 2 diabetes. Diabetologia 2017: 60(9): 1586-1593.
      [13]  Rena G, et al. The mechanisms of action of metformin. Diabetologia 2017: 60(9): 1577-1585.
      [14]  American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2013: 36(Suppl 1): S67-S74.
      [15]  Zheng Y, et al. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018: 14(2): 88-98.
      [16]  International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium: International Diabetes Federation, 2017. Available at: https://diabetesatlas.org/resources/2017-atlas.html. Accessed August 2019.
      [17]  Davies MJ, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Disease Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018 Dec; 41(12): 2669-2701
      [18]  Zinman, B. Initial combination therapy for type 2 diabetes mellitus: is it ready for prime time? Am J Med 2011: 124(Suppl 1): S19-S34.

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