Galvus Product Analysis

Transcription

1 Galvus Product Analysis Ref Code: DMKC Publication Date: 12/07/2016 Author: Rajan Sharma

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3 TABLE OF CONTENTS 4 PRODUCT PROFILES 4 Galvus : Diabetes type 2 LIST OF FIGURES 8 Figure 1: Galvus brand franchise for type 2 diabetes SWOT analysis 10 Figure 2: drug assessment of Galvus 10 Figure 3: drug assessment scorecard for Galvus compared to Januvia LIST OF TABLES 4 Table 1: Galvus franchise products 4 Table 2: Galvus drug profile 5 Table 3: Eucreas drug profile 6 Table 4: Overview of pivotal trial data for Galvus franchise in diabetes 3

4 PRODUCT PROFILES Galvus : Diabetes type 2 PRODUCT PROFILE Analyst Outlook Galvus (vildagliptin; Novartis) was the second-to-market dipeptidyl peptidase-iv (DPP-IV) inhibitor in many countries, but was unable to show superiority to Januvia (sitagliptin; Merck & Co). Non-superior efficacy and liver safety signals caused registration delays and lack of approval in the US market. However, fixed-dose combination Eucreas (vildagliptin/metformin; Novartis) launched before the competitor Janumet (sitagliptin/metformin; Merck & Co) in some European markets, and has attracted more sales there than Merck & Co's drug. Novartis offers vildagliptin as Galvus franchise products, which are listed below. Table 1: Galvus franchise products Product name Combination preparation Galvus vildagliptin Eucreas vildagliptin + metformin Source: Drug Overview Galvus is a member of the DPP-IV inhibitor class. DPP-IV is an enzyme responsible for the rapid degradation of the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandially from the gut (Mest and Mentlein, 2005). Inhibition of DPP-IV augments the amount of active GLP-1, which in turn triggers increased insulin secretion from the pancreas in a glucose-dependent manner and suppresses the release of glucagon, resulting in lowered blood glucose levels (Mentlein, 1999; Ahrén, 2005). The franchise product Eucreas addresses the fact that Galvus is generally used as a second- or thirdline treatment option as an add-on to metformin. 4

5 Table 2: Galvus drug profile Molecule vildagliptin Mechanism of action DPP-IV inhibitor Originator Novartis Marketing company Novartis Approved indication Type 2 diabetes Target patient population Monotherapy or add-on to metformin and/or sulfonylurea, or thiazolidinedione, or insulin Contraindications Hypersensitivity; moderate and severe renal or hepatic impairment; diabetic ketoacidosis; type 2 diabetes Formulation Oral; 50mg tablet Pricing strategy $59 for one month s supply in UK (ex-factory) Dosing frequency Twice daily First launch date 2008 (5EU), 2010 (Japan) Primary patent expiry Q (EU), Q (Japan) Geographic availability Japan, 5EU Alternative names Equa (Japan), Jalra (Germany) 2015 global total franchise sales $1,140m 5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); DPP-IV = dipeptidyl peptidase-iv Source: Medtrack 5

6 Table 3: Eucreas drug profile Molecule vildagliptin + metformin Mechanism of action DPP-IV inhibitor + biguanide Originator Novartis Marketing company Novartis Approved indication Type 2 diabetes Target patient population Monotherapy or add-on to sulfonylurea or insulin Contraindications Hypersensitivity; renal or hepatic impairment, dehydration, sepsis, lactic acidosis; diabetic ketoacidosis; type 1 diabetes Formulation Oral; 50/850mg, 50/1,000mg tablets Pricing strategy $59 for one month s supply in UK (ex-factory) Dosing frequency Twice daily First launch date 2008 (5EU), 2010 (Japan) Primary patent expiry Q (EU) Geographic availability 5EU Alternative names Icandra (Germany), Zomarist (Spain) 5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); DPP-IV = dipeptidyl peptidase-iv Source: Medtrack DEVELOPMENT OVERVIEW The table below shows pivotal trial data for the Galvus franchise. 6

7 Table 4: Overview of pivotal trial data for Galvus franchise in diabetes Phase Sample size Target Study design Dosing Results Source patients tested and duration III 632 Type 2 Double-blind, 50mg or Vildagliptin (50mg once daily): HbA1c -0.8% Dejager et al., diabetes, drug- placebo- 100mg once 2007 naïve controlled, daily or 50mg Vildagliptin (50mg twice daily): HbA1c -0.8% dose-ranging twice daily, for RCT 24 weeks Vildagliptin (100mg once daily): HbA1c -0.9% Placebo: HbA1c -0.3% III 544 Type 2 Double-blind, 50mg or Vildagliptin (50mg) relative to placebo: HbA1c Bosi et al., diabetes, placebo- 100mg once -0.7%, FPG -0.8mmol/l, PPG -1.9mmol/l, beta uncontrolled on metformin controlled, RCT daily for 24 weeks cell function +5.2pmol/min/m/mmol/l, weight ±0.0kg Vildagliptin (100mg) relative to placebo: HbA1c -1.1%, FPG -1.7mmol/l, PPG - 2.3mmol/l, beta-cell function +5.7pmol/min/m/mmol/l, weight +1.2kg III 463 Type 2 Double-blind, 100mg once Vildagliptin from baseline: HbA1c -1.0%, Göke et al., diabetes, drug- active daily, or 2g weight +0.5kg, AE in 82.2% patients, 2008 naïve comparator, metformin, for gastrointestinal AE in 25.0% patients RCT 104 weeks Metformin from baseline: HbA1c -1.5%, weight -2.5kg, AE in 87.3% patients, gastrointestinal AE in 45.6% patients III 576 Type 2 Double-blind, 50mg twice Vildagliptin + metformin from baseline: HbA1c Bolli et al., diabetes, active daily, or 30mg -0.9%, FPG -1.4mmol/l, weight -1.6kg, serious 2007 uncontrolled comparator, pioglitazone, AE in 2.0% patients on metformin RCT for 24 weeks Pioglitazone + metformin from baseline: HbA1c -1.0%, FPG -2.1mmol/l, weight +1.9kg, serious AE in 4.6% patients 7

8 Table 4: Overview of pivotal trial data for Galvus franchise in diabetes Phase Sample size Target Study design Dosing Results Source patients tested and duration III 2,789 Type 2 Double-blind, 50mg twice Vildagliptin + metformin from baseline: HbA1c Ferranini et al., diabetes, non-inferiority, daily, or -0.44%, FPG -1.01mmol/l, weight -0.23kg, 2009 HbA1c RCT titrated 1.7% patients experienced hypoglycemic % on metformin glimepiride, for events, serious AE in 7.1% patients 52 weeks Glimepiride + metformin from baseline: HbA1c -0.53%, FPG -1.14mmol/l, weight +1.56kg, 16.2% patients experienced hypoglycemic events, serious AE in 9.5% patients III 632 Type 2 Double-blind, 50mg or Vildagliptin (50mg once daily): HbA1c -0.8% Dejager et al., diabetes, drug- placebo- 100mg once 2007 naïve controlled, daily or 50mg Vildagliptin (50mg twice daily): HbA1c -0.8% dose-ranging twice daily, for RCT 24 weeks Vildagliptin (100mg once daily): HbA1c -0.9% Placebo: HbA1c -0.3% AE = adverse events; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; PPG = postprandial glucose (measured after 2 hours); RCT = randomized controlled trial Source: various (see above) Galvus development showed liver safety signals A liver signal in patients taking the 100mg, once-daily dose of vildagliptin was reported in clinical trials and resulted in delays to registration (Ligueros-Saylan et al., 2010; Smith, 2007). The liver toxicity issues meant that a European marketing authorization was only granted for the lower 50mg dose and warnings about the hepatotoxicity were added to the label (EMA, 2013a). The authorization was granted for the 50mg dose after a meta-analysis from Phase II and Phase III clinical trials indicated no increased risk of hepatic events or enzyme elevations indicative of drug-induced liver toxicity (Ligueros-Saylan et al., 2010). SWOT ANALYSIS 8

9 Figure 1: Galvus brand franchise for type 2 diabetes SWOT analysis Source: CLINICAL AND COMMERCIAL ATTRACTIVENESS The figure below depicts 's drug assessment summary for Galvus in relation to 9

10 the other marketed non-insulin antidiabetic products. Figure 2: drug assessment of Galvus Source: The figure below shows Galvus's drug assessment scorecard compared to Januvia. 10

11 Figure 3: drug assessment scorecard for Galvus compared to Januvia Source: Twice-daily dosing and safety profile have hindered uptake Galvus shows no efficacy benefit over Januvia, and its twice-daily dosing along with some negative safety signals make the drug less attractive than other DPP-IV inhibitors. A warning was added to Galvus's label as a result of the liver safety signal in trials and monitoring of liver enzymes is recommended in patients using vildagliptin (Ligueros-Saylan et al., 2010). This means increased costs for payers and decreased convenience for patients using Galvus compared to other DPP-IV inhibitors. Liver toxicity is an unacceptable side effect for antihyperglycemic therapeutics, and Novartis dealt with this issue by replacing the 100mg once-daily dose with twice-daily 50mg doses that did not show hepatic toxicity in clinical studies. However, a twice-a-day dosing regimen is less convenient and decreases patient compliance, putting Galvus at a disadvantage compared to once-daily DPP-IV inhibitors. Galvus is unable to capitalize on its broad indication Galvus does have a broad indication, but is unable to fully capitalize because more favorable alternatives are available. In December 2011, Galvus received an indication expansion for use in type 2 diabetes patients with moderate or severe renal impairment (EMA, 2013a). This patient subpopulation comprises up to one quarter of type 2 diabetes patients, so the indication expansion significantly broadened the target market for Galvus (Keane et al., 2003; Ritz et al., 1999). However, most other DPP-IV inhibitors also have indication expansions for use in renally impaired patients. believes that Tradjenta (linagliptin; Boehringer Ingelheim/Eli Lilly) will be the more successful DPP-IV inhibitor in this niche market, as it does not need dose adjustment or liver 11

12 enzyme monitoring and its once-daily dosing is more convenient. Eucreas has had some success in the EU markets Twice-daily Eucreas is the main driver of Galvus franchise sales in Europe (Novartis, 2013). Kombiglyze (saxagliptin/metformin; AstraZeneca) and Jentadueto (linagliptin/metformin; Boehringer Ingelheim/Eli Lilly) are Eucreas s main competitors but, like Eucreas, these drugs are only available as twice-daily formulations. Thus, Eucreas is not at a disadvantage to its main competitors. Its first-to-market fixeddose combination status in some European countries has helped the drug to gain market share, and expects physician familiarity to continuously drive brand sales in line with the growth of the type 2 diabetic population. Galvus is not available in the US Galvus is not marketed in the US, and not having access to the biggest antidiabetic market significantly restricts its commercial success. A New Drug Application (NDA) was submitted to the US Food and Drug Administration (FDA) in March 2006, but in February 2007 the FDA requested that Novartis undertake a study in patients with renal impairment (Smith, 2007). In July 2008 Novartis withdrew its US application entirely, and it is assumed that no launch will take place there, cutting it off from the most lucrative market (Johnson and Winslow, 2008). Safety issues will affect growth to a small extent The use of DPP-IV inhibitors and GLP-1 agonists potentially increases the risk for acute pancreatitis and may be related to changes in pancreatic tissue, which predicts will have a small detrimental effect on the growth of Galvus s market share. Singh et al. (2013) published a study derived from administrative patient data, stating that the risk of acute pancreatitis was nearly twice as high in patients taking incretin mimetics such as DPP-IV inhibitors and GLP-1 agonists. In March 2013, the FDA and European Medicines Agency announced that they would launch an investigation into the safety of incretin mimetics, largely triggered by a study from a group of researchers who found precancerous cellular changes in the pancreases of patients using DPP-IV inhibitors or GLP-1 agonists (FDA, 2013; EMA, 2013). Shortly after, in July 2013, both agencies announced that their safety reviews did not show an unfavorable risk/benefit ratio and that incretin mimetics continued to be a safe treatment option (EMA, 2013c). The FDA also stated that epidemiological studies and close monitoring of adverse events were ongoing (Scrip, 2013). expects physicians to be slightly more reluctant to prescribe incretin mimetics because of these unconfirmed findings, despite the regulatory agencies affirmation of the drug classes' safety. However, in the absence of many alternatives, the effect on class growth will be small. Bibliography Ahrén B (2005) What mediates the benefits associated with dipeptidyl peptidase-iv inhibition? Diabetologia, 48, <DOI> /s </DOI>. 12

13 Bolli G, Dotta F, Rochotte E, Cohen SE (2007) Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes, Obesity and Metabolism, 10(1), <DOI> /j x</DOI>. Bosi A, Camiasca RP, Collober C, Rochotte E, Garber AJ (2007) Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care, 30, <DOI> / dc </doi>. Dejager S, Razac S, Foley E, Schweizer A (2007) Vildagliptin in drug-naïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Hormone and Metabolic Research, 39(3), <DOI> /s </DOI>. EMA (2013a) EMA Galvus Product Information. Available from: ed_ jsp&mid=wc0b01ac058001d124 [Accessed 7 May 2013]. EMA (2013b) European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type 2 diabetes. Available from: jsp&mid=WC0b01ac058004d5c1 [Accessed 26 March 2013]. EMA (2013c) Investigation into GLP-1 based diabetes therapies concluded. Available from: jsp&mid=WC0b01ac058004d5c1 [Accessed 30 July 2013]. FDA (2013) Drug Safety and Availability > FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Available from: [Accessed 25 March 2013]. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, Shao Q, Dejager S (2009) Fifty-twoweek efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism, 11, <DOI> /j x</DOI>. Göke B, Hershon K, Kerr D, Pascuel AC, Schweizer A, Foley J, Shao Q, Dejager S (2008) Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2 diabetes: comparison with metformin. Hormone and Metabolic Research, 40(12), <DOI> /s </DOI>. Johnson A, Winslow R (2008) Drug Makers Say FDA Safety Focus Is Slowing New-Medicine Pipeline - WSJ.com. Available from: [Accessed 13 May 2013]. 13

14 Keane WF, Brenner BM, Zeeuw D De, Grunfeld J-P, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM (2003) The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney International, 63, <DOI> /j x</DOI>. Ligueros Saylan M, Foley J, Schweizer A, Couturier A, Kothny W (2010) An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials. Diabetes, Obesity and Metabolism, 12, <DOI> /j x</DOI>. Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regulatory Peptides, 85, 9 24 <DOI> /S (99) </DOI>. Mest H-J, Mentlein R (2005) Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes. Diabetologia, 48, <DOI> /s </DOI>. Novartis (2013) Novartis quarterly results - Q Available from: [Accessed 7 May 2013]. Ritz E, Rychlík I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. American Journal of Kidney Diseases, 34, <DOI> /S (99) </DOI>. Scrip (2013) Scripintelligence - FDA CONCURS: No confirmation of new GLP-1, DPP-4 pancreatic concerns. Available from: [Accessed 30 July 2013]. Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB (2013) Glucagonlike Peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a populationbased matched case-control study. JAMA Internal Medicine, 173, <DOI> /jamainternmed </DOI>. Smith A (2007) FDA holds Novartis Galvus back from U.S. market. Available from: [Accessed 13 May 2013]. 14