New Drugs for the Primary Care Provider: What You Need to Know

New Drugs for the Primary Care Provider: What You Need to Know Faculty Financial Disclosure Gerald W. Smetana, MD, has no financial relationships to disclose. Gerald W. Smetana, MD Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Objectives Learn which recently approved drugs will have the largest impact on primary care practice Understand the efficacy, side effects, and cost of important novel drugs in primary care practice Learn the role of recently approved medications and their place among existing therapies Important New Drugs for 2014: What We Need to Know Relevant for PCP Novel Drugs No Me Too Drugs FDA New Drug Approvals in 2013: Few Potentially Novel Drugs for Primary Care 2014: Most New Drugs Do Not Meet These Criteria Me Too Drugs, 9 Novel Drugs: 2 Biologicals, 9 Subspecialty Meds, 15 1

Three Novel Drugs for Primary Care Practice Historical Perspective Dalcetrapib for the Rx of low HDL cholesterol levels Rivaroxaban for treatment of DVT/PE Canagliflozin for the treatment of type 2 diabetes Man has an inborn craving for medicine The desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures Even in minor ailments, which would yield to dieting or to simple home remedies, the doctor s visit is not thought to be complete without the prescription. William Osler 1895 Mr. Hartmann Dalcetrapib for Low HDL Levels 66 yo man with CAD and diabetes LDL 86 on atorvastatin HDL 30 Will medication to increase my HDL decrease my risk of MI? The HDL Hypothesis HDL cholesterol is inversely related to cardiovascular risk Drug treatment to raise HDL cholesterol to date has not improved CV outcomes The key question: Is HDL an etiologic factor in CV risk or merely a marker for risk? Theory Behind CETP Inhibition CETP is cholesterol ester transfer protein Cohort of individuals in Japan with defective CETP have high HDL CETP promotes transfer of cholesterol esters from HDL to other proteins Component of reverse cholesterol transport of HDL back to liver for excretion Blocking CETP could raise HDL levels First CETP inhibitor studied was torcetrapib 2

ILLUMINATE Mechanism of Torcetrapib Toxicity:? Off Target Effect ILLUMINATE Trial: Torcetrapib Increases: CV Events, CV Mortality, and Noncardiac Mortality Torcetrapib added to atorvastatin increased HDL by 72% Increased cardiac death Doubled rates of noncardiac death Increased systolic bp by 5.4 mm Hg Decreased K+ levels Proposed aldosterone mechanism Independent from CETP inhibition? NEJM 2007;357:2109 Anacetrapib and Dalcetrapib Were Designed to Avoid Off Target Effects Do they reduce cardiovascular risk? Status of CETP Inhibition Through December 2012 1. Torcetrapib increases CV mortality 2. Anacetrapib and dalcetrapib have no off target effects but effect on CV risk unknown RCT: Effect of Dalcetrapib in Patients with Recent ACS N=15,871 Patients hospitalized with ACS or MI Medical Rx +/- PCI All patients receive Rx for LDL when indicated (98% statin use) 4-12 weeks after event, randomly assigned to dalcetrapib 600 mg qd vs. placebo Composite primary CV endpoint at 3 years Dalcetrapib Increases HDL by 31-40 % LDL Unchanged (mean 76 mg/dl) HDL Cholesterol mg/dl 36% P < 0.001 NEJM 2012;367:2089 3

Key Points Implications for Practice CETP inhibition raises HDL levels by > 30-120% Off target effect may explain increased mortality with torcetrapib Dalcetrapib has no off target effects but does not reduce CV risk Anacetrapib does not increased blood pressure but no outcome data yet Proxy outcomes do not predict clinical events Great caution needed CETP inhibition is attractive in theory but no CV benefit proven This is second trial to show harm or no benefit from CETP inhibition Suggests that low HDL may be a marker for CV risk rather than etiologic REVEAL trial of the impact of anacetrapib on CV risk is still ongoing Advise for Mr. Hartmann Continue a statin with goal LDL < 100 Stay with the tried and true Don t hold your breath for new meds for HDL Smile Rivaroxaban to Treat DVT and Pulmonary Embolus Ms. Virchow 28-year-old woman Recent air travel from NRT to LAX Developed LE DVT after the flight LENI s positive Doesn t want to hassle with warfarin How about rivaroxaban? Why Revisit Rivaroxaban? FDA approved July 2011 for VTE prophylaxis after orthopedic surgery Approved November 2011 for stroke prevention in AF New indication for the Rx of DVT and PE 4

Anticoagulation: Challenges with Standard Treatment LMWH Requires daily injection Expensive Warfarin Narrow therapeutic range Requires frequent monitoring Major bleeding complications > 3% per year Among top 10 FDA adverse event reports History of Anticoagulants 1922 1939 1950 s 1993 2001 2010 2011 Heparin Warfarin Fondaparinux Dicumarol Enoxaparin LMWH s Dabigatran Rivaroxaban Desirable Attributes for the Ideal Anticoagulant Oral administration Predictable anticoagulant response No monitoring Rapid onset of action Rapid reversibility Safe antidote No major side effects Targets for Novel Anticoagulants Antithrombin activation Idraparinux (once weekly derivative of fondaparinux Direct thrombin (factor IIa) inhibitors Ximelagatran (withdrawn due to liver toxicity) Dabigatran Factor Xa inhibitors Apixaban Rivaroxaban There is a Reason Why We Didn t Become Hematologists Rivaroxaban Inhibits Factor Xa X VIIa VIIIa Xa IXa Extrinsic Pathway Intrinsic Pathway Va Rivaroxaban Apixaban Prothrombin (II) Fibrinogen Thrombin (IIa) Dabigatran Fibrin 5

Rivaroxaban: Pharmacology Brief Summary of VTE Prophylaxis Data: Rivaroxaban is Superior to Enoxaparin and Has Comparable Bleeding Rates Rapid onset after PO dose Half life of 5-9 hours Once daily dosing Predictable anticoagulant response No monitoring required Surgery N Composite Events % RRR RECORD 1 THA 4541 3.7 vs 1.1 70% RECORD 2 THA 2509 9.3 vs 2.0 79% RECORD 3 TKA 2531 18.9 vs 9.6 49% RECORD 4 TKA 3148 10.1 vs 6.9 31% Lancet 2008;372:6 NOAC: Indirect Comparisons for Stroke Prevention in AF Apixaban Marginally Favored Event %/year Stroke plus major emboli Rivaroxaban Rocket AF Dabigatran RELY Apixaban ARISTOTLE 1.7/2.2 1.1/1.7 1.3/1.60 Stroke 2.6/3.1 1.0/1.6 1.2/1.5 Mortality 1.9/2.2 3.6/4.1 3.5/3.9 Major 3.6/3.4 3.1/3.4 2.1/3.1 bleeding CNS bleeding 0.5/0.7 0.1/0.4 0.3/0.5 DVT and Pulmonary Embolus Are Morbid Events 300,000 to 600,00 cases / year in U.S. 10-30% will die within one month of diagnosis 1/3 of patients will have recurrence within 10 years ½ of patients with DVT develop postphlebitic syndrome http://www.cdc.gov/ncbddd/dvt/data.html Outcomes for Rx of DVT/PE for 6 Months of Standard Therapy with LMWH and Warfarin EINSTEIN DVT Trial of Rivaroxaban vs. Standard Rx DVT PE Mortality % 12.2 20.6 % 3.6 4.9 Major bleeding % 2.3 2.1 N = 3449 Proximal DVT No PE GFR > 30 ml/min Exclusions Liver disease Active bleeding Bp > 180/110 Pregnancy Ann Intern Med 2010;578:589 NEJM 2010;363:2499 6

EINSTEIN Acute DVT Study: Random Rx Assignments Rivaroxaban 15 mg bid x 3 weeks, then 20 mg qd 3449 patients Enoxaparin 10 mg/kg bid until INR > 2 Primary Endpoint = Recurrent Symptomatic VTE Acute Rx: Rivaroxaban was Non- Inferior for at 6 and 12 Months Rx for 3, 6, or 12 months Warfarin to INR 2-3. Rx for 3, 6, or 12 months Continued Rx: Comparison of Rivaroxaban to Placebo Safety Outcomes in Acute DVT Study: No Significant Differences Compared to Standard Rx Re-randomized to rivaroxaban 20 qd or placebo for an additional 6 or 12 months after completing acute Rx Event Rivaroxaban % Enoxaparin / Warfarin % Major bleeding 0.8 1.2 Fatal bleeding < 0.1 0.3 Non-major 7.3 7.0 bleeding Fatal PE 0.2 0.3 Study d/c 4.9 4.7 Indirect Comparisons to Other Novel Anticoagulants for Rx DVT/PE Indirect Comparisons to Other Novel Anticoagulants for Rx DVT/PE Rivaroxaban Dabigatran Apixaban Study EINSTEIN-DVT RE-COVER AMPLIFY # subjects 3449 2564 5395 Primary outcome Outcome vs. standard Rx 2.1% vs. 3.0% 2.4% vs. 2.1% 2.3% vs. 2.7% Major bleeding 0.8% vs. 1.2% 1.6% vs. 1.9% 0.6% vs. 1.8%* Rivaroxaban Dabigatran Apixaban Study EINSTEIN-DVT RE-COVER AMPLIFY # subjects 3449 2564 5395 Primary outcome Outcome vs. standard Rx 2.1% vs. 3.0% 2.4% vs. 2.1% 2.3% vs. 2.7% Major bleeding 0.8% vs. 1.2% 1.6% vs. 1.9% 0.6% vs. 1.8%* Curr Cardiol Rep 2014;16:463 Outcomes comparable. Apixaban has marginally less bleeding Curr Cardiol Rep 2014;16:463 Outcomes comparable. Apixaban has marginally less bleeding 7

Indirect Comparisons to Other Novel Anticoagulants for Rx DVT/PE Other Considerations Rivaroxaban Dabigatran Apixaban Study EINSTEIN-DVT RE-COVER AMPLIFY # subjects 3449 2564 5395 Primary outcome Outcome vs. standard Rx 2.1% vs. 3.0% 2.4% vs. 2.1% 2.3% vs. 2.7% Major bleeding 0.8% vs. 1.2% 1.6% vs. 1.9% 0.6% vs. 1.8%* Outcomes comparable. Apixaban has marginally less bleeding Drug interactions with CYP3A4 inhibitors Must be taken with food Contraindicated during pregnancy (C) Dose adjustment for moderate CKD Must instruct patients to not miss any doses No specific antidote for reversal Approach to bridging uncertain Curr Cardiol Rep 2014;16:463 FDA Approved Indications: Only Rivaroxaban Approved for All 3 Indications Monthly Cost of Outpatient Anticoagulation Dabigatran Apixaban Rivaroxaban Stroke prevention in AF Stroke Prevention in AF Stroke Prevention in AF Postoperative VTE Prophylaxis Rx of DVT and PE Item Cost Rivaroxaban 20 mg qd $295 Dabigatran 150 mg bid $323 Apixaban 5 mg bid $292 Warfarin 5 mg qd $15 INR measurement q 2 weeks $160 $80 x 2 Phlebotomy charge = $15 x 2 $30 Total cost of warfarin $205 plus? Rx Price Quotes.com Feb. 2014 Rivaroxaban: Key Points Single daily oral dose Non-inferior to warfarin in preventing recurrent VTE Bleeding rates comparable to standard therapy with LMWH and heparin No monitoring required No dietary restrictions No antidote if emergency surgery or major bleeding occurs An appropriate alternative to standard therapy What to Advise Ms. Virchow? LMWH followed by warfarin for at least 3-6 months is standard Rx Rivaroxaban is an acceptable alternative in order to avoid monitoring 8

Mr. Sugarman Canagliflozin for Treatment of Type 2 Diabetes 15-year history of type 2 diabetes PMHx hypertension, obesity A1c 8.5% on metformin alone What about adding this new medication canagliflozin? Is this better than adding glyburide? FDA approval May 29, 2013 Percentage with Diabetes Number and Percentage of U.S. Population with Diagnosed Diabetes 8 7 6 5 4 3 2 1 Percentage with Diabetes Number with Diabetes 25 20 15 10 5 Number with Diabetes (Millions) Age adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) O B ES 1994 2000 2009 I T Y No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Diabetes D 1994 2000 2009 IA B ET 0 1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09 Year CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics 0 E S No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics History of Diabetes Medications Canagliflozin is a Novel SGL2 Inhibitor 1921 Insulin 1942 Sulfonylureas 1994 Metformin 1999 Rosiglitazone 2005 Exenatide 2006 Sitagliptin 2013 Canagliflozin Sodium-glucose co-transporter 2 = SGL2 Selective membrane protein expressed in kidney Transports glucose from proximal tubular lumen to epithelial cells Canagliflozin blocks SGL2, prevents glucose reabsorption, and causes glucosuria Decreases blood glucose 9

Effect of Canagliflozin Monotherapy in Type 2 Diabetes N=584 A1c 7-10% at baseline Randomly assigned to: Canagliflozin 100 mg qd Canagliflozin 300 mg qd Placebo 26 week follow up Primary endpoint = change in A1c Diabetes Obes Metab. 2013;15:372 Most Patients Achieved 7% A1c Goal at 300 mg qd Dose 70 60 50 40 30 20 10 0 Placebo Cana 100 mg Cana 300 mg A1c < 7% A1c < 6.5% P < 0.01 P > 0.05 Adverse Effects Among Pooled Studies Adverse Effects Among Pooled Studies Event Placebo Canagliflozin 100 mg qd % Canagliflozin 300 mg qd % Any 75.8 76.6 77.0 Rx discontinuation 5.0 5.6 7.3 Constipation 0.9 2.8 2.3 UTI 4.0 5.9 4.3 Polyuria 0.8 5.3 4.6 Balanitis 0.6 4.2 3.7 Vaginal candidiasis 3.2 10.4 11.4 Orthostasis < 0.1 0.3 0.9 Rash / urticaria NA < 2 < 2 Event Placebo Canagliflozin 100 mg qd % Canagliflozin 300 mg qd % Any 75.8 76.6 77.0 Rx discontinuation 5.0 5.6 7.3 Constipation 0.9 2.8 2.3 UTI 4.0 5.9 4.3 Polyuria 0.8 5.3 4.6 Balanitis 0.6 4.2 3.7 Vaginal candidiasis 3.2 10.4 11.4 Orthostasis < 0.1 0.3 0.9 Rash / urticaria NA < 2 < 2 Mean Change in A1c and Weight for Approved Drugs for Diabetes Cost: AWP for Selected Agents Agent A1c (%) Δ Weight (kg) Insulin DCCT 0.2 + 2.4 conventional Insulin DCCT intensive 1.5 + 9.8 Sulfonylureas 1.1-1.9 + 2.8 to + 3.6 Metformin 0.9-1.4-0.6 to -0.8 Thiazolidinediones 0.-1.5 +2.6 to +3.5 GLP-1 agonists 0.4 to 0.9-0.9 to -2.8 DPP-4 inhibitors 0.6-0.9 0 to -1.0 Canagliflozin 0.9-1.1-2.2 to 3.3 Oral Monthly Cost (USD) Glipizide 10 mg qd 4 Metformin 1500 mg qd 30 Pioglitazone 15 mg qd 45 Sitagliptin 100 mg qd 246 Canagliflozin 100 mg qd 263 Injectable Exenatide 10 mcg bid 350 Insulin Glargine 2 pens 90 Medical Letter May 2013 10

What To Add After Metformin? Advantages Disadvantages Sulfonylurea Most A1c reduction Hypoglycemia Glitazones No hypoglycemia Weight gain Fluid retention GLP-1 Agonists DPP-4 Inhibitors Insulin Canagliflozin No hypoglycemia Weight loss No hypoglycemia Effective Weight loss BP reduction Injections Nausea Less effective Long term side effects? Injections Hypoglycemia Yeast infections UTIs Other Considerations Less A1c reduction (0.6%) for patients with CKD Reduces systolic bp by 4-8 mm Hg LDL increase 8 mg/dl Small increase in serum PO 4 and Mg Rarely may cause hyperkalemia, hypotension Does not cause hypoglycemia in monotherapy Small reduction in BMD Dapagliflozin, available in Europe, denied by FDA due to possible risk of breast and bladder cancer Key Points Dose 100 to 300 mg qd Adjust for CKD; contraindicated for GFR < 45 A1c reduction comparable to other agents Glucosuria causes weight loss More weight loss than any other Rx May cause polyuria and orthostasis Yeast and urinary tract infections? Potential for long term CA risk Very expensive Summary Dalcetrapib raises HDL without affecting blood pressure, but does not reduce CV risk Rivaroxaban is non-inferior to warfarin for the treatment of DVT/PE and requires no monitoring Canagliflozin reduces A1c and weight; though long term safety is unknown A Final Thought For some patients, though conscious that their condition is perilous, recover their health simply through contentment with the goodness of their physician. Hippocrates (460-375 BC) 11