2017 New Drug Update

Transcription

1 2017 New Drug Update Tom Frank, Pharm.D., BCPS Director of Research and Education UAMS Northeast I have no conflicts of interest to report 1

2 Objectives Discuss trends in drug development Describe indications, pharmacology, adverse effects, and dosing of the products discussed Compare these products with other similar products in the participant s practice Zurampic (lesinurad) Ironwood 2

3 Lesinurad Pharmacology Indicated for reducing uric acid in combination with a xanthine oxidase inhibitor in patients who are not at target with XOI only Reduces uric acid levels by inhibiting function of transporter proteins in uric acid reabsorption in the kidney Lesinurad Pharmacokinetics Bioavailability 100% Peak concentration 1 4 hours after dosing 98% protein bound Metabolism by CYP 2C9 to inactive metabolites Half life 5 hours No dose adjustment needed for mild moderate renal impairment; do not initiate if CrCl < 45ml/min Drug interactions: CYP 2C9 inhibitors and inducers, sildenafil, amlodipine, colchicine, avoid valproate, ocp s less effective, limit aspirin 3

4 Lesinurad Clinical Trials Compared to placebo in randomized, double blind study over 12 months All patients got allopurinol but inadequate response Compared lesinurad 200mg, 400mg and placebo daily Primary end point: uric acid 6.5mg/dl End point reached in 54%, 59% and 27% Gout flare rate and tophus dissolution rate not different between groups Lesinurad Clinical Trials Lesinurad has been evaluated in a trial when febuxostat had been the uricosuric agent Patients did not reach target uric acid of < 5mg/dl Randomized to lesinurad 200mg, 400mg or placebo plus febuxostat Goal reached in 57% on lesinurad plus febuxostat and 47% on febuxostat only 4

5 Lesinurad Adverse Effects Headache Influenza Blood creatinine increased GERD Cardiovascular events observed in clinical trials, causal relationship not established Contraindicated in ESRD kidney transplant, dialysis patients, tumor lysis syndrome, Lesch Nyhan syndrome Lesinurad Dosing 200mg once daily used in combination with a xanthine oxidase inhibitor Take in the morning with food or water Discontinue if CrCl drops below 45ml/min 5

6 Xiidra (lifitegrast) Shire 6

7 Lifitegrast Pharmacology Indicated for treatment of signs and symptoms of dry eye disease Beta 2 integrin antagonist, binds to lymphocyte function associated antigen 1 (LFA 1) Blocks interaction of LFA 1 with ligand intercellular adhesion molecule 1 (ICAM 1) May inhibit T cell adhesion to ICAM 1 and reduce secretion of inflammatory cytokines Lifitegrast Pharmacokinetics Trough plasma concentrations were measurable in 19% of patients who were tested 7

8 Lifitegrast Clinical Trials Randomized, double masked trials over 12 weeks compared lifitegrast 5% to placebo in patients with dry eye disease Efficacy end points: change from baseline in inferior corneal staining score (ICSS) and eye dryness score (EDS) ICSS scores were not statistically different EDS improved by 36% in the treatment group and 22% in the placebo group 8

9 Lifitegrast Clinical Trials Randomized, double masked 12 week trial compared lifitegrast 5% to placebo in patients with dry eye disease Co primary end points was the mean change in the visual related function subscales and changes in the ICSS score The efficacy end point for visual related function was not met The ICSS was statistically better in the treatment group Lifitegrast Adverse Effects Instillation site irritation Dysgeusia Reduced visual acuity 9

10 Lifitegrast Dosing Instill one drop twice daily into each eye Discard single use container Remove contact lens prior to administration and wait 15 minutes following administration 10

11 Basaglar (insulin glargine injection) Boehringer Ingelheim/Lilly Insulin glargine Pharmacology Long acting insulin indicated for improvement in glycemic control in adults and pediatric patients with T1DM and T2DM Recombinant human insulin analog with amino acid sequence same as that of Lantus Insulin glargine stimulates peripheral glucose uptake and inhibits hepatic glucose production 11

12 Insulin glargine Pharmacokinetics ph of product in the vial is 4 Maximum insulin concentration in 12 hours, no pronounced peak Serum insulin levels decline to baseline by 24 hours Drug interactions: ACE inhibitors, ARB s; atypical antipsychotics, corticosteroids, niacin, protease inhibitors, alcohol, beta blockers, albuterol Insulin glargine Clinical Trials Basaglar compared to another insulin glargine product, 24 week open label study in adult and pediatric patients with inadequately controlled T1DM Insulin lispro used for fast acting glucose control Baseline HgbA1c : 7.75% vs 7.79% HgbA1c adjusted mean change from baseline: 0.35% vs 0.46% (non inferior) Proportion with HgbA1c < 7%: 43% vs. 32% 12

13 Insulin glargine Clinical Trials A double blind, active control study involving patients with T2DM over 24 weeks has compared the glucose lower effect of Basaglar plus oral antidiabetic medications to another insulin glargine product plus oral medication 60% were insulin naïve at the time of entry into the study Baseline HgbA1c was 8.35% and 8.31% Change in HbgA1c was 1.3% vs. 1.3% Proportion of patients achieving HgbA1c < 7% was 48% vs. 52% Insulin glargine Adverse Effects Hypoglycemia Hypertension Sinusitis Cataract Bronchitis 13

14 Insulin glargine Dosing Individualize dose Administer subcutaneously one daily, any time of day but at the same time every day Do not mix with any other insulin in the same syringe Maximum 80 units per injection Discard 28 days after first start using a KwikPen Review questions for self assessment: Which of the following should also be in the medication profile of a patient receiving Zurampic (lesinurad)? Colchicine Allopurinol Probenecid High dose aspirin 14

15 Answer allopurinol 15

16 Adlyxin (lixisenatide) Sanofi Lixisenatide Pharmacology GLP 1 Receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus GLP 1 agonist effect increases glucose dependent insulin release, decreases glucagon secretion and slows gastric emptying 16

17 Lixisenatide Pharmacokinetics Peak concentration hours after injection Eliminated by GFR and proteolytic degradation Half life 3 hours Increased levels in patients with decreased renal function Drug interactions: delays in gastric emptying may change absorption pattern of some drugs give acetaminophen or antibiotics one hour before, OCP s one hour before or 11 hours after Lixisenatide Clinical Trials Lixisenatide 20mcg compared to placebo over 12 weeks: HgbA1c 0.83% vs. 0.18%; FGP change 15mg/dl vs. 1.4mg/dl Lixisenatide 20mcg added to metformin compared to metformin plus placebo: HgbA1c 0.72% vs 0.26%; FPG change 16mg/dl vs. 7.2mg/dl Lixisenatide 20mcg added to basal insulin plus metformin compared to basal insulin/metformin/placebo: HgbA1c 0.71% vs. 0.34% Lixisenatide compared to liraglutide over 24 weeks, added to metformin; additional reduction in HgbA1c 1.21% for lixisenatide vs. 1.83% for liraglutide 17

18 Lixisenatide Clinical Trials Cardiovascular safety has been examined in a double blind, placebo controlled trial T2DM with history of acute coronary syndrome in past six months (n=6068) Received lixisenatide 20mcg daily or placebo plus standard diabetes medications Median observation time 25 months Primary composite CV endpoint reached in 13.4% in the lixisenatide group and 13.2% in the control group Lixisenatide Adverse Effects Nausea Vomiting Headache Diarrhea Dizziness 18

19 Dosing Initial dose 10mcg subcutaneously once daily for 14 days On day 15, increase dose to 20mcg once daily 19

20 Soliqua 100/33 (Insulin glargine/lixisenatide) Sanofi Insulin glargine/lixisenatide Pharmacology Combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM inadequately controlled on basal insulin or lixisenatide Insulin glargine lowers blood glucose by stimulating peripheral glucose uptake Lixisenatide is a GLP 1 receptor agonist that increases glucosedependent insulin release, decreases glucagon secretion and slows gastric emptying 20

21 Insulin glargine/lixisenatide Pharmacokinetics Insulin glargine released at rates similar to single ingredient product Lixisenatide in the combination has lower Cmax and comparable AUC to single ingredient product Half life insulin glargine 12 hours, lixisenatide 3 hours Drug interactions: usual insulin precautions, with lixisenatide precautions regarding delayed gastric emptying Insulin glargine/lixisenatide Clinical Trials Open label, randomized parallel group trial compared iglarlixi to insulin glargine only and lixisenatide only Patients had been treated at least 3 months with or without a second oral agent but had inadequate glycemic control All patients stayed on metformin during run in and through the 30 week study Mean baseline HgbA1c was 8.1%, doses titrated to achieve a FPG of mg/dl Maximum dose iglarlixi 60units/20mcg, insulin glargine 60 units, lixisenatide 20mcg 21

22 Insulin glargine/lixisenatide Clinical Trials After 30 weeks, changes in HgbA1c were, 1.6%, 1.3% and 0.9% Patients with HgbA1c < 7%: 73.7%, 59.4% and 33% Change in body weight: 0.3kg, +1.1kg and 2.3kg Insulin glargine/lixisenatide Adverse Effects Hypoglycemia Nasopharyngitis Diarrhea Upper respiratory infection Headache 22

23 Insulin glargine/lixisenatide Dosing Start with iglarlixi dose of 15 units if on less than 30 units of basal insulin per day or lixisenatide; give within one hour prior to first meal of the day If patient has been on units of glargine, start with iglarlixi 30 units per day Maximum iglarlixi dose is 60 units per day Titrate up or down by 2 4 units each week to achieve the desired result 23

24 Zinplava (bezlotoxumab) Merck Bezlotoxumab Pharmacology Indicated to reduce the recurrence of C. difficile in patients receiving antibacterial therapy for C. difficile who are at high rick for C. difficile infection recurrence Monoclonal antibody designed to bind to C. difficile toxin B Prevents binding of toxin B to colonic cells This monoclonal antibody binds to the B2 region of the combined repetitive oligopeptide (CROP) on toxin B 24

25 Bezlotoxumab Pharmacokinetics Elimination half life 19 days Metabolized by catabolism No meaningful differences found related to use in patients with impaired renal or hepatic function, no differences based on advanced age Bezlotoxumab Clinical Trials Evaluated in two randomized, double blind, placebo controlled trials All patients received standard of care antibiotics for treatment of CDI In study 1 patients were randomized to: (1) actoxumab (2)bezlotoxumab (3) actoxumab plus bezlotoxumab or (4) placebo Actoxumab arm stopped early (safety and efficacy concerns) Primary evaluation end point: recurrence of CDI over 12 week observation period 25.9%, 16.4%, 15.9% and 27.6% respectively Secondary end point: global cure 47%, 60%, 58% and 55% 25

26 Bezlotoxumab Clinical Trials Similar trial design but actotoxumab only arm dropped Follow up period extended to 12 months CDI recurrence rates: bezlotoxumab 15.7%, actotoxumab plus bezlotoxumab 14.9% and placebo 25.7% Global cure rates: bezlotoxumab 66%, actotoxumab plus bezlotoxumab 57% and placebo 52% Bezlotoxumab Adverse Effects Nausea Pyrexia Headache Infusion related reactions Heart failure 26

27 Bezlotoxumab Dosing 10mg/kg, infused over 60 minutes 27

28 Eucrisa (crisaborole) Anacor Crisaborole Pharmacology A phosphodiesterase 4 inhibitor indicated for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older Increases cyclic AMP levels which suppresses release of cytokines Changes downstream regulation of nuclear factor kappa b and nuclear factor of activated T cell signaling pathways 28

29 Childhood atopic dermatitis A typical localization of atopic dermatitis in children is the region around the mouth. In this child, there is lichenification and fissuring and crusting. Source: Eczema/Dermatitis, Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, 7e Citation: Wolff K, Johnson R, Saavedra AP. Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, 7e; 2013 Available at: Accessed: January 30, 2017 Copyright 2017 McGraw-Hill Education. All rights reserved (A) Childhood atopic dermatitis One of the hallmarks of atopic dermatitis is lichenification in the flexural regions as shown in this picture. Note the thickening of the skin with exaggerated skin lines and erosions. (B) Atopic dermatitis in black child. Pruritic follicular papules on posterior leg. Follicular eczema pattern is more common in African and Asian children. Source: Eczema/Dermatitis, Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, 7e Citation: Wolff K, Johnson R, Saavedra AP. Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, 7e; 2013 Available at: Accessed: January 30, 2017 Copyright 2017 McGraw-Hill Education. All rights reserved 29

30 Crisaborole Pharmacokinetics Mean plasma concentration after eight days of application: 127ng/ml 97% bound to plasma protein Hydrolyzed to inactive metabolites Renal excretion Drug interactions: not inducers or inhibitors of CYP system Crisaborole Clinical Trials Randomized double blind, vehicle controlled trials 29 days duration Patients with atopic dermatitis covering 5 95% of treatable body surface area, age range 2 79 years Baseline severity scores (Investigator's Static Global Assessment) ISGA score 2 in 38.5% and 61.5% with ISGA score of 3 After 29 days a score of clear (0) or almost clear(1) was reached in 32%on treatment vs. 25% using vehicle in study 1 and 31% vs 18% in study 2 Pruritus improvement by one grade or more shown in 63% vs. 53% 30

31 Crisaborole Application site pain Adverse Effects Crisaborole Dosing Apply a thin layer twice a day to affected areas 31

32 Review questions for self assessment Which of the following is most likely to have afavorable impact on weight loss in a patient with T2DM? Insulin glargine Lixisenatide Pioglitazone Insulin glargine combined with lixisenatide Answer Lixisenatide 32

33 Zepatier (elbasvir/grazoprevir) Merck 33

34 Elbasvir/grazoprevir Pharmacology Indicated as a fixed dose combination for HCV genotypes 1 and 4, with and without ribavirin Elbasviris an inhibitor of NS5A Grazoprevir is an inhibitor of NS3/4A Inhibits proteolytic activity of genotypes 1a, 1b and 4 Naming Conventions Regarding Antivirals NS5B polymerase inhibitors NS5A inhibitors NS3/4A protease inhibitors BUVIR (e.g. sofosbuvir, dasabuvir) ASVIR (e.g. ledipsavir, ombitasvir, velpatasvir) PREVIR (e.g. simeprevir, paritaprevir) 34

35 Elbasvir/grazoprevir Pharmacokinetics Elbasvirpeak in 3hrs., grazoprevir peak in 2 hrs. Can be taken without regard to food Both are extensively protein bound Metabolism primarily by CYP 3A Half life: elbasvir 24 hours, grazoprevir 31 hours Eliminated in feces Higher levels in female, geriatric and Asian population Elbasvir/grazoprevir Pharmacokinetics Contraindicated in moderate or severe hepatic impairment Drug interactions: contraindicated with phenytoin, carbamazepine, rifampin, St. Johns wort, efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine 35

36 Elbasvir/grazoprevir Clinical Trials Placebo controlled trial evaluating elbasvir/grazoprevir once daily in patient with HCV genotypes 1 or 4, with or without cirrhosis Placebo group received active drug in a deferred fashion Patients treated for 12 weeks, therapeutic end point was SVR12 End point reached in 95% Similar rates for 1a and 1b, cirrhosis and non cirrhosis Elbasvir/grazoprevir Clinical Trials Double blind, placebo controlled trial; patients with genotype 1 with and without cirrhosis Patients with CKD stage 4 and 5 (including HD) One tablet daily for 12 weeks SVR 12 for the treatment group 95% SVR in patients with cirrhosis 86% 36

37 Elbasvir/grazoprevir Clinical Trials Randomized, open label trial compared elbasvir/grazoprevir once daily for 12 weeks to elbasvir/grazoprevir plus ribavirin for 16 weeks Patient with genotype 1 or 4; with or without cirrhosis, with or without HCV/HIV1 coinfection Patients had failed PegIFN plus RBV therapy previously SVR12 for genotype 1 after 12 weeks of elbasvir/grazoprevir 94% SVR12 after 16 weeks of elbasvir/grazoprevir plus RIB was 97% 5% relapse rate in 12 week group Elbasvir/grazoprevir Adverse Effects Fatigue Headache Nausea Usual ribavirin concerns if added 37

38 Elbasvir/grazoprevir Dosing Genotype 1a, treatment naïve, PegIFN experienced without baseline polymorphism: one tablet daily for 12 weeks Genotype 1a, treatment naïve, PegIFN experienced with baseline polymorphism: one tablet daily for 16 weeks Genotype 1b, treatment naïve or PegIFN/RBV experienced: one tablet daily for 12 weeks Genotype 1a or 1b: Peg/IFN/RBV/NS3/4A protease inhibitor experienced: elbasvir/grazoprevir plus ribavirin for 12 weeks Genotype 4, treatment naïve: one tablet daily for 12 weeks Genotype 4, PegIFN/RBV experienced: elbasvir/grazoprevir plus ribavirin for 16 weeks 38

39 Epclusa (sofosbuvir/velpatasvir) Gilead Sofosbuvir/velpatasvir Pharmacology Indicated for treatment of adult patients with hepatitis C genotype 1,2,3,4,5 or 6 Sofosbuvir is an NS5B polymerase nucleotide inhibitor Velpatasvir is an NS5A inhibitor 39

40 Sofosbuvir/velpatasvir Pharmacokinetics Sofosbuvir 65% protein bound, velpatasvir > 99.5% protein boundd Increased absorption when taken with high fat meal Sofosbuvir metabolized by cathepsin A to GS ; velpatasvir metabolized by CYP system Half life: GS hours, velpatasvir 15 hours Excretion sofosbuvir 80% in the urine, velpatasvir 94% in the feces Sofosbuvir/velpatasvir Pharmacokinetics Drug interactions: velpatasvir inhibits P gp (increased levels of dabigatran, digoxin, rosuvastatin, tenofovir); velpatasvir has low solubility in low acid environment; efavirenz and carbamazepine reduce sofosbuvir/velpatasvir levels; sofosbuvir is a P gp substrate, reduced levels when given with CYP inducers; important interaction with amiodarone serious symptomatic bradycardia (particularly in those already taking beta blockers) 40

41 Sofosbuvir/velpatasvir Clinical Trials Sofosbuvir/velpatasvir has been evaluated in a randomized, doubleblind, placebo controlled trial that evaluated 12 weeks of treatment in patients with genotype 1,2,4,5 or 6 HCV infection Primary outcome of evaluation was SVR 12. The end point was reached in 98% with genotype 1a, 99% with genotype 1b, 100% with genotype 2, 100% with genotype 4, 97% with genotype 5 and 100% with genotype 6. None of the patients receiving placebo achieved the end point. Sofosbuvir/velpatasvir Clinical Trials A randomized, open label trial has compared 12 weeks of sofosbuvir/velpatasvir to 24 weeks of treatment with sofosbuvir plus ribavirin in patients with genotype 3 HCV infection Patients were also stratified on the basis of cirrhosis and prior treatment experience The SVR 12 was 95% for the sofosbuvir/velpatasvir group and 80% for the SOF + RBV group. 41

42 Sofosbuvir/velpatasvir Clinical Trials Sofosbuvir/velpatasvir has been evaluated in a open label trial in patients with genotype 1,2,3,4,5 or 6 HCV and decompensated cirrhosis Patients received (1)sofosbuvir/velpatasvir only for 12 weeks, (2)sofosbuvir/velpatasvir plus ribavirin for 12 weeks or (3)24 weeks of sofosbuvir/velpatasvir only Best results numerically were with the sofosbuvir/velpatasvir plus ribavirin for 12 weeks (SVR 12 = 94%, 3% virologic failure) Sofosbuvir/velpatasvir Adverse Effects Headache Fatigue Nausea Asthenia Insomnia Ribavirin adverse effects and precautions if added to treatment 42

43 Sofosbuvir/velpatasvir Dosing One tablet (sofosbuvir 400mg and velpatasvir 100mg) taken once daily with or without food for 12 weeks Patients with decompensated cirrhosis one tablet daily plus ribavirin for 12 weeks 43

44 Veltassa (patiromer) Relypsa Patiromer Pharmacology Patiromer is a cation exchange polymer indicated for treatment of hyperkalemia A sodium free, non absorbed cation exchange polymer (SNAP) Contains calcium sorbitol counter ion Binds potassium in the lumen of the GI tract 44

45 Patiromer Pharmacokinetics Not systemically absorbed Excreted in feces No dose adjustments based on renal or hepatic function Initial serum potassium reduction seen at 7 hours Drug interactions: (potential risk) separate patiromer 3 hours before or after amlodipine, cinaclet, ciprofloxacin, clopidogrel, furosemide, levothyroxine, lithium, metformin, metoprolol, trimethoprim, verapamil, warfarin Patiromer Clinical Trials Efficacy has been evaluated in two part randomized withdrawal study Hyperkalemia patients with CKD Patiromer dose titrated based on potassium level at baseline After four weeks, mean decrease was 0.65mEq/L (average baseline potassium 5.31mEq/L) Mean decrease 1.23mEq/L (average baseline potassium was 5.74mEq/L Patients at target were re randomized to (A) continue patiromer or (B) change to placebo After four weeks: patiromer stayed same, placebo group had potassium increase of 0.72mEq/L 45

46 Patiromer Adverse Effects Constipation Hypomagnesemia Diarrhea Nausea Abdominal discomfort Flatulence Patiromer Dosing Start with 8.4gm once daily Pour packet into 30ml water and stir Add 60ml more water and stir Drink it immediately Administer with food Do not take in its powdered form 46

47 Review questions for self assessment Which patient group would need ribavirin added to Epclusa for treatment of hepatitis C? Decompensated cirrhosis Pregnant Genotype 3 Previous treatment failures 47

48 Answer Decompensated cirrhosis Nucala (mepolizumab) Glaxo 48

49 Mepolizumab Pharmacology Add on maintenance treatment of severe asthma in patients 12 years of age and older who have an eosinophilic phenotype Interleukin 5 antagonist Binds to the alpha chain of the IL 5 receptor complex on the eosinophil cell surface Reduction in eosinophils in sputum and blood with selective inhibition of eosinophilic inflammation Mepolizumab Pharmacokinetics Subcutaneous administration produces bioavailability of 80% 2 fold accumulation at steady state Small volume of distribution Degraded by widely available proteolytic enzymes Half life days No specific dosing changes recommended based on race, gender, age, renal or hepatic impairment Drug interactions: no studies conducted 49

50 Mepolizumab Clinical Trials Evaluated in a multi center, double blind, placebo controlled study on patients with severe asthma who had one of the following: sputum eosinophil count > 3%, fractional exhaled nitric oxide concentration 50ppb, peripheral blood eosinophil count 300 cells/microliter or rapid deterioration of asthma control after a dose reduction in inhaled or oral steroids Patients received intravenous mepolizumab doses of 75mg, 250mg, 750mg or placebo every four weeks for 52 weeks Primary end point of evaluation was the rate of clinically significant asthma exacerbations Exacerbation rates were: 1.24 per patient per year, 1.46 per patient per year, 1.15 per patient per year and 2.4 per patient per year in the placebo group Mepolizumab Clinical Trials Mepolizumab has been evaluated in a randomized 32 week, active control trial involving patients with recurrent asthma exacerbations and eosinophilic inflammation despite high dose inhaled corticosteroids with or without oral steroids Patients received either mepolizumab 75mg IV, mepolizumab 100mg SQ or placebo every four weeks Primary end point of evaluation was the frequency of exacerbation requiring steroids or the need for hospitalization Exacerbation rates after 32 weeks were: 0.93 exacerbations per year in the 75mg group, 0.83 exacerbations per year in the 100mg group and 1.74 exacerbations per year in the placebo group Patients who enrolled on the basis of historical blood eosinophil count of 300 cells per microliter or greater in the past 12 months but had a baseline blood eosinophil count of less than 150 cells per microliter had no exacerbation benefit compared to placebo 50

51 Mepolizumab Adverse Effects Headache Injection site reaction Back pain Fatigue Systemic allergic hypersensitivity Herpes zoster injections Mepolizumab Dosing 100mg SQ once every four weeks Does not treat acute bronchospasm Do not discontinue systemic or inhaled corticosteroids abruptly Treat patient with pre existing helminth infections before starting mepolizumab; if patient becomes infected while being treated and does not respond, discontinue mepolizumab until parasite resolved 51

52 Exondys 51 (eteplirsen) Sarcepta 52

53 Eteplirsen Pharmacology Antisense oligonucleotide indicated for treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping Labeling states: clinical benefit of eteplirsen has not been established. Synthetic strand of nucleic acid that binds to exon 51 of the dystrophin gene producing skipping of the exon during RNA transcription This allows formation of a truncated partially functional dystrophin protein. 53

54 Eteplirsen Pharmacokinetics Peak concentration near the end of the infusion Protein binding 6 17% No dose accumulation with weekly doses Primarily renal elimination Half life 3 4 hours Dystrophin level after 180 weeks of treatment 0.93% of the dystrophin level in a healthy person Drug interactions: in vitro data indicates lack of drug interactions due to protein binding, cytochrome P450 or drug transporter interactions 54

55 Eteplirsen Clinical Trials Eteplirsen was evaluated in three trials of boys with DMD and gene deletion 51 First trial (n=12) looked at two doses (30mg/kg and 50mg/kg) compared to placebo and measured dystrophin levels as a primary outcome Clinical outcome was a 6 minute walk test after 24 weeks Changes in dystrophin levels correlated with dose size Six minute walk test was not different between the treatment group and the placebo group Eteplirsen Clinical Trials The same patients (n=12) were re randomized in an open label continuation study for an additional four years Patients received either 30mg/kg/week or 50mg/kg/week (n=6 in each group) The mean dystrophin level was 0.16% of normal at baseline and 0.44% of normal after week 48 The primary clinical efficacy outcome was the six minute walk test Study failed to provide evidence of clinical benefit of eteplirsen compared to the external control group. 55

56 Eteplirsen Adverse Effects Balance disorder Vomiting Contact dermatitis Eteplirsen Dosing 30mg/kg once weekly as a minute IV infusion 56

57 Review questions for self assessment Which of the following medications would be least likely to necessitate use of Veltassa (patiromer) in a CKD patient? Spironolactone Losartan Metoprolol Lisinopril Answer metoprolol 57

58 Nuplazid (pimavanserin) Acadia 58

59 Pimavanserin Pharmacology Atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis Inverse agonist and antagonist with high affinity for 5HT2a receptors. Has low affinity for 5HT2c receptors and no affinity at dopaminergic, histaminergic, cholinergic or adrenergic receptors Pimavanserin Pharmacokinetics Peak concentration 6 hours after dosing Primarily hepatic metabolism by CYP 3A4 and CYP 3A5 to an active metabolite, AC 279 Primarily fecal elimination of the AC 279 desmethylated metabolite Half life 57 hours parent compound, 200 hours for AC 279 Drug interactions: strong CYP 3A4 inhibition (e.g. ketoconazole) reduce pimavanserin dose by half; strong CYP 3A4 inducers increased pimavanserin dose may be needed; caution when used with drugs known to cause prolongation of QT interval 59

60 Pimavanserin Clinical Trials Pimavanserin has been evaluated in a randomized, multi center, double blind, parallel group, placebo controlled trial involving Parkinsons disease patients who had psychotic symptoms for at least a month prior to entry into the trial Patients had to have an MMSE of at least 21 points out of 30 and no delirium Patients received a two week non pharmacological brief psychosocial therapy to help elicit a placebo response ahead of baseline Patients were randomized to pimavanserin 40mg/day or placebo Primary end point of evaluation was the change in baseline in the Scale for Assessment of Positive Symptoms (SAPS) hallucination or delusions global item measured on day 43 Secondary end points were Clinical Global Impression Severity (CGI S) and improvement (CGI I) Primary end point showed a 37% change from baseline while the placebo group showed a 14% change (p=0.0006) Secondary end points also showed significant improvement from baseline compared to the placebo group. Pimavanserin Adverse Effects Peripheral edema Nausea Confusional state Black box warning regarding risk of death in dementia related psychosis 60

61 Pimavanserin Dosing Take two 17mg tablets daily Can take with or without food 61

62 Trulance (plecanatide) Synergy Plecanatide Pharmacology Guanylate cyclase C agonist indicated for treatment of chronic idiopathic constipation Stimulates guanylate cyclase C receptor on luminal surface of intestinal epithelium Activation increases concentrations of cyclic GMP Stimulates secretion of chloride and bicarbonate into intestinal lumen 62

63 Plecanatide Pharmacokinetics Minimally absorbed, negligible systemic availability Metabolized in the GI tract by proteolysis No excretion studies conducted Drug interactions: plecanatide not inhibited or induced by cytochrome P450 or P gp Plecanatide Clinical Trials Efficacy of plecanatide has been established in two double blind, placebocontrolled, randomized trials of 12 weeks duration involving patients with chronic idiopathic constipation Patients received either plecanatide 3mg once daily or placebo At baseline, patients reported three or fewer defecations per week The efficacy of plecanatide was assessed using responder analysis and change from baseline in CSBM and SBM end points A responder was defined as at least 3 CSBM s in a given week and increase of at least one CSBM from baseline for at least 9 out of the 12 week treatment period and at least 3 of the last 4 weeks of the study Responder rates study 1: 21% vs. 10%. Responder rates study 2: 21% vs. 13% 63

64 Plecanatide Adverse Effects Diarrhea Plecanatide Dosing 3mg orally once daily Can be crushed and mixed with applesauce or water for patients with swallowing difficulty 64

65 Review questions for self assessment Based on current pricing, the cost per day of treating signs or symptoms of dry eye with Xiidra (lifitegrast) will be: $1 per day $5 per day $10 per day >$10 per day Answer >$10 per day 65

66 66