AAIP 8/13/2020 .I have no relationships with commercial interests related to the content of this presentation. J. Russell May, Pharm.D., FASHP Clinical Professor University of Georgia College of Pharmacy ® After attending the presentation and discussion, the .Lefamulin (Xenleta ) by Nabriva Therapeutics attendee should be able to: .Cefiderocol (Fetroja ®) by Shiongi .Bremelanotide (Vyleesi®) by Amag Compare and contrast newly approved drugs with older agents ® regarding their pharmacology, pharmacokinetics, efficacy, safety, .Lasmiditan (Reyvow ) by Lilly dosage and cost. .Ubrogepant (Ubrelvy ®) by Allergan Apply the “formulary approach” to evaluating new drugs. .Eptinezumab-jjmr (Vyepti ®) by Lundbeck Identify other recently approved medications and discuss their ® indications and potential usefulness .Crizanlizumab-tmca (Adakveo ) by Novartis Discuss any pipeline drugs that may be significant releases in the .Voxelotor (Oxbryta ®) by Global Blood therapeutics next few years. .Solriamfetol (Sunosi®) by Jazz . A finite list of therapeutic agents For a drug to be recommended for addition to our . Established value in light of current medical Formulary, it must meet at least one of the following: opinion . New Pharmacological Class . Sufficiently broad to meet the usual clinical . More Efficacious problems . Safer . Avoids duplication of clinical effect . Pharmacokinetic Advantage (clinically relevant) . Subject to continuing revision based on new . More Cost Effective therapeutic knowledge 1 AAIP 8/13/2020 Lefamulin (Xenleta®) Pharmacology • A pleuromutilin antibacterial: A NEW CLASS • Inhibits bacterial protein synthesis • Active against: • Bactericidal: S. pneumonia, H. influenza, and M. pneumonia • Bacteriostatic: S. aureus and S. pyrogenes • NOT active against: • Enterobacteriaceae and Pseudomonas aeruginosa • Indication • Treatment of adults with community-acquired bacterial pneumonia caused by susceptible microorganisms https://www.pharmacytimes.com/publications/issue/2020/February2020/xenleta-from-nabriva-therapeutics Lefamulin (Xenleta®) Lefamulin (Xenleta®) Pharmacokinetics Efficacy • Absorption • Two randomized, double-dummy, non-inferiority • Bioavailability of oral tablets ~ 25% trials (n = 1289) • Distribution Trial 1: lefamulin IV/PO for 5 - 10 days versus • Protein binding: 95 – 97% moxifloxacin IV/PO for 7 – 10 days if MRSA found • Volume of distribution: 86.1 L linezolid added • Metabolism Trial 2: 5 days oral versus moxifloxacin oral for 7 days Early response rates • Primarily via CYP3A4 • Trial 1: 87.3 % (L) 90.2% (M) • Elimination • Trial 2: 90.8% (L) 90.8% (M) • Half-life ~ 8 hours • Excreted primarily in feces Data on file with manufacturer Lefamulin (Xenleta®) Lefamulin (Xenleta®) Safety Dosage and Cost • Drug interactions • 150 mg every 12 hours IV over 60 minutes • Avoid this drug with moderate to strong 3A4 • Must be diluted in 250 ml of 10 mM citrate buffered inhibitors or inducers 0.9% sodium chloride (supplied) • Concomitant use with CYP3A4 substrates that • 600 mg every 12 hours PO prolong QT interval is contraindicated • May prolong QT interval • 1 hour before or 2 hours after food • Potential risk to fetus • Swallow whole • Excreted into breast milk • Adjustment to q24hr in severe hepatic impairment • Common adverse effects • ~ $275 per day (IV or PO) • Diarrhea – 12% Nausea – 5% • Vomiting - 3% IV site reactions – 7% 2 AAIP 8/13/2020 Lefamulin (Xenleta®) New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective https://www.fetroja.com/ Cefiderocol (Fetroja®) Cefiderocol (Fetroja®) Pharmacology Pharmacokinetics • An IV cephalosporin antibiotic • Metabolism – minimal <10% • Similar structure to cefepime • Elimination – Urine (90% unchanged) • Catechol group = siderophore • Half-life 2 – 3 hours • Siderophores • Iron chelating molecules • Transport iron into bacterial cells • Note: spectrum of activity: • Cefiderocol – binds ferric iron and uses bacterial • No gram + coverage iron transport system to penetrate gram negative • No anaerobic coverage cell wall • Indication: treatment of cUTIs caused by gram – • BUT: activity against many MDR organisms bacteria in adults with limited or no alternative • ESBLs treatment options • Carbampenemases Cefiderocol (Fetroja®) Cefiderocol (Fetroja®) Efficacy Safety • Randomized, double-blind, non-inferiority trial vs imipenem (N = 448)* • • All organisms carbapenem susceptable Most common • 2 gm IV q8hr (C) vs 1 gm IV q8hr (I) • GI related: nausea, vomiting, diarrhea and • cUTIs including pyelonephritis caused by gram - bacteria constipation (2 – 4 %) • Clinical response/micro eradication 73% (C) vs 55% (I) = non-inferior • Randomized, double-blind, non-inferiority trial vs meropenem (N = 298) • Others • Most organisms were carbapenem susceptible • Rash, cough, increased liver enzymes, • Nosocomial pneumonia infection site reactions, candidiasis, • All cause mortality and clinical cure rates similar • Randomized open-label trial (N = 150) headache, and hypokalemia • All critically ill with carbapenem resistant infections • Pregnancy – no data • Versus best available therapy “BAT” (mostly colistin based- combination therapy) • Likely present in breast milk • Infection related deaths 21% (C) vs 8% (BAT) *Portsmouth S et al. Lancet Infect Dis 2018;18:1319, others unpublished 3 AAIP 8/13/2020 Cefiderocol (Fetroja®) Cefiderocol (Fetroja®) Dosage and Cost • 2 gm IV q8hr infused over 3 hours for 7 – 14 days • CrCl >120: q6hr New Pharmacological Class ? • CrCl 30 – 59: 1.5 gm q8hr More Efficacious ? • CrCl 15 – 29: 1 gm q8hr Safer? • ESRD: 0.75 gm q12h with or without HD Pharmacokinetic Advantage (clinically relevant) More Cost Effective • Cefiderocol $7699.90 • Meropenem $237.80 • Ceftolozane/tazobactam $2629.60 • Ciprofloxacin $65.10 Bremelanotide (Vyleesi®) Pharmacology • A melanocortin receptor agonist • Exact mechanism of action is unknown • Activation of melanocortin receptor subtypes including MCR4, thought to play a role in female arousal, sexual desire, and orgasm* • A subcutaneous injection • Indication • Treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) • NOT for men or postmenopausal women https://www.medscape.com/viewarticle/915229 *Uckert et al. Expert Opin Investig Drugs 2014;23:1477 Bremelanotide (Vyleesi®) Bremelanotide (Vyleesi®) Efficacy Pharmacokinetics • Two unpublished 24-week double blind, placebo- • Tmax = 1 hour controlled trials (n = 1247) • Metabolism – hydrolysis to amino acids • Patients with at least 6 months duration of HSDD • Elimination • Self administered SC injection, 45 minutes prior to • Urine: 64.8% anticipated sexual activity no more than once per 24 hours • Feces: 22.8% and 12 times per month • Half-life = around 2.7 hours • Modest increases in sexual desire score 25% vs 17% • Modest decrease in distress score 35% vs 31% • Duration of effect unknown • A 40 % dropout rate before completion of study • No trials comparing it to flibanserin 4 AAIP 8/13/2020 Bremelanotide (Vyleesi®) Bremelanotide (Vyleesi®) Safety Dosage • Most common • 1.75 mg SC in abdomen or thigh at least 45 prior to anticipated • Nausea 40% Vomiting 5% Flushing 20% sexual activity • Injection site reactions 13% Headache 11% • Antiemetic therapy required in 13% • No more than one dose in 24 hours • Most common reason for dropouts was nausea • Use of > 8 doses per month not recommended • Transient increases in blood pressure and decreases in heart • If no improvement after 8 weeks trial, stop therapy rate • Resolves within 12 hours Cost • Hyperpigmentation 1% (MC1R activation): face, gingiva, Flibanserin $400 (30 day supply) breasts Bremelanotide $269.70 per auto-injector • These women took 8 doses per month • Up to 38% in those who used it daily for 8 days • No interaction with alcohol Bremelanotide (Vyleesi®) New Pharmacological Class More Efficacious ? Safer ? Pharmacokinetic Advantage (clinically relevant) More Cost Effective https://www.biospace.com/article/eli-lilly-s-reyvow-wins-fda-approval-for-acute-treatment-of-migraine/ Lasmiditan (Reyvow®) Lasmiditan (Reyvow®) Pharmacology Pharmacokinetics • Oral serotonin (5HT )receptor antagonist 1F • Tmax = 1.8 hours • First “ditan”: selectively bonds to 5HT on 1F • Metabolized by non-CYP enzymes trigeminal neurons > inhibits pain pathways • Do not use in severe hepatic impairment • Unlike triptans, no vasoconstrictive effects* • Elimination • Indication: • Urine 66% as metabolites, 3% unchanged • Acute treatment of migraine in adults with or • Half-life = 5.7 hours without aura *Raffaelli et al. Expert Opin Pharmacother. 2017;18:1409 Oswald and Schuster. J Pain Res. 2018;11:2221 5 AAIP 8/13/2020 Lasmiditan (Reyvow®) Lasmiditan (Reyvow®) Efficacy Safety • Two double-blind trials vs placebo (n = 5100) • Most common (dose-related) • Patients had 3 – 8 migraine episodes per month • Dizziness • Lasmiditan 50 mg, 100 mg, 200 mg or placebo within 4 • Paresthesia hours of migraine onset • Sedation • Measured pain freedom and freedom from migraine • Others (dose-related) bothersome symptoms (photo-phono phobia, nausea) • Fatigue, nausea and vomiting, muscle weakness, Lasmiditan Pain Freedom* MBS Freedom* Pain Relief* vertigo, incoordination, lethargy, palpitations, cognitive 50 mg 28.6% 40.8% 59.0% changes and confusion 100 mg 28.4% 40.9% 61.5% • Hypersensitivity 0.2% 200 mg 35.5% 44.7% 62.0% • Angioedema, rash Placebo 18.3% 31.5% 44.5% • Serotonin syndrome was also reported Kuca et al. Neurology 2018;91:e2222