New Drugs: Gotta Catch ‘Em All! Part II

Timothy Chiu, PharmD, BCPS Pharmacist Evidence Analyst & Strategist Monica Yoshinaga, PharmD, BCPS Pharmacist Evidence Analyst & Strategist Doris Kao, PharmD, BCPS, FCSHP Supervisor

Kaiser Permanente Drug Information Services Disclosure

Tim Chiu, Monica Yoshinaga, and Doris Kao work for Kaiser Permanente and have no potential conflicts of interest to disclose. Learning Objectives

At the completion of this activity, the At the completion of this activity, the pharmacist will be able to: pharmacy technician will be able to: 1) Describe selected new drug approvals 1) List four or more new drug approvals and trends at the Food and Drug by the FDA from October 2015 to July Administration (FDA) from October 2015 2016. through July 2016. 2) Cite indications for at least three major 2) Name at least three new drugs oncology new drug approvals and some approved for cancer indications. of the treatments to which they may offer alternatives. 3) Cite genotypes treated for by recently 3) Name two recently approved approved Hepatitis C medications. medications for Hepatitis C. New Drug Approvals: 2015 CDER New Molecular Entity (NME) and New Biologic 2015 License Application (BLA) Filings and Approvals * • Approved 45 novel drugs 50 40 41 41 41 • More than average number approved 40 36 45 annually in the past decade 41 39 • Expedited pathways 30 23 30 • 27 (60%) of novel drugs designated in 27 20 one or more expedited categories 21 • Fast Track: 14 10 • Breakthrough Therapy: 10 • Priority Review: 24 0 • 2010 2011 2012 2013 2014 2015 Accelerated Approval: 6 2016 (YTD) NME/BLA Approvals NME/BLA Filings • Approved 16 novel drugs *The 2015 filed numbers include those filed in CY 2015 plus those currently pending filing (i.e., within their 60 day filing period) in CY 2015.

R1. FDA New Drug Approvals. Drugs@FDA. R2. FDA-TRACK. http://bit.ly/2c4PNim. Total Drug Expenditures: 2015

New Therapies ↑$24.2B

Total Drug Protected Generic Expenditures Brands Spending ↑ 12.2% ↑$28.3B ↑$7.9B $424B

Patent Expiries ↓$14.2B

R4. IMS Institute, Medicines Use and Spending in the US. April 2016 New Therapies: 2015

Major Drivers ◦ Specialty Medicines: ↑21.5% ◦ Hepatitis C: 250,000 patients treated ◦ Multiple Sclerosis: new oral medicines ◦ HIV Combination Therapy ◦ Oncology: 35% of all new drugs: breakthrough targeted mechanisms ◦ Inflammatory Conditions ◦ Diabetes: Insulin, DPP-IV Inhibitors, SGLT2 Inhibitors, GLP-1 Agonists

R4. IMS Institute, Medicines Use and Spending in the US. April 2016 aripiprazole lauroxil (Aristada) injectable atypical antipsychotic

FDA Approval: October 6, 2015 Indication: Treatment of schizophrenia Notes: ◦ Long-acting injectable ◦ Different active moiety than aripiprazole extended-release injectable suspension (Abilify Maintena), which is dosed monthly Dosing: ◦ Establish tolerability with oral aripiprazole prior to initiating treatment ◦ IM injection in deltoid or gluteal muscle by a healthcare professional ◦ Start at dose of 441 mg, 662 mg, or 882 mg monthly or 882 mg dose every 6 weeks ◦ Administer oral aripiprazole with the first injection for 21 consecutive days

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. aripiprazole lauroxil (Aristada) injectable atypical antipsychotic

Efficacy: ◦ Efficacy data from oral aripiprazole trials ◦ 12 week, randomized, DB, PBO-controlled fixed-dose trial in patients with acute schizophrenia stabilized on oral aripiprazole (n=622) ◦ Efficacy assessed with PANSS, observed statistically significant separation on PANSS total score change from PBO Safety: ◦ Atypical Antipsychotic Boxed Warning: Increased mortality in elderly patients with dementia-related psychosis ◦ Adverse reaction incidence ≥5% and at least twice that for placebo): akathisia

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. patiromer (Veltassa) non-absorbed, cation exchange polymer that contains a calcium- sorbitol counterion to bind potassium

FDA Approval: October 21, 2015 Indication: To treat hyperkalemia, a serious condition in which the amount of potassium in the blood is too high. Notes: ◦ Limitations of Use: Veltassa should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. Dosing: ◦ Starting dose: 8.4 grams administered orally once daily with food. ◦ Adjust dose by 8.4 grams daily as needed at one week intervals to obtain desired serum potassium target range.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. patiromer (Veltassa) non-absorbed, cation exchange polymer that contains a calcium- sorbitol counterion to bind potassium

Efficacy: ◦ Three pivotal RCTs: AMETHYST-DN, PEARL-HF and OPAL-HK. ◦ All trials demonstrated that patiromer significantly reduced serum potassium levels in hyperkalemic patients with CKD and on renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. Safety: ◦ Boxed Warning: Binding to other medications. Administer other oral medications at least 6 hours before or 6 hours after Veltassa. ◦ Warnings and Precautions: binding of other orally administered medications, worsening of gastrointestinal motility, hypomagnesemia. ◦ Adverse reactions: constipation (7.2%), hypomagnesemia (5.3%), diarrhea (4.8%).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com asfotase alfa (Strensiq) enzyme replacement therapy

FDA Approval: October 23, 2015 (Orphan Drug, Fast Track, Breakthrough Therapy designations, Priority Review) Indication: Treatment of perinatal/infantile- and juvenile-onset hypophosphatasia (HPP) Notes: ◦ Human recombinant tissue-nonspecific alkaline phosphatase ◦ First FDA-approved treatment for patients with this rare (severe forms: 1:100,000 newborns) genetic metabolic disease that affects the development of bones and teeth Dosing: ◦ Weight-based: 2 mg/kg three times/wk or 1 mg/kg six times/wk ◦ Perinatal/infantile-onset HPP – may increase to 3 mg/kg three times/wk if needed due to inadequate efficacy

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. asfotase alfa (Strensiq) enzyme replacement therapy

Efficacy: ◦ 2 prospective, open-label, single-arm clinical trials demonstrated significant improvement in survival and invasive ventilation-free survival in patients with perinatal/infantile-onset HPP compared with untreated natural history controls ◦ Survival at point of last contact: 91% (asfotase alfa) vs 27% (historical controls) (Hazard ratio 0.14; 0.05- 0.39) ◦ 1 prospective, open-label, single-arm clinical trial (n=8) in juvenile-onset HPP demonstrated improvements in gait/mobility, growth and radiographic assessments compared with untreated natural history controls Safety: ◦ ADEs ≥10%: injection site reactions, lipodystrophy, ectopic calcifications, hypersensitivity reactions

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) Integrase strand transfer inhibitor, CYP3A enzyme inhibitor plus nucleoside and nucleotide reverse transcriptase inhibitor combination

FDA Approval: November 5, 2015 Indication: Complete treatment of HIV-1 infection in adults and pediatric patients ≥12 years ◦ Antiretroviral naïve or ◦ (1.) replace the current antiretroviral regimen, (2.) virologically-suppressed, (3.) on a stable antiretroviral regimen ≥ 6 months Notes: ◦ Prior to initiation, patients should be tested for hepatitis B infection, and baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed in all patients. Dosing: ◦ Oral: One tablet once daily.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) Integrase strand transfer inhibitor, CYP3A enzyme inhibitor plus nucleoside and nucleotide reverse transcriptase inhibitor combination Efficacy: ◦ Non-inferior to Stribild for viral suppression (HIV-1 RNA< 50copies/mL) at 48 weeks. ◦ > 90% virological success in HIV-infected patients with renal insufficiency at 48 weeks. Safety: ◦ Boxed Warning: ◦ Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. ◦ Post treatment acute exacerbation of hepatitis B. ◦ Contraindication: contraindicated with drugs that are highly dependent on CYP3A for clearance. ◦ Warnings and Precautions: Lactic acidosis/severe hepatomegaly with steatosis, ↓BMD, fat redistribution, immune reconstitution syndrome, pancreatitis, renal toxicity. ◦ Adverse reactions: (>5%) diarrhea, nausea, fatigue, and headache.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com daratumumab (Darzalex) anti-CD38, recombinant human IgG1 monoclonal antibody

FDA Approval: November 16, 2015 Indication: Treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double-refractory to a PI and an IMiD Notes: ◦ First approved monoclonal antibody in multiple myeloma, may offer immunostimulary benefits ◦ May interfere with cross-matching and red blood cell antibody screening as well as determination of complete response Dosing: ◦ 16 mg/kg IV per dose; infusion rate and dose frequency titration required for infusion reaction risk ◦ Administer in a healthcare setting prepared to infusion reactions ◦ Pre- and post-infusion medications required, plus prophylaxis for herpes zoster reactivation

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. daratumumab (Darzalex) anti-CD38, recombinant human IgG1 monoclonal antibody

Efficacy: ◦ Approval based on 2 pivotal trials (GEN501, SIRIUS); both Phase 2, single-arm, open-label ◦ Approximately 30% of patients treated with daratumumab responded to therapy, despite being a heavily pretreated population ◦ Responses appear durable (duration of response ranged from 1.2 to 13.1+ months) ◦ Recent data presentations from CASTOR and POLLUX trials, which evaluated daratumumab as part three- drug combination regimens for relapsed/refractory multiple myeloma in earlier lines of therapy

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. daratumumab (Darzalex) anti-CD38, recombinant human IgG1 monoclonal antibody

Progression-Free Survival Overall Survival

Safety: ◦ Common adverse reactions include infusion reactions, fatigue, back pain, nausea, pyrexia, cough, and upper respiratory tract infection ◦ Warnings include infusion reactions, interference with serological testing, and interference with determination of complete response R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R5. Usmani. ASH 2015. Abst 29. ixazomib (Ninlaro) second generation oral proteasome inhibitor

FDA Approval: November 20, 2015 Indication: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy Notes: ◦ First FDA approved oral proteasome inhibitor ◦ May have a lower risk of contributing to peripheral neuropathy vs. bortezomib, though a head-to- head trial is needed to draw any conclusion Dosing: ◦ 4 mg PO on days 1, 8, and 15 every 28-day cycle ◦ Take at least one hour before or at least two hours after food ◦ Lenalidomide is administered Days 1-21 and dexamethasone is administered Days 1, 8, 15, and 22 of each cycle

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. ixazomib (Ninlaro) second generation oral proteasome inhibitor

Efficacy: ◦ TOURMALINE-MM1 (Phase 3, double-blind, placebo-controlled, n=722) ◦ Adding ixazomib to lenalidomide and dexamethasone resulted in a 26% reduction in risk of progression or death (median progression-free survival [PFS] of 20.6 months in study arm vs. 14.7 months in placebo arm) ◦ PFS benefit also observed in subgroup of patients with high-risk cytogenetics ◦ Modest improvement in response rate with addition of ixazomib (78% vs. 72% in placebo arm) Progression-Free Survival

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R6. Ixazomib. Dossier. 2015. ixazomib (Ninlaro) second generation oral proteasome inhibitor

Safety: ◦ Common adverse reactions include diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, edema, and back pain ◦ Warnings include thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, edema, cutaneous reactions, and hepatotoxicity

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. Influenza vaccine, adjuvanted (Fluad) Influenza virus vaccine, inactivated

FDA Approval: November 24, 2015 Indication: For active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and B contained in the vaccine. Notes: ◦ (ACIP) recommends routine annual vaccination with the seasonal influenza vaccine for all persons ≥6 months of age Dosing: ◦ IM: 0.5 mL/dose (1 dose per season).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. Influenza vaccine, adjuvanted (Fluad) Influenza virus vaccine, inactivated

Efficacy: ◦ 95% seroconversion Safety: ◦ Contraindication: history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein . ◦ Warnings and Precautions: Guillain-Barré syndrome, allergic reactions, latex allergy, altered immunocompetence, sycope, vaccine effectiveness. ◦ Adverse reactions: moderate: pain, tenderness, myalgia, fatigue, headache, arthralgia, chills, nausea, vomiting

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. elotuzumab (Empliciti) anti-SLAMF7, recombinant humanized IgG1 monoclonal antibody

FDA Approval: November 30, 2015 Indication: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who received one to three prior therapies Notes: ◦ In early studies, no responses seen as a single-agent treatment for patients with relapsed/refractory multiple myeloma Dosing: ◦ 10 mg/kg IV per dose; infusion rate and dose frequency titration required for infusion reaction risk ◦ Premedications required ◦ Lenalidomide is administered Days 1-21 and dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. elotuzumab (Empliciti) anti-SLAMF7, recombinant humanized IgG1 monoclonal antibody

Efficacy: ◦ ELOQUENT-2 (Phase 3, randomized, open-label, placebo-controlled, n=646) ◦ Adding elotuzumab to lenalidomide and dexamethasone resulted in a 30% reduction in risk of progression or death (median PFS of 19.4 months in study arm vs. 14.9 months in placebo arm) ◦ PFS benefit also observed in subgroup of patients with high-risk cytogenetics ◦ Improvement in response rate also observed with addition of elotuzumab (78.5% vs. 65.5% in placebo arm) Progression-Free Survival

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R7. Lonial. NEJM. 2015. elotuzumab (Empliciti) anti-SLAMF7, recombinant humanized IgG1 monoclonal antibody

Safety: ◦ Common adverse reactions include fatigue, diarrhea, constipation, pyrexia, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia ◦ Warnings include infusion reactions, infections, second primary malignancies, hepatoxicitiy, and interference with determination of complete response

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sebelipase alfa (Kanuma) enzyme replacement therapy

FDA Approval: December 8, 2015 Indication: Treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency Notes: ◦ Hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme ◦ LAL deficiency (LAL-D): autosomal recessive lysosomal storage disorder; complications due to lysosomal buildup of cholesteryl esters and TGs Dosing: ◦ Weight-based: intravenous infusion qwk in infants with rapidly progressive LAL-D and every other week for pediatric and adult patients with LAL-D

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sebelipase alfa (Kanuma) enzyme replacement therapy

Efficacy: ◦ Open-label, single-arm trial of infants with Wolman disease (n=9) assessing survival at age 12 months compared to untreated natural history controls (n=21) ◦ 6 infants survived beyond 12 months old compared to 0 infants ◦ 20-week, double-blind, PBO-controlled trial in children and adults with LAL-D (n=66) ◦ Statistically significant improvement in percent change from baseline in LDL-c (mean difference of -22% [95% CI – 33%, -15%]), other statistically significant improvements noted for HDL-c, non-HDL-c, TGs Safety: ◦ Patients with rapidly progressive disease presenting within the first 6 months of life (≥30%): diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticarial ◦ Pediatric and adult patients (≥8%): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea ◦ Warnings and Precautions: hypersensitivity reactions including anaphylaxis, hypersensitivity to eggs/egg products

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sugammadex (Bridion) modified gamma cyclodextrin, a selective relaxant binding agent

FDA Approval: December 15, 2015 Indication: Reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Notes: ◦ Should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Dosing: ◦ For rocuronium and vecuronium: 2-4 mg/kg is recommended based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. ◦ For rocuronium only: 16 mg/kg, reverse neuromuscular blockade soon (approximately 3 minutes) after a single dose of 1.2 mg/kg of rocuronium.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sugammadex (Bridion) modified gamma cyclodextrin, a selective relaxant binding agent

Efficacy: ◦ Sugammadex reverses moderate and profound neuromuscular blockade induced by rocuronium and vecuronium faster and more consistently than neostigmine. ◦ Sugammadex quickly reverses neuromuscular blockade induced high-dose rocuronium within three minutes of administration. Safety: ◦ Contraindications: patients with a history of a hypersensitivity reaction. ◦ Warnings and Precautions: anaphylaxis and hypersensitivity, marked bradycardia, respiratory function, prolonged neuromuscular blockade, other. ◦ Adverse reactions: (>5%) nausea, vomiting, abdominal pain, hypertension, hypotension, dizziness and headache.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com elbasvir and grazoprevir (Zepatier) An estimated 2.7-3.9 inhibitor of HCV NS5A, inhibitor of HCV NS3/4A protease million people in the United States have chronic hepatitis C. FDA Approval: January 28, 2016 Indication: Indicated with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in adults Notes: ◦ Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance- associated polymorphisms is recommended prior to initiation of treatment Dosing: ◦ With or without ribavirin. One tablet taken orally once daily for 12 -16 weeks

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. elbasvir and grazoprevir (Zepatier) inhibitor of HCV NS5A, inhibitor of HCV NS3/4A protease

Efficacy: ◦ 96% achieved SVR12 (sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy). Safety: ◦ Contraindications: ◦ Patients with moderate or severe hepatic impairment (Child-Pugh B or C), ◦ Organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz. ◦ Warnings and Precautions: increase of ALT, drug interactions, including ribavirin. ◦ Adverse reactions: fatigue (13%), headache (12%), and nausea (9%).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com brivaracetam (Briviact) oral and injectable anticonvulsant

FDA Approval: February 18, 2016 Indication: Adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy Notes: ◦ Available as tablets, oral solution, injection for IV use ◦ C-V controlled substance Dosing: ◦ Starting dosage: 50 mg BID, adjust down to 25 mg BID or up to 100 mg BID based on tolerability and therapeutic response ◦ Adjust dose if patient has hepatic impairment

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. brivaracetam (Briviact) oral and injectable anticonvulsant % Reduction Study, Group Over PBO Efficacy: ◦ 3 multicenter fixed-dose, randomized, DB, PBO-controlled PBO (n=100) --- trials in patients with partial-onset seizures not adequately 1 50 mg/day (n=99) 9.5% controlled by AEDs (total n=1550) 100 mg/day (n=100) 17.0% ◦ Primary efficacy outcomes: percent reduction in 7-day and PBO (n=96) --- 28-day partial-onset seizure frequency (see table) 2a 50 mg/day (n=101) 16.9%* Safety: ◦ Warnings and Precautions: suicidal behavior and ideation, PBO (n=259) --- neurological and psychiatric adverse reactions, 3b 100 mg/day (n=252) 25.2%* hypersensitivity (bronchospasm and angioedema), 200 mg/day (n=249) 25.7%* withdrawal (should be gradually withdrawn) ◦ Adverse reactions ≥ 5% and at least 2% more frequently *Statistically significant based on testing than PBO: somnolence/sedation, dizziness, fatigue, N/V procedure with alpha = 0.05 a Based on 7-day seizure frequency b Based on 28-day seizure frequency

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. obiltoxaximab (Anthim) chimeric IgG1 kappa monoclonal antibody (mAb) that binds the PA component of B. anthracis toxin

FDA Approval: March 18, 2016 Indication: ◦ Adult and pediatric patients for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. ◦ Prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate. Notes: Administer in appropriately monitored settings which are equipped to manage anaphylaxis. Dosing: ◦ Premedication with diphenhydramine is recommended. Single dose of 16 mg/kg administered intravenously over 90 minutes. ◦ Pediatric dosing based on weight.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. obiltoxaximab (Anthim) chimeric IgG1 kappa monoclonal antibody (mAb) that binds the PA component of B. anthracis toxin

Efficacy: ◦ Animal studies: Single intravenous dose resulted in statistically significant improvement in survival relative to placebo, (up to 93% versus 0%) Safety: ◦ Boxed Warning: Due to the risk of hypersensitivity and anaphylaxis, it should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. ◦ Warnings and Precautions: hypersensitivity and anaphylaxis. ◦ Adverse reactions: headache (8%), pruritus (4%), URI (5%), cough (3%), vessel puncture site bruise or swelling (3%), nasal congestion (2%), infusion site pain (2%), urticaria (2%), pain in extremity (2%).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor

FDA Approval: April 11, 2016 Indication: Treatment of patients with chronic lymphocytic leukemia with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy Notes: ◦ Recent data suggests clinical benefit may be achieved even in patients previously treated with ibrutinib or idelalisib ◦ Being studied in other B-cell malignancies, including multiple myeloma, acute myelogenous leukemia, and non-Hodgkin’s lymphomas ◦ Administration in the hospital for earlier doses may be needed based on tumor lysis syndrome (TLS) risk Dosing: ◦ Requires initial ramp-up dosing (by week) due to potential for TLS ◦ Administer with a meal and water, perform prophylaxis for TLS

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor

Efficacy: ◦ M13-982 (Phase 2, open-label, single-arm, n=106) ◦ Responses seen in 80% of patients treated with venetoclax (7.5% were complete remissions or complete remission with incomplete marrow recovery) ◦ Responses appear durable, where the median duration of response has not been reached after approximately 12 months Cumulative Incidence of Response Duration of Response

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R8. Stilgenbauer. Lancet Oncol. 2016. venetoclax (Venclexta) B-cell lymphoma 2 (BCL-2) inhibitor

Safety: ◦ Common adverse reactions include neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue ◦ Warnings include TLS, neutropenia, and do not administer live attenuated vaccines prior to, during, or after venetoclax therapy

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. pimavanserin (Nuplazid) oral atypical antipsychotic

FDA Approval: April 29, 2016 (breakthrough therapy designation, priority review) Indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis Notes: ◦ First drug to be approved to treat hallucinations and delusions associated with PD Dosing: ◦ 34 mg (two 17 mg tablets once daily) without titration and with or without food Efficacy: ◦ 6-week, randomized, PBO-controlled, parallel-group study (n=199)

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. pimavanserin (Nuplazid) oral atypical antipsychotic

Efficacy: Endpoint Tx Group Mean Baseline Score LS Mean Change from PBO-subtracted (SD) Baseline (SE) Differencea (95% CI) SAPS-PD pimavanserin 15.9 (6.12) -5.79 (0.66) -3.06* (-4.91, -1.20) PBO 14.7 (5.55) -2.73 (0.67) -- SAPS-PD pimavanserin 11.1 (4.58) -3.81 (0.46) -2.01 (-3.29, -0.72) b Hallucinations PBO 10.0 (3.80) -1.80 (0.46) -- SAPS-PD pimavanserin 4.8 (3.59) -1.95 (0.32) b Delusions PBO 4.8 (3.82) -1.01 (0.32) -0.94 (-1.83, -0.04) a Difference (drug minus placebo) in least-squares mean change from baseline b Supportive analysis * Statistically significantly superior Safety: ◦ Atypical Antipsychotic Boxed Warning: Increased mortality in elderly patients with dementia- related psychosis ◦ Warnings and Precautions: QT interval prolongation ◦ Adverse reactions (≥5% and twice the rate of placebo): peripheral edema, confusional state

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. obeticholic acid (Ocaliva) farnesoid X receptor agonist

FDA Approval: May 27, 2016 Indication: Treatment of primary biliary cholangitis (PBC) in combination with or without ursodeoxycholic acid (UDCA). Notes: ◦ Antihistamine or bile acid binding resin added for patients with intolerable pruritus. Dosing: ◦ Oral: Initial: 5 mg once daily; if an adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months, increase to 10 mg once daily (maximum: 10 mg/day). ◦ Adjust dose for hepatic impairment, Child-Pugh Class B and C. ◦ Adjust dose for patients with intolerable pruritus from Ocaliva.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. obeticholic acid (Ocaliva) farnesoid X receptor agonist

Efficacy: Pivotal, phase 3 RCT. Ocaliva 10 mg Ocaliva titration Placebo (N=73) (N=70) (N=73) Primary Composite Endpoint Responder rate (%) 48% 46% 10% ALP < 1.67 time ULN 55% 47% 16% ↓ ALP 15% or greater 78% 77% 29% Total bilirubin ≤ ULN 82% 89% 78% Safety: ◦ Contraindication: patients with complete biliary obstruction. ◦ Warnings and Precautions: liver-related adverse effects, severe pruritus, reduction in HDL-C. ◦ Adverse reactions: pruritus (70%), fatigue (25%), abdominal pain (10%), rash (10%), arthralgia (10%), oropharyngeal pain (8%), dizziness (7%), constipation (7%), peripheral edema (7%), palpitations (7%), pyrexia (7%), thyroid function abnormality (6%), eczema (6%).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com daclizumab (Zinbryta) interleukin-2 receptor blocking antibody

FDA Approval: May 27, 2016 Indication: Treatment of adult patients with relapsing forms of multiple sclerosis (MS) Notes: ◦ Reserve for patients with inadequate response to 2 or more MS drugs due to safety profile Dosing: ◦ Self-administered 150 mg subcutaneously once monthly

Efficacy: ◦ 2 DB, RCTs in patients with relapsing MS (RMS) – 1 active-controlled trial (n=1841) comparing to interferon beta-1a (Avonex) and 1 PBO-controlled trial (n=412) ◦ Primary outcomes of annualized relapse rate; both studies found statistically significant effect on ARR

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. daclizumab (Zinbryta) interleukin-2 receptor blocking antibody

Safety: ◦ Available only through a restricted distribution program (Zinbryta REMS Program) ◦ Boxed Warning: Hepatic injury including autoimmune hepatitis and other immune-mediated disorders ◦ Contraindications: Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN, history of autoimmune hepatitis or other autoimmune condition involving the liver ◦ Warnings and Precautions: hypersensitivity reactions, infections, depression and suicide ◦ Adverse reactions (≥5% and ≥2% higher than comparator): nasopharyngitis, URI, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema and lymphadenopathy compared with interferon beta-1a (Avonex); and URI, depression, rash, pharyngitis, and increased ALT compared with PBO

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sofosbuvir and velpatasvir (Epclusa) nucleotide analog HCV NS5B polymerase inhibitor and an NS5A inhibitor combination Of every 100 people infected with the HCV: • 75–85 people → chronic HCV infection • 60–70 people → chronic liver disease • 5–20 people → cirrhosis in 20–30 years • 1–5 people → die from cirrhosis or liver cancer FDA Approval: June 28, 2016 Indication: Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection. Notes: ◦ Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended. Dosing: ◦ One tablet taken orally once daily with or without food for 12 weeks.

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. sofosbuvir and velpatasvir (Epclusa) nucleotide analog HCV NS5B polymerase inhibitor and an NS5A inhibitor combination

Efficacy: ◦ ASTRAL-1 RCT: Overall SVR12 for sofosbivir/velpatasvir patients was 99.0% for genotypes 1, 2, 4, 5 and 6. (p< 0.001). ◦ ASTRAL-2 and ASTRAL-3 RCTs: SVR12 for sofosbivir/velpatasvir patients was 99.0% and 95% for genotypes 2, and 3 and was superior to sofosbuvir/ribavirin. (p< 0.001). Safety: ◦ Contraindication: patients for whom ribavirin is contraindicated. ◦ Warnings and Precautions: serious bradycardia when administered with amiodarone, decreased therapeutic effect with drugs that are inducers of P-gp and/or inducers of CYP2B6, CYP2C8, or CYP3A4. ◦ Adverse reactions: Headache (22%), fatigue (15%), Irritability (≥5%), insomnia (5%), depression (1%), skin rash (2%), nausea (9%), increased serum lipase (>3X ULN: 3% to 6%), weakness (5%), increased creatine phosphokinase (≥10X ULN: 1% to 2%).

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. Biomedtracker Pharma Intelligence. Biomedtracker.com defibrotide sodium (Defitelio) oligonucleotide mixture with profibrinolytic properties

FDA Approval: March 30, 2016 Indication: Treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) Notes: ◦ Severe VOD occurs in approximately 2% of patients that receive HSCT, with mortality rate of 84% ◦ For the target patient population, survival rates 100 days post-HSCT with supportive care only range from 21-31% ◦ May protect endothelial cells from damage caused by chemotherapy, tumor necrosis factor-alpha, serum starvation, and perfusion Dosing: ◦ 6.25 mg/kg IV every 6 hours (as 2-hour infusion); treat for min of 21 days (until resolution of VOD or max of 60 days)

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. defibrotide sodium (Defitelio) oligonucleotide mixture with profibrinolytic properties

Efficacy: ◦ Over 3 studies (n=528), survival rates at 100 days post-HSCT were 38-45% Safety: ◦ Common adverse reactions include hypotension, diarrhea, nausea, and epistaxis ◦ Warnings include hemorrhage and hypersensitivity reactions ◦ Concomitant anththrombotic/fibrinolytic therapy is contraindicated

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. Test Questions

1. Which of the following new drugs and indications is incorrectly matched up? a. daclizumab (Zinbryta) – treatment of multiple sclerosis b. asfotase alfa (Strensiq) – treatment of hypophosphatasia c. pimvanserin (Nuplazid) – treatment of Parkinson’s disease d. brivaracetam (Briviact) – treatment of partial onset seizures Test Questions

2. Which of the following are true? a. Both elbasvir/grazoprevir and sofosbuvir/velpatasvir are indicated for HCV infection. b. Sofosbuvir/velpatasvir was shown to be superior to sofosbuvir/ribavirin for genotype 4, 5,6. c. Elbasvir/grazoprevir is associated with drug-drug interactions while sofosbuvir/veltapasvir is not. d. Both elbasvir/grazoprevir and sofosbuvir/velpatasvir are dosed once daily. a and d. Test Questions

3. Which of the following are false? a. Daratumumab and elotuzumab are both monoclonal antibodies recently approved for the treatment of multiple myeloma. b. Ixazomib is the first oral proteasome inhibitor approved for the treatment of multiple myeloma. c. Elotuzumab is approved as monotherapy for the treatment of multiple myeloma. d. Venetoclax does not require ramp-up dosing for the treatment of chronic lymphocytic leukemia c and d. References

R1. Prescribing Information: U.S. FDA. Drugs @ FDA. R2. BiomedTracker. http://www.biomedtracker.com/ R3. FDA Drug Approvals. Drugs@FDA. R4. IMS Institute, Medicines Use and Spending in the US. April 2016. http://www.imshealth.com/en/thought- leadership/ims-institute/reports/medicines-use-and-spending-in-the-us-a-review-of-2015-and-outlook-to-2020. Accessed April 2016. R5. Usmani S, Weiss B, Bahlis NJ, et al. Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Presented at: The 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 29. R6. Takeda Pharmaceuticals International Co. Submission of Clinical and Economic Data Supporting Formulary Consideration of Ninlaro (ixazomib). Formulary Dossier. November 20, 2015. R7. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. R8. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Session Code: 1. Write down the course code. Space has been provided in the daily program-at-a- glance sections of your program book.

2. To claim credit: Go to www.cshp.org/cpe before December 1, 2016.