WE WANT to HEAR from YOU Abarca Created the Drug Intelligence Newsletter to Keep Our Clients and Partners Apprised of Critical and Impending Changes to Patient Care

April 2019

WE WANT TO HEAR FROM YOU Abarca created the Drug Intelligence Newsletter to keep our clients and partners apprised of critical and impending changes to patient care. If there are any topics that you would like to learn more about, or feedback for our Clinical Team, please contact David Capó, Clinical Epidemiologist, at [email protected].

CLINICAL UPDATES, OUTCOMES, & REAL-WORLD EVIDENCE New Pulmonary Arterial Hypertension (PAH) Guidelines Rollout | ACCP In March, the American College of Chest Physicians (ACCP) published an update of the CHEST Guideline and Expert Panel Report on Therapy for Pulmonary Arterial Hypertension (PAH) in Adults[1]. Highlights from the updates include: 1. ACCP now suggests prescribing an initial Letairis™ (ambrisentan; Gilead) and Adcirca™ (tadalaﬁl, currently available as a generic) combination to improve 6-min walk distance (6MWD) in treatment- naive World Health Organization (WHO) functional class (FC) II and III PAH; and to add Adcirca™ to improve 6MWD among stable or symptomatic PAH patients on background Letairis™ 2. Incorporating palliative care services in the management of PAH patients 3. A revamped, evidence-based, and consensus-driven, treatment algorithm to guide the clinician through an organized approach to PAH management (below) PAH Combination Therapy Algorithm

Combination therapy with ambrisentan and tadalfil (Recommendation 10; weak Yes recommendation, moderate quality evidence) Treatment Naïve PAH Is the patient willing or able to patients with WHO FC II tolerate combination therapy*?

No Monotherapy with either bosentan, macitentan, ambrisentan, riociguat, sildenafil, or tadalafil

Combination therapy with ambrisentan and tadalfil (Recommendation 10; weak Treatment Naïve PAH Yes recommendation, moderate quality evidence) patients with WHO FC II Is the patient willing or able to without evidence of rapid tolerate combination therapy*? disease progression or poor prognosis No Monotherapy with either bosentan, macitentan, ambrisentan, riociguat, sildenafil, or tadalafil

Chronic Obstructive Pulmonary Disease (COPD) Updated Guidelines | GOLD The Global Initiative for Chronic Obstructive Lung Disease (GOLD) updated their Chronic Obstructive Pulmonary Disease (COPD) Clinical Practice Guidelines[2] in October of 2018. The highlights include: 1. A combination long-acting beta-agonists (LABA)/long‐acting muscarinic antagonist (LAMA) has the greatest quality of life improvement compared to placebo or its individual bronchodilator components. 2. In advanced COPD, fixed triple therapy Trelegy Ellipta™ (umeclidinium-vilanterol-fluticasone; GSK) has forced expiratory volume in one second (FEV1) and exacerbations’ benefits compared to Spiriva™ (tiotropium; Boehringer) or inhaled corticosteroids (ICS)/ LABA combination therapy. 3. Daliresp™ (roflumilast; AstraZeneca) is more useful after a hospitalization for an acute exacerbation. 4. If prone to exacerbations, azithromycin or erythromycin treatment for one year can reduce the risk of recurrence.

Initial Treatment in Stable COPD

Group C Group D • • ≥ 2 moderate LAMA LAMA • LAMA – long-acting exacerbations or • muscarinic antagonist ≥ 1 leading to LABA + LAMA • LABA – long-acting beta hospitalization • agonist LABA + ICS • ICS – inhaled corticosteroid • mMRC – modified Group A Group C Medical Research Council dyspnea 0 or 1 moderate A long acting questionnaire exacerbations A bronchodilator bronchodilator • CAT – COPD (not leading to Assessment Test hospitalization) LABA

LAMA

mMRC 0-1 CAT <10 mMRC ≥ 2 CAT ≥ 10

Adapted from MirzaS (2018) COPD Guidelines: A Review of the 2018 GOLD Report. Mayo Clin Proc. Oct; 93 (10): 1488-1502

[3] HAVE YOU MET THE NEW MEDS ON THE BLOCK? | JAN – MAR 2019 2019 Manufactur Drug Approva Category For the treatment of: er l New Drugs Approved Excessive sleepiness in adult patients Sunosi™ (solriamfetol) Tab Jazz Pharma 20-Mar Selective DNRI with narcolepsy or OSA Sage Positive allosteric modulator Zulresso™ (brexanolone) IV 19-Mar Postpartum depression Therapeutics of GABAA receptor. Rocklatan™ (netarsudil- Rho kinase inhibitor + Elevated IOP in patients with open- Aerie Pharma 12-Mar latanoprost) Ophthalmic Solution Prostaglandin analog angle glaucoma or ocular hypertension Trazimera™ (trastuzumab- HER-2/ Neu receptor HER-2+ breast cancer, metastatic Pfizer 11-Mar qyyp) IV [Herceptin’s biosimilar] antagonist gastric & GEJ adenocarcinoma Spravato™ (esketamine) Nasal Adults with treatment-resistant Janssen 5-Mar NMDA receptor antagonist Spray depression Herceptin Hylecta™ HER-2/ Neu antagonist + Genentech 28-Feb HER-2 overexpressing breast cancer (trastuzumab-hyaluronidase) SC Recombinant hyaluronidase Adhansia XR™ Adlon ADHD in patients aged 6 years and 27-Feb CNS stimulant (methylphenidate) Caps Therapeutics older Esperoct™ (turoctocog alfa) IV Novo Nordisk 19-Feb Factor VIII molecule Adults and children with hemophilia A Egaten™ (triclabendazole) Tabs Novartis 13-Feb Benzimidazole anthelmintic Fascioliasis by liver flukes vWF directed antibody Adults with aTTP. Combined + plasma Cablivi™ (caplacizumab) IV Ablynx NV 6-Feb fragment exchange & immunosuppression Jeuveau™ (prabotulinumtoxin Purified type A botulinum Temporary improvement of moderate- Evolus 1-Feb A) IM toxin to-severe glabellar “frown” lines Wixela Inhub™ (fluticasone- Mylan 31-Jan Corticosteroid + LABA Asthma and COPD salmeterol) Inhalation Powder Gloperba™ (colchicine) Solution Romeg 30-Jan Uricosuric agent Prophylaxis of gout flares in adults Tosymra™ (sumatriptan) Spray Dr Reddy Labs 25-Jan Serotonin receptor agonist Acute migraine in adults Ontruzant™ (trastuzumab-dttb) Samsung HER-2/ Neu receptor HER-2+ breast cancer, metastatic 18-Jan IV [Herceptin’s biosimilar] Bioepis antagonist gastric & GEJ adenocarcinoma New Indications Advanced TCC, metastatic NSCLC, Tecentriq™ (atezolizumab) IV Genentech 18-Mar PD-L1 blocking antibody combined with Abraxane™ for metastatic triple-negative breast cancer Avycaz™ (avibactam- β-lactamase inhibitor + 3rd HABP, VABP, cIAI, cUTI including Allergan 14-Mar ceftazidime) IV generation cephalosporin pediatric patients 3 months and older Moderate-to-severe atopic dermatitis in Sanofi + IL-4 receptor alpha Dupixent™ (dupilumab) SC 11-Mar adolescents, and add-on maintenance Regeneron antagonist for moderate-to-severe asthma Adults with type 2 diabetes Soliqua 100/33™ (glargine- Long acting insulin + GLP-1 Sanofi 27-Feb uncontrolled on oral antidiabetic lixisenatide) SC agonist therapy Lonsurf™ (tipiracil-trifluridine) Taiho Thymidine phosphorylase + Previously treated metastatic colorectal 22-Feb Caps Oncology Nucleoside inhibitor and gastric & GEJ adenocarcinoma NSCLC, HNSCC, Hodgkins, PMBL, TCC, Human PD-1 blocking Keytruda™ (pembrolizumab) IV Merck 15-Feb HCC, MCC, MSI-H, Gastric, Cervical antibody cancer and adjuvant in melanoma MCL, WM, SLL, MZL, chronic GvHD, and Imbruvica™ (ibrutinib) Tabs Janssen 28-Jan BTK inhibitor treatment-naïve CLL with Gazyva IV Vulvar and vaginal atrophy due to Osphena™ (ospemifene) Tabs Duchesnay 25-Jan Estrogen agonist/ antagonist menopause, including dyspareunia and moderate-to-severe vaginal dryness Fluzone Quadrivalent™ Inactivated influenza virus Influenza immunization, 0.5 mL dose Sanofi 23-Jan (influenza vaccine) IM vaccine approved in children aged ≥ 6 months

Abbreviations: ADHD, Attention-deficit/ hyperactivity disorder; aTTP, Acquired thrombotic thrombocytopenic purpura; BTK, Bruton’s tyrosine kinase; cIAI, Complicated intra-abdominal infections; CLL, Chronic lymphocytic leukemia; CNS, Central nervous system; COPD, Chronic obstructive pulmonary disease; cUTI, Complicated urinary tract infections; DNRI, Dopamine & norepinephrine reuptake inhibitor; GABAA, Gamma-aminobutyric acid A; GEJ, Gastroesophageal junction; GLP-1, Glucagon-like peptide-1; GvHD, Graft versus host disease; HABP, Hospital-acquired bacterial pneumonia; HCC, Hepatocellular carcinoma; HER-2+, Human epidermal growth factor receptor positive; HNSCC, Head & neck squamous cell carcinoma; IL-4, Interleukin-4; IM, Intramuscular; IOP, Intraocular pressure; IV, Intravenous; LABA, Long-acting beta2-adrenergic agonist; MCC, Merkel cell carcinoma; MCL, Mantle cell lymphoma; MSI-H, Microsatellite instability-high cancer; MZL, Marginal zone lymphoma; NMDA, Non-competitive N-methyl D-aspartate; NSCLC, Non-small cell lung cancer; OSA, Obstructive sleep apnea; PD-1, Programmed death receptor-1; PD-L1, Programmed death- ligand 1; PMBL, Primary mediastinal large B-cell lymphoma; SC, Subcutaneous; SLL, small lymphocytic lymphoma; TCC-UC, Transitional cell carcinoma/ Urothelial carcinoma; VABP, Ventilator-associated bacterial pneumonia; vWF, Von Willebrand factor; WM, Waldenström’s macroglobulinemia. 3

SEEING OPPORTUNITY READY FOR THESE HIGHLY ANTICIPATED DRUGS?

Treatment-Resistant Depression (TRD)

Up to 7% of US adults experience at least one major depressive disorder (MDD) episode each year. Treatment- resistant depression (TRD) refers to failure of at least 2 trials of antidepressant monotherapies, and affects approximately one in three patients with depression. TRD treatments include upgrading antidepressants or augmenting existing prescriptions with non-antidepressant medications (such as atypical antipsychotics). Among those with TRD, there are patients with refractory depression--showing symptoms over long periods of time, multiple relapses, and many sequential treatment regimens with inadequate responses. For these highly resistant and difficult to treat patients, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are available. Spravato™ (esketamine; Janssen) is a Nmethyl-D-aspartate (NMDA) receptor antagonist nasal spray that was approved in March. The table below summarizes the median days to relapse on Spravato™, compared to placebo, for 48 weeks among TRD patients with a stable depression rating scale response.[4]

TIME TO RELAPSE - SUSTAIN-1 TRIAL [4]

Stable Responders Median Days to Hazard Ratio Annual (N = 121) Relapse (95% CI) (95% CI) Cost Placebo + Oral antidepressants 88 (46, 196) 1.00 $3,909 Spravato™ (esketamine) + Oral 635 (264, 635) 0.30 (0.16, $30,800 antidepressants 0.55)

Postpartum Depression (TRD)

Postpartum depression can interfere with the maternal-infant bonding and lead to thoughts of. In March, the FDA granted breakthrough status to Zulresso™ (brexanolone; Sage Thank you, pharmacists. Therapeutics) as the first-ever drug designated for postpartum depression. It is chemically identical to endogenous Pharmacists in our community play a allopregnanolone, an allosteric modulator of gamma- critical role in maintaining and aminobutyric acid-A (GABAA) receptors, which become improving the health of our members. dysregulated in the postpartum period. Zulresso™ is And, in recognition of Pharmaceutical administered under medical supervision as a continuous infusion Week, we want to personally thank the over a total of 60 hours (2.5 days) and requires a Risk Evaluation and Mitigation Strategy (REMS) program due to its risks of talented and dedicated pharmacists of excessive sedation or sudden loss of consciousness during Puerto Rico for your willingness to go administration. Mothers must have continuous pulse oximetry all in for the patients they serve. Your monitoring during the 60-hour infusion and be accompanied by contagious passion is an inspiration to their child while receiving the infusion. The figure below us all, and we are proud to call you summarizes the remission results for the Hamilton Rating Scale partners and friends. for Depression (HAM-D) at hour 60 for the individual key studies in Zulresso™ FDA Package Insert.[5] Remission is defined as a HAM-D total score of ≤ 7, out of the 17-items in the HAM- D scale.

HAM-D REMISSION AT HOUR 60 FOR KEY PACKAGE INSERT STUDIES [5]

Study 202A Study 202B Study 202c 100% p=0.008 p=0.001 p=0.003

80% 70%

HAM-D = 17-Item 61% Hamilton Rating 60%

Scale for Depression 51%

D Remission D 60 Hour at Remission - 39% 40% 31%

20% 16%

9% Patients Achieving HAM Achieving Patients 0% N=10 N=11 N=39 N=37 N=43 N=49 N=52

Brexanolone 90 Brexanolone 60 Placebo

Adapted from Zulresso™ (brexanolone) [package insert]. Sage Therapeutics; 2019.

Sources [1] Klinger JR, Elliott CG, Levine DJ, et al. (2019). Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest; Mar; 155(3):565-586 [2] Global Initiative for Chronic Obstructive Lung Disease. (2018). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2018 Report. [online] Available at: https://goldcopd.org/wp- content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. [Accessed 25 March. 2019] [3] U.S. Food and Drug Administration. (2019). Recent New and Generic Drug Approvals - March 25, 2019. [online] Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event/ [Accessed 25 March. 2019] [4] Institute for Clinical and Economic Review. (2019). Esketamine for the Treatment of Treatment Resistant Depression: Effectiveness and Value Draft Evidence Report. Journal of the American Heart Association. Aug 19;5(8). [5] Zulresso™ (brexanolone) [package insert]. [online] Available at: https://icer-review.org/topic/depression/ [Accessed 15 ABARCA January. 2019

Disclaimer: The information contained in this newsletter is for informational purposes only and does not constitute clinical or medical advice. The information presented in this newsletter is, to the best of our knowledge, accurate as of publication. However, we take no responsibility for inaccuracies or other errors present in this newsletter. The recipient of this newsletter may not copy, distribute, or display this newsletter without Abarca’s express written consent.

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