Migraine 2/6/2019. New Medications in Neurology. Learning Objectives. Disclosure. Learning Objectives. Midwinter Meeting February 9, 2019

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1 New Medications in Neurology Erica Marini, PharmD, MS, BCPS Clinical Pharmacist University of Utah Health Imaging and Neurosciences Center Midwinter Meeting February 9, Disclosure Learning Objectives No conflicts of interest. No discussion of off-label uses of drugs. At the conclusion of this activity, pharmacists should be able to successfully: 1. Describe new medications in neurology with regard to efficacy and safety 2. Discuss important counseling points for new neurology medications 3. Evaluate the potential place in therapy for new medications 3 4 Learning Objectives At the conclusion of this activity, pharmacy technicians should be able to successfully: 1. Identify new neurology medications and their corresponding disease state 2. Differentiate new medications in neurology based on route and setting of administration 3. Describe potential barriers to access to new medications Migraine 5 6 1

2 The Year of CGRP Calcitonin gene-related peptide Found mostly in the central and peripheral nervous system where it plays a role in pain modulation, sensitization, and perception Also a potent vasodilator with other biologic effects on cardiac, skeletal, and smooth muscle, the endocrine system, and the gastrointestinal system CGRP Agents Approved in 2018: Aimovig (erenumab) Ajovy (fremanezumab) Emgality (galcanezumab) Durham PL, Silberstein 7 SD, Comparison of Agents Indication Mechanism of Action Dosing Adverse Effects Erenumab CGRP receptor antagonist 70mg OR 140mg SQ monthly Injection site reactions Constipation Fremanezumab Galcanezumab Prevention of chronic and episodic migraine Inhibit CGRP ligand binding to receptor 225mg SQ monthly OR 675mg SQ every 3 months Injection site reactions 240mg SQ once, then 120mg SQ monthly Injection site reactions Agents were not shown to be immunosuppressive or interfere with other biological effects of CGRP Comparison of Agents Episodic Migraine <15 days/month Headache days per month at baseline Change from baseline in mean monthly migraine days Patients reporting at least 50% reduction in mean monthly migraine days Erenumab 70mg 140mg Fremanezumab Monthly Quarterly Galcanezumab % 50.0% 47.7% 44.4% 62% Aimovig [package insert]. Ajovy [package insert]. Emgality [package insert] 9 See references Comparison of Agents Comparison of Agents Chronic Migraine >15 days/month Headache days per month at baseline Change from baseline in mean monthly migraine days Patients reporting at least 50% reduction in mean monthly migraine days Erenumab 70mg 140mg Fremanezumab Monthly Quarterly Galcanezumab % 41.2% 40.8% 37.6% 28% Erenumab 70mg 140mg Fremanezumab Monthly Quarterly Galcanezumab Wholesale Acquisition Cost $575/injector $575/injector $575/injector See references Red Book. IBM Corporation

3 Summary of CGRP Agents Generally, agents are considered similar in efficacy Adverse effects are minimal, however ligand agents (Emgality or Ajovy ) may be more appropriate for patients with existing constipation First medications developed for prevention of migraine, but insurances still require step therapy with agents traditionally used for migraine prevention prior to approval Additional CGRP agents being studied, including for acute treatment Question 1 AB is a 50 year old female with chronic migraine and irritable bowel syndrome, constipation predominant. The provider asks you for a recommendation on a CGRP agent. Which do you recommend: A. Ajovy (fremanezumab) B. Emgality (galcanezumab) C. Aimovig (erenumab) D. Either 1 or 2 See references Question 2 The provider accepts your recommendation of CGRP agent and sends the prescription to the pharmacy. The patient sends a message later that day that they could not pick up the prescription. What are potential barriers to access to this medication? A. Prior authorization required B. Pharmacy does not have in stock C. Co-payment cost is too high D. All of the above Hereditary Polyneuropathy Hereditary Transthyretin-Mediated Amyloidosis Hereditary Transthyretin-Mediated Amyloidosis Onpattro Patient Brochure Onpattro Patient Brochure

4 hattr Agents Approved in 2018: j Onpattro (patisiran) Indication: treatment of the polyneuropathy of hereditary transthyretinmediated amyloidosis in adults Mechanism of Action: antisense oligonucleotide inhibitor of human transthyretin (TTR) protein synthesis, resulting in reduction of TTR protein Dosing: 284 mg once a week Administration: SQ injection, first dose supervised 19 Tegsedi [package insert] 20 Efficacy Data 113 adult patients with polyneuropathy caused by hattr amyloidosis randomized to treatment; 77% completed full 66 weeks Primary endpoint: change in modified Neuropathy Impairment Score +7 and Norfolk Quality of Life- Diabetic Neuropathy (QoL-DN) from baseline to Week 66 Mean change in mnis+7 in Tegsedi patients +5.8 vs in placebo patients (p<0.001) Mean change in QoL-DN in Tegsedi patients +1.0 vs in placebo patients (p<0.001) Common Side Effects: Injection site reactions (49%) Nausea (31%) Headache (26%) Fatigue (25%) Thrombocytopenia (24%) Fever (20%) Peripheral edema (19%) Chills (18%) Anemia (17%) Vomiting (15%) Myalgia (15%) Decreased renal function (14%) Other side effects occuring in >5% of patients: Arrhythmia, arthralgia, pre-syncope/syncope, decreased appetite, paresthesia, dyspnea, elevated LFTs, orthostasis, influenza-like illness, contusion, bacterial infection, eosinophilia, dry mouth Tegsedi [package insert] Benson M, Tegsedi [package insert] 22 Onpattro (patisiran) Precautions: Black Box Warning: Thrombocytopenia and Glomerulonephritis Sudden thrombocytopenia <25 x10 9 /L occurred in 3 patients, resulting in fatal intracranial hemorrhage in 1 patient; weekly platelet counts recommended Three patients developed glomerulonephritis; 2 recovered with immunosuppression, 1 remains on dialysis. Serum creatinine, estimated glomerular filtration rate (egfr), urinalysis, and UPCR every 2 weeks REMS program Hypersensitivity leading to treatment discontinuation occurred in 6 patients Decrease in serum Vitamin A levels Liver effects: Increased ALT/AST, immune-mediated biliary disease Platelet clumping Antibody development Indication: treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults Mechanism of Action: antisense oligonucleotide inhibitor of human transthyretin (TTR) protein synthesis, resulting in reduction of TTR protein Dosing: 0.3mg/kg every 3 weeks for patients <100kg; 30mg every 3 weeks for patients >100kg Administration: IV infusion Tegsedi [package insert] 23 Onpattro [package insert] 24 4

5 Onpattro (patisiran) Efficacy Data 148 adult patients with polyneuropathy caused by hattr amyloidosis randomized to treatment; 93% completed full 18 months Primary endpoint: change in modified Neuropathy Impairment Score +7 from baseline to Month 18 Mean change in Onpattro patients -6.0 vs in placebo patients (p<0.001) Improvements also seen in QOL, 10-meter walk test, and stabilization of weight via modified BMI Onpattro (patisiran) Common Side Effects: Upper respiratory infections (29%) Infusion-related reactions (19%) Other side effects occurring in >5% of treated patients: dyspepsia, dyspnea, muscle spasms, arthralgia, erythema, bronchitis, vertigo Precautions: Extravasation was reported rarely in trials Decrease in serum Vitamin A levels 4 cases of atrioventricular block reported Onpattro [package insert] Adams D, Onpattro [package insert] 26 Summary of hattr Neuropathy Agents First in class agents and first approved for disease state While studied only in neuropathy of hattr, its mechanism would suggest that these agents may be helpful in other symptoms of hattr While not compared in head to head trials, Onpattro (patisiran) appears to have similar efficacy with a better safety profile than Wholesale Acquisition Cost Onpattro : $9,500 for 2mg/1ml vial Tegsedi : not available Question 3 Which hattr polyneuropathy agent has a Black Box Warning for thrombocytopenia and glomerulonephritis? A. B. Onpattro (patisiran) C. Neither D. Both Red Book. IBM Corporation Inbrija (levodopa inhalation powder) Movement Disorders

6 Inbrija (levodopa inhalation powder) Inbrija (levodopa inhalation powder) Indication: Intermittent treatment of OFF episodes in patients with Parkinson s Disease (PD) treated with carbidopa/levodopa Mechanism of Action: Levodopa converts to dopamine in the brain and relieves symptoms of PD Dosing: Inhale contents of 2 caps (84mg total) as needed, up to 5 times per day Administration: Inhalation powder; medication comes in capsules that are puncture inside the inhaler, med is delivered via breath-actuated inhaler *Counseling on administration will be very important* Efficacy Data 114 patients with at least 2 hours of OFF time per day received active drug Primary endpoint: change in Unified Parkinson s Disease Rating Scale from OFF state to 30 minutes post-dose Mean change in Inbrija patients -9.8 vs -5.9 in placebo patients (p=0.009) 58% of Inbrija patients reported that they were still ON after 60 min vs 36% for placebo (p=0.003) Inbrija [package insert] Inbrija (levodopa inhalation powder) Common Side Effects: Related to inhaler use: cough (15%), discolored sputum (5%) Related to dopamine intake: Nausea (5%), dyskinesia (4%) Precautions: Impulse control disorders Hallucinations Withdrawal symptoms following rapid dose escalation of dopamine therapies Question 4 Which of the following is NOT an important counseling point for Inbrija (levodopa)? A. Swallow the capsule whole, do not crush B. Inhale the contents of two capsules per dose C. Pierce the capsule prior to inhalation Wholesale Acquisition Cost: Not yet available Onpattro [package insert] Epidiolex (cannabidiol) Seizure Indication: treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older These disorders are generally severe, treatment resistant, and occur early in life Mechanism of Action: Unknown Dosing: 2.5mg/kg twice daily then titrated as directed/needed up to 10mg/kg twice daily Administration: Oral solution, should be measured only with a calibrated measuring device Epidiolex is registered as a Schedule V controlled substance. 35 Epidiolex [package insert] 36 6

7 Epidiolex (cannabidiol) Efficacy Data: Lennox Gastaut 396 patients age 2-55 with inadequate seizure control on 1 or more AEDs Primary endpoint: percent change in frequency of drop seizures Additionally, benefit was seen in secondary endpoints of total seizure frequency and Subject/Caregiver Global Impression of Change scores Similar efficacy shown in Dravet Syndrome Epidiolex (cannabidiol) Common Side Effects: Side effects are dose-related; 2.7% of patients on 10mg/kg/day discontinued due to adverse effects, and 11.8% on 20mg/kg/day Elevated LFTs, decreased appetite, diarrhea, somnolence, lethargy, agitation, rash Precautions: Monitor hepatic enzymes One case of angioedema in clinical trials Suicidal ideation and behavior (included in all anti-epileptic labeling) Concerns with abrupt withdrawal (included in all anti-epileptic labeling) Interactions with CYP system Wholesale Acquisition Cost: $1,235 per 100mg/100mL bottle Thiele EA, Devinsky O, Devinsky O, Epidiolex [package insert] 37 Epidiolex [package insert] Red Book. IBM Corporation Question 5 True or False. Epidiolex (cannabidiol) is FDA approved for all types of seizure disorder. A. True B. False Other New Approvals in Neurology Diacomit (stiripentol)- treatment of seizures associated with Dravet Syndrome in patients 2 years or older taking clobazam Ocrevus (ocrelizumab)- treatment of relapsing or primary progressive forms of multiple sclerosis Radicava (edaravone)- treatment of amyotrophic lateral sclerosis Austedo (deutetrabenazine)- treatment of tardive dyskinesia in adults AND chorea associated with Huntington s disease Ingrezza (valbenazine)- treatment of adults with tardive dyskinesia Xadago (safinamide)- to treat OFF episode of Parkinson s disease in adults on carbidopa/levodopa Firdapse (amifampridine)- treatment of Lambert-Eaton myasthenic syndrome in adults Emflaza (deflazacort)- treatment of Duchenne muscular dystrophy in patients 5 years of age or older Questions? Package inserts for respective drugs cited in reference slide

8 References References 1. Levin M, Silberstein SD, Gilbert R, et al. Basic considerations for the use of monoclonal antibodies in migraine. Headache. 2018; 58(10): Durham PL. CGRP receptor antagonists a fresh approach to migraine therapy?. N Engl J Med. 2004;350(11): Aimovig [package insert]. Thousand Oaks, CA: Amgen Pharmaceuticals; Goadsby PJ et al. Trial of erenumab for episodic migraine. N Engl J Med Nov 30;377(22): Dodick DW et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia Jan 1: Tepper S, et al. Safety and efficacy erenumab for preventive treatment of chronic migraine: a randomized, double blind placebo controlled phase 2 trial. Lancet Neurol Jun;16(6): Ajovy [package insert]. North Wales, PA: TEVA Pharmaceuticals USA; Silberstein SD, Dodick, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Eng J Med. 2017;377(22): Dodick, Silberstein SD, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018; 319(19): Emgality [package insert]. Indianapolis, IN: Eli Lilly and Company; Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE 1 Randomized Clinical Trial. JAMA Neurol Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE 2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018: Onpattro Patient Brochure. 2018, content/uploads/2018/08/onpattro Patient Brochure.pdf. 14. Tegsedi [package insert]. Boston, MA: Akcea Therapeutics, Inc.; Benson M, Waddington Cruz M, Berk J, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Eng J Med. 2018;379: Onpattro [package insert]. Boston, MA: Alnylam Pharmaceuticals; Adams D, Gonzalez Duarte A, O Riordan W, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Eng J Med 2018; 379: Inbrija [package insert]. Ardsley, NY: Acorda Therapeutics, Inc.; Epidiolex [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox Gastaut syndrome (GWPCARE4): a randomised, double blind, placebo controlled phase 3 trial. Lancet (London, England). 2018;391(10125): doi: /s (18) Devinsky O, Patel A, Cross J et al. Effect of Cannabidiol on Drop Seizures in the Lennox Gastaut Syndrome. New England Journal of Medicine. 2018;378(20): doi: /nejmoa Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21): doi: /nejmoa Diacomit [package insert]. Beauvais, France: Biocodex; Ocrevus [package insert]. South San Francisco, CA: Genentech, Inc.; Radicava [package insert]. Jersey City, NJ: Mitsubishi Tanabe Pharma Corporation; Austedo [package insert]. North Wales, PA: TEVA Pharmaceuticals USA; Ingrezza [package insert]. San Diego, CA: Neurocrine Biosciences, Inc.; Xadago [package insert]. Louisville, KY: US Worldmeds, LLC; Firdapse [package insert]. Coral Gables, FL: Catalyst Pharmaceuticals, Inc.; Emflaza [package insert}. South Plainfield, NJ; PTC Therapeutics, Inc.;