Midwinter Meeting February 9, 2019 New in Neurology

Erica Marini, PharmD, MS, BCPS Clinical Pharmacist University of Utah Health Imaging and Neurosciences Center

2 Disclosure

No conflicts of interest. No discussion of off-label uses of drugs.

3 Learning Objectives

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

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

5 Migraine

6 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

Durham PL, 2014. Silberstein7 SD, 2018. CGRP Agents Approved in 2018: Aimovig™ (erenumab) Ajovy™ (fremanezumab) Emgality™ (galcanezumab)

8 Comparison of Agents Erenumab Fremanezumab Galcanezumab Indication Prevention of chronic and episodic migraine Mechanism of Action CGRP receptor Inhibit CGRP ligand binding to receptor antagonist Dosing 70mg OR 140mg SQ 225mg SQ monthly 240mg SQ once, then monthly OR 120mg SQ monthly 675mg SQ every 3 months Adverse Effects Injection site Injection site Injection site reactions reactions reactions Constipation Agents were not shown to be immunosuppressive or interfere with other biological effects of CGRP

Aimovig™ [package insert]. Ajovy™ [package insert]. 9 Emgality™ [package insert] Comparison of Agents

Episodic Migraine Erenumab Fremanezumab Galcanezumab <15 days/month 70mg 140mg Monthly Quarterly Headache days per month 8 8 7.7 7.8 9.2 at baseline Change from baseline in 3.2 3.7 3.0 2.9 4.7 mean monthly migraine days Patients reporting at least 43.3% 50.0% 47.7% 44.4% 62% 50% reduction in mean monthly migraine days

See references 3-12 10 Comparison of Agents

Chronic Migraine Erenumab Fremanezumab Galcanezumab >15 days/month 70mg 140mg Monthly Quarterly Headache days per month 18 18 12.8 13.2 19.4 at baseline Change from baseline in 6.6 6.6 4.6 4.3 4.8 mean monthly migraine days Patients reporting at least 39.9% 41.2% 40.8% 37.6% 28% 50% reduction in mean monthly migraine days

11 See references 3-12 Comparison of Agents

Erenumab Fremanezumab Galcanezumab 70mg 140mg Monthly Quarterly

Wholesale Acquisition Cost $575/injector $575/injector $575/injector

12 Red Book. IBM Corporation 2019. 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

See references 3-12 13 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

14 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 ?

A. Prior authorization required B. Pharmacy does not have in stock C. Co-payment cost is too high D. All of the above

15 Hereditary Polyneuropathy

16 Hereditary Transthyretin-Mediated Amyloidosis

Onpattro Patient Brochure. 2018. 17 Hereditary Transthyretin-Mediated Amyloidosis

18 Onpattro Patient Brochure. 2018. hATTR Agents Approved in 2018: j Tegsedi™ (inotersen) Onpattro™ (patisiran)

19 Tegsedi™ (inotersen)

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: 284 mg once a week

Administration: SQ injection, first dose supervised

Tegsedi™ [package insert] 20 Tegsedi™ (inotersen)

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 +25.5 in placebo patients (p<0.001) • Mean change in QoL-DN in Tegsedi patients +1.0 vs +12.7 in placebo patients (p<0.001)

Tegsedi™ [package insert] 21 Benson M, 2018. Tegsedi™ (inotersen)

Common Side Effects: • Anemia (17%) • Injection site reactions (49%) • Vomiting (15%) • Nausea (31%) • Myalgia (15%) • Headache (26%) • Decreased renal function (14%) • Fatigue (25%) • Other side effects occuring in >5% of patients: Arrhythmia, arthralgia, • Thrombocytopenia (24%) pre-syncope/syncope, decreased appetite, paresthesia, dyspnea, • Fever (20%) elevated LFTs, orthostasis, • Peripheral edema (19%) influenza-like illness, contusion, bacterial infection, eosinophilia, dry • Chills (18%) mouth

Tegsedi™ [package insert] 22 Tegsedi™ (inotersen)

Precautions: • Black Box Warning: Thrombocytopenia and Glomerulonephritis • Sudden thrombocytopenia <25 x109/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

Tegsedi™ [package insert] 23 Onpattro™ (patisiran)

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

Onpattro™ [package insert] 24 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 +28.0 in placebo patients (p<0.001) • Improvements also seen in QOL, 10-meter walk test, and stabilization of weight via modified BMI

Onpattro™ [package insert] 25 Adams D, 2018. 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] 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 Tegsedi™ (inotersen)

• Wholesale Acquisition Cost • Onpattro™: $9,500 for 2mg/1ml vial • Tegsedi™: not available

Red Book. IBM Corporation 2019 27 Question 3

Which hATTR polyneuropathy agent has a Black Box Warning for thrombocytopenia and glomerulonephritis?

A. Tegsedi™ (inotersen) B. Onpattro™ (patisiran) C. Neither D. Both

28 Movement Disorders

29 Inbrija™ (levodopa inhalation powder)

www.inbrija.com 30 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*

Inbrija™ [package insert] 31 Inbrija™ (levodopa inhalation powder)

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)

32 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

Wholesale Acquisition Cost: Not yet available

Onpattro™ [package insert] 33 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

34 Seizure

35 Epidiolex™ (cannabidiol)

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.

Epidiolex™ [package insert] 36 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

Thiele EA, 2018. Devinsky O, 2018. Devinsky O, 2017. 37 Epidiolex™ [package insert] 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

Epidiolex™ [package insert] Red Book. IBM Corporation 2019 38 Question 5

True or False. Epidiolex™ (cannabidiol) is FDA approved for all types of seizure disorder.

A. True B. False

39 Other New Approvals in Neurology

40 • 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™ ()- treatment of tardive dyskinesia in adults AND chorea associated with Huntington’s disease • Ingrezza™ ()- treatment of adults with tardive dyskinesia • Xadago™ (safinamide)- to treat OFF episode of Parkinson’s disease in adults on carbidopa/levodopa • Firdapse™ ()- treatment of Lambert-Eaton myasthenic syndrome in adults • Emflaza™ (deflazacort)- treatment of Duchenne muscular dystrophy in patients 5 years of age or older

Package inserts for respective drugs cited in reference slide. 41 Questions?

42 References

1. Levin M, Silberstein SD, Gilbert R, et al. Basic considerations for the use of monoclonal antibodies in migraine. Headache. 2018; 58(10):1689-1696.

2. Durham PL. CGRP-receptor antagonists—a fresh approach to migraine therapy? . N Engl J Med. 2004;350(11):1073-5.

3. Aimovig™ [package insert]. Thousand Oaks, CA: Amgen Pharmaceuticals; 2018.

4. Goadsby PJ et al. Trial of erenumab for episodic migraine. N Engl J Med. 2017 Nov 30;377(22):2123-2132.

5. Dodick DW et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018 Jan 1:333102418759786.

6. 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. 2017 Jun;16(6):425- 434.

7. Ajovy™ [package insert]. North Wales, PA: TEVA Pharmaceuticals USA; 2018.

8. Silberstein SD, Dodick, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Eng J Med. 2017;377(22):2113-2122.

9. Dodick, Silberstein SD, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized . JAMA. 2018; 319(19):1999-2008.

10. Emgality™ [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.

11. 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. 2018.

12. 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. 2018:333102418779543.

13. Onpattro Patient Brochure. 2018, https://www.onpattro.com/wp-content/uploads/2018/08/ONPATTRO-Patient-Brochure.pdf.

14. Tegsedi™ [package insert]. Boston, MA: Akcea Therapeutics, Inc.; 2018.

15. Benson M, Waddington-Cruz M, Berk J, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Eng J Med. 2018;379:22-31.

43 References

16. Onpattro™ [package insert]. Boston, MA: Alnylam Pharmaceuticals; 2018.

17. Adams D, Gonzalez-Duarte A, O-Riordan W, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Eng J Med 2018; 379:11-21.

18. Inbrija™ [package insert]. Ardsley, NY: Acorda Therapeutics, Inc.; 2018.

19. Epidiolex™ [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018

20. 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):1085-1096. doi:10.1016/S0140-6736(18)30136-3

21. 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):1888-1897. doi:10.1056/nejmoa1714631

22. 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):2011-2020. doi:10.1056/NEJMoa1611618

23. Diacomit™ [package insert]. Beauvais, France: Biocodex; 2018.

24. Ocrevus™ [package insert]. South San Francisco, CA: Genentech, Inc.; 2018.

25. Radicava™ [package insert]. Jersey City, NJ: Mitsubishi Tanabe Pharma Corporation; 2017.

26. Austedo™ [package insert]. North Wales, PA: TEVA Pharmaceuticals USA; 2017.

27. Ingrezza™ [package insert]. San Diego, CA: Neurocrine Biosciences, Inc.; 2018.

28. Xadago™ [package insert]. Louisville, KY: US Worldmeds, LLC; 2017.

29. Firdapse™ [package insert]. Coral Gables, FL: Catalyst Pharmaceuticals, Inc.; 2018.

30. Emflaza™ [package insert}. South Plainfield, NJ; PTC Therapeutics, Inc.; 2017.

44