New Drug Update Rachael McCaleb, PharmD, BCPS

New Drug Update 2016-2017 Rachael McCaleb, PharmD, BCPS
Assistant Professor, Department of Pharmacy Practice University of Arkansas for Medical Sciences College of Pharmacy

Disclosures I have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

Pharmacist Objectives
Recognize drugs that gained FDA approval within the last year Describe indications, doses, formulations, adverse effects, and drug interactions of recently approved drugs Summarize clinical data for recently approved drugs Identify information regarding the recently approved drugs that should be communicated to patients

Technician Objectives
List new drugs that gained FDA approval within the last 12 months Identify doses and formulation of the recently approved drugs Be able to state the indication for the recently approved drugs

Impact of Public Health
36% First-in-Class Drugs 41% Rare or “Orphan” Diseases

used expedited development and review methods
Innovation 73% used expedited development and review methods Fast Track 36% Priority Review 68% Breakthrough 32% Accelerate Approval 27%

Access 95% First Cycle Approval 86% Approved First in US

NOVEL DRUGS Exondys 51 Kisqali Rydapt Mavyret Lartruvo Xadago Tymlos Besponsa Zinplava Bavencio Imfinzi Eucrisa Symproic Radicava Rubraca Zejula Kevzara Spinraza Dupixent Baxdela Trulance Ocrevus Bevyxxa Parsabiv Austedo Tremfya Emflaza Ingrezza Nerlynx Siliq Brineura Vosevi Xermelo Alunbrig Idhifa

Hepatology

Sofosbuvir/velpatasvir/voxilaprevir (Vosevi®)
Indication: Treatment of chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in adults without cirrhosis or with compensated cirrhosis who have previously been treated with an HCV regimen containing an NS5A inhibitor Approval Date: July 18, 2017 MOA: Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase Velpatasvir is an inhibitor of HCV NS5A Voxilaprevir is an inhibitor of hepatitis C virus (HCV) NS3/4A protease Vosevi (sofosbuvir, velpatasvir, voxilaprevir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; July 2017.

Dosage: One tablet (sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg) once daily for 12 weeks Boxed Warning: Risk of Hepatitis B reactivation Adverse Reactions: Headache, fatigue, diarrhea, and nausea Precautions: Bradycardia Cost: ~$90,000/treatment Vosevi (sofosbuvir, velpatasvir, voxilaprevir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; July 2017.

POLARIS-1 Trial (N=415) Double-blind, placebo-control trial Genotype 1-6 NS5A inhibitor experienced without cirrhosis or with compensated cirrhosis Genotype 1: randomized to Vosevi or placebo for 12 weeks Genotype 2-6: all Vosevi Results: Majority genotype 1 (72%) SVR12 overall and by subgroups, % (95% CI) * Superiority to 85% (p < 0.001) Bourlière M. NEJM 2017; 376:

POLARIS-4 Trial (N=333) Open-label, active comparator trial Genotype 1-4 who have failed other direct-acting antivirals not NS5A inhibitor without cirrhosis or with compensated cirrhosis Genotype 1-3: randomized to Vosevi or sofosbuvir-velpatasvir for 12 weeks Genotype 4: all Vosevi Results: SVR12 overall and by subgroups, % * * Superiority to 85% (p < 0.001) Bourlière M. NEJM 2017; 376:

POLARIS-2 & 3 Trials (N=219) Open-label, active comparator trial POLARIS 2: Genotype 1,2 and 4-6 without cirrhosis or with compensated cirrhosis POLARIS 3: Genotype 3 who were direct-acting antivirals naïve with compensated cirrhosis Randomized to Vosevi for 8 weeks or sofosbuvir-velpatasvir for 12 weeks Results: POLARIS 2: SVR rate: Vosevi (95%) and sof-vel (98%) [Voseiv did not meet noninferiority to sof-vel] POLARIS 3: SVR rate was 96% for both treatment groups Lacobson IM, et al. Gastroenterology. 2017; 153:

Glecaprevir/pibrentasvir (Mavyret®)
Indication: Treatment of chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in adults without cirrhosis or with compensated cirrhosis Approval Date: August 3, 2017 MOA: Glecaprevir is an inhibitor of hepatitis C virus (HCV) NS3/4A protease Pibrentasvir is an inhibitor of HCV NS5A Can be treated with either or not both Zepatier (1/4) Mavyret (glecaprevir/pibrentasvir) [prescribing information]. North Chicago, IL: AbbVie Inc; August 2017.

Dosage: Treatment naïve: 8 weeks (no cirrhosis) or 12 weeks (compensated cirrhosis) Treatment experience: 8-16 weeks depending on genotype and prior treatment Boxed Warning: Risk of Hepatitis B reactivation Adverse Reactions: Headache and fatigue Cost: $15,840/month St johns wort interaction Mavyret (glecaprevir/pibrentasvir) [prescribing information]. North Chicago, IL: AbbVie Inc; August 2017.

Clinical Trials Snapshot ENDURANCE 1/3/4 (Treatment naïve without cirrhosis) SURVEYOR 1/2 (Treatment naïve without cirrhosis or with compensated cirrhosis (only 2)) EXPEDITION 1/4 (Treatment naïve with compensated cirrhosis) 4 (CKD stage 4/5) MAGELLAN 1 (NS5A experience without cirrhosis or with compensated cirrhosis) ENDURANCE-3 Open-label, active-control (sofosbuvir and daclatasvir) Mavyret (glecaprevir/pibrentasvir) [prescribing information]. North Chicago, IL: AbbVie Inc; August 2017.

Clinical Trials Snapshot Results: N=2300 92-100% of patients who received Mavyret for 8, 12 or 16 weeks duration had no virus detected in the blood 12 weeks after finishing treatment Overall 98 percent cure rate 97.5% cure rate – GT1-6 treatment naïve patients without cirrhosis after 8 weeks of treatment 98% cure rate with compensated cirrhosis patients Mavyret (glecaprevir/pibrentasvir) [prescribing information]. North Chicago, IL: AbbVie Inc; August 2017.

Dermatology

Crisaborole (Eucrisa®)
Indication: Topical treatment of mild to moderate atopic dermatitis in patients ≥2 years of age Approval Date: December 14, 2016 MOA: Inhibits phosphodiesterase 4 (PDE-4) and results in increased intracellular cyclic adenosine monophosphate (cAMP) levels Exact mechanism not well understood First line treatment for flare ups consists of topical corticosteroids titrated up in potency so that the flare up is managed with the least potent steroid as possible. Second line treatment for moderate to severe atopic dermatitis consists of topical calcineurin inhibitors such as tacrolimus or pimecrolimus. Eucrisa (crisaborole) [prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals Inc; December 2016.

Dosage: Apply a thin film to affected area(s) 2 times daily Adverse Reactions: Application site pain Cost: 2% ointment (60 g tube): $696.00 Eucrisa (crisaborole) [prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals Inc; December 2016.

Clinical Trial Snapshot Trial 1 & 2 (N=1522) Multicenter, double-blind, vehicle-control trials Patients age 2-79 years Randomized to crisaborole or vehicle applied twice daily for 28 days Results: At baseline, 38.5% of the subjects had an Investigator’s Static Global Assessment [ISGA] score of 2 (mild), and 61.5% had an ISGA score of 3 (moderate Trial 1 Trial 2 Day 29 Crisaborole (N=503) Vehicle (N=256) Crisaborole (N=513) Vehicle (N=250) ISGA 0/1 w/2-grade improvement from baseline 32.8% 25.4% 31.4% 18.0% Investigator's Static Global Assessment (ISGA) Eucrisa (crisaborole) [prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals Inc; December 2016.

Dupilumab (Dupixent®)
Indication: Treatment of adult moderate-severe atopic dermatitis Approval Date: March 28, 2017 MOA: Human monoclonal IgG4 antibody targeting IL-4Rα subunit, dual interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokine antagonism which binds to the IL-4Rα subunit and prevents the inflammation induced by IL-4 and IL-13 JP Morgan Healthcare Conference, January 14, 2014 Dupixent (dupilumab) [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals; March 2017.

Dosage: 600 mg then 300 mg subcutaneous every other week Adverse Events: Injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, and other herpes simplex virus infection Precautions: Hypersensitivity, conjunctivitis/keratitis, and comorbid asthma Cost: $3414/monthly for maintenance Safety/efficacy in asthma unknown Dupixent (dupilumab) [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals; March 2017.

Clinical Trial Snapshot SOLO 1 & 2 Trials Multicenter, double-blind, placebo-control phase III trial 16 weeks Patients 18 yrs or older and IGA score ≥3 Randomized to dupilumab 300 mg once weekly OR every 2 weeks OR placebo Results: Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Dupilumab patients had more TCS/TCI and systemic rescue free days SOLO 1, N=671 SOLO 2, N=708 Dupilumab qw Dupilumab q2w Placebo Dupilumab q2w % achieved IGA score 0/1 37 P<0.001 38 10 36 8 % achieved EASI-75 52 51 15 48 44 12 Simpson EL, et al. NEJM. 2016;375:

Clinical Trial Snapshot LIBERTY AD CHRONOS Trial (N=161) Multicenter, double-blind, placebo-control phase III trial 52 week Patients 18 years or older, ISGA score ≥3, EASI score ≥16 Randomized to dupilumab 300 mg once weekly OR every 2 weeks OR placebo PLUS topical corticosteroids Results: Dupilumab patients had more TCS/TCI and systemic rescue free days Dupilumab qw Dupilumab q2w Placebo % achieved ISGA score 0/1 40 P<0.0001 36 13 % achieved EASI-75 64 65 22 Eczema Area and Severity Index (EASI) Blauvelt A, et al. The Lancet, 2017;389:

Oxymetazoline hydrochloride (Rhofade®)
Indication: Treatment of persistent facial erythema associated with rosacea in adults Approval Date: January 19, 2017 MOA: Relatively selective alpha1A-receptor agonist that when applied topically may decrease erythema through direct vasoconstriction Rhofade (oxymetazoline) [prescribing information]. Irvine, CA: Allergan; January 2017.

Dosage: Apply a pea-sized amount to entire face once daily Adverse Reactions: application site dermatitis, worsening inflammatory lesions of rosacea, and application site pruritus, erythema, and pain Precautions: May impact blood pressure, potentiation of vascular insufficiency, and risk of angle closure glaucoma Cost: 1% cream (30 g) $570.00 Alpha-adrenergic agonists as a class may impact blood pressure Rhofade (oxymetazoline) [prescribing information]. Irvine, CA: Allergan; January 2017.

Clinical Trial Snapshot Trial 1 & 2 (N=885) Double-blind, vehicle-controlled trials Randomized to oxymetazoline or vehicle once daily for 29 days Assessed success using the 5-point clinician erythema assessment (CEA) scale and the 5-point subject self-assessment (SSA) scale Success defined as a 2-grade improvement on both CEA and SSA Results: Statistical analyses were not performed on any of the data for these trials (stated on clinicaltrials.gov) - There are alternatives that have been proven to be effective, most of which are available at a cheaper price - Exclude until more complete trial information and statistical analyses are made available Oxymetazoline HCl spray 0.05% Metronidazole Cream 0.75% Azelaic Acid Gel 15% Trial 1 Trial 2 Time-point (hr) Rhofade (N=222) Vehicle (N=218) Rhofade (N=224) (N=221) 3 12% 6% 14% 7% 6 16% 8% 13% 5% 9 18% 9% 12 15% Rhofade (oxymetazoline) [prescribing information]. Irvine, CA: Allergan; January 2017.

Brodalumab (Siliq®) Indication: Treatment of moderate to severe plaque psoriasis in adult patients Approval Date: February 15, 2017 MOA: Humanized IgG2 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor Inhibits the release of proinflammatory cytokines and chemokines Siliq (brodalumab) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; February 2017.

Brodalumab (Siliq®) Dosage: 210 mg subcutaneous at weeks 0, 1, and 2 then 210 mg once every 2 weeks Discontinue if inadequate response after week 12 or 16 Boxed Warning: Suicidal ideation and behavior Adverse Events: arthralgia, headache, fatigue, neutropenia, influenza, and tinea infections Precautions: Infections, tuberculosis, Crohn’s disease, and immunizations Cost: $6300 then $4200/month 4 completed suicides in clinical trials Higher rate of fungal infections Treat latent TB before therapy SILIQ is contraindicated in patients with Crohn’s disease No live immunizations Siliq (brodalumab) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; February 2017.

Clinical Trial Snapshot
Brodalumab (Siliq®) Clinical Trial Snapshot AMAGINE 2 & 3 Trials Multicenter, double-blind, placebo-control phase III Patients with moderate to severe plaque psoriasis Randomized to brodalumab 140 or 210 mg, ustekinumab, or placebo every 2 weeks for 12 weeks Results: 52 week extension Patients on BRO underwent repeat randomization: BRO 210 mg q2wks, 140 mg q2wks, 140 mg q4wks, or 140 mg q8wks Patients on PLB switched to BRO 210 mg q2wks Patients on UST continued UST q12wks Results: AMAGINE 2: 1331 (90%) patients remained in study at week 52 55/300 (18%) of UST received rescue therapy with BRO AMAGIEN 3: 1370 (91%) patients remained in study at week 52 69/313 (22%) of UST received rescue therapy with BRO 210 and 140 mg q2wks was more effective AMAGINE-2 AMAGINE-3 PLB N=309 UST N=300 BRO 140 N=610 BRO 210 N=612 N=315 N=313 N=629 N=624 PASI 75 % (95% CI), p value vs UST 8 (5-12) 70 (65-75) 67 (63-70), 0.33 86 (83-89), 0.08 6 (4-9) 69 (64-74) 69 (65-73), 0.95 85 (82-88), 0.007 sPGA score 0-1 4 (2-7) 61 (55-67) 58 (54-62), 0.49 79 (75-82), <0.001 57 (52-63) 60 (56-64), 0.44 80 (76-83), <0.001 PASI 100 1 (0-2) 22 (17-27) 26 (22-29), 0.08 44 (41-49), <0.001 0.3 (0-2) 19 (14-23) 27 (24-31), 0.007 37 (33-41), <0.001 Psoriasis Area Severity Index (PASI); Static Physicians Global Assessment (sPGA) Lebwohl, M, et al. NEJM, 373:

Guselkumab (Tremfya®)
Indication: Treatment of moderate to severe plaque psoriasis in adult patients Approval Date: July 13, 2017 MOA: Humanized IgG2 monoclonal antibody that selectively binds with the interleukin IL-23 cytokine and inhibits its interaction with the IL-23 receptor Inhibits the release of proinflammatory cytokines and chemokines Tremfya (guselkumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; July 2017.

Dosage: 100 mg subcutaneous at weeks 0 & 4, then every 8 weeks Adverse Reactions: Upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections Precautions: Infections, tuberculosis Cost: $11,620.80/dose $81, annually Tremfya (guselkumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; July 2017.

Clinical Trial Snapshot VOYAGE 1 & 2 Trials Multicenter, double-blind phase III trials Moderate to severe plaque psoriasis Guselkumab 100 mg, adalimumab, or placebo Study design VOYAGE 1 wk12plb switch to gus VOYAGE 2 wk 28 1/3 gus group switched to plb, rest stayed on gus; ada responders switch to placebo and NR to gus VOYAGE 1 VOYAGE 2 Blauvelt, A, et al. J Am Acad Dermatol, 76: Reich K, et al. J Am Acad Dermatol, 76:

Clinical Trial Snapshot VOYAGE 1 VOYAGE 2 Endpoint Guselkumab (N=329) Adalimumab (N=334) Guselkumab (N=496) Adalimumab (N=2) IGA response of 0/1 (cleared or minimal) Week 16, n(%) 280 (85.1) 220 (65.9) 417 (84.1) 168 (67.7) Week 24, n(%) 277 (84.2) 206 (61.7) 414 (83.5) 161 (64.9) Week 48, n(%) 265 (80.5) 185 (55.4) NA IGA response of 0 (cleared) 157 (47.7) 88 (26.3) 215 (43.3) 71 (28.6) 173 (52.6) 98 (29.3) 257 (51.8) 78 (31.5) 166 (50.5) 86 (25.7) PASI 75 response 300 (91.2) 244 (73.1) 428 (86.3) 170 (68.5) 241 (72.2) 442 (89.1) 176 (71.0) 289 (87.8) 209 (62.6) PASI 90 response 241 (73.3) 166 (49.7) 347 (70.0) 116 (46.8) 264 (80.2) 177 (53.0) 373 (75.2) 136 (54.8) 251 (76.3) 160 (47.9) Bold, P < for guselkumab vs. adalimumab Blauvelt, A, et al. J Am Acad Dermatol, 76: Reich K, et al. J Am Acad Dermatol, 76:

Clinical Trial Snapshot NAVIGATE Trial (N=853) Multicenter, double-blind phase III trial Adult patients with moderate to severe plaque psoriasis All patients received ustekinumab at Weeks 0 and 4 At week 16, patients with inadequate response to ustekinumab (n=268) Randomized to continue ustekinumab or guselkumab 100 mg Responders continue ustekinumab (n=585) Results: Higher mean number of visits at which patients had an IGA score of 0 or 1 compared to ustekinumab (1.5 vs 0.7; p<0.001) More patients achieving an IGA score of 0 or 1 compared to ustekinumab (31.1% vs 14.3%; p<0.001) Greater proportions of guselkumab patients achieved PASI75/90/100 Langley RG, et al. Br J Dermatol. Published Online First. [7/21/2017]

Infection Disease

Bezlotoxumab (Zinplava®)
Indication: Reduce recurrence of Clostridium difficile infection (CDI) in patients who are receiving standard-of-care treatment for CDI Approval Date: October 21, 2016 MOA: Human IgG1 monoclonal antibody which binds to C. difficile toxin B and neutralizes it to prevent its toxic effects. A particular concern with the management of CDI is disease recurrence in 20-30% of patients after successful treatment. Patients who have experienced at least one recurrence of CDI are at significantly increased risk of additional recurrences. Bezlotoxumab was originally developed in combination with actoxumab, a monolclonal antibody targeting C. difficile toxin A. Zinplava (bezlotoxumab) [prescribing information]. Whitehouse Station, NJ; Merck & Co, Inc: October 2016.

Dosage: 10 mg/kg single infusion during antibacterial treatment for CDI Pharmacokinetics: Elimination half-life of ~19 days Adverse Reactions: Nausea, pyrexia, and headache Precautions: Exacerbation of heart failure (HF) Cost: 100 kg patient - $ Therefore, the use bezlotoxumab in patients with heart failure should be reserved when the benefit outweighs the risk. Adverse events Serious adverse events Death Negative HF at baseline 22.2% 8.3% 1.6% Positive HF at baseline 30.5% 19.4% 7.1% Zinplava (bezlotoxumab) [prescribing information]. Whitehouse Station, NJ; Merck & Co, Inc: October 2016.

Clinical Trial Snapshot MODIFY 1 & 2 Trials (N=2655) Multicenter, double-blind, placebo control trials Adults with primary or recurrent C. difficile infections Randomized to single dose bezlotoxumab (10 mg/kg), actoxumab plus bezlotoxumab (10 mg/kg), or placebo MODIFY 1 included actoxumab 10 mg/kg arm [data suggest lack of efficacy and not included in MODIFY 2] Also received standard-of-care antibiotics (metronidazole, vancomycin, or fidaxomicin) for 10 to 14 days Wilcox MH, et al. NEJM. 2017;376:

Clinical Trial Snapshot Clinical cure of the initial episode of CDI occurred in about 80% of patients treated with bezlotoxumab or placebo Incidence of sustained cure through 12 weeks was significantly higher with bezlotoxumab than with placebo in MODIFY II (67% vs 52%), but not in MODIFY I (60% vs 55%) Wilcox MH, et al. NEJM. 2017;376:

Clinical Trial Snapshot Goldstein, et al (N=295) 12 month extension trial for MODIFY 2 295/996 (30%) who completed the main 12-week study entered the extension phase Results: Goldstein, et al. ASM Microbe June 16-20, Boston, MA.

Delafloxacin (Baxdela®)
Indication: Treatment of acute bacterial skin and skin structure infections Approval Date: June 19, 2017 MOA: Inhibits DNA gyrase (topoisomerase II) and topoisomerase IV enzymes Unique Characteristics: No issue with QTc interval or other cardiac events and phototoxicity Activity is enhanced in acidic conditions Indeed, delafloxacin is > 8 times more potent than moxifloxacin against S. aureus at pH 5.5; however, at a higher pH the difference decreases. Baxdela (delafloxacin) [prescribing information]. Lincolnshire, IL: Melinta Therapeutics Inc; June 2017.

Dosage: Oral – 450 mg every 12 hours for 5 to 14 days IV – 300 mg every 12 hours for 5 to 14 days Renal adjustments: GFR 15 – 29 mL/min: IV 200 mg every 12 hours GFR <15 mL/min: use not recommended Adverse Reactions: Nausea, diarrhea, headache, transaminase elevations and vomiting Cost: Not currently available Baxdela (delafloxacin) [prescribing information]. Lincolnshire, IL: Melinta Therapeutics Inc; June 2017.

Clinical Trial Snapshot Study 1 (N=660) Multicenter, double-blind trial Patient with acute bacterial skin and skin structure infections Randomized to IV delafloxacin 300 mg q12 hr OR vancomycin plus aztreonam Study 2 (N=850) Randomized to IV delafloxacin 300 mg q12 hr (6 doses) then oral 450 mg q12 hr OR vancomycin plus aztreonam Baxdela (delafloxacin) [prescribing information]. Lincolnshire, IL: Melinta Therapeutics Inc; June 2017.

Clinical Trial Snapshot Clinical Response at hours Study 1 Study 2 Treatment Difference (95% CI) Delafloxacin (300 mg IV) N=331 Vancomycin + Aztreonam N=329 Delafloxacin (300 mg IV and 450 mg Oral) N=423 N=427 Objective clinical response, n(%) 259 (78.2) 266 (80.9) -2.6 (-8.8, 3.6) 354 (83.7) 344 (80.6) 3.1 (-2, 8.3) Investigator-assessed success, n(%) 270 (81.6) 274 (83.3) -1.7 (-7.6, 4.1) 369 (87.2) 362 (84.8) 2.5 (-2.2, 7.2) Both IV and oral Baxdela monotherapy was statistically non-inferior to the combination of vancomycin plus aztreonam at the FDA primary endpoint of early clinical response at hours Baxdela (delafloxacin) [prescribing information]. Lincolnshire, IL: Melinta Therapeutics Inc; June 2017.

Cardiology

Betrixaban (Bevyxxa®)
Indication: Prophylaxis of VTE in adults hospitalized for an acute medical illness who are at risk for thromboembolic complications Approval Date: June 23, 2017 MOA: Factor Xa (FXa) inhibitor, selectively blocks the active site of Fxa, decreases thrombin generation (TG) Bevyxxa (betrixaban) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; June 2017.

Dosage: 160 mg as a single dose on day 1, followed by 80 mg once daily for 35 to 42 days CrCl mL/min: reduce dose by 50% Adverse Reactions: Bleeding Precautions: Risk of bleeding, severe renal impairment, concomitant P-gp inhibitors Cost: Not currently available Bevyxxa (betrixaban) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; June 2017.

Clinical Trial Snapshot APEX Trial (N=7513) Multicenter, double-blinded, active-control trial Patients 40 years or older hospitalized for at 96 hours for acute medical illness with reduced mobility or risk factors for VTE Randomized to enoxaparin 40 mg daily 10±4 days plus oral placebo OR enoxaparin placebo daily 10±4 days plus oral betrixaban 160 mg then 80 mg for days Analyses performed on different cohorts Cohort 1: elevated D-dimer level Cohort 2: age 75 years or older Cohen AT, et al. NEJM. 2016;375:

Clinical Trial Snapshot APEX Trial (N=7513) Results: Bevyxxa reduced the incidence of DVT and PE blood clots compared with those taking enoxaparin plus placebo (4.4 percent vs. 6.0 percent) with no significant increase in major bleeding (0.67 percent vs percent). The most frequent reason for treatment discontinuation was bleeding, with an incidence rate for all bleeding episodes of 2.4 percent and 1.2 percent for betrixaban and enoxaparin, respectively Cohen AT, et al. NEJM. 2016;375:

Immunology

Sarilumab (Kevzara®) Indication: Treatment of moderate to severe active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more DMARDs Approval Date: May 22, 2017 MOA: Inhibitor of interleukin-6 (IL-6) mediated signaling through sIL-6R and mIL-6R, leads to reduction in CRP levels Kevzara (sarilumab) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; May 2017.

Sarilumab (Kevzara®) Dosage: 200 mg subcutaneous every 2 weeks
Adverse Reactions: Neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections Precautions: Serious infections, lab abnormalities, GI perforation, live vaccines Cost: $43,200 annually Do not use during active infection Neutropenia, thrombocytopenia, increases LFTs, lipid abnormalities GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids Kevzara (sarilumab) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; May 2017.

Sarilumab (Kevzara®) Clinical Trial Snapshot Genovese et al. (N=1197) Moderate to severe RA Sarilumab 200 or 150 mg OR placebo q2wks Concomitant MTX Results: DAS28-CRP <2.6 (remission) at 24 weeks Sarilumab 200 mg: 33.1% Sarilumab 150 mg: 37.8% Placebo:20% DAS28-CRP <2.6 (remission) at 52 weeks Sarilumab 200 mg: 55.6% Sarilumab 150 mg: 47.8% Placebo:38.7% Sarilumab resulted in less radiographic progression of damage compared to placebo Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) Genovese MC, et al. Arthritis Rheumatol. 2015;67:

Sarilumab (Kevzara®) Clinical Trial Snapshot TARGET Trial (N=546) Moderate to severe RA Sarilumab 200 or 150 mg OR placebo q2wks Concomitant methotrexate Results: Statistically significant improvements in ACR 20/50/70 at 24 weeks compared to placebo Statistically significant improvements in DAS28-CRP and greater proportion achieved remission (DAS28-CRP <2.6) compared to placebo Statistically significant and clinically relevant improvements in physical function compared with placebo Fleischmann R, et al. Arthritis Rheumatol. 2017;69:

Sarilumab (Kevzara®) Clinical Trial Snapshot MONARCH Trial (N=369) Moderate to severe RA Sarilumab 200 mg or adalimumab 40 mg q2wks Results: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001) Statistically significant improvements in ACR 20/50/70 response rates compared to adalimumab Greater proportion achieved remission compared to adalimumab (7.1% vs 2.7%; p=0.0468) Neutropenia occurred more frequently with sarilumab compared to adalimumab but no significant difference in infection rates Burmester GR, et al. Ann Rheum Dis. Published Online First: [11/17/2016].

Endocrinology

Dapagliflozin/saxagliptin (Qtern®)
Indication: Improve glycemic control in adults with type 2 diabetes mellitus (T2DM) Approval Date: February 28, 2017 MOA: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor Dapagliflozin/saxagliptin (Qtern) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP ; February 2017.

Dosage: 10 mg dapagliflozin/5 mg saxagliptin tablet once daily Discontinue if GFR <60 mL/min Adverse Reactions: Upper respiratory tract infection, urinary tract infection, and dyslipidemia Precautions: Pancreatitis, heart failure, hypotension, ketoacidosis, AKI, UTI, hypoglycemia, increased LDL, bladder cancer Cost: Not currently available Dapagliflozin/saxagliptin (Qtern) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP ; February 2017.

Clinical Trial Snapshot Combination of saxagliptin and dapagliflozin with metformin versus placebo Statistically significant reductions in HbA1c in comparison to patients treated with placebo Combination of saxagliptin and dapagliflozin added to metformin versus saxagliptin or dapagliflozin alone added to metformin Statistically superior reductions in HbA1c in comparison to patients treated with single agent plus metformin Dapagliflozin/saxagliptin (Qtern) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP ; February 2017.

Etelcalcetide (Parsabiv®)
Indication: Treatment of secondary hyperparathyroidism (HPT) in adults with chronic kidney disease (CKD) on hemodialysis Approval Date: February 8, 2017 MOA: Synthetic peptide calcimimetic, activates the calcium-sensing receptor (CaSR) on the parathyroid gland, resulting in decreased PTH secretion PARSABIV has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with CKD who are not on hemodialysis and is not recommended for use in these populations Etelcalcetide is an injectable calcimimetic with a longer elimination half-life than cinacalcet. The injectable formulation improves adherence and reduces pill burden, while the frequency of gastrointestinal adverse events has been comparable between cinacalcet and etelcalcetide. The longer half-life of etelcalcetide reduces the fluctuation of biochemical markers of mineral and bone metabolism, but it remains to be determined whether such a sustained effect results in improved outcomes. Parsabiv (etelcalcetide) [prescribing information]. Thousand Oaks, CA: Amgen Inc; February 2017.

Dosage: 5 mg IV bolus 3 times weekly following hemodialysis Maximum maintenance dose – 15 mg 3 times weekly Minimum maintenance dose – 2.5 mg 3 times weekly Adverse Reactions: Hypocalcemia, muscle spasms, diarrhea, nausea, vomiting, headache, and paresthesia Precautions: Hypocalcemia (sometimes severe), worsening heart failure, upper GI bleeding, and adynamic bone Cost: Anticipated availability is currently undetermined Hypocalcemia – QT prolong and arrhythmias, seizures HF- monitor not limitation for use, MOA not well known GI bleeding- 2 patients in the active group, exact cause known Parsabiv (etelcalcetide) [prescribing information]. Thousand Oaks, CA: Amgen Inc; February 2017.

Clinical Trial Snapshot Study 1 & 2 (N=1023) CKD patients with secondary hyperparathyroidism receiving hemodialysis IV etelcalcetide thrice weekly (max dose 15 mg) PTH target < 300 pg/mL Results: >30% reduction from baseline in PTH during the etelcalcetide: 77% versus 11% in Study 1, and 79% versus 11% in Study 2 PTH levels of 300 pg/mL or less during the etelcalcetide: 52% versus 6% in Study 1, and 56% versus 5% in Study 2 Parsabiv (etelcalcetide) [prescribing information]. Thousand Oaks, CA: Amgen Inc; February 2017.

Clinical Trial Snapshot Block et al (NCT ) (N=683) Randomized, double-blind, active-control trial IV etelcalcetide vs oral cinacalcet for 26 weeks Results: >30% reduction in PTH from baseline Etelcalcetide (68.2%) Cinacalcet (57.7%) P for noninferiority, <0.001; P for superiority, 0.004 Etelcalcetide treated patients achieved lower calcium and phosphate concentrations at week 26 Heart failure events: 10 (3%) etelcalcetide: 5(serious) 2 (0.6%) cinacalcet: 1 (serious) Predialysis PTH >500 pg/mL The median average weekly etelcalcetide dose during the efficacy assessment phase was 15.0 mg (interquartile range [IQR], mg) and the median average daily cinacalcet dose was 51.4 mg (IQR, mg). >50% reduction: 52.4% ete and 40.2% cina Etelcalcetide also yielded more potent reductions in serum concentrations of the phosphatonin FGF23 and 2 markers of high-turnover bone disease However, self-reported symptoms of nausea and vomiting were not significantly different between the 2 randomized groups. longer-term safety data will be required Block GA, et al. JAMA; 317:

Gastroenterology

Plecanatide (Trulance®)
Indication: Treatment of chronic idiopathic constipation in adult patients Approval Date: January 19, 2017 MOA: Plecanatide and its active metabolite bind and agonize guanylate cyclase-C on the luminal surface of intestinal epithelium, intestinal fluid increases and GI transit time is increased Same class as linaclotide (Linzess®) Trulance (plecanatide) [prescribing information]. New York, NY: Synergy Pharmaceuticals; January 2017.

Dosage: 3 mg once daily Can be crushed Boxed Warning: Risk of serious dehydration in pediatric patients Adverse Reactions: Diarrhea, abdominal distension and tenderness, flatulence and increases in ALT and AST Cost: $424.17/ 30 tablets Trulance (plecanatide) [prescribing information]. New York, NY: Synergy Pharmaceuticals; January 2017.

Clinical Trial Snapshot Miner et al (N=1394) Multicenter, double-blind, placebo-controlled trial Randomized to plecanatide 3 or 6 mg or placebo daily for 12 weeks Results: Placebo Plecanatide 3 mg Plecanatide 6 mg % of durable overall CSBM responders 10.2 21† 19.5† Increase in mean weekly CSBM frequency from baseline 1.2 2.5† 2.2† Increase in mean weekly SBM frequency from baseline 1.3 3.2† 3.1† Complete Spontaneous Bowel Movement (CSBM) † P<0.001 Miner PB, et al. Am J Gastroenterol. 2017;112:

Telotristat etiprate (Xermelo®)
Indication: Treatment of carcinoid syndrome diarrhea (in combination with somatostatin analog therapy) in adults with symptoms inadequately controlled by somatostatin analog therapy Approval Date: February 28, 2017 MOA: Inhibits tryptophan hydroxylase (TPH), TPH is the rate-limiting enzyme in serotonin synthesis, reducing the frequency of carcinoid syndrome diarrhea Carcinoid syndrome is a cluster of symptoms that can develop in patients with metastatic neuroendocrine tumors (mNETs) and the related diarrhea results from the overproduction of serotonin by these tumors. Somatostatin analogs usual treatment (TPH converts tryptophan to 5-hydroxytryptophan and will finally be converted to serotonin. TPH is the rate-limiting enzyme in serotonin synthesis.) Xermelo (telotristat ethyl) [prescribing information]. The Woodlands, TX: Lexicon Pharmaceuticals Inc; February 2017.

Dosage: 250 mg by mouth three times daily Can use with octreotide: administer octreotide at least 30 minutes after Adverse Reactions: Headache and nausea Cost: $ per month Loperamide: <$40/month and Ondansetron: ~$2500/month Xermelo (telotristat ethyl) [prescribing information]. The Woodlands, TX: Lexicon Pharmaceuticals Inc; February 2017.

Clinical Trial Snapshot TELESTAR Trial (N=135) Double-blind, placebo-controlled phase III trial 12 weeks, additional 24 weeks open-label extension Patients with 4-12 bowel movements/day on somatostatin analogs 1:1:1 randomization to placebo, telotristat etiprate 250 mg or 500 mg Results: Statistically significant decrease in bowel movements/day (placebo= -0.9, 250mg dose= -1.7, 500mg dose= -2.1) p<0.001 Odds Ratio: 250 mg: 3.49 (95% CI, 1.33 to 9.16) and 500 mg: 3.11 (95% CI, 1.20 to 8.10) Statistically significant reductions in u5-HIAA levels for both telotristat etiprate doses compared to placebo Serotonin is metabolized into 5-hydyroxyindoleacetic acid (5-HIAA), a biomarker measurable in the urine and often used to follow treatment response in patients with carcinoid syndrome In clinical trials, some patients treated with a higher than recommended dosage of telotristat developed severe constipation, Antidiarrheal agents, such as loperamide and/or diphenoxylate-atropine (Lomotil), can be used for control of refractory diarrhea. For more severe diarrhea, the opiates paregoric and tincture of opium may be prescribed. A few reports demonstrate that serotonin receptor antagonists, such as ondansetron, can alleviate diarrhea in patients with the carcinoid syndrome in whom treatment with somatostatin analogs is not successful Kulke MH, et al. J Clin Oncol. 2017;35:14-23.

Naldemedine (Symproic®)
Indication: Treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain Approval Date: March 23, 2017 MOA: Functions as a peripherally acting mu-opioid receptor antagonist, decrease the constipating effects of opioids Alvimopan Methylnaltrexone Naloxegol Symproic (naldemedine) [prescribing information]. Stamford, CT: Purdue Pharma; August 2017.

Dosage: 0.2 mg by mouth daily Adverse Reactions: Abdominal pain, diarrhea, and nausea Precautions: Gastrointestinal Perforations: reported with use of other peripherally acting opioid antagonist agents Opioid Withdrawal: patients with disruptions to the blood-brain barrier at increased risk Cost: Not available Symproic (naldemedine) [prescribing information]. Stamford, CT: Purdue Pharma; August 2017.

Clinical Trial Snapshot COMPOSE 1 & 2 Trials (N=1100) Multicenter, double-blind, phase III trials Patients with stable opioid regimen (≥30 mg morphine equivalent) for ≥1 month Randomized to receive naldemedine 0.2 mg or placebo for 12 weeks Results: COMPOSE 1 COMPOSE 2 Treatment Difference (95% CI) Naldemedine (N=273) Placebo (N=272) Naldemedine (N=276) Placebo (N=274) Responders, n(%) 130 (48) 94(35) 13 (5, 21) p=0.002 145 (53) 92 (34) 19 (11,27) P<0.0001 Hale M, et al. Lancet Gastroenterol Hepatol. 2017;2:

Musculoskeletal

Ocrelizumab (Ocrevus®)
Indication: Treatment of relapsing or primary progressive forms of multiple sclerosis (PPMS) in adult patients Approval Date: March 28, 2017 MOA: Selectively targets and binds to the cell surface to deplete CD20 expressing B-cells through antibody-dependent cell-mediated phagocytosis and cytotoxicity, as well as complement-mediated cytolysis RMS is the most common form of the disease and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of full or partial recovery. PPMS is a debilitating form of the disease marked by steadily worsening symptoms but typically without distinct relapses or periods of remission. Themswire.com Ocrevus (ocrelizumab) [prescribing information]. South San Francisco, CA: Genetech, Inc; March 2017.

Dosage: Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion Subsequent doses: 600 mg intravenous infusion every 6 months Adverse Reactions: RMS: Upper respiratory tract infections and infusion reactions PPMS: Upper/lower respiratory tract infections, infusion reactions, and skin infections Precautions: Infusion reactions, infections, and malignancies Cost: $19,500/300 mg Infusion reactions: first time highest (pre-medicate to reduces likelihood) Infections: Respiratory, herpes, Progressive Multifocal Leukoencephalopathy (not seen in clinical trials but can happen with CD20), HepB Malignancies: breast cancer Ocrevus (ocrelizumab) [prescribing information]. South San Francisco, CA: Genetech, Inc; March 2017.

Clinical Trial Snapshot ORATORIO Trial (N=732) Age with PPMS Randomized to receive IV ocrelizumab 600mg or placebo Results: Fewer patients had disability progression confirmed at 12 weeks compared to placebo (32.9 vs 39.3%; HR 0.76 (0.59,0.98) RRR 24%; p=0.03) Fewer patients had disability progression confirmed at 24 weeks compared to placebo (29.6 vs 35.7%; HR 0.75 (0.58,0.98) RRR 25%; p=0.04) At week 120, total volume of brain lesions decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001) Overall rates of adverse effects did not differ Montalban X, et al. NEJM. 2017;376:

Clinical Trial Snapshot OPERA 1 & 2 Trials (N=1656) Age with RMS Randomized to receive IV ocrelizumab 600mg q24wks or interferon beta-1a 44 mcg three times weekly Results: Annualized relapse rate was lower with ocrelizumab vs interferon beta-1a OPERA 1: 0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001 OPERA 2: 0.16 vs. 0.29; 47% lower rate; P<0.001 Fewer patients had disability progression confirmed at 12 and 24 weeks compared to interferon beta-1a Mean number of MRI confirmed throughout week 96 OPERA 1: 94% lower number of lesions with ocrelizumab, P<0.001 OPERA 2: 95% lower number of lesions, P<0.001 More infusion reactions with Ocrevus Hauser SL, et al. NEJM. 2017;376:

Abaloparatide (Tymlos®)
Indication: Treatment of postmenopausal women with osteoporosis at high risk for fracture Approval Date: April 28, 2017 MOA: Analog of human parathyroid hormone peptide, stimulates of osteoblast function and increased bone mass Teriparatide Tymlos (abaloparatide) [prescribing information]. Waltham, MA: Radius Health; April 2017.

Dosage: 80 mcg subcutaneous once daily Supplied in prefilled pen that delivers 30 daily doses Boxed Warning: Risk of osteosarcoma Adverse Reactions: Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo Precautions: Orthostatic hypotension, hyperca;cemia, and hypercalciuria Cost: $1950/month Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended Forteo: ~$3500 Tymlos (abaloparatide) [prescribing information]. Waltham, MA: Radius Health; April 2017.

ACTIVE Trial (N=2463) Mutlicenter, double-blind, phase III trial Randomized to daily blinded abaloparatide 80 mcg or placebo or open-labeled teriparatide 20 mcg for 18 months Results: Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. Patients w/fracture, n(%) Aba v Plb Aba v Ter Ter v Plb Aba Plb Ter HR P value Vertebral fracture 4 (0.6) 30 (4.2) 6 (0.8) RR, 0.14 (0.05, 0.39) <0.001 --- RR, 0.2 (0.08, 0.47) Nonvertebral fracture 18 (2.7) 33 (4.7) 24 (3.3) 0.57 (0.31, 1) 0.049 0.79 (0.43, 1.45) 0.44 0.72 (0.42, 1.22) 0.22 Clinical fracture 27 (4) 49 (8.3) 35 (4.8) (0.35, 0.91) 0.02 0.81 (0.49, 1.33) 0.40 0.71 (0.46, 1.09) 0.11 Miller PD, et al. JAMA. 2016;316:

ICER Comparative Effectiveness: Vertebral Fractures Relative Risk Abaloparatide 80mcg 0.76 ( ) Teriparatide 20mcg 0.44 ( ) 0.57 ( ) ZA 5mg 0.13 ( ) 0.17 ( ) 0.30 ( ) Placebo Exclude both abaloparatide and teriparatide. The drugs would have to be discounted by at least 59% to reach cost effectiveness at any reasonable cost/QALY. ICER Comparative Effectiveness: Nonvertebral Fractures Relative Risk Abaloparatide 80mcg 0.83 ( ) Teriparatide 20mcg 0.69 ( ) 0.82 ( ) ZA 5mg 0.51 ( ) 0.61 ( ) 0.75 ( ) Placebo CTAF ICER Anabolic Therapies for Osteoporosis in Postmenopausal Women: Effectiveness and Value 7/17/17

Neurology

Deutetrabenazine (Austedo®)
Indication: Treatment of chorea associated with Huntington’s disease Approval Date: April 3, 2017 MOA: Causes reversible reduction of dopamine release by selectively inhibiting pre-synaptic vesicular monoamine transporter type 2 (VMAT2); decreasing the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and depleting the monoamine stores. Deuteration reduces the breakdown of active metabolites A rare and fatal neurodegenerative disorder, HD affects more than 35,000 people in the United States. Chorea – involuntary, random and sudden, twisting and/or writhing movements – is one of the most striking physical manifestations of this disease and occurs in approximately 90% of patients. “Chorea is a major symptom for many living with Huntington disease. It impacts patients’ functionality and activities of daily living, and there have been limited treatment options for these patients Austedo (deutetrabenazine) tablets [prescribing information]. North Wales, PA; Teva Pharmaceuticals USA, Inc, April 2017.

Dosage: Initially, 6 mg daily; increase dose weekly by 6 mg up to maximum of 48 mg/day Conversion from tetrabenazine: See package insert Therapy interrupted for >7 days: Retitrate Boxed Warning: Increased risk of depression and suicidal thoughts Adverse Reactions: Drowsiness, diarrhea, dry mouth, and fatigue Precautions: Neuroleptic malignant syndrome, parkinsonism, somnolence Cost: $11, /month (48 mg max dose) Doses >12mg dosed BID CYD2D6 inhibitors max daily dose 36 mg Austedo (deutetrabenazine) tablets [prescribing information]. North Wales, PA; Teva Pharmaceuticals USA, Inc, April 2017.

Clinical Data Snapshot Huntington Study Group Trial (N=90) Multicenter, randomized, double-blind, placebo control trial 90 ambulatory patients with baseline total maximal chorea score ≥8 Received either deutetrabenzine or placebo for 12 weeks Results: Statistically significant improvement in total maximal chorea; mean between-group difference was -2.5 units (95% CI, –3.7 to –1.3) (P < .001) Significant more patients in deutetrabenzine group reported success by the PGIG scale compared to placebo (51% vs 20%; treatment difference 31.3; 95% CI, , P=0.002) Similar improvements in CGIC scale and SF-36 subscale No significant difference in Berg Balance Test Chorea score rangings from 0-28 improvements in patient-centered end points, such as PGIC and SF-36 physical functioning component scales Although there was no improvement in balance, there was also no worsening in the measures of gait, which is meaningful since worsened balance is a potential adverse effect of lower dopamine effect induced by neuroleptics or vesicular monoamine transporter inhibitors. Huntington Study Group, et al. JAMA. 2016;316:40-50.

Valbenazine (Ingrezza®)
Indication: Treatment of adults with tardive dyskinesia Approval Date: April 11, 2017 MOA: Causes reversible reduction of dopamine release by selectively inhibiting pre-synaptic vesicular monoamine transporter type 2 (VMAT2); alleviating the symptoms associated with dopamine hypersensitivity Alternatives: Off-label use: benztropine, propranolol, clonidine, pramipexole, tetrabenazine, ropinirole, trihexyphenidyl, deutetrabenazine Tardive dyskinesia (TD) is a disorder that results in involuntary, repetitive body movements.[1] This may include grimacing, sticking out the tongue, or smacking of the lips. TD is associated with treatments that block dopamine receptors in the brain, such as antipsychotics and other medications. In patients with TD, these treatments are thought to result in irregular dopamine signalling in one of the regions of the brain that controls movement. Because antipsychotic drugs are dopamine-receptor antagonists, abnormalities in dopamine signaling (e.g., the supersensitivity of postsynaptic dopamine receptors after prolonged administration of antipsychotic agents) have long been suspected to cause tardive dyskinesia. The finding that valbenazine inhibits vesicular monoamine transporter 2 (VMAT2) was therefore important in the early stages of development of the drug. VMAT2 transports dopamine from the cytosol into synaptic vesicles and ultimately sustains the ability of presynaptic neurons to engage in synaptic neurotransmission Davis MC, et al. NEJM. 2017; 376: Ingrezza (valbenazine) [prescribing information]. San Diego, CA: Neurocrine Biosciences Inc; April 2017.

Dosage: 40 mg once daily can increase to 80 mg once daily in one week Dosage adjustment Strong CYP3A4 inducer ---- use not recommended Strong CYP3A4 inhibitor mg once daily maximum dose Strong CYP2D6 inhibitor dose reduction may be necessary Renal/Hepatic Impairment Dosing CrCl <30 mL/min ---- use not recommended Child-Pugh class B/C mg once daily Adverse Reactions: somnolence and QT prolongation (not clinically significant at concentrations expected with recommended dosing Precautions: Somnolence and QT prolongation Cost: 40 mg - $6,330/month • Deutetrabenazine mean total daily dose was 38.8 mg/d ($9,568.08/month) • Tetrabenazine mean total daily dose was 57.9 mg/d ($10,512.32/month) Ingrezza (valbenazine) [prescribing information]. San Diego, CA: Neurocrine Biosciences Inc; April 2017.

Clinical Data Snapshot KINECT 3 Trial (N=234) Multicenter, double-blind, placebo control, phase III trial Randomized to valbenazine 40 or 80 mg OR placebo once daily At 6 weeks, placebo group was re-randomized to either valbenazine 40 or 80 mg once daily Therapy was stopped at week 48 and analysis occurred at week 52 Results: LS mean change from Baseline to week 6 in AIMS dyskinesia score was: 80mg: −3.2 vs −0.1 placebo group (P<.001) 40 mg: −1.9 vs −0.1 placebo group; (P=.002) Reduction in AIMS dyskinesia score continued during week 12-48 At week 52, score increased following discontinuation Hauser RA, et al. Am J Psychiatry. 2017;174:

Clinical Data Snapshot At the end of week 6, participants receiving 80 mg of valbenazine had a significantly greater reduction in tardive dyskinesia scores than those receiving placebo (-3.2 vs -0.1; P<0.0001) and 40 mg compared to placebo (-1.9 vs -0.1; p=0.002). During the extension period, all participants received 40 or 80 mg per day of valbenazine, and the persistence of improvement in tardive dyskinesia scores supported the efficacy of the 80-mg dose. This efficient trial design, coupled with the use of blinded central video raters, allowed the study to determine the durability of valbenazine’s efficacy. Furthermore, most patients had had a recurrence of symptoms when assessed 4 weeks after completing treatment. This trial thus supported the assessment of a sustained clinical outcome through judicious use of multiple design elements — such as crossover from placebo to active treatment, dose comparison, rater evaluation of withdrawal, and well-blinded AIMS rating — and highlighted the utility of remote assessment in clinical trials Davis MC, et al. NEJM. 2017;376:

ARM-TD Trial (N=117) Multicenter, double-blind, placebo control trial Randomized to deutetrabenazine or placebo once daily fro 12 weeks Results: LS mean change from Baseline to week 12 in AIMS dyskinesia score was: Deutetrabenazine: −3.0 vs −1.6 placebo group (treatment difference -1.4, P=0.019) Clinical Data Snapshot Fernandez HH, et al. Neurology. 2017;88:

Edaravone (Radicava®)
Indication: Treatment of amyotrophic lateral sclerosis (ALS) Approval Date: May 5, 2017 MOA: Free radical and peroxynitrite scavenger that prevents oxidative damage to cell membranes and may contribute to inhibiting the progression of ALS Radicava (edaravone) [prescribing information]. Jersey City, NJ: MT Pharma America Inc; May 2017.

Dosage: Initial cycle: 60 mg IV once daily for 14 days, followed by a 14-day drug-free period Subsequent cycles: 60 mg IV once daily for 10 days within a 14-day period, followed by a 14-day drug-free period 60 minute infusion Adverse Reactions: Contusion, gait disturbance, and headache Cost: 30 mg - $651.60 ~$18,000/month Radicava (edaravone) [prescribing information]. Jersey City, NJ: MT Pharma America Inc; May 2017.

Clinical Trial Snapshot Edaravone ALS Study Group Trial (N=137) Double-blind, parallel-group, placebo-control trial Japanese patients with ALS Functionality retained most ADLs, normal respiratory function, disease 2 or less years Randomized to edaravone 60 mg or placebo for 6 months Results: LS mean change from Baseline to week 24 in ALSFRS-R score was: −5.01 edaravone vs −7.5 placebo group (treatment difference 2.49; 95% CI , P=0.0013) Writing Group; Edaravone (MCI-186) ALS 19 Study Group, et al. Lancet Neurol. 2017;16:

Safinamide (Xadago®) Indication: Adjunctive treatment to levodopa/carbidopa in patients with Parkinson disease (PD) experiencing "off" episodes Not for monotherapy Approval Date: March 21, 2017 MOA: Inhibitor of MAO-B, blocking the catabolism of dopamine Safinamide more selective for MAO-B vs MAO-A (1000-fold) than selegiline (127-fold) and rasagiline (103-fold) Reduces diet restrictions MAO-B inhibition is reversible Better clinical manageability and limiting possible drug–drug interactions Xadago (safinamide) [prescribing information]. Louisville, KY: US WorldMeds; June 2017. Kulisevsky J. Eur Neurol Rev. 2017;9:

Safinamide (Xadago®) Dosage: 50 mg once daily, can increase up to 100 mg daily in 2 weeks Adverse Reactions: Dyskinesia, fall, nausea, and insomnia Contraindications: Other MAO inhibitors, opioids, SNRIs, tricyclic antidepressants, cyclobenzaprine, methylphenidate, amphetamine, St. John's wort Cost: 50 and 100 mg - $ (30) Xadago (safinamide) [prescribing information]. Louisville, KY: US WorldMeds; June 2017.

Safinamide (Xadago®) Clinical Trial Snapshot Borgohain et al (N=669) Multicenter, double-blind, placebo-control, phase III trial Randomized to safinamide 100 or 50 mg daily or placebo for 24 weeks Results: Significant difference in mean total “on” time with both safinamide groups compared to placebo Significant improvements in motor scores with both safinamide groups compared to placebo No significant between-group differences with treatment-emergent adverse events When compared to placebo, safinamide does show significant improvement in motor function with minimal adverse events. There are a lot of other options in drug therapy for this indication, especially for the attenuation of OFF phenomena. Safinamide was particularly efficacious in combination with levodopa but was shown to be safer and have a better side effect profile than that of levodopa and the dopamine agonists. This may be an advantage of safinamide use if it allows the reduction of levodopa and dopamine agonist dosing in the treatment of PD patients. Future clinical trials need to be done comparing safinamide with other MAOis such as rasagiline or selegiline to determine its place in therapy Borgohain R, et al. Movement Disorders. 2014;29:

Safinamide (Xadago®) SETTLE Trial (N=549) Multicenter, double-blind, placebo-control, phase III trial Randomized to safinamide daily or placebo for 24 weeks Results: Similar results as Study 016 0.96 hour improvement from placebo Did not reach significance for improvement in motor scores Clinical Trial Snapshot NS P=0.05 and change Schapira HV, et al. JAMA Neurology. 2017;74:

Oncology

Rucaparib (Rubraca®) Indication: Treatment of advanced ovarian cancer in patients with deleterious BRCA mutation (germline and/or somatic) who have been treated with two or more chemotherapies Approval Date: December 19, 2016 MOA: Inhibits poly (ADP-ribose) polymerase (PARP) enzymes, which play a role in DNA repair, resulting in DNA damage, apoptosis, and cell death Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; February 2017.

Rucaparib (Rubraca®) Doseage: 600 mg twice daily
Available in multiple tablet strengths (200, 250, and 300 mg) Dose reductions for toxicities Adverse Reactions: Nausea, fatigue, anemia, vomiting, decreased appetite, thrombocytopenia Increase SCr, ALT, AST, cholesterol and pancytopenia Cost: $8244/month or ~$100,000 annually Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; February 2017.

Rucaparib (Rubraca®) Clinical Trial Snapshot Study 1 & 2 (N=106) Two multicenter, single arm, open label trials 100% had an ECOG performance status of 0 or 1 and all had received at least 2 prior platinum-based chemotherapies Rucaparib 600 mg twice daily Results: Investigator-assessed Objective response rate: 54% (complete response 9%; partial response 45% Median duration of response: 9.2 (6.6, 11.6) Independent radiology review Objective response rate: 42% Median duration of response: 6.7 (5.5, 11.1) Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; February 2017.

Ribociclib (Kisqali®)
Indication: Treatment of advanced or metastatic hormone receptor-positive, breast cancer Used in combination with an aromatase inhibitor Approval Date: March 13, 2017 MOA: Cyclin-depended kinase inhibitor specifically for 4 and 6 to block retinoblastoma protein phosphorylation and prevents progression through the cell cycle at G1 phase Same as palbociclib (Ibrance) Ribociclib being a CDK4 and 6 inhibitor seems to inhibit the growth of the breast cancer cells by partly preventing the phosphorylation of the Rb protein, needed for the cell to pass the G1/S checkpoint see G1/S transition as part to cell proliferation. Kasqali (ribociclib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; March 2017.

Dosage: 600 mg by mouth Once daily for 21 days, 7 days off Can dose adjust down to 200 mg for toxicities Adverse Reactions: Peripheral edema, nausea, vomiting, neutropenia, leukopenia, decrease platelet count, alopecia Precautions: QT prolongation, neutropenia and hepatobiliary toxicity Cost: 600 mg dose - $13, per month ~$250/tablet QT Prolong = day 14 of 1st cycle and before every cycle for the 1st 6 cycles Monitor Kasqali (ribociclib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; March 2017.

Clinical Trial Snapshot MONALEESA-2 (N=668) Multicenter, double-blind, placebo-control phase III trial Randomized to ribociclib 600mg plus letrozole or placebo plus letrozole Median f/u: 15.3 months Results: PFS significantly longer with ribociclib group Hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10−6 for superiority PFS at 18 months: (63% ribociclib and 42.2% placebo) OS not nature Safety – more neutropenia, anemia, and increases in ALT and AST w/ribociclib locally confirmed, HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease Eastern Cooperative Oncology Group performance status22 of 0 or 1 (on a 5-point scale on which a higher score indicates greater disability) and adequate bone marrow and organ function 44% lower relative risk of progression Median duration of progression-free survival was not reached in the ribociclib group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group Neutropenia ribociclib 74.3% vs 5.2 Hortobagyi GN, et al. NEJM; 375:

Neratinib (Nerlynx®) Indication: Extended adjuvant treatment of early stage HER2 positive breast cancer Approval Date: July 17, 2017 MOA: Irreversible tyrosine kinase inhibitor of HER1, HER2, and HER 4, demonstrates antitumor activity in EGFR and/or HER2 expressing cancer Nerlynx (neratinib) [prescribing information]. Los Angeles, CA: Puma Biotechnology, Inc.; July 2017.

Neratinib (Nerlynx®) Dosage: 240 mg (6 40 mg tablets) once daily with food for 1 year Adverse Reactions: Diarrhea, nausea, abdominal pain/distention, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, weight decreased and urinary tract infection Precautions: Diarrhea and hepatotoxicity Cost: $12,600/month Pre-medicate for diarrhea for 1st 2 cycles Nerlynx (neratinib) [prescribing information]. Los Angeles, CA: Puma Biotechnology, Inc.; July 2017.

Neratinib (Nerlynx®) Clinical Trial Snapshot ExteNET Trial (N=2840) Multicenter, double-blind, placebo control, phase III trial Stage 1-2 HER2 positive breast cancer completed trastuzumab therapy at least 2 yrs prior Randomized to neratinib 240 mg or placebo Median f/u 24 months Results: Pre-medicate for diarrhea for 1st 2 cycles Neratinib (N=1420) Placebo (N=1420) HR (95% CI) Invasive disease-free survival event, n 70 109 0.67 ( ) p=0.0091 2-yr invasive disease-free survival rate, % (95% CI) 93.9 ( ) 91.6 (90-93) Adverse events Diarrhea (Grade 3-4), n (%) 562 (40) 23 (2) Chan A, et al. Lancet Oncol. 2016;17:

Niraparib (Zejula®) Indication: Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy In patients with or without BRCA 1/2 mutations Approval Date: March 27, 2017 MOA: Poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, inhibiting PARP enzymatic activity results in DNA damage, apoptosis and cell death Zejula (niraparib) [prescribing information]. Waltham, MA: Tesaro Inc; March 2017.

Niraparib (Zejula®) Dosage: 300 mg by mouth daily
Begin no later than 8 weeks following platinum-containing regimen Adverse Reactions: Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, mucositis, diarrhea, dyspepsia, fatigue, and AST/ALT elevation Precautions: Myelodysplastic Syndrome/Acute Myeloid Leukemia, Bone marrow suppression, and CV effects Cost: $17,700/ month Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Grade 3-4 hypertension occurred in 9% of ZEJULA treated patients compared to 2% of placebo treated patients in Trial 1. Zejula (niraparib) [prescribing information]. Waltham, MA: Tesaro Inc; March 2017.

Niraparib (Zejula®) Clinical Trial Snapshot NOVA Trial (N=553) Multicenter, double-blind, placebo-control trial Received at least 2 prior platinum-containing regimens and responded to the most recent regimen Randomized 2:1 to niraparib 300mg or placebo daily Median f/u 16.9 months Results: (Interim) *HRD=homologous recombination deficiency (Decreased rates of homologous recombination have been found to cause inefficient DNA repair. HRD-positive cells are more susceptible to the effects of DNA damaging agents such as platinum agents or PARP inhibitors.) Germline BRCA mutation No Germline BRCA mutation with HRD* positivity No Germline BRCA mutation Niraparib Placebo Median PFS=21m Median PFS=5.5m Median PFS=12.9m Median PFS=3.8m PFS=9.3m PFS=3.9m PFS HR 0.27 (95%CI, ), p<0.001 PFS HR, 0.38 (95%CI, 0.24- 0.59), p<0.001 PFS HR, 0.45 (95%CI, ), p<0.001 Mirza, MR, et al. NEJM. 2016;375:

Niraparib (Zejula®) NOVA Trial (N=553) Adverse Events Neutropenia, thrombocytopenia, and anemia (>10%) Clinical Trial Snapshot Niraparib n=367 Placebo n=179 NNH Any grade >3 TEAE, % 74.1 22.9 2 Any TEAE leading to DC 14.7 2.2 8 Any TEAE leading to death Mirza, MR, et al. NEJM. 2016;375:

Brigatinib (Alunbrig®)
Indication: Treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib Approval Date: April 28, 2017 MOA: ALK tyrosine kinase inhibitor, was designed for potent activity against a broad range of ALK resistance mutations Crizotinib (Xalkori) Ceritinib (Zykadia) Alectinib (Alecensa) Brigatinib (Alunbrig) Mechanisms of acquired resistance to crizotinib typically involve changes in the ALKgene or activation of signaling pathways that bypass ALK. secondary ALK kinase domain mutations, including the recalcitrant G1202R mutation, have been identified in patients whose disease progressed with ceritinib or alectinib after crizotinib therapy Alunbrig (brigatinib) [prescribing information]. Cambridge, MA: Ariad Pharmaceuticals Inc; April 2017.

Dosage: 90 mg by mouth daily after 7 days increase to 180 mg daily Minimum dose: 60 mg daily Adverse Reactions: Nausea, diarrhea, fatigue, cough, and headache Precautions: Interstitial lung disease, HTN, bradycardia, visual disturbance, CPK elevations, pancreatic enzyme elevations, and hyperglycemia Cost: $95/tablet (30 mg tablet) ~$17,000/month (180 mg dosing) Crizotinib (Xalkori) ($18000) Ceritinib (Zykadia) Alectinib (Alecensa) Brigatinib (Alunbrig) Mechanisms of acquired resistance to crizotinib typically involve changes in the ALKgene or activation of signaling pathways that bypass ALK. secondary ALK kinase domain mutations, including the recalcitrant G1202R mutation, have been identified in patients whose disease progressed with ceritinib or alectinib after crizotinib therapy Alunbrig (brigatinib) [prescribing information]. Cambridge, MA: Ariad Pharmaceuticals Inc; April 2017.

Clinical Trial Snapshot ALTA (N=222) Two-arm, open-label, multicenter trial Locally advanced/metastatic ALK-positive NSCLC with progression on crizotinib Randomized to brigatinib 90 or 180 mg once daily Median f/u: 8 months Results: Objective response rate: 45% brigatinib 90 mg 54% brigatinib 180 mg Mean progression free survival: 9.2 months brigatinib 90 mg months brigatinib 180 mg TEAEs: GI symptoms, headache, cough Both before and after matching, BRG had significantly longer PFS compared to CER and ALEC, significantly longer OS than CER, and a trend toward longer OS than ALEC. Reckamp, K. L., Lee, J., Huang, J., Proskorovsky, I., Reichmann, W., Krotneva, M., ... & Huang, H. (2017). Matching-adjusted indirect comparison (MAIC) of relative efficacy for brigatinib vs. ceritinib and alectinib in crizotinib-resistant anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC). Kim DW, et al. J Clin Oncol. 2017;35:

Oncology Besponsa® (inotuzumab ozogamicin)
Treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia Humanized CD22-directed monoclonal antibody-drug IV infusion Boxed warning: Hepatotoxicity and increased risk of post-transplant non-relapse mortality Clinical Trial Results: 218 evaluated patients 35.8% who received Besponsa experienced complete remission (CR) for a median 8.0 months 17.4% who received alternative chemotherapy experienced CR for a median 4.9 months Besponsa (inotuzumab ozogamicin) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; August 2017.

Oncology Vyxeos® (daunorubicin and cytarabine) N=309 Vyxeos
Treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes Liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor IV infusion Clinical Trial Results: In the Vyxeos arm, patients received 44mg/100mg per m2 (daunorubicin and cytarabine) liposome intravenously via a 90 minute infusion on days 1, 3 and 5 of induction (days 1 and 3 if a second induction was needed) and 29mg/65mg per m2 (daunorubicin and cytarabine) liposome on days 1 and 3 for consolidation. Patients in the 7+3 arm received induction with cytarabine 100mg/m2/day on days 1-7 by continuous infusion and daunorubicin 60mg/m2/day on days 1-3. For consolidation, cytarabine was dosed on days 1-5 and daunorubicin on days 1-2. N=309 Vyxeos 7+3 regimen HR (95% CI); p value Median overall survival, months 9.6 5.9 0.69 (0.52,0.9); p=0.005) Complete response rate, % 38 26 P=0.036 All-cause 30-day mortality, % 6 11 Vyxeos (daunorubicin and cytarabine [liposomal]) [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals Inc; August 2017

Enasidenib (IDHIFA®) Indication: Treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with an isocitrate dehydrogenase-2 (IDH2) mutation Approval Date: August 1, 2017 MOA: Small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme that works by blocking several enzymes that promote cell growth Idhifa (enasidenib) [prescribing information]. Summit, NJ: Celgene Corporation; August 2017.

Enasidenib (IDHIFA®) Dosage: 100 mg daily by mouth until disease progression Boxed Warning: Differentiation syndrome Adverse Reactions: Nausea, vomiting, diarrhea, increased levels of bilirubin, and decreased appetite Precautions: Electrolyte imbalance, hematologic effects, hepatotoxicity, GI toxicity, and tumor lysis syndrome Cost: $29,846.40/month Idhifa (enasidenib) [prescribing information]. Summit, NJ: Celgene Corporation; August 2017.

Enasidenib (IDHIFA®) Endpoint IDHIFA N=199
Study 1 (N=199) Multicenter, open-label, single arm, two-cohort trial Patients with relapsed or refractory AML and IDH2 mutation received enasidenib 100 mg daily Median f/u: 6.6 months Results: Endpoint IDHIFA N=199 Median duration of response, months (95% CI) Complete remission, n(%); (95% CI) 37 (19); (13-25) 8.2 ( ) Complete remission w/partial hematological recovery, n(%); (95% CI) 9 (4); (2-8) 9.6 (0.7-NA) Idhifa (enasidenib) [prescribing information]. Summit, NJ: Celgene Corporation; August 2017.

Midostaurin (Rydapt®)
Indication: Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutationpositive Not monotherapy Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL) Approval Date: April 27, 2017 MOA: Small molecule that inhibits multiple receptor tyrosine kinases Rydapt (midostaurin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2017.

Dosage: AML: 50 mg orally twice daily with food on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation ASM, SM-AHN, and MCL: 100 mg orally twice daily with food Adverse Reactions: Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection Precautions: Pulmonary toxicity Cost: $4497/cycle for AML OR ~$18,000/month Rydapt (midostaurin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2017.

Clinical Trial Snapshot RATIFY Trial (N=717) Multicenter, double-blind, placebo control, phase III trial Patients with newly diagnosed AML not previously treated with antineoplastic Randomized to standard chemotherapy plus midostaurin or placebo Median f/u: 59 months Results: Midostaurin N=360 Placebo N=357 HR (95% CI) Media overall survival, months 74.7 25.6 0.78 ( ), p=0.009 Event-free survival, months 8.2 3.0 p=0.002 Stone RM, et al. NEJM. 2017;377:

Oncology Bavencio® (avelumab)
Adults and pediatric patients ≥12 years with metastatic Merkel cell carcinoma (MCC) Patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy Programmed death ligand-1 (PD-L1) blocking antibody IV infusion Clinical Trial Results: JAVELIN Merkel 200 Trial – MCC Overall response rate: 33% Duration of response: 2.8 – months JAVELIN Solid Tumor Trial – UC Overall response rate: 16.1% Duration of response: 1.4 – months Immune-mediated pneumonitis, hepatitis, colitis JAVELIN Solid >/= 6 month followup N=161 Bavencio (avelumab) [prescribing information]. Rockland, MA: EMD Serono Inc; May 2017.

Oncology Imfinzi® (durvalumab)
Treatment of patients with locally advanced or metastatic urothelial carcinoma who: Have disease progression during or following [within 12 months] platinum-containing chemotherapy Programmed death-ligand 1 (PD-L1) blocking antibody IV infusion Boxed warning: Hepatotoxicity and increased risk of post-transplant non-relapse mortality Clinical Trial Results: N=182 Imfiniz 10 mg/kg q2wks Objective response rate, n (%) 31 (17%) Response of 6 months or longer, n 31 Response of 12 months or longer, 5 Imfinzi (durvalumab) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; April 2017.

Oncology Lartruvo® (olaratumab) Olaratumab+ doxorubicin Doxorubicin
Treatment (in combination with doxorubicin) of adults with soft tissue sarcoma (STS) Platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody IV infusion Clinical Trial Result: 133 patients randomized to olaratumab+doxorubicin or doxorubicin Olaratumab+ doxorubicin Doxorubicin HR (95% CI) Progression free survival, months (95% CI) 6.6 ( ) 4.1 ( ) 0.67 ( ) p=0.0615 Objective response rate, % (95% CI) 18.2 ( ) 11.9 ( ) Median overall survival, months (95% CI) 26.5 ( ) 14.7 ( ) 0.46 ( ) p=0.0003 Lartruvo (olaratumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; October 2016. Tap WD, et al. Lancet. 2016;388:

New Drug Update 2016-2017 Rachael McCaleb, PharmD, BCPS
Assistant Professor, Department of Pharmacy Practice University of Arkansas for Medical Sciences College of Pharmacy

Additional Information Will not be discussed during this presentation

Genetic Disease

Cerliponase alfa (Brineura®)
Indication: To slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) Approval Date: April 27, 2017 MOA: Hydrolytic lysosomal N-terminal tripeptidyl peptidase Deficiency in TPP1 activity results in the accumulation of lysosomal storage, leading to progressive decline in motor function Batten disease Brineura (cerliponase alfa) [prescribing information]. Novato, CA:BioMarin Pharmaceutical Inc; April 2017.

Dosage: Intraventricular infusion 300 mg once every other week followed by administration of 2 mL intraventricular electrolytes Adverse Reactions: pyrexia, ECG abnormalities, decreased/increased CSF protein, vomiting, seizures, hypersensitivity, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension Cost: $64,800/dose Batten disease Brineura (cerliponase alfa) [prescribing information]. Novato, CA:BioMarin Pharmaceutical Inc; April 2017.

Clinical Trial Snapshot Package Insert Trial (N=24) Single arm trial Cerliponase alfa 300 mg QOW for 48 weeks (extension 96 weeks) Compare to historical cohort Results: 22 patients treated with Brineura and evaluated for efficacy at week 96, 21 (95%) did not decline 21/42 (50%) patients in the historical cohort experienced an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale over 96 weeks Batten disease Brineura (cerliponase alfa) [prescribing information]. Novato, CA:BioMarin Pharmaceutical Inc; April 2017.

C1 esterase inhibitor (Haegarda®)
Indication: Prophylaxis against hereditary angioedema (HAE) in adults and adolescents Approval Date: July 2017 MOA: C1 inhibitor therapy in patients with a C1 inhibitor deficiency (as in HAE), is thought to suppress the activation of plasma kallikrein and factor XIIa which prevents bradykinin production Haegarda (C1 Esterase Inhibitor [Human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; June 2017.

Dosage: 60 IU/kg q 3-4 days Lyophilized powder supplied in single-use vials Adverse Reactions: Injection site reaction, hypersensitivity, nasopharyngitis and dizziness Cost: 2000 unit vial ($ ) 3000 unit vial ($ ) Alternative: cinryze 1000 IU q 3-4 days and Danazol oral 200 mg 2-3 times daily Cinryze ~$6500 for 100 units Haegarda (C1 Esterase Inhibitor [Human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; June 2017.

Clinical Trial Snapshot COMPACT Trial (N=90) Multicenter, double-blind, placebo-control, crossover trial Randomized to either Haegarda 60 IU/kg or 40 IU/kg for 16 weeks and placebo for the other 16 weeks Results: 1.The % of responders (95% CI) with a ≥50% reduction in the time-normalized number of HAE attacks on HAEGARDA relative to placebo was 83% (73%, 90%). 2.The percentages of subjects with ≥70% and ≥90% reductions in comparison to placebo in the timenormalized number of HAE attacks were 83% and 58% on 60 IU/kg and 67% and 43% on 40 IU/kg. 3.Seventy-one percent (71%) of subjects on 60 IU/kg and 53% of subjects on 40 IU/kg had ≥1 HAE attack per 4 week period on placebo and <1 HAE attack per 4 week period on HAEGARDA. Haegarda 60 IU/kg (N=45) Haegarda 40 IU/kg (N=45) Haegarda Placebo Number of HAE Attacks (Number/month) Mean (SD) 0.5 (0.8) 4 (2.3) 1.2 (2.3) 3.6 (2.1) Min, Max 0.0, 3.1 0.6, 11.3 0.0, 12.5 0.0, 8.9 Treatment difference LS Mean (95% CI) -3.5 (-4.2, -2.8) -2.4 (-3.4, -1.5) P-value <0.001 Haegarda (C1 Esterase Inhibitor [Human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; June 2017.

Musculoskeletal

Nusinersen (Spinraza®)
Indication: Treatment of spinal muscular atrophy (SMA) in pediatric and adult patients Approval Date: December 23, 2016 MOA: Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency Spinraza (nusinersen) [prescribing information]. Cambridge, MA: Biogen; June 2017.

Dosage: 12 mg per dose Loading dose: 4 doses (3 doses every 14 days then 1 dose 30 days after the third dose) Maintenance dose: every 4 months Adverse Reactions: joint contracture and pyrexia Cost: $30000/mL, provided in a single-use 5mL vial $150,000/vial = 1 dose Year 1 Years 2 and each year after Based on 1 year, LD + MD 6 doses, 1st year. 3 doses every year thereafter $900,000 $450,000 Spinraza (nusinersen) [prescribing information]. Cambridge, MA: Biogen; June 2017.

Clinical Trial Snapshot Study 1 (N=20) Phase II, open label, dose-escalation study Improvement in developmental motor milestones (HINE-2 and CHOP-INTEND) Ongoing trials Phase 3 in infantile-onset SMA Study CS4: Patients with later-onset SMA Interim analysis (N=126) Study stopped based on highly statistically significant treatment effect Findings not yet reviewed by FDA No placebo group (early onset or Type 1) Validity of assessments Spinraza (nusinersen) [prescribing information]. Cambridge, MA: Biogen; June 2017.

Eteplirsen (Exondys 51®)
Indication: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Approval Date: September 19, 2016 MOA: Binds to exon 51 of dystrophin pre-messenger RNA (mRNA), resulting in exclusion of this exon during mRNA processing. Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It is one of nine types of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Symptom onset is in early childhood, usually between ages 3 and 5. The disease primarily affects boys, but in rare cases it can affect girls. A similar drug was also in clinical trials, drisapersen, which is a 2'-O-methyl phosphorothioate antisense oligo that, like eteplirsen, triggers skipping of dystrophin exon 51. In January 2016, the FDA rejected drisapersen (Kyndrisa) for lack of efficacy, effectively shifting focus to eteplirsen. approach to increasing production of dystrophin in muscle is exon skipping.32 This approach involves anti-sense oligonucleotide (AON) drugs that are able to bind specifically to dystrophin RNA while it is being transcribed and processed/spliced. The general strategy is to introduce an AON molecule that pairs with a target sequence in the pre-mRNA for dystrophin. This pairing causes the nuclear splicing machinery to skip over the target sequence, thereby excluding one or more mutation-bearing exons that would prevent production of the dystrophin protein. The end result is a shorter but still functional dystrophin molecule. The initial target for development for exon skipping was exon 51, since about 13% of boys with DMD have a frameshift mutation that can be treated by inducing a skip of exon 51 (although there is some disagreement about the actual percentage, with some estimates being as high as 17%). Exondys 51 (eteplirsen) [prescribing information]. Cambridge, MA; Sarepta Therapeutics, Inc: September 2016.

Dosage: 30 mg/kg once weekly Administered by IV infusion over 35 to 60 minutes Supplied as: 100 mg/2 mL and 500 mg/2 mL single dose vial Adverse Reactions: Balance disorder and vomiting (>35% incidence compared to placebo) Cost: 100 mg/2 mL - $ Exondys 51 (eteplirsen) [prescribing information]. Cambridge, MA; Sarepta Therapeutics, Inc: September 2016.

Clinical Data Snapshot Mendell, et al. (2013) (N=12) Randomized, double-blind, placebo-controlled Boys aged 7-13 years with DMD and ability to walk m on 6MWT 3 cohorts (placebo, 30 mg/kg/wk, 50 mg/kg/wk) for 24 weeks At week 24, placebo cohort randomized to 30 mg/kg/wk or 50 mg/kg/wk (open-label extension) Results: Statistically significant increase in dystrophin positive fibers by week 48 Statistical differences compared to placebo for 6MWT as a 67.3 m difference from baseline in the 30 mg/kg group and 87.4 m in the 50 mg/kg group Patients had to have been on stable glucocorticoids (prednisone or deflazacort) for 24 weeks to be enrolled Mendell JR, et al. Ann Neurol. 2013;74:

Clinical Data Snapshot Mendell et al. (2016) Evaluated longitudinal effect of eteplirsen versus historical control Patients: ambulatory DMD patients ≥7 years old Results: At 36 months eteplirsen patients showed a statistically and clinically meaningful difference in 6MWT decline of 151m compared to placebo Loss of ambulation over 3 years Eteplirsen group: 2/12 Placebo group: 6/13 Study schema. Twelve Duchenne muscular dystrophy patients were randomized (R) to 1 of 3 cohorts in double-blind, placebo-controlled Study 201: Cohort 1, eteplirsen 30 mg/kg/wk; Cohort 2, eteplirsen 50 mg/kg/wk; and Cohort 3,placebo-treated, referred to as “placebo/delayed.” At week 25, placebo/delayed patients in Cohort 3 switched to open-labeltreatment with either 30 or 50 mg/kg/wk eteplirsen. Patients were maintained on the same dose of eteplirsen under open-label extension Study 202. All patients underwent biceps biopsies at baseline and deltoid biopsies at week 48 for analysis ofdystrophin. Additional biceps biopsies were obtained at week 12 (from patients in Cohort 2 and 2 patients in Cohort 3) orweek 24 (from patients in Cohort 1 and 2 patients in Cohort 3). The 6-minute walk test was the primary functional outcomemeasure and was performed pretreatment and post-treatment through week 48 (every 4 weeks through week 36 and thenweek 48). Mendell JR, et al. Ann of Neurol. 2016;79:

Deflazacort (Emflaza®)
Indication: Treatment of Duchenne muscular dystrophy (DMD) in patients ≥5 years Approval Date: February 9, 2017 MOA: Corticosteroid prodrug; its active metabolite acts on the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects Emflaza (deflazacort) [prescribing information]. Northbrook, IL: Marathon Pharmaceuticals; February 2017.

Dosage: 0.9 mg/kg/day by mouth Adverse Reactions: Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis Precautions: Alterations in endocrine function. Immunosuppression, GI perforation, behavior/mood disturbances, effects on bone, and ophthalmic effects Cost: 6, 18, 30, and 36 mg tablet - $294/tab Oral suspension mg/mL - $298/mL Emflaza (deflazacort) [prescribing information]. Northbrook, IL: Marathon Pharmaceuticals; February 2017.

Clinical Trial Snapshot Griggs et al (N=196) Multicenter, double-blind, placebo control, phase III trial Boys (5-15 years) with DMD Randomized to deflazacort 0.9 or 1.2 mg/kg/d, prednisone 0.75 mg/kg/d, or placebo for 12 weeks Re-randomized to active drug during extension phase (12-52 weeks) Results: The current study showed that both DFZ and PRED were superior to placebo over 12 weeks in improving motor strength Griggs RC, et al. Neurology. 2016;87:

New Drug Update Rachael McCaleb, PharmD, BCPS

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