2017 New Drug Update. Robert Lipsy PharmD, FASHP Southwest Clinical Pharmacy Seminar February 25 and Tucson, Az. Conflicts of Interest None

Transcription

1 2017 New Drug Update Robert Lipsy PharmD, FASHP Southwest Clinical Pharmacy Seminar February 25 and Tucson, Az. Conflicts of Interest None New Drugs

2 New Drugs December 2016 New Drugs December 2017 FDA Ratings P = Priority S = Standard BLA = Biologic Not Ranked

3 Pre-test Questions Sofosbuvir in combination with velpatasvir is approved for treating what Hepatitis Genotypes? A. 1, 2, 4, 6 B. 1, 2, 5, 6 C. 1, 2, 3, 4, 5, 6 D. 1, 2, 4, 5, 6 Pre-test Questions FDA accelerated approval is based on A. Tumor response B. Tumor response and improved quality of life C. Tumor response and decreased mortality D. Improved quality of life E. Improved quality of life and decreased mortality Bezlotoxumab (Zinplava) Human monoclonal antibody to C. difficile toxin B Reduce recurrence of C. difficile infection Single IV infusion at or about initiation of standard antimicrobial therapy Worsening HF in patients with history of HF 3

4 Bezlotoxumab Adverse reaction Bezlotoxumab with SoC N=786 % Placebo with SoC N=781% Nausea 7 5 Pyrexia 5 3 Headache 4 3 Bezlotoxumab Trial 1 Bezlotoxumab N N=386 Placebo N N=395 Adjusted Difference (95% CI) Sustained Clinical Response 232 (60.1) 218 (55.2) 4.8 (-2.1, 11.7) Reason for failure to achieve sustained clinical response Clinical Failure 87 (22.5) 68 (17.2) Recurrence 67 (17.4) 109 (27.6) Bezlotoxumab Trial 1 Bezlotoxumab N N=395 Placebo N N=378 Adjusted Difference (95% CI) Sustained Clinical Response 264 (66.8) 197 (52.1) 14.6 (7.7, 21.4) Reason for failure to achieve sustained clinical response Clinical Failure 69 (17.5) 84 (22.2) Recurrence 62 (15.7) 97 (25.7) 4

5 Olaratumab (Larturvo) Adult soft tissue sarcoma Not amenable to curative treatment with radiotherapy or surgery Platelet-derived growth factor receptor alpha blocking antibody Olaratumab 15 mg/kg IV infusion Days 1 and 8 of each 21-day cycle Administer with doxorubicin for first 8 cycles Diphenhydramine and dexamethasone Day 1, cycle 1 Infusion reactions, neutropenic fever/infection or Grade 4 neutropenia Olaratumab Olaratumab + Doxorubacin N = 64 All Grades Grades 3-4 All Grades Doxorubacin N = 65 Grades 3-4 Alopecia Decreased appetite Neuropathy Headache Anxiety Dry eyes

6 Olaratumab Olaratumab + Doxorubacin N = 64 All Grades Grades 3-4 All Grades Doxorubacin N = 65 Grades 3-4 Hyperglycemia Increased aptt Hypokalemia Hypophosohatemia Increased alkaline phosphatase Hypomagnesemia Lymphopenia Neutropenia Thrombucytopenia Olaratumab Olaratumab + Doxorubacin N = 64 All Grades Grades 3-4 All Grades Doxorubacin N = 65 Grades 3-4 Nausea Mucositis Vomiting Diarrhea Abdominal pain Fatigue Infusion Rxn Musculoskeletal pain Olaratumab Olaratumab + Doxorubacin N = 66 Doxorubacin N = 67 Overall Survival Number of Deaths 39 (59%) 52 (78%) Median, months (95% CI) 26.5 (20.9, 31.7) 14.7 (9.2, 17.1) Hazard Ratio (95% CI) 0.52 (0.34, 0.79) P- value P<0.05 Progression-Fee Survival Number of Events 37 (56%) 34 (51%) Median, months (95% CI) 8.2 (5.5, 9.8) 4.4 (3.1, 7.4) Hazard Ratio (95% CI) 0.74 (0.46, 1.19) Objective Response Rate (Cr + PR) (95% CI) 18.2% (9.8, 29.6) 7.5% (2.5, 16.6) CR, n 3 (4.5%) 1 (1.5%) PR, n 9 (13.6%) 4 (6%) 6

7 Atezolizumab (Tecentriq) Locally advanced or metastatic urothelial carcinoma Programmed death-ligand 1 (PD-L1) blocking antibody Disease progression during platinumcontaining therapy or within 12 months of neoadjuvant or adjuvant therapy Accelerated approval based on tumor response Atezolizumab 1200 mg IV infusion over 60 min every 3 weeks No dose reductions; hold for toxicity Immune-related endocronpathies Hypophysitis, thyroid, adrenal insufficiency, Type-1 diabetes Immune-related Pneumonitis, hepatitis, colitis Atezolizumab Immune-related myasthenic syndrome/myasthenia Gravis, Guillian- Barre or meningoencephalitis Immune-related pancreatitis Infection Ocular inflammatory toxicity Infusion reaction Embryo-fetal toxicity 7

8 Atezolizumab Adverse Reaction All Grades % Grades 3-4 % Nausea 25 2 Constipation Diarrhea 18 1 Abdominal pain 17 4 Vomiting 17 1 Fatigue 52 6 Pyrexia 21 1 Peripheral edema 18 1 UTI 22 9 Atezolizumab Adverse Reaction All Grades % Grades 3-4 % Decreased appetite 26 1 Back/neck pain 15 2 Arthralgia 14 1 Hematuria 14 3 Dyspnea 16 4 Cough Rash Pruritus Atezolizumab Adverse Reaction Grades 3-4 % Lymphopenia 10 Hyponatremia 10 Anemia 8 Hyperglycemia 5 Increased Alkaline phosphatase 4 Increased creatinine 3 Increased ALT 2 Increased ALT 2 Hyalbuminemia 1 8

9 Atezolizumab All Patients N = 310 # of IRF-assessed Confirmed responders ORR % (95% CI) 14.8% (11.1, 19.3) PD-L1 Expression Subgroups PD-L1 Expression of < 5% in IC s PD-L1 Expression of > 5% in IC s % (5.9, 14.3) 26.0% (17.7, 35.7) Complete response % Partial response % Median duration, months (range) NR (2.1+, 13.8+) 12.7 (2.1+, 12.7) NR (4.2, 13.8+) Rucaparib Rubraca Advanced ovarian cancer BRCA mutation Two or more previous chemotherapies Poly (ADP-ribose) polymerase (PARP) inhibitor 600 mg orally, daily, with or without food Modify for toxicity Rucaparib Adverse Reaction Grade 1-2 Grade 3-4 Nausea 77 5 Vomiting 46 4 Constipation 40 2 Diarrhea 34 2 Abdominal Pain 32 3 Asthenia / Fatigue Anemia Thrombocytopenia 21 5 Dysgusia Decreased Appetite 39 3 Dyspnea

10 Rucaparib Adverse Reaction Grade 1-4 Grade 3-4 Increased Creatinine 92 1 ALT AST 73 5 Cholesterol 40 2 Decreased Hemoglobin Lymphocytes 45 7 Platelets 39 6 Absolute neutrophil count Rucaparib Investigator-assessed Independently-assesses Objective response rate (95% 54% (44, 64) 42% (32, 52) CI) Complete response 9% Partial response 45% Median duration in months 9.2 (6.6, 11.6) 6.7 (5.5, 11.1) ORR platinum sensitive 66% (54, 76) platinum resistant 25% (9, 49) platinum refractory 0% (0, 41) Prasterone (Intrarosa) Inactive endogenous steroid converted to androgens and/or estrogens Moderate to severe dyspareunia due to menopause One vaginal insert daily at bedtime Abnormal genital bleeding = contraindication Current or history of breast cancer = warning 10

11 Prasterone Vaginal discharge 14.2% Abnormal Pap smear 2.1% Prasterone Placebo N = 157 Prasterone N = 325 Dyspareunia Baseline Mean Severity Week 12 Mean Severity Mean Change in Severity (1.02) (1.00) (SD) Difference from placebo P value % Superficial Cells Baseline Mean Week 12 Mean Mean Change (SD) 1.75 (3.33) (10.35) Difference from placebo P Value - < Prasterone Placebo N = 157 Prasterone N = 325 %Parabasal Cells Baseline Mean Week 12 Mean Mean Change (SD) (29.58) (36.26) Difference from placebo P value - < Vaginal ph Baseline Mean Week 12 Mean Mean Change (SD) (0.74) (0.94) Difference from placebo P Value - <

12 Lixisenatide (Adlyxin) GLP-1 receptor agonist Type 2 diabetes mellitus 10 mcg SC daily for 14 days then 20 mcg SC daily One hour before the first meal of the day Discard after 14 days Lixisenatide Anaphylaxis 0.1% Pancreatitis 21 cases per 10,000 patient years (placebo 17) Acute kidney injury Worsening of chronic renal railure Lixisenatide Adverse Reaction Lixisenatide % Placebo % Nausea 25 6 Vomiting 10 2 Headache 9 6 Diarrhea 8 6 Dizziness 7 4 Dyspepsia Constipation Abdominal distension Abdominal pain upper Abdominal pain Injection site reaction

13 Lixisenatide Background therapy Placebo % Lixisenatide % Monotherapy Symptomatic / Severe 2 / 0 2 / 0 Metformin Symptomatic / Severe 1 / 0 3 / 0 Sulfonylurea +/- metformin Symptomatic / Severe 11 / 0 15 / 0.2 Pioglitazone +/- metformin Symptomatic / Severe 1 / 0 3 / 0 Basal insulin +/- metformin Symptomatic / Severe 23 / 0 28 / 1 Basal insulin +/- sulfonylurea Symptomatic / Severe 22 / 0 47 / 0 Glargine and metformin +/- TZD Symptomatic / Severe 14 / 0 22 / 0.4 Lixisenatide Mean reduction in HbA1c versus placebo % (95% CI) Monotherapy (-0.9, -0.4) Metformin ( -0.64, -0.28) Sulfonylurea +/- metformin (-0.45, -0.09) (-0.72, -0.45) Pioglitazone +/- metformin (-0.65, -0.32) Basal insulin +/- metformin (-0.56, -0.17) 0.23 (0.11, 0.35) Basal insulin +/- sulfonylurea (-1.0, -0.52) Glargine and metformin +/- TZD (-0.43, -0.12) Nusinsersen (Spinraza) Survival motor neuron-2 (SMN-2)-directed antisense oligonucleotide Spinal muscular atrophy Intrathecal Days 0, 14, 28, 58, then every 4 months Thrombocytopenia (11%) Possible renal toxicity Elevated urine protein 69%, placebo 20% 13

14 Nusinersen Adverse Reactions Nusinersen n=80 % Sham procedure N=41 % Lower respiratory infection Upper respiratory infection Constipation Teething 14 7 Upper respiratory tract 6 2 congestion Aspiration 5 2 Ear infection 5 2 Scoliosis 5 2 Nusinersen Endpoint nusinersen sham Motor Milestone (HINE Section 2) Achievement of a response 21 (40%) P< (0%) CHOP-INTEND Improvement from baseline At least 4 points 33 (63%) 1 (3%) CHOP-INTEND Worsening from baseline At least 4 points 2 (4%) 12 (40%) Children s Hospital of Philadelphia Infant Test of Neuromuscular Disorders Eteplirsen (Exondys 51) Antisense oligonucleotide Duchenne muscular dystrophy Binds to exon 51 of dystropin pre-mrna Allows for production of internally truncated dystropin protein Accelerated approval based on increased dystrophin in skeletal muscle Infusion 30 mg/kg weekly 14

15 Eteplirsen Adverse Reaction Eteprilsen Placebo Balance disorder 38% 0% Vomiting 38% 0% Contact dermatitis 25% 0% Open label Contusion > 10% Excoriation > 10% Arhralgia > 10% Rash > 10% Catheter site pain > 10% URI > 10% Transient erythema Day of infusion Facial flushing Day of infusion Elevated temperature Day of infusion Eteplirsen Baseline % normal dystrophin Week 48 % normal dystrophin Change from Baseline Mean p=0.008 Crisaborole (Eucrisa) Mild to moderate atopic dermatitis Phosphodiesterase 4 inhibitor Hypersensitivity including contact urticarial Application site pain 4% vs. vehicle 1% 15

16 Crisaborole Success in ISGA Crisaborole N=503 Trial 1 Trial 2 Vehicle N=256 Crisaborole N=513 Vehicle N= % 25.4% 31.4% 18.0% Lifitegrast (Xiidra) Lymphocyte function-associated antigen-1 (LFA-1) antagonist Dry eye disease One drop twice a day Single use container discard after using in each eye Lifitegrast 5% to 25% Irritation Dysgeusia Reduced acuity 1% to 5% Conjunctival hyperemia Headache Tearing Eye (discharge, discomfort, pruritus) pruritus 16

17 Visit Vehicle (SD) Lifitegrast Lifitegast (SD) Difference (95% CI) Study 1 Baseline 51.8 (23.55) 51.6 (24.69) Day (25.29) (25.36) -7.3 (-16.1, 1.4) Study 2 Baseline 41.6 ( (28.64) Day (28.78) (31.48) -4.7 (-8.9, -0.4) Study 3 Baseline 69.2 (16.76) 69.7 (16.95) Day (28.60) (28.40) (-16.4, -8.3) Study 4 Baseline 60.0 (17.08) 68.3 (16.88) Day (28.03) (28.91) -7.5 (-11.6, -3.5) Sofosbuvir and Velpatasvir (Epclusa) Nucleotide analogue NS5B polymerase inhibitor / NS5A inhibitor Hepatitis C genotype 1-6 Without cirrhosis or with compensated cirrhosis One tablet (400 mg / 100 mg) daily, 12 weeks With decompensated cirrhosis One tablet daily with ribavirin, 12 weeks Sofosbuvir and Velpatasvir Bradycardia with amiodarone Not recommended egfr < 30 ml/min/1.73 m2 no P-gp inducers and potent CYP 2B6, 2C8, 3A4 inducers rifampin, St. John s Wort, carbamazepine 17

18 Sofosbuvir and Velpatasvir ADRs in patients without cirrhosis or with compensated cirrhosis Headache 22% Fatigue 15% Nausea 9% Asthenia 5% Insomnia 5% Equal to or less frequent than placebo Higher in patients with decompensated cirrhosis Sofosbuvir and Velpatasvir Trial 1 19% cirrhosis, 32% treatment experienced SVR %, No on treatment failures Trial 2 14% cirrhosis, 15% treatment experienced SVR 99%, No on treatment failures Trial 3 30% cirrhosis, 26% treatment experienced SVR 95% (5% higher without cirrhosis), No on treatment failures Trial 4 30% cirrhosis, 26% treatment experienced SVR 94%, ( G1) (85 G3), Some on treatment failures Plecanatide (Trulance) Guanylate cyclase-c agonist Chronic idiopathic constipation Oral, 3 mg one time daily, with or without food Swallow whole Adults only 18

19 Plecanatide Diarrhea 5% vs 1% placebo Severe 6% vs. 3% Discontinuation 2% vs. 0.5% Other ADRs < 2%, > placebo Sinusitis, URI, flatulence, abdominal pain, increased ALT and AST Plecanatide < 3 BM per week, rare loose stool without laxative, not use manual maneuvers, not meet criteria for IBS-C 25% of time straining, hard or lumpy, incomplete, sensation of blockage Less than 3 SBM with feeling of complete evacuation in each or 2 weeks Bristol Stool Form Scale 6 or 7 in < 25% SBM Plecanatide One of three: BSFS of 1-2 in 25% Straining on days of SBN 25% 25% incomplete Response is 3 CSBM and an increase of 1 CSBM from baseline for at least 9 of 12 weeks and 3 of the last 4 weeks Plenaclatide 21% placebo 10-13% 19

20 Post-test Questions Sofosbuvir in combination with velpatasvir is approved for treating what Hepatitis Genotypes? A. 1, 2, 4, 6 B. 1, 2, 5, 6 C. 1, 2, 3, 4, 5, 6 D. 1, 2, 4, 5, 6 Post-test Questions Sofosbuvir in combination with velpatasvir is approved for treating what Hepatitis Genotypes? A. 1, 2, 4, 6 B. 1, 2, 5, 6 C. 1, 2, 3, 4, 5, 6 D. 1, 2, 4, 5, 6 Post-test Questions FDA accelerated approval is based on A. Tumor response B. Tumor response and improved quality of life C. Tumor response and decreased mortality D. Improved quality of life E. Improved quality of life and decreased mortality 20

21 Post-test Questions FDA accelerated approval is based on A. Tumor response B. Tumor response and improved quality of life C. Tumor response and decreased mortality D. Improved quality of life E. Improved quality of life and decreased mortality 21

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23 Advances in Pharmacotherapy 2016 Robert Lipsy PharmD, FASHP FAzPA Arizona Pharmacy Association Annual Convention June Chandler, Az. New Approvals New Molecular Entities New Biologics New Combinations / Use Oral Injection Oral/Injection Ophthalmic Inhalation Topical FDA Ratings P = Priority S = Standard BLA = Biologic Not Ranked