Dr Doug White. Prof Ed Gane. 7:00-7:55 AbbVie Breakfast Session 1. Joining the Dots in Psoriasis 2. Reaching for a Cure for Hep C

Transcription

1 Dr Doug White Consultant Rheumatologist Waikato DHB Senior lecturer University of Auckland Prof Ed Gane University of Auckland Director New Zealand Liver Transplant Unit Auckland City Hospital 7:00-7:55 AbbVie Breakfast Session 1. Joining the Dots in Psoriasis 2. Reaching for a Cure for Hep C

2 Eliminating HCV in New Zealand no longer a dream Professor Ed Gane NZ Liver Transplant Unit, Auckland City Hospital, University of Auckland, Auckland Clinical Studies

3 This is an educational meeting designed to share clinical data and promote scientific exchange. This slide set was created in consultation with AbbVie, and is intended to be read as a whole without modification. The views and opinions of the presenter are independent and do not necessarily reflect those of AbbVie Limited. AbbVie Limited (New Zealand) do not endorse the use of unregistered products or products outside of their registered indications. Please refer to the Data Sheet for licensed indications. This can be accessed at through your AbbVie representative or through Medical Information on AbbVie Limited, Wellington, NZ. 11 June 2016.

4 Disclosures Professor Gane has served as a consultant or scientific advisor for AbbVie, Gilead, Janssen, MSD, and Roche

5 Hepatitis C is silent global epidemic of 21 st Century Most HCV infected individuals live within Asia-Pacific million now infected NORTH AMERICA 3 M SOUTH AMERICA 7 M MIDDLE EAST 15 M AFRICA 20 M EUROPE 12 M INDIA 6 M AUSTRALIA 250,000 CHINA M SOUTHEAST ASIA 32 6 M NZ 50,000 Gower, E., Estes C., Hindman, S., Razavi-Shearer, K., Razavi, H. Global epidemiology and genotype distribution of the hepatitis C virus. Journal of Hepatology 2014.

6 Risk Factors for HCV infection in Australia and New Zealand 1. Transmission through blood products»blood donors screened since 1990 (Aus); 1992 (NZ) Eradicated post-transfusion hepatitis (HCV) 2. Transmission through injecting drug use»accounts for >90% chronic HCV in ANZ»Peak age of infection years»peak incidence

7 % Total HCV+ Total Viremic Infected (2013) Characteristics of the local HCV Population Age and gender MoH HCV Pilots MoH Modeling ,000 7,000 Total number infected >50,000 6,000 Estimated undiagnosed 5,000 = 50% Median age at diagnosis = 47 years 4,000 Duration of infection 3,000 >25 years 2,000 1,000 - Age (years) Hepatitis Foundation Report Nov 2014 Age (years) Gane E, et al. NZ Med J 2014; Dec 2014

8 Characteristics of the local HCV Population Proportion with Cirrhosis HCV Pilots in Bay of Plenty and Wellington 788 Fibroscans performed in community 12% have established cirrhosis 23% have at least severe fibrosis

9 Characteristics of the local HCV Population Genotype distribution 6130 patients genotyped at LabPlus ( ) 56% are GT-1 Gane E, et al. NZ Med J 2014; Dec 2014

10 # HCCs per annum Disease burden from hepatitis C is increasing as the infected population gets older Liver Transplants (ANZLTR) Liver Cancer (NZLTU) 26 th Australian and New Zealand Liver Transplant Registry. R%20 26 th REPORT-% pdf. Accessed July 205.

11 Disease burden from hepatitis C is projected to treble in Australia and New Zealand by 2030 Australia New Zealand Liver transplant Decompensation HCC Razavi H, Waked I, Sarrazin C, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm. J Viral Hepat 2014; 21 Suppl 1:

12 Numbers started on treatment Peg-IFN for GT1 Peg-IFN for GT 2/3 Boceprevir for GT 1 Treatment rate by year in New Zealand Most patients are waiting for all-oral therapy PHARMAC data on file. ACS, CCST data on file WHAD, 28 July, 2015

13 These new therapies can allow us to control the disease burden of HCV in New Zealand 1% 50% cured 2% 90% cured (i.e. only cirrhotics) 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 - Cirrhosis 1,200 1, % 90% cured Decompensation HCC Liver related Deaths Gane et al. NZMJ. 2014

14 These new therapies can allow us to ELIMINATE HCV in New Zealand within 15 years 1% 50% cured 2% 90% cured (i.e. only cirrhotics) 10% 90% cured 60,000 Total Infected Cases (Viraemic) 50,000 40,000 30,000 20,000 10,000 - Gane et al. AASLD 2014

15 What would it take to eliminate HCV from NZ? 1. Identify the 20,000 who remain undiagnosed Targeted testing in Primary Care Point-of-care AUSTRALIAN testing ELIMINATION in Prisons, NEX, STRATEGY CADS 2. Fund 1 st March DAA therapy 2016 DAAs for all funded HCV+ by for 2020 all HCV+ 3. Quadruple Community numbers prescribing treated through by 2020 GPs, (2000 CADSp.a.) by moving Planned treatment 12,000 per out annum to the (5-fold community increase) Primary Likely >20,000 care per annum (10-fold increase) NEX, CADS, Prisons treatment as prevention HCV eliminated before 2025

16 What would it take to eliminate HCV from NZ? The NZ Elimination Strategy has started! PHARMAC announcement 1.30pm 9 th June 2016 "Pharmac is also funding two new hep C treatments, Harvoni and Viekira Pak, which are a major advancement in treatment with cure rates of more than 90 per cent. "These new treatments will make a considerable difference to the lives of many New Zealanders and their families," he said. Pharmac chief executive Steffan Crausaz said From 1 July, specialists will be able to prescribe Viekira Pak and Viekira Pak-RBV for all eligible patients. From 1 October, once additional support has been put in place, Viekira Pak would be funded on prescriptions written by all eligible prescribers, including GPs, he said. WHAD, July 28th 2015

17 VIEKIRA PAK: mode of action HCV Receptor binding and endocytosis Transport and release 3. MID-/LATE LIFECYCLE INHIBITION NS5A inhibitor 1. EARLY INHIBITION NS3/4A protease inhibitor Paritaprevir (PTV) Translation and polyprotein processing (+) RNA ER Fusion and uncoating ER GOLGI RNA replication Ombitasvir (OBV) Replication, virion assembly, and egress 2. MID-LIFECYCLE INHIBITION non-nucleoside NS5B polymerase inhibitor Dasabuvir (DSV) Lindenbach & Rice. Nature 2005:436;

18 Daily blister pack, twice-daily dosing Co-formulated paritaprevir/ritonavir (PTV/r) 75 mg/50 mg plus ombitasvir (OBV) 12.5 mg tablets Dasabuvir (DSV) 250 mg tablets VIEKIRA PAK is taken with food as three tablets in the morning and one in the evening. Paritaprevir is boosted with ritonavir (a CYP3A inhibitor that increases systemic exposure of paritaprevir). AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

19 Daily blister pack, twice-daily dosing Co-formulated paritaprevir/ritonavir (PTV/r) 75 mg/50 mg plus ombitasvir (OBV) 12.5 mg tablets Dasabuvir (DSV) 250 mg tablets Ribavirin, weight-based dose, 200 mg tablets Example: 1000mg RBV dose (patient 75kg) VIEKIRA PAK-RBV is taken with food, morning and evening. Most patients should start on 1000 or 1200 mg, depending on bodyweight. Ribavirin should be taken with food, morning and evening. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015. Ribavirin is a synthetic nucleoside analogue with HCV antiviral activity.

20 Indication VIEKIRA PAK and VIEKIRA PAK-RBV are indicated for the treatment of genotype 1 chronic hepatitis C, including patients with compensated cirrhosis. Duration of therapy and addition of ribavirin are dependent on patient population. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

21 Medsafe-approved* regimen: non-cirrhotic patients Patient Population Treatment Duration GT1a VIEKIRA PAK-RBV* 12 weeks GT1b VIEKIRA PAK 12 weeks *VIEKIRA PAK can be considered for treatmentnaïve non-cirrhotic patients with genotype 1a. VIEKIRA PAK-RBV is recommended in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. 12 weeks with VIEKIRA PAK-RBV are recommended for most cirrhotics; 24 weeks of VIEKIRA PAK-RBV are recommended for cirrhotic patients with genotype 1a and a previous null response to pegifn/rbv Note: this regimen is the same as that approved in Australia, Canada, and Switzerland, but differs from the USFDA label. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

22 Pooled trial data: non-cirrhotic patients Efficacy with NZ s recommended regimen 403/ / 50 36/ 36 83/ / / 33 26/ 26 32/ 32 AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

23 Pooled trial data: non-cirrhotic patients Efficacy with NZ s recommended regimen 403/ / 50 36/ 36 83/ / / 33 26/ 26 32/ 32 AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

24 Pooled trial data: Cirrhotic patients Efficacy with NZ s recommended regimen Overall SVR12 was 97% with the recommended regimen GT1a: 95% GT1b: 100% 61/ 66 14/ 15 11/ 11 39/ 42 22/ 22 14/ 14 95% in patients with compensated cirrhosis 6/ 7 25/ 25 AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015.

25 Pooled adverse event rates (all grades) % Non-cirrhotic patients (SAPPHIRE I and II) Non-cirrhotic patients (PEARL II, III and IV) Adverse Event* VIEKIRA PAK-RBV 12 weeks N = 770 Placebo 12 weeks N = 255 VIEKIRA PAK-RBV 12 weeks N = 401 VIEKIRA PAK 12 weeks N = 509 Fatigue 263 (34%) 67 (26%) 120 (30%) 135 (26%) Nausea 172 (22%) 38 (15%) 63 (16%) 43 (8%) Pruritus 121 (16%) 11 (4%) 48 (12%) 31 (6%)** Insomnia 108 (14%) 19 (7%) 49 (12%) 26 (5%) Asthenia 104 (13%) 17 (7%) 36 (9%) 20 (4%) Anaemia 41 (5%) 0 30 (7%) 1 (0.2%) This is a side-by-side tabulation of pooled adverse event rates in Phase 3 trials, based on AE >5% in VIEKIRA PAK-RBV compared to Placebo. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015. Table 14, pp45-46.

26 Pooled adverse event rates (all grades) % Non-cirrhotic patients (SAPPHIRE I and II) Non-cirrhotic patients (PEARL II, III and IV) Adverse Event* VIEKIRA PAK-RBV 12 weeks N = 770 Placebo 12 weeks N = 255 VIEKIRA PAK-RBV 12 weeks N = 401 VIEKIRA PAK 12 weeks N = 509 Fatigue 263 (34%) 67 (26%) 120 (30%) 135 (26%) Nausea 172 (22%) 38 (15%) 63 (16%) 43 (8%) Pruritus 121 (16%) 11 (4%) 48 (12%) 31 (6%)** Insomnia 108 (14%) 19 (7%) 49 (12%) 26 (5%) Asthenia 104 (13%) 17 (7%) 36 (9%) 20 (4%) Anaemia 41 (5%) 0 30 (7%) 1 (0.2%) This is a side-by-side tabulation of pooled adverse event rates in Phase 3 trials, based on AE >5% in VIEKIRA PAK-RBV compared to Placebo. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December2015. Table 14, pp45-46.

27 Pooled analysis: safety and tolerability Overall, adverse events were frequent, but manageable. Non-cirrhotic patients: Adverse events were generally mild (grade 1). Rates of serious adverse events were very low Fewer than 1% discontinuations overall (similar to placebo). Cirrhotic patients: Adverse events were generally mild or moderate. Serious adverse events occurred in 5.5% of patients overall. Treatment discontinuation due to adverse events was low (2.1%). Hepatic decompensation was rare (1.1%), and unrelated to study drug. 1 Feld JJ, et al. N Engl J Med 2014; 370: Zeuzem S, et al. N Engl J Med 2014; 370(17): Andreone P, et al. Gastroenterol 2014;147: Ferenci P, et al. N Engl J Med 2014;370(21): Poordad F et al. N Engl J Med 2014:370;

28 Summary: Lab results with VIEKIRA PAK No patient in the pivotal trials discontinued study drug due to laboratory abnormalities. ALT About 1% of patients experienced ALT elevations >5xULN.* ALT elevations were generally asymptomatic and transient (during first 4 weeks of treatment). Cirrhosis was not a risk factor for elevated ALT *The main risk factor was concurrent use of systemic oestrogen; co-administration is now contraindicated.) Bilirubin 2% of the patients given VIEKIRA PAK and 15% of patients given VIEKIRA PAK-RBV experienced bilirubin elevations (>2xULN). Bilirubin elevations were transient (peaked by first week), predominately indirect bilirubin, and not linked to ALT elevations. 1 Feld JJ, et al. N Engl J Med 2014; 370: Zeuzem S, et al. N Engl J Med 2014; 370(17): Ferenci P, et al. N Engl J Med 2014;370(21): Andreone P, et al. Gastroenterol 2014;147:

29 Ribavirin 1. Ribavirin (RBV) causes a dose-related haemolysis 2. RBV dose is 600mg bid if >75kg and 400/600 if <75kg reduce to 600mg/day if Hb <100g/L discontinue if haemoglobin is <85g/L. Caution if renal dysfn or severe vascular disease 3. In the clinical trials of VIEKIRA PAK: Clinically significant anaemia in 5% of patients RBV dose reduction in only 8.5% of patients 98.5% of patients with dose reduction were cured *Haemoglobin should be monitored carefully in patients with pre-existing cardiac disease, and RBV permanently reduced to 600mg/day if Hb decreases >20g/L during any 4-week period, and discontinued if it remains <120g/L despite reduction. AbbVie Limited. VIEKIRA PAK-RBV Data Sheet. Medsafe New Zealand; July Table 17, p49

30 Suggested Community Treatment Algorithm Secondary Care Discharge Avoid reinfection 30

31 Suggested monitoring during VIEKIRA PAK FBC, LFTs at Day 1, Week 2, 4 and 8 HCV RNA at Post-treatment Week 12 AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December

32 Precautions for VIEKIRA PAK Not recommended in patients with decompensated cirrhosis (Child-Pugh B or C). Caution if albumin <32 or platelets <100 Not recommended for HCV genotypes other than 1. Not recommended during pregnancy or breastfeeding Safety & effectiveness in children (<18 years) or elderly (>70 years) have not yet been established. Risk of hepatotoxicity with ethinyloestrodiol OC. Important interactions with drugs that are metabolised by CYP3A, are moderate or strong inducers of CYP3A, or are strong inducers or inhibitors of CYP2C AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December

33 Drug interactions with VIEKIRA PAK All direct-acting antivirals, including VIEKIRA PAK interact with drug metabolising enzymes or transporters. Ribavirin is associated with additional drug interactions. All patients should undergo a careful medicines review before treatment. 1. NZ Medsafe-approved Data Sheet: Please first refer to the New Zealand label for all drug interactions, including contraindicated medications, and precautions. 2. University of Liverpool website: Searchable by alphabetical list of drugs or by drug class. 3. AbbVie Medical Information: , medinfoanz@abbvie.com AbbVie has Data on File, built up through the clinical development programme and post-marketing experience.

34 NZ Data Sheet: drug interactions with VIEKIRA PAK No restrictions Abacavir Buprenorphine Dolutegravir b Duloxetine Emtricitabine Escitalopram Lamivudine Metformin Methadone Naloxone Norethisterone c Paracetamol Raltegravir Sulfamethoxazole Tenofovir Trimethoprim a Refer to Medsafe-approved Data Sheets. b Registered but not reimbursed in NZ. c NZ Spelling for Norethindrone. d Alfuzosin, Astemizole, Bepridil, Carisoprodol Caution / dose adjustment / clinical monitoring a Alprazolam Amiodarone Amlodipine Atazanavir Cyclosporine Darunavir, Darunavir/Ritonavir Diazepam Digoxin Fluticasone Flecainide Furosemide Ketoconazole Lidocaine (systemic) Mexiletine Omeprazole Pravastatin Propafenone Rosuvastatin Tacrolimus Warfarin Contraindicated/ not recommended Atorvastatin Carbamazepine Colchicine in renal or hepatic impairment Efavirenz Ergotamine and its derivatives Ethinyloestradiol-containing products Fusidic Acid Gemfibrozil Oral Midazolam Phenobarbital Phenytoin Quetiapine Rifampicin Rilpivirine b Ritonavir Sildenafil e Simvastatin Salmeterol St. John s Wort (Hypericum Perforatum) Terfenadine Triazolam Cyclobenzaprine, Disopramide, Hydrocodone, Blonanserin, Cisapride, Lovastatin, Pimozide, and Quinidine are listed in the Data Sheet as drug-interactions, but are not registered or reimbursed in NZ. e Contraindicated for treatment of pulmonary arterial hypertension; for erectile dysfunction, reduced dose frequency is recommended. Liverpool website but not NZ Data Sheet. AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. Medsafe New Zealand; December 2015.

35 Drug-drug interactions: Liverpool app Liverpool HIV & HEPATITIS Pharmacology Group. Hepatitis Drug Interactions. (Accessed Feb 2016).

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39 AbbVie s DDI database More than 1200 medications were permitted & managed in AbbVie s Phase II and III trials. Fewer than 1.5% of patients screened were excluded from trials due to prohibited medications. Abbvie is continuing to evaluate drug interactions with a range of compounds. Patients were taking the following classes of medication: Comedication Classes N Non-opioid analgesics 696 Anti-hypertensives 616 Anti-depressants 508 Proton pump inhibitors (GI agents) 385 Anti-histamines 337 Opioids 257 Hormone replacement therapies 226 Steroids 196 Anti-infectives 164 Anti-diabetics 122 Anti-epileptics 70 Statins and lipid-lowering agents 53 Anti-psychotics 41 Hormonal contraceptives 23 PDE5 inhibitors 19

40 Selecting the Correct Medications to Avoid DDIs Identify all co-medications including physician-prescribed, selfprescribed, herbal, and recreational* Check for alternatives with the help of a specialist if necessary Check for potential interactions with DAA regimen Summary of Product Characteristics NO Use with caution Contraindicated Is the co-medication absolutely necessary? Stop co-medication Proceed NO * Including grapefruit, which is a strong inhibitor of CYP3A4. YES NO Adjust DAA dose; proceed with monitoring Alternatives available? Courtesy of David Back NO Change DAA regimen YES Change to alternative Proceed 40

41 Summary: VIEKIRA PAK and VIEKIRA PAK-RBV High certainty of cure* EFFICACY: SVR12 = 97% for patients with genotype 1 HCV, with or without cirrhosis, including previous null responders to pegifn/rbv. Low rates of failure RESISTANCE PROFILE: Low rates of virologic failure (<2%) Low rates of discontinuation SAFETY: Well-tolerated regimen with low rates of discontinuations due to adverse events (0.5%) *Cure defined as 25 IU/mL HCV RNA 12 weeks after end of treatment (SVR12). SVR12 for VIEKIRA PAK and VIEKIRA PAK-RBV was 97% in patients with GT1 HCV (with or without cirrhosis; pooled analysis Phase III trial cohorts; n=1096). AbbVie Limited. VIEKIRA PAK and VIEKIRA PAK-RBV Data Sheets. MedsafeNew Zealand; December

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43 VIEKIRA PAK and VIEKIRA PAK-RBV are fully funded prescription medicines with an Xpharm distribution arrangement. Please review full Data Sheets before prescribing. These are available from AbbVie Limited at and from Medsafe at VIEKIRA PAK is a combination therapy containing paritaprevir/ritonavir/ombitasvir (75/50/12.5 mg) tablets and dasabuvir (250 mg) tablets. VIEKIRA PAK-RBV contains VIEKIRA PAK, plus ribavirin (200 mg*) tablets. INDICATIONS: VIEKIRA PAK and VIEKIRA PAK-RBV are indicated for the treatment of genotype 1 chronic hepatitis C, including patients with compensated cirrhosis. CONTRAINDICATIONS: VIEKIRA PAK: Severe hepatic impairment (Child-Pugh C); Hypersensitivity to components or excipients of VIEKIRA PAK or VIEKIRA PAK- RBV; Concomitant administration with: astemizole, carbamazepine, colchicine (in renal or hepatic impairment), efavirenz, ergotamine and its derivatives, ethinyloestradiol-containing medicines (e.g. oral contraceptives), fusidic acid, gemfibrozil, midazolam, phenobarbital,phenytoin, rifampicin, St. John s Wort (Hypericum perforatum), salmeterol, sildenafil (when used for pulmonary arterial hypertension), simvastatin, terfenadine or oral triazolam. Please refer to the full Data sheets for a complete list. VIEKIRA PAK-RBV As above, and: Pregnancy, including men whose partners are pregnant (Cat X); History of severe cardiac disease in previous 6 months; Haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia). PRECAUTIONS: VIEKIRA PAK: Moderate hepatic impairment (Child-Pugh B); for patients with compensated cirrhosis, monitor for clinical signs and symptoms of hepatic decompensation or failure, and discontinue treatment in patients who develop evidence of hepatic decompensation; HCV genotypes other than 1; not studied in patients previously treated with VIEKIRA PAK or other direct-acting antiviral agents; not studied in patients younger than 18 or older than 70; pregnancy (B3); discontinue breastfeeding prior to initiation; See Data Sheets for concomitant medicines for which dose adjustment or monitoring is recommended; monitor changes in laboratory parameters including bilirubin and alanine transaminase (ALT); VIEKIRA PAK-RBV: As above, and use two forms of contraception to avoid pregnancy; monitor haemoglobin in patients with pre-existing cardiac disease; monitor uric acid in patients predisposed to gout; reduce dose of ribavirin and monitor haemoglobin in patients with renal impairment. INTERACTIONS: See Data Sheets for medicines for which dose adjustment and/or monitoring should be considered. ADVERSE EFFECTS: VIEKIRA PAK: Fatigue, nausea, pruritus, insomnia and asthenia. VIEKIRA PAK-RBV: As above, and: anaemia, diarrhoea, vomiting, decreased appetite, dizziness, headache, sleep disorder, cough, dyspnoea, dry skin, and rash. DOSAGE AND ADMINISTRATION: VIEKIRA PAK: recommended dose is two paritaprevir/ritonavir/ombitasvir (75/50/12.5 mg) tablets once daily (in the morning) and one dasabuvir (250 mg) tablet taken with food twice daily (morning and evening) for 12 weeks. VIEKIRA PAK-RBV: As above, for 12 or 24 weeks, with ribavirin, the recommended dose of ribavirin depends on a patient's bodyweight (<75 kg = 1000 mg; 75 kg = 1200 mg), and should be taken with food in two doses (morning and evening). Ribavirin monotherapy is not effective and ribavirin must only be used in combination with VIEKIRA PAK. See full Data Sheets for additional information on duration of therapy and use in special populations. *Other presentations including ribavirin 400 mg and/or 600 mg tablets are not currently available in New Zealand. AbbVie is a registered Trademark of AbbVie Inc. VIEKIRA PAK is a registered Trademark of AbbVie Ireland Unlimited Company AbbVie Limited, PO Box 11437, Manners Street, Wellington 6142, New Zealand. NZ-HEP June 2016.