Boceprevir and telaprevir: efficacy and side effects, what have we learned in 2013

Fred Poordad, MD VP, Academic and Clinical Affairs The Texas Liver Institute Professor of Medicine University of Texas Health Science Center San Antonio, Texas

Disclosures

• Grant/Research support: , Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, , GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck & Co., Novartis, Pharmasset, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, , ViroChem Pharma, ZymoGenetics; • Speaker: Gilead, Merck, Vertex, Salix, Onyx/Bayer, Kadmon, Janssen • Consultant/Advisor: Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, GlobeImmune, Inhibitex Pharmaceuticals, Merck & Co., Pharmasset, Santaris Pharmaceuticals, Tibotec/Janssen, Theravance.

Outline

• Creating the infrastructure to treat HCV successfully

• Dealing with interferon side effects

• Who responds well to the first wave protease inhbitors

• Factors that can help decide who should be treated

• Adverse events of first wave protease inhibitors and who not to treat Optimizing Adherence: A Collaborative Care Approach

Hepatologists Gastroenterologists Internists/ID

Social workers NPs/PAs/RNs Collaborative Care Approach

Medication Other medical reimbursement specialists specialists

Yozviak JL, et al. 2011 International Conference on Viral Hepatitis. Abstract 70752. Gujral H, et al. Cleve Clin J Med. 2004;71(suppl 3):S33-S37. Patient Education Is the Foundation of HCV Management

• HCV transmission – Review CDC recommendations and go over high risk behavior risks • HCV natural history for that patient based on host/viral factors

• Liver healthy lifestyle – Achieve and/or maintain a normal BMI – Avoid alcohol

• Drug–drug interactions with HCV PIs – Careful history • Avoid pregnancy during and for 6 mos after RBV-based therapy

Organ Systems Affected by Interferon

Constitutional Ophthalmologic Events Disorders

Neuropsychiatric Infectious Events Diseases

Dermatologic Autoimmune Disorders Disorders

Cardiovascular Hematologic Disorders Disorders

Pulmonary GI Events Events

Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol. 2011;8:212-223. Peginterferon and Depression (Incidence 20%-60%)

Contributors Symptoms • Pre-existing depressive and/or • Depression-specific symptoms anxiety symptoms - Low mood - Anhedonia • Depression during previous - Anxiety treatment - Cognitive complaints • RBV-induced anemia - Suicidal ideation and/or suicide (severe depression) • Long treatment duration • Neurovegetative symptoms • Lack of social support - Fatigue • Thyroid dysfunction - Anorexia - Pain • HIV coinfection - Psychomotor slowing • Organic brain impairment • HTR1A allelic variation

Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol. 2011;8:212-223. Sung H, et al. Curr Hepatitis Rep. 2011;10:33-44. Ribavirin: Anemia

• Signature adverse event IDEAL Study: Hemoglobin – Incidence: up to 30% LD pegIFN alfa 2b + RBV (n=1008) • Common reason for SD-pegIFN alfa 2b + RBV (n=1000) PegIFN alfa 2a + RBV (n=1034) – Dose reduction: 9% to 22% 31% – Discontinuation: ~5% 30% • Hemoglobin reduction within the first 4 25% weeks of therapy – 2.5 to 3.0 g/dL

• Impact (%) Patients – Persistent fatigue, shortness of breath, lower quality of life scores 3.8% 2.1% 2.5%

Hemoglobin Discontinued: <10 g/dL Hemoglobin Sung H, et al. Curr Hepatitis Rep. 2011;10:33-44. <8.5 g/dL Reddy KR, et al. Gastroenterol. 2010;139:1972-1983. LD: low-dose; SD: standard-dose. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol. 2011;8:212-223.

Ribavirin: Dermatologic Adverse Events

• Ribavirin monotherapy – May cause rash and pruritus Ribavirin Ribavirin Rash Interrupted • Combination with peginterferon – Increase incidence of dermatologic adverse events than with either drug alone • Generalized pruritus • Skin xerosis • Eczematiform lesions (extremities) • Management – Transient rashes • Topical corticosteroids • Ribavirin treatment interruption not needed – Discontinue ribavirin • Acute hypersensitivity reaction

Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol. 2011;8:212-223. Sung H, et al. Curr Hepatitis Rep. 2011;10:33-44. Ribavirin: Teratogenic Events

• Pregnancy Category X Pregnancy 6 Months First – Contraindicated in pregnant woman and in the Outcomes Prior LMP Trimester male partners of pregnant women (2003-2009) (n=173) (n=173) • Avoid pregnancy during and 6 months post Direct exposure 90.6 9.4 ribavirin treatment completion outcomes (%) – Use 2 reliable forms of effective contraception Live births 52.9 4.7 Miscarriage 11.8 2.4 • Ribavirin-induced testicular toxicity Elective termination 25.9 2.4 – Recovery within 1 or 2 spermatogenesis cycles Fetal death/still birth -- -- following cessation of ribavirin therapy Indirect exposure 87.3 10.9 • Ribavirin pregnancy registry outcomes (%) – Birth defect rate Live births 53.6 7.3 • Direct exposure: 6.1% (1.2-16.9) Miscarriage 10.9 3.6 • Indirect exposure: 4.3 (0.9-12.2) Elective termination 21.8 -- Fetal death/still birth 0.9 --

Sung H, et al. Curr Hepatitis Rep. 2011;10:33-44. Roberts SS, et al. Birth Defects Res A Clin Mol Teratol. 2010;88:551-559. http://www.ribavirinpregnancyregistry.com/. The Addition of First Wave DAAs: Protease Inhibitors Telaprevir and Boceprevir

SVR Rates With BOC or TVR + PR According to Treatment History

100 Relapsers Naive Partial Responders Null Responders 69-83 80 63-75

60 40-59

SVR (%) SVR 29-40 40

20

0

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364: 2417-2428. Bronowicki JP, et al. EASL 2012. Abstract 11. Who is a Reasonable Candidate for Treatment Now?

• First Criteria: – must be interferon willing and responsive

• Secondary Considerations: – May not be able to safely wait for future therapies. Ie) advancing liver disease – May not have access to future therapies – May have non-hepatic complications of HCV such as cryoglobulinemia, etc – May want to be cured for non-medical reasons

Some Baseline Predictors Can Help Guide Us

• Subtype • Past treatment experience • Fibrosis • Ethnicity • IL28B Status • BMI/DM

Baseline Predictors of SVR: SPRINT 2 and RESPOND 2

Poordad F, et al. Gastroenterology 2012;143(3):608-618 . SVR According to Race

ADVANCE (TVR): Naive Patients With Genotype 1 HCV

T12PR 100 PR48

80 75 74 75

62 60 46 44 39 SVR (%) SVR 40 25 20 n/N = 244/ 147/ 16/ 7/ 26/ 15/ 245/ 143/ 325 318 26 28 35 38 328 323 0 White Black Latino Non-Latino

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. SVR According to Race

SPRINT-2 (BOC): Naive Patients With Genotype 1 HCV

BOC/PR48 100 BOC/PR RGT PR48 80 68 67 60 53 42 40 SVR (%) SVR 40

23 20 n/ 213/ 211/ 125/ 29/ 22/ 12/ N = 311 316 311 55 52 52 0 Nonblack Black

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. IL-28B Predicts SVR with Boceprevir and Telaprevir SVR % SVR

SPRINT 2 ADVANCE Poordad, et al. Gastroenterology. 2012;143(3):608-618 Jacobson, et al. Presented at the European Association for the Study of the Liver Annual Meeting; March 30–April 3, 2011; Berlin, Germany. Abstract 1369 On Treatment Response is Best Assessment of IFN Response

High SVR rates in Early Viral Responders

SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients

. 57% of patients undetectable at week 8 and eligible for shorter therapy

HCV RNA undetectable HCV RNA detectable at Week 8, at Weeks 8 through24 undetectable at Week 24

Nonblacks Blacks 100 97 96 95 100 93 100 87 88 80 74 74 80 62 66 58 60 60

40 40 SVR (%) SVR

20 20 37/ 78/ 143/ 52/ 137/ 48/ n/ 3/ 8/ 13/ 7/ 18/ 7/ 40 118 147 70 142 65 N = 3 13 15 12 19 8 0 0 PR48 BOC/PR BOC/PR PR48 BOC/PR BOC/PR RGT 48 Wks RGT 48 Wks

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. IL-28B CC Polymorphism is the Best Predictor of Early Response

CC

CT + TT RNA by TW8 by - RNA HCV % Patients with undetectable

118 158 41 80 132 304 50 156

SPRINT-2 RESPOND-2 *Decision point for short vs. long treatment duration with RGT Early Interferon Response (Lead-In) Further Defines Likelihood of Success for Non-CC Patients

1 1 0 2 2 56 83 58 27 19 20 37 83 109 20 6 10 13 23 26 2 3 4 75 102 72 51 45 117 111 133 25 25 26 28 34

CC CT TT

Poordad F, et al. Gastroenterology 2012;143(3):608-618 . Early Responders do Well Early Response has Two Critical Time Points

• Week 4 of Interferon and Ribavirin when using Lead In

• Week 8 (4 weeks into boceprevir dosing)

• Week 4 and 12 of Telaprevir based therapy Those with advanced fibrosis do not do well

SVR by Fibrosis Stage With Boceprevir or Telaprevir

Fibrosis Stage SVR Rate (Phase III Trials), % Treatment-naive patients (TVR and BOC)[1,2] Stage 0/1/2 67-78 Stage 3/4 41-62 Treatment-experienced patients Stage 0/1/2 (BOC)[3] 66 Stage 3/4 (BOC)[3] 44 Relapser (TVR)[4] . No/minimal/portal 86 . Bridging 85 . Cirrhosis 84 Partial responder (TVR)[4] . No/minimal/portal 72 . Bridging 56 . Cirrhosis 34 Null responder (TVR)[4] . No/minimal/portal 41 . Bridging 39 . Cirrhosis 14

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. EASL 2011. Abstract 5. REALIZE: SVR by Baseline Fibrosis Stage and Prior Response

Prior Relapsers Prior Partial Responders Prior Null Responders

Pooled T12/PR48 PBO/PR48

SVR (%)

n/N= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10

No, minimal Bridging Cirrhosis No, minimal Bridging Cirrhosis No, minimal Bridging Cirrhosis Stage or portal fibrosis or portal fibrosis or portal fibrosis fibrosis fibrosis fibrosis

27 Zeuzem S, et al. EASL 2011, Abstract 5. CUPIC: French early access program

79 118 43 61 32 43 1 8 190 295 85 116 80 135 9 28

H. Fontaine et al, Abstract 60. EASL, April 2013 High SAE rate when albumin<3.5 g/dL and platelets< 100,000/mL

Boceprevir (n=191) Telaprevir (n=295) Serious adverse event 321 in 97 patients 535 in 160 patients (51.0%) (54.2%) Deaths* 3 (1.6%) 7 (2.4%) Grade 3/4 infections 8 (4.2%) 27 (9.1%) Hepatic decompensation 9 (4.7%) 15 (5.1%) Rash (grade 3 / SCAR) 2 (1.0%) / - 16 (5.4%) / 2 (0.6%) Anemia (Hb < 8g/dL) 19 (10%) 38 (12.9%) EPO use / blood TF 119 (62.6%) / 26 (13.7%) 168 (57%) / 53 (18%)

TVR* – 3 septicemia, 1 variceal bleed, 1 HE, 1 pulm neoplasia , 1 pneumonia BOC* – 1 pulm infection, 1 aneurysmal bleed, 1 septicemia

H. Fontaine et al, Abstract 60. EASL, April 2013 Comparison of Lead-in Arms of Treatment Experienced Trials

SVR % SVR

* Pooled data from RGT and Arm 3

Zeuzem, et al. N Engl J Med. 2011;364(25):2417-28 Bacon BR, et al. NEJM. 2011;364:1207-1217.

SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL VL) (BOC Arms Combined) 100 91 83 79 80

60 50 48 49

% SVR % 38 40 33 30 21 16 20 9 0 3 6 10 10 23 15 23 0 5 29 25 33 0 2 160 8 28 20 11 0 70 31 29 440 31 98 51 40 28 23 0 <3 3-4 4-5 >5 <3 3-4 4-5 >5 <3 3-4 4-5 >5

RESPOND-2 SPRINT-2 Combined Poordad, et al. Gastroenterology. 2012;143(3):608-618 Studies Side Effects of First Wave Protease Inhibitors Prevalence of Anemia in Clinical Trials

• In 2%–4% of patients, anemia must be classified as an SAE • Up to 4% of patients stop PI therapy due to anemia

• Overall, any SAE occurred in about 9%–12% – What are the results in real-life patients? – Higher rate of discontinuation in patients with…?

Patients(%) • Advanced age • Cardiovascular diseases • Pulmonary disorders • Renal dysfunction • ???

BOC = boceprevir; PI = protease inhibitor; PR = PEG-IFN + ribavirin; SAE = serious adverse event; T12 = telaprevir.

Poordad F, et al. N Engl J Med 2011;364(13):1195-206; Jacobson33 IM, et al. N Engl J Med 2011; 364(25):2405-16; Sherman KE, et al. N Engl J Med 2011;365(11):1014-24. Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management:Primary Efficacy Results 100 RBV DR EPO 90 82 82

80 71 71 70 60 50 40 30 20 10 10 % % of Patients (95% CI) 10 203 205 178 178 19 19 249 251 249 251 0 196 197 EOT Response SVR Relapse

Poordad F, et al. Gastroenterology 2013;145(5):1035-1044 SVR Rates Similar Between Groups Regardless of Viremia Status at Start of Primary Anemia Management

RBV RBV EPO EPO DR DR

111 107 67 71 129 124 120 127

Poordad F, et al. Gastroenterology 2013;145(5):1035-1044 SVR by Percent Total RBV Dose Received in Patients Who Received ≥80% of Treatment Duration

6 9 20 34 100 9 12 24 38 109

* Assigned Total RBV Dose = Per-protocol assigned total RBV dose for the entire treatment36 period Poordad F, et al. Gastroenterology 2013;145(5):1035-1044 Poordad F, et al. Gastroenterology 2013;145(5):1035-1044 Drug-Drug Interactions With PIs

.HCV PIs are CYP3A4 inhibitors .Until the drug is specifically studied, magnitude of the impact of PI on its level is not known .HCV PI metabolism differs – Boceprevir: primarily aldo-ketoreductase and partially CYP3A4/5 – Telaprevir: CYP3A4 .Exercise caution with ALL coadministered Contraindications to BOC and TVR as Listed in Prescribing Information

Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2] Alpha 1-adrenoreceptor Alfuzosin Alfuzosin antagonist Anticonvulsants Carbamazepine, phenobarbital, N/A phenytoin Antimycobacterials Rifampin Rifampin Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin inhibitors Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for tx of Sildenafil or tadalafil when used for tx pulmonary arterial hypertension of pulmonary arterial hypertension Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam, midazolam triazolam *Studies of drug-drug interactions incomplete.

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. Stopping Rules

Drug Regimen Timepoint Criteria Stopping Rule Action TVR + Week 4 or HCV RNA >1000 IU/mL Discontinue all therapy pegIFN/RBV Week 12 Discontinue Week 24 Detectable HCV RNA pegIFN/RBV Discontinuation of Any pegIFN/RBV for any Discontinue TVR reason BOC + Week 12 HCV RNA >100 IU/mL Discontinue all therapy pegIFN/RBV Week 24 Detectable HCV RNA Discontinue all therapy Discontinuation of Any pegIFN/RBV for any Discontinue BOC reason

Telaprevir package insert; Boceprevir package insert. Summary

• Clearly Eligible for Telaprevir/Boceprevir • Interferon and ribavirin eligible/willing AND: – Relapsers to pegylated interferon based regimens – IL-28B CC variants who are naïve or relapsers – Any patient with demonstrated interferon responsiveness using lead-in

• Marginally Eligible – Naïve patients with advancing fibrosis – No other options available and with fibrosis

• Not Recommended – Interferon non-responsive or ineligible based on past treatment or lead-in – Minimal fibrosis – At risk for DDI – Baseline anemia or signficant renal disease – Albumin < 3.5 g/dL and platelets < 100,000/mL

Conclusions

• Interferon and ribavirin based regimens have a variety of adverse events associated with them

• Anemia is the single most common laboratory and clinical adverse event requiring intervention with first wave protease inhibitors

• Emerging therapies have a better adverse event profile compared to controls and current standards of care

• Treat only those with good baseline or on-treatment predictors of response