Christophe Hézode Hôpital Henri Mondor, Créteil, France Paris, 30 January 2012 Triple therapy today: Safety management in clinical practice

Telaprevir placebo-controlled Phase II/III studies: summary of AEs during telaprevir/placebo phase Patients, % T12/PR (750 mg q8h) n=1346 Placebo/PR48 n=764 Leading to discontinuation of all study drugs*(%) Skin and subcutaneous tissue disorders Pruritus (SSC) % Rash (SSC) % Blood and lymphatic system disorders Anemia (SSC) % Gastrointestinal disorders Nausea3929<0.5 Diarrhea2619<0.5 Hemorrhoids123<0.5 Anorectal discomfort82<0.5 Anal pruritus61<0.5 Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf *Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for rash and anemia) SSC: special search category

Boceprevir Phase III studies: summary of AEs over course of therapy Patients, % BOC RGTBOC44/PR48PR SPRINT-2 (naïve) 1 n=368n=366n=363 Anemia*49 29 Dysgeusia* Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) RESPOND-2 (experienced) 2 n=162n=161n=80 Anemia* Dysgeusia* Dry skin**21228 Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) Rash ‡ Poordad F, et al. N Engl J Med 2011;364:1195– Bacon BR, et al. N Engl J Med 2011;364:1207–17 *p<0.001 for boceprevir arms versus PR **p=0.009 (BOC RGT) and p=0.004 (BOC44/PR48) versus PR ‡ p=0.01 (BOC RGT) and p=0.05 (BOC44/PR48) versus PR

Specific adverse events with DAAs: rash

Grading of skin eruption severity  Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body) Cacoub P et al, J Hepatol 2012;56: Week 3 Focal maculo-papular lesions of the trunk (grade 1) Moderate pruritus No criteria of severity

Grading of skin eruption severity  Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)  Moderate: diffuse rash involving ≤50% of body surface area Cacoub P et al, J Hepatol 2012;56: Week 6 Maculo-papular rash of the trunk and limbs (grade 2) Moderate pruritus No criteria for severity

Grading of skin eruption severity  Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)  Moderate: diffuse rash involving ≤50% of body surface area  Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment Cacoub P et al, J Hepatol 2012;56:455-63

Estimating body surface area (BSA) 9% Front 18% Back 18% 9% 18% Hettiaratchy S, et al. BMJ 2004;329:101–3 Adult bodyBSA Perineum1% Arm9% Head (front and back)9% Leg18% Chest18% Back18%

Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase >90% of all rash = mild/moderate Incidence of rash (%) Features:  Typically pruritic and eczematous, and involving <30% BSA  Progression was infrequent (<10% of cases) Time to onset:  Approximately 50% of rashes started during the first 4 weeks  But rash can occur at any time during telaprevir treatment Incidence of rash (%) (n=1346)(n=764) T12/PR arm Cacoub P et al, J Hepatol 2012;56:455-63

Grading of skin eruption severity  Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)  Moderate: diffuse rash involving ≤50% of body surface area  Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment  SCAR: Collective term for severe drug-related skin conditions that can be associated with significant morbidity SCAR: Severe Cutaneous Adverse Reaction Cacoub P et al, J Hepatol 2012;56:455-63

 Collective term for severe drug-related skin conditions that can be associated with significant morbidity Severe Cutaneous Adverse Reaction: SCAR reported with telaprevir 3 cases suggestive of SJS* 11 cases suggestive of DRESS* (of which 1 case considered not related to telaprevir, onset 11 weeks after telaprevir discontinuation) SCAR encompasses several conditions Acute generalized exanthematous pustulosis (AGEP) and Erythema Multiforme Major (EMM) Drug rash/reaction with eosinophilia and systemic symptoms (DRESS) Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) *In placebo-controlled Phase II/III trials, 0.4% of patients had suspected DRESS; in telaprevir clinical experience, less than 0.1% of patients had SJS Cacoub P et al, J Hepatol 2012;56:455-63

When to suspect DRESS Alert criteria: –Onset from 6–10 weeks after first dose –Rapidly progressing exanthema –Prolonged fever (>38.5°C) –Facial oedema What to do?  If any DRESS alert criteria are found, the patient should be assessed for the following confirmation criteria –Enlarged lymph nodes (at least 2 sites) –Eosinophilia (≥700/μL or ≥10%) –Atypical lymphocytes –Internal organ involvement –Liver: ALT, alkaline phosphatase ≥2 x upper limit of normal –Kidney: rise in creatinine ≥150% basal level  If any DRESS confirmation criteria are also found: –Stop all drugs –Hospitalize the patient –Consult a dermatologist What to do?  If any DRESS alert criteria are found, the patient should be assessed for the following confirmation criteria –Enlarged lymph nodes (at least 2 sites) –Eosinophilia (≥700/μL or ≥10%) –Atypical lymphocytes –Internal organ involvement –Liver: ALT, alkaline phosphatase ≥2 x upper limit of normal –Kidney: rise in creatinine ≥150% basal level  If any DRESS confirmation criteria are also found: –Stop all drugs –Hospitalize the patient –Consult a dermatologist Cacoub P et al, J Hepatol 2012;56:455-63

When to suspect SJS/TEN Rapidly progressing exanthema Skin pain Mucosal involvement at ≥2 sites Blisters or epidermal detachment Atypical/typical target lesions What to do?  Stop all drugs  Hospitalize the patient  Consult a dermatologist What to do?  Stop all drugs  Hospitalize the patient  Consult a dermatologist Cacoub P et al, J Hepatol 2012;56:455-63

Drug considerations: mild and moderate rash Treating patients with mild or moderate rash  Emollients  Topical corticosteroids  Permitted systemic antihistaminic drugs may be tried for the treatment of associated pruritus  Limit exposure to sun/heat and wear loose-fitting clothes  Add oatmeal to bathing water Treating patients with mild or moderate rash  Emollients  Topical corticosteroids  Permitted systemic antihistaminic drugs may be tried for the treatment of associated pruritus  Limit exposure to sun/heat and wear loose-fitting clothes  Add oatmeal to bathing water Rash Mild Moderate Monitor for progression or systemic symptoms until the rash is resolved For moderate rash, consider consultation with a dermatologist. For moderate rash that progresses, permanent discontinuation of telaprevir should be considered If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted. Interruption of ribavirin may be required sooner if the rash worsens despite discontinuation of telaprevir Peginterferon alfa may be continued unless interruption is medically indicated For moderate rash that progresses to severe (≥50% body surface area), permanently discontinue telaprevir Cacoub P et al, J Hepatol 2012;56:455-63

Drug considerations: severe rash and SCAR Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment SCAR: generalized bullous eruption, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment SCAR: generalized bullous eruption, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) TELAPREVIR must not be restarted if discontinued Rash Severe SCAR Permanently discontinue telaprevir immediately. Consultation with a dermatologist is needed Monitor for progression or systemic symptoms until the rash is resolved. If no improvement within 7 days of stopping telaprevir (or earlier if rash worsens), sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon should be considered Permanent and immediate discontinuation of telaprevir, peginterferon and ribavirin is required Consult with a dermatologist Cacoub P et al, J Hepatol 2012;56:455-63

Specific AEs with DAAs: anemia

Summary of anemia data from the boceprevir SPRINT-2 study over course of therapy Incidence and severity of anemia increased with boceprevir combination treatment compared with PR alone BOC RGT Control Hemoglobin <10 to 8.5 g/dLHemoglobin <8.5 g/dL Patients (%) BOC44/ PR48 BOC RGT ControlBOC44/ PR48 Poordad F, et al. N Engl J Med 2011;364:1195–206

Summary of anemia data from Phase II and III placebo-controlled studies Telaprevir EU SmPC Incidence and severity of anemia increased with telaprevir combination treatment compared with PR alone T12/PR Placebo/ PR48 T12/PR Placebo/ PR48 Hemoglobin <10 g/dLHemoglobin <8.5 g/dL Patients (%)

Hemoglobin shifts on telaprevir treatment: placebo-controlled Phase II and III studies Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf Number of patients Week BL T12/PR (750mg q8h) Placebo/PR Mean +/– SE T12/PR (750mg q8h) Placebo/PR BL Weeks

Management of anemia observed with telaprevir and boceprevir in clinical trials Telaprevir Phase II/III placebo- controlled trials 1 Boceprevir trials 2–4 Ribavirin dose reductions due to anemia 21.6% (telaprevir arms) vs 9.4% (control) 26% (boceprevir arms) vs 13% (control) EPO useNot permitted (1% use) 43% (boceprevir arms) vs 24% (control) Transfusions Telaprevir/placebo dosing phase: 2.5% (telaprevir arms) vs 0.7% (control) Overall study period: 4.6% (telaprevir arms) vs 1.6% (control) 3% (boceprevir arms) vs <1% (control) Discontinuation Telaprevir alone: 1.9% vs 0.5% control All treatment at the same time: 0.9% (telaprevir arm) vs 0.5% (control) 0–3% (boceprevir arms) vs 0–1% (control) 3,4 1. Telaprevir EU SmPC; 2. Boceprevir EU SmpC 3. Poordad F, et al. N Engl J Med 2011;364:1195–206; 4. Bacon BR, et al. N Engl J Med 2011;364:1207–17

ADVANCE and ILLUMINATE (telaprevir): SVR rates by anemia status and RBV dose reduction SVR (%) n/N= T12PR 267/361 PR 46/92 Anemia PR 108/262 T12PR 384/524 No anemia Sulkowski M, et al. J Hepatol 2011;54(Suppl. 1):S195 T12PR 243/320 PR 37/69 PR 117/285 T12PR 408/565 RBV dose reduction No RBV dose reduction Erythropoietin alfa (EPO) was not allowed in ADVANCE and ILLUMINATE; RBV: ribavirin SVR was defined as undetectable HCV RNA 24 weeks after last planned dose

95/129 SPRINT-2 (boceprevir): SVR rates by EPO use and RBV dose reduction (pooled boceprevir arms) Sulkowski M, et al. J Hepatol 2011;54(Suppl. 1):S194 SVR (%) No anemiaAnemia 212/36329/37109/15330/44 n/N= Data shown for pooled boceprevir arms; SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward

PR BOC+PR If Hb <10 g/dl: ↓RBV and not EPO allowed If Hb < 10 G/dl: EPO use RVS Prospective study comparing EPO use or RBV dose reduction

Specific AEs with DAAs: anorectal signs

 Reported under various terms such as anal pruritus, anorectal discomfort as well as hemorrhoids in 25% of patients treated with telaprevir –Onset is most commonly in the first 2 weeks of treatment  Mechanism is unknown  Non specific topical treatment, ± including local anesthetic (rectal burning), ± topical steroidal ointment (pruritus)  Systemic antihistamine could be used  Progressive improvement and resolution after telaprevir discontinuation  Triple therapy can be continued Anorectal signs and symptoms

Safety in cirrhotic patients

REALIZE (telaprevir): Safety Cirrhotics (F4) n=139 Non-cirrhotics (F0–3) n=391 Discontinuation of all study drugs during TVR treatment phase 10 (7%)17 (4%) Hemoglobin ≤10g/dL ≤8.5g/dL 63 (46%) 19 (14%) 156 (40%) 49 (13%) Neutrophils Grade 3 (500 to <750/mm 3 ) Grade 4 (<500/mm 3 ) Grade 3/4 35 (25%) 10 (7%) 45 (32%) 68 (17%) 9 (2%) 77 (19%) Platelets Grade 3 (25,000 to <50,000/mm 3 ) Grade 4 (<25,000/mm 3 ) Grade 3/4 16 (12%) 2 (1%) 18 (13%) 12 (3%) 1 (<1%) 13 (3%) Pol S et al, AASLD 2011

CUPIC: telaprevir – preliminary safety findings Patients, n (%)Telaprevir (n=176) Serious AEs90 (51)* Discontinuation due to serious AE21 (12) Death3 (1.7) Rash Grade 3 SCAR 12 (6.8) 0 Infection (Grade 3/4)6 (3.4) Other AEs (Grade 3/4)92 (52) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 58 (33) 23 (13) 96 (55) 32 (18) Neutropenia Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 20 (11) 2 (1) 5 (3) Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 26 (15) 12 (7) *228serious AEs in 90 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony stimulating factor Hézode C, et al, Hepdart 2011

CUPIC: Boceprevir – preliminary safety findings Patients, n (%)Boceprevir (n=134) Serious AEs39 (29)* Discontinuation due to serious AE8 (6) Death1(1) Rash Grade 3 SCAR 0000 Infection (Grade 3/4)0 Other AEs (Grade 3/4)43 (32) Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion 41 (31) 8 (6) 70 (52) 8 (6) Neutropenia Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 10 (7) 5 (4) 7 (5) Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000) 8 (6) 3 (2) *86serious AEs in 39 patients; SCAR: severe cutaneous adverse reaction; EPO: erythropoetin; G-CSF: granulocyte-colony stimulating factor Hézode C, et al, Hepdart 2011

Conclusions Additional side effects with DAAs include: –Telaprevir: rash, anemia, anorectal itching –Boceprevir: anemia, dysgeusia, neutropenia Rash: –Most rashes (>90%) are mild and compatible with ‘treating-through’ –Few cases of severe cutaneous reactions (SJS, DRESS) (resolved with treatment discontinuation) Anemia: –Increased with telaprevir and boceprevir –Strategies for treating anemia include RBV dose reduction, EPO use and blood transfusions Cirrhosis: - The safety profile of DAAs among compensated cirrhotic patients treated in the CUPIC cohort is poor but compatible with use in real-life practice - Patients with cirrhosis should be treated with cautious and should be carefully monitored