telaprevir_emincivekem

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Hepatitis Web Study

Use of & Telaprevir (Incivek) in the Treatment of Chronic Hepatitis C Virus

Presentation Prepared by: David Spach, MD and Nina Kim, MDLast Updated: July 26, 2011

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Hepatitisweb study

Background and DosingTelaprevir (Incivek)

HEPATITIS C: TREATMENT

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Telaprevir (Incivek)


• Approval- FDA Approved May 23, 2011

• Indications- In combination with Peginterferon-alfa and Ribavirin (PR)- Chronic HCV genotype 1 infection- Adults (> 18 years of age) with compensated liver disease, including cirrhosis- Treatment-naïve or prior interferon-based treatment

• Dosing- 750 mg (two 375-mg tablets) three times daily with food (not low fat)- Treat with PR for 12 weeks (followed by additional 12 or 36 weeks PR)

• Adverse Effects- Rash, anemia, nausea, fatigue, headache, diarrhea, pruritus, and anal or rectal irritation and pain

Source: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

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Dosing of Peginterferon-alfa and Ribavirin when Used with Telaprevir


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*In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL.


Telaprevir (Incivek)Response Guided Therapy


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Telaprevir Response-Guided TherapyTreatment Naïve and Prior Relapse Patients


Telaprevir: Response Guided Therapy (RGT) for Treatment Naïve and Prior Relapse Patients

Undetectable

Telaprevir-12 wks

Peginterferon + Ribavirin-24 wks

Telaprevir-12 wks

Peginterferon + Ribavirin-48 wks

RGT

Hepatitisweb studySource: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

Telaprevir (Incivek)Treatment Futility Rules for All Patients


PR = Peginterferon + Ribavirin*In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL.

0 12 244

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Hepatitisweb study

Adverse EffectsTelaprevir (Incivek)


Hepatitisweb studySource: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

Telaprevir (Incivek)Adverse Effects


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Hepatitisweb study

Telaprevir (Incivek)Mild Skin Rash


Source: Photograph Courtesy of John Scott, MD, University of Washington

Hepatitisweb study

Telaprevir (Incivek)Mild Skin Rash


• Assessment- Localized rash and/or rash with limited distribution- With or without associated pruritus

• Management- Continue all medications for HCV therapy- Use good skin care practices- Consider oral antihistamine + topical corticosteroid- Monitor and re-assess if progression occurs*

Source: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

*Stop telaprevir if becomes severe or systemic symptoms develop; OK to continue Peginterferon and Ribavirin, but if rash persists within 7 days of stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin

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Telaprevir (Incivek)Good Skin Care for Telaprevir-Associated Rash


• Apply skin moisturizers at least twice a day • Avoid perfumes and other scented skin care products• Use hypoallergenic products• Keep hydrated• Wear loose-fitted clothing• Avoid scratching• Use unscented and mild laundry detergent• Avoid using dryer sheets with clothes in dryer• Limit sun exposure and use sun screen when out in sun• Avoid hot showers and hot baths• Consider using a nonsoap cleanser• Apply skin moisturizers after bathing (before drying off)

Source: Vertex Pharmaceuticals.

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Hepatitisweb study

Telaprevir (Incivek)Moderate Skin Rash



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Telaprevir (Incivek)Moderate Skin Rash


• Assessment- Diffuse rash and/or rash with limited distribution- With or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration

• Management- Continue all medications for HCV therapy- Use good skin care practices- Consider oral antihistamine + topical corticosteroid- Monitor and re-assess if progression occurs*


*Stop telaprevir if becomes severe or systemic symptoms develop; OK to continue Peginterferon and Ribavirin, but if does not improve within 7 days after stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin

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Hepatitisweb study

Telaprevir (Incivek)Severe Skin Rash



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Telaprevir (Incivek)Severe Skin Rash


• Assessment- Generalized rash with or without pruritus

OR- Rash with vesicles, bullae, or ulcerations (other than SJS)

• Management- Stop Telaprevir (do not restart)- May continue Peginterferon + Ribavirin- Use good skin care practices- Consider oral antihistamine + topical corticosteroid- Monitor and re-assess*


*If rash does not improve within 7 days of stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin

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Telaprevir (Incivek)Serious Skin Rash (DRESS or SJS)


• Assessment- Stevens-Johnson Syndrome (SJS): Generalized rash with symptoms that may

include fever, target lesions, and mucosal erosions or ulcerationsOR

- Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Presenting signs and systemic symptoms may include rash, fever, facial edema, and evidence of internal organ involvement (eg. hepatitis, nephritis). May occur with or without eosinophilia.

• Management- Stop all drugs immediately- Promptly refer for urgent medical care- Do NOT restart Telaprevir at any time in future


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Hepatitisweb study

Drug InteractionsTelaprevir (Incivek)


Hepatitisweb studySource: Vertex Pharmaceuticals.

Telaprevir (Incivek)Drug-Drug Interactions: Contraindicated Medications


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Hepatitisweb study

ResistanceTelaprevir (Incivek)


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Viral Breakthrough & Telaprevir Resistance


• 14 (8.7%) viral breakthroughs were observed

• Half of these occurred before or at week 4

• Viral breakthroughs were more frequent in patients with HCV genotype 1a (11/14) than 1b (3/14).

• 11 (79%) of 14 patients with viral breakthrough had variants harboring mutations (V36M, V36M/R155K, or A156S) associated with decreased susceptibility to telaprevir

• No differences in number and type of mutations were observed across arms

Source: Marcellin P, et. al. Gastroenterology. 2011;140:459-68.

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Telaprevir for Chronic HCV InfectionResistance Among those who did not Achieve SVR


• Treatment-emergent resistance mutations occurred in 62% of subjects from ADVANCE, ILLUMINATE and REALIZE trials who did not achieve SVR.

• Resistance mutations occurred in nearly 100% of subjects who failed during initial 12 weeks of triple therapy, and in majority of those who failed after 12 weeks or who relapsed.

• On-treatment virologic failure was more frequent in subjects with genotype 1A compared with 1B.

• On-treatment virologic failure was more frequent in subjects with prior history of null response.


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Telaprevir for Chronic HCV InfectionResistance Among those who did not achieve SVR


• Treatment-emergent resistance mutations occurred in 62% of subjects from ADVANCE, ILLUMINATE and REALIZE trials who did not achieve SVR.


Hepatitisweb studySource: Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.

Telaprevir and BoceprevirGenotypic Resistance


Mutation Telaprevir Boceprevir

V36A/M + +

T54S/A + +

V55A In vitro +

Q80R/K - -

R155K/T/Q + +

A156S + +

A156T/V + In vitro

D168A/V/T/H - -

V170A/T In vitro +

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Hepatitisweb study

Treatment DataTelaprevir (Incivek)


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Summary of Telaprevir (Incivek) Studies

• Telaprevir (Incivek) Studies in Treatment-Naïve- PROVE 1: Phase 2b- PROVE 2: Phase 2b - ADVANCE (Study 108): Phase 3 - ILLUMINATE (Study 111): Phase 3

• Telaprevir (Incivek) Studies in Previously Treated- PROVE 3: Phase 2b- REALIZE (Study C216): Phase 3

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Hepatitisweb study

Telaprevir in Treatment NaivePROVE1


Hepatitisweb studySource: McHutchison JG, et. al. N Engl J Med. 2009;360:1827-38.

Telaprevir for Chronic Untreated HCV InfectionPROVE1: Study Design


Drug DosingTelaprevir = 1250 mg on day 1, then 750 mg tidPeginterferon alfa-2a = 180 µg weeklyRibavirin = 1000 mg/d for wt < 75 kg; 1200 mg/d for wt > 75 kg

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Telaprevir (Incivek)Adverse Effects in Prove Trial


• Rash: Telaprevir versus Standard of Care- Overall incidence – 50% (TPV arms) vs 20% (PR controls)- Grade 3 (TPV versus PR Controls):

PROVE 1: 5-9% versus 1%PROVE 2: 3-7% versus 0%PROVE 3: 3-5% versus 0%

- Grade 4 (PROVE 3): 5% versus 0%

• Pruritus: 50-60%

• Anemia: Incremental Hgb decrease of ~1 g/dL

McHutchinson JG, et. al. N Engl J Med. 2009;360:1827-1838.Hezode C, et. al. N Engl J Med. 2009;360:1841-1850.McHutchinson JG, et. al. N Engl J Med. 2010;362:1292-1303.

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PegIFN + RBV

Telaprevir

Source: McHutchison JG, et. al. N Engl J Med. 2009;360:1827-38.

Telaprevir for Chronic Untreated HCV InfectionPROVE1 Study: Treatment Regimens


PegIFN + RBV

Telaprevir

PegIFN + RBV

Telaprevir

PegIFN

T12PR12

T12PR24

T12PR48

PR48

12 24 48

N=17

N=79

N=79

N=75

Week 0

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Telaprevir for Chronic Untreated HCV InfectionPROVE1 Study: Results

Percentage of Patients with SVR



T = Telaprevir; PR = Peginterferon + Ribavirin

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Percentage of Patients with Relapse




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Percentage of Patients with SVR and Relapse



SVR = Sustained Virologic Response; T = Telaprevir; PR = Peginterferon + Ribavirin

Hepatitisweb studySource:McHutchison JG, et. al. N Engl J Med. 2009;360:1827-38.

Telaprevir for Chronic Untreated HCV InfectionPROVE1 Study: Conclusions


Conclusion: “Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events.”

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Hepatitisweb study

Telaprevir in Treatment NaivePROVE2


Hepatitisweb studySource: Hézode C, et al. N Engl J Med. 2009;360:1839-50.

Telaprevir for Chronic Untreated HCV InfectionPROVE2: Study Design



Hepatitisweb study

PegIFN + RBV

Telaprevir

Source: Hézode C, et al. N Engl J Med. 2009;360:1839-50.

Telaprevir for Chronic Untreated HCV InfectionPROVE2 Study: Treatment Regimens


PegIFN + RBV

Telaprevir

PegIFN + RBV

Telaprevir

PegIFN

T12PR12

T12PR24

T12P12

PR48

12 24 48

N=82

N=81

N=78

N=82

Week 0

Hepatitisweb study





SVR = Sustained Virologic Response; T = Telaprevir; P = Peginterferon; PR = Peginterferon + Ribavirin

Hepatitisweb study


Percentage of Patients with Relapse



T = Telaprevir; P = Peginterferon; PR = Peginterferon + Ribavirin

Hepatitisweb study


Percentage of Patients with SVR and Relapse



SVR = Sustained Virologic Response; T = Telaprevir; P = Peginterferon; PR = Peginterferon + Ribavirin

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Serious Adverse Events




Hepatitisweb studySource: Hézode C, et al. N Engl J Med. 2009;360:1839-50.

Telaprevir for Chronic Untreated HCV InfectionPROVE2 Study: Conclusions


Conclusion: “In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin.”

Hepatitisweb study

Hepatitisweb study

Telaprevir in Treatment NaiveADVANCE


Hepatitisweb studySource: Jacobson IM, et. al. N Engl J Med. 2011;364:2405-16.

Telaprevir for Chronic Untreated HCV InfectionADVANCE: Study Design


Drug DosingTelaprevir = 750 mg tidPeginterferon alfa-2a = 180 µg weeklyRibavirin = 1000 mg/d for wt < 75 kg; 1200 mg/d for wt > 75 kg


Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Treatment Regimens


8 24 48Week 0

Telaprevir+

PegIFN + RBV

Placebo+

PegIFN + RBV

Telaprevir+

PegIFN + RBV

PegIFN + RBV

12

eRVR: PegIFN+ RBV

No eRVR: PegIFN + RBV

T8PR 24 or 48

T12PR 24 or 48

PR48

N =364

N =363

N =361

PegIFN+ RBV

eRVR: PegIFN + RBV

No eRVR: PegIFN + RBV

Hepatitisweb study

Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results


Source: Jacobson IM, et. al. N Engl J Med. 2011;364:2405-16.



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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: RVR and eRVR Rates

Percentage of Patients with RVR and eRVR



T = Telaprevir; PR = Peginterferon + Ribavirin; RVR = rapid virologic response; eRVR = extended rapid virologic response

Hepatitisweb study

Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results According to eRVR




T = Telaprevir; PR= Peginterferon + Ribavirin; SVR = Sustained Virologic ResponseeRVR = extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12)

Hepatitisweb study

Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results According to eRVR




SVR = Sustained Virologic Response; T = Telaprevir; PR = Peginterferon + Ribavirin; eRVR = extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12)

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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results According to Race





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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results According to Baseline HCV RNA





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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Results According to Liver Histology


Source: Jacobson IM, et. al. Hepatology. 2010;52 (Supplement 1):427A. Abstract 211.



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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Adverse Effects

Adverse Effects: Anemia




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Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Adverse Effects

Percentage of Patients with Rash




Hepatitisweb studySource: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

Telaprevir in Treatment-Naïve Subjects (ADVANCE)SVR Rates by IL28B rs12979860 Genotype


PR48 = Peginteron/Ribavirin x 48 weeks PR/T12 = Peginteron/Ribavirin + Telaprevir x 12 weeks


Telaprevir for Chronic Untreated HCV InfectionADVANCE Study: Conclusions


Conclusion: “Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients.”

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Hepatitisweb study

Telaprevir in Treatment NaiveILLUMINATE


Hepatitisweb studySource: Sherman KE, et. al. Hepatology. 2010;52 (Supplement 1):401A. Abstract LB-2.

Telaprevir for Chronic Untreated HCV InfectionILLUMINATE: Study Design


Drug DosingTelaprevir = 750 mg tidPeginterferon alfa-2a = 180 µg weeklyRibavirin = 1000 mg/d for wt < 75 kg; 1200 mg/d for wt > 75 kg


Telaprevir for Chronic Untreated HCV InfectionILLUMINATE Study: Treatment Regimens


48Week 0 12

Without eRVR

With eRVR

20 24

Telaprevir

PR

PR

PR

PR

T12PR 24 or 48

PR = Peginterferon + RibavirineRVR = extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12)

eRVR (+)T12/PR24

eRVR (-)T12/PR48

eRVR (+)T12/PR48

Hepatitisweb study

Telaprevir for Chronic Untreated HCV InfectionILLUMINATE Study: Results


Source: Sherman KE, et. al. Hepatology. 2010;52 (Supplement 1):401A. Abstract LB-2.


SVR = Sustained virologic response; T = Telaprevir; PR = Peginterferon + RibavirineRVR = extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12)

Hepatitisweb study

Telaprevir for Chronic Untreated HCV InfectionILLUMINATE Study: Key Findings


• 24 weeks of Peg-IFN non-inferior to 48 weeks in patients with eRVR

• Overall SVR 72%- SVR 60% blacks- SVR 63% cirrhotics

• 88-92% of those who achieved eRVR achieved SVR

• 7% stopped treatment early due to virologic failure

• 17% stopped early due to fatigue or anemia

Source: Sherman KE, et. al. Hepatology. 2010;52 (Supplement 1):401A. Abstract LB-2.


Telaprevir for Chronic Untreated HCV InfectionILLUMINATE Study: Conclusions


Conclusion: “Among patients who achieved eRVR, a 24-week telaprevir-based regimen was noninferior to 48-week telaprevir-based regimen (92% SVR compared to 87.5%). Response-guided treatment led to 71.9% SVR overall and nearly two-thirds of the patients were eligible for shorter duration of treatment. Permanent discontinuation of all study drugs due to adverse events occurred in 17.4% of patients. Among eRVR randomized patients, there were moreadverse events and adverse event-related treatment discontinuationsin the 48-week versus 24-week arm. These results supportresponse-guided therapy for telaprevir-based regimens in treatment-naïve patients.”

Hepatitisweb study

Hepatitisweb study


Telaprevir in Treatment Experienced PROVE3

Hepatitisweb studySource: McHutchison JG, et al. N Engl J Med. 2010;362:1292-303.

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Study Design



Hepatitisweb study

Peginterferon + Ribavirin

Telaprevir

Source: McHutchison JG, et al. N Engl J Med. 2010;362:1292-303.

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Treatment Regimens



Telaprevir


Telaprevir

Peginterferon

T12

PR24

T24

PR48

T24

P24

PR48

N=115

N=113

N=111

N=114

12 24 480Week

Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Results




SVR = sustained virologic response; T = Telaprevir; P = Peginterferon; PR = Peginterferon + Ribavirin

Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Results Based on Prior History




SVR = sustained virologic response; T = Telaprevir; P = Peginterferon; PR = Peginterferon + Ribavirin

Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Results

Adverse Events




Hepatitisweb studySource: McHutchison JG, et al. N Engl J Med. 2010;362:1292-303.

Telaprevir for Previously Treated Chronic HCV InfectionPROVE 3 Study: Conclusions


Conclusion: “In this In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirinwas more effective than retreatment with peginterferon alfa-2a and ribavirin alone.”

Hepatitisweb study

Hepatitisweb study


Telaprevir in Treatment Experienced REALIZE

Hepatitisweb studySource: Zeuzem S, et al. N Engl J Med. 2011;364:2417-28.

Telaprevir for Previously Treated Chronic HCV InfectionREALIZE Study: Study Design


Drug DosingTelaprevir = 750 mg q8hPeginterferon alfa-2a = 180 µg weeklyRibavirin = 1000 mg/d for wt < 75 kg; 1200 mg/d for wt > 75 kg

Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV Infection (REALIZE) Definitions for Type of Previous Response to Peginterferon + Ribavirin


• No Response: Reduction of less than 2 log10 in HCV RNA after 12 weeks of therapy

• Partial Response: Reduction of 2 log10 or more in HCV RNA after 12 weeks of therapy, but with detectable HCV RNA

• Relapse: undetectable HCV RNA at the end of a previous course of therapy but HCV RNA positivity thereafter

Source: Zeuzem S, et al. N Engl J Med. 2011;364:2417-28.

Hepatitisweb study


Telaprevir


Telaprevir for Previously Treated Chronic HCV InfectionREALIZE: Treatment Regimens



Telaprevir


T12

PR36

T12

PR48

PR48

N=266

N=264

N=132

12 24 480Week 364 16

Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionREALIZE Study: Results





Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionREALIZE: Results Based on Prior History





Hepatitisweb study

Telaprevir for Previously Treated Chronic HCV InfectionREALIZE: Adverse Effects

Adverse Effects: Anemia



T = Telaprevir; P = Peginterferon + Ribavirin

Hepatitisweb studySource: Zeuzem S, et al. N Engl J Med. 2011;364:2417-28.

Telaprevir for Previously Treated Chronic HCV InfectionREALIZE Study: Conclusions


Conclusion: “Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase.”

Hepatitisweb studySource: Vertex Pharmaceuticals.

Telaprevir in Previously Treated Subjects (REALIZE)SVR Rates by IL28B rs12979860 Genotype


PR48 = Peginteron/Ribavirin x 48 weeks PR/T12 = Peginteron/Ribavirin + Telaprevir x 12 weeks

Hepatitisweb study

Hepatitisweb study

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