FDA Hepatitis Update - INCIVEK (telaprevir)

May 23, 2011

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On May 23, 2011, FDA approved INCIVEK (telaprevir), a hepatitis C virus (HCV)

protease inhibitor. INCIVEK is the second direct acting antiviral drug against

the hepatitis C virus to be approved.

INCIVEK (telaprevir), in combination with peginterferon alfa and ribavirin, is

indicated for the treatment of genotype 1 chronic hepatitis C in adult patients

with compensated liver disease, including cirrhosis, who are treatment-naïve

(patients who have not received interferon-based drug therapy for their

infection) or who have previously been treated with interferon-based treatment

and not responded adequately, including prior null responders, partial

responders, and relapsers.

The current standard of care for patients with hepatitis C infection is

peginterferon alfa and ribavirin taken for 48 weeks. Less than 50 percent of

patients respond to this therapy.

The following points should be considered when initiating treatment with

INCIVEK:

• INCIVEK must not be administered as monotherapy and must only be prescribed

with both peginterferon alfa and ribavirin.

• A high proportion of previous null responders (particularly those with

cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had

telaprevir resistance-associated substitutions emerge on treatment with INCIVEK

combination treatment.

• INCIVEK efficacy has not been established for patients who have previously

failed therapy with a treatment regimen that includes INCIVEK or other HCV

NS3/4A protease inhibitors

DOSAGE AND ADMINISTRATION

INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment

The recommended dose of INCIVEK tablets is 750 mg (two 375-mg tablets) taken

orally 3 times a day (7-9 hours apart) with food (not low fat).

For specific dosage instructions for peginterferon alfa and ribavirin, refer to

their respective prescribing information.

Duration of Treatment

The recommended duration of treatment with INCIVEK is 12 weeks in combination

with peginterferon alfa and ribavirin. HCV-RNA levels should be monitored at

weeks 4 and 12 to determine combination treatment duration and assess for

treatment futility (Tables 1 and 2).

Table 1: Recommended Treatment Duration (See also Table 2 for Treatment Futility

Rules)

Treatment-Naïve and Prior Relapse Patients

HCV-RNAa

Triple Therapy

INCIVEK,

peginterferon alfa and ribavirin

Dual Therapy

peginterferon alfa and ribavirin

Total Treatment Duration

Undetectable at Weeks 4 and 12

First 12 weeks

Additional 12 weeks

24 weeks

Detectable (1000 IU/mL or less) at Weeks 4 and/or 12

First 12 weeks

Additional 36 weeks

48 weeks

Prior Partial and Null Responder Patients

Triple Therapy

INCIVEK,

peginterferon alfa and ribavirin

Dual Therapy

peginterferon alfa and ribavirin

Total Treatment Duration

All Patients

First 12 weeks

Additional 36 weeks

48 weeks

aIn 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.

For the purpose of assessing response-guided therapy eligibility at weeks 4 and

12 (see Table 1), an “undetectable” HCV-RNA result is required; a confirmed

“detectable but below limit of quantification” HCV-RNA result should not be

considered equivalent to an “undetectable” HCV-RNA result.

Treatment-naïve patients with cirrhosis who have undetectable HCV-RNA at weeks 4

and 12 of INCIVEK combination treatment may benefit from an additional 36 weeks

of peginterferon alfa and ribavirin (48 weeks total)

Dose Reduction

To prevent treatment failure, the dose of INCIVEK must not be reduced or

interrupted. Refer to the respective prescribing information for dose

modification of peginterferon alfa and ribavirin.

Discontinuation of Dosing

Patients with inadequate viral response are unlikely to achieve SVR, and may

develop treatment-emergent resistance substitutions. Discontinuation of therapy

is recommended in all patients with (1) HCV-RNA levels of greater than or equal

to 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV-RNA

levels at Treatment Week 24 (see Table 2).

Table 2: Treatment Futility Rules: All Patients

HCV-RNA

Action

Week 4 or Week 12: Greater than 1000 IU/mL

Discontinue INCIVEK and peginterferon alfa and ribavirin (INCIVEK treatment

complete at 12 weeks)

Week 24: Detectable

Discontinue peginterferon alfa and ribavirin If peginterferon alfa or ribavirin

is discontinued for any reason, INCIVEK must also be discontinued.

CLINICAL TRIAL RESULTS

The approval of INCIVEK is based on safety and efficacy data in approximately

2250 adult subjects who were previously untreated (ADVANCE and ILLUMINATE) or

who had failed previous peginterferon alfa and ribavirin therapy (REALIZE) in

clinical studies

Treatment-Naïve Adults

Study 108 (ADVANCE)

Study 108 was a randomized, double-blind, parallel-group, placebo-controlled,

trial conducted in treatment-naïve subjects (had received no prior therapy for

HCV, including interferon or pegylated interferon monotherapy). INCIVEK was

given for the first 8 weeks of treatment (T8/PR regimen) or the first 12 weeks

of treatment (T12/PR regimen) in combination with Peg-IFN-alfa-2a/RBV for either

24 or 48 weeks. Subjects who had undetectable HCV-RNA at weeks 4 and 12

(extended Rapid Virologic Response [eRVR]) received 24 weeks of

Peg-IFN-alfa-2a/RBV treatment, and subjects who did not have undetectable

HCV-RNA at weeks 4 and 12 (no eRVR) received 48 weeks of Peg-IFN-alfa-2a/RBV

treatment. The control regimen (Pbo/PR48) had a fixed treatment duration, with

telaprevir matching placebo for the first 12 weeks and Peg-IFN-alfa-2a/RBV for

48 weeks.

The 1088 enrolled subjects had a median age of 49 years (range: 18 to 69); 59%

of the subjects were male; 23% had a body mass index greater than or equal to 30

kg/m2; 9% were Black; 11% were Hispanic or Latino; 77% had baseline HCV-RNA

levels greater than 800,000 IU/mL; 15% had bridging fibrosis; 6% had cirrhosis;

59% had HCV genotype 1a; and 40% had HCV genotype 1b.

Table 10 shows the response rates for the T12/PR and Pbo/PR48 groups.

Treatment Outcome

T12/PR

N = 363

n/N (%)

Pbo/PR48

N = 361

n/N (%)

Overall SVR

79% (285/363)

46% (166/361)

eRVR

58% (212/363)

8% (29/361)

SVR in eRVR subjects

92% (195/212)

93% (27/29)

No eRVR

42% (151/363)

92% (332/361)

SVR in no eRVR subjects

60% (90/151)

42% (139/332)

Outcome for Subjects without SVR

On-treatment virologic failurea

7% (26/363)

29% (105/361)

Relapseb

4% (11/298)

24% (53/220)

Otherc

11% (41/363)

10% (37/361) a On-treatment failure includes subjects who met a protocol-defined

virologic stopping rule or who had detectable HCV-RNA at the time of their last

dose of INCIVEK and subjects who had viral breakthrough on peginterferon

alfa/ribavirin.

b Relapse rates are calculated with a denominator of subjects with undetectable

HCV-RNA at the end of treatment.

c Other includes subjects with detectable HCV-RNA at the time of their last

study drug but who did not have viral breakthrough, and subjects with a missing

SVR assessment.

In the T8/PR group, the overall SVR rate was 72%. The eRVR rate was 57% and the

SVR rate for eRVR subjects was 87%. The SVR rate for no eRVR subjects was 52%.

More subjects in the T8/PR group experienced virologic breakthrough after Week

12 while receiving peginterferon alfa and ribavirin alone, 16% compared to 10%

in T12/PR group.

SVR rates were higher (absolute difference of at least 22%) for the T12/PR group

than for the Pbo/PR48 group across subgroups by sex, age, race, ethnicity, body

mass index, HCV genotype subtype, baseline HCV-RNA (less than 800,000, greater

than or equal to 800,000 IU/mL), and extent of liver fibrosis. However, there

were small numbers of subjects enrolled in some key subgroups. In the T12/PR

group:

Twenty-one subjects had cirrhosis at baseline and the overall SVR in these

subjects was 62% (13/21). Among subjects with cirrhosis, 43% (9/21) achieved an

eRVR and of those 78% (7/9) achieved SVR.

Twenty-six subjects were Black/African Americans. The overall SVR among

Black/African American subjects was 62% (16/26). Among these subjects, 31%

(8/26) achieved an eRVR and of those 89% (8/9) achieved SVR.

Study 111 (ILLUMINATE)

Study 111 was a randomized, open label trial conducted in treatment naïve

subjects. The study was designed to compare SVR rates in subjects achieving eRVR

who were treated with INCIVEK for 12 weeks in combination with

Peg-IFN-alfa-2a/RBV for either 24 weeks (T12/PR24 regimen) or 48 weeks (T12/PR48

regimen).

The 540 enrolled subjects had a median age of 51 years (range: 19 to 70); 60%

were male; 32% had a body mass index greater than or equal to 30 kg/m2; 14% were

Black; 10% were Hispanic or Latino; 82% had baseline HCV-RNA levels greater than

800,000 IU/mL; 16% had bridging fibrosis; 11% had cirrhosis; 72% had HCV

genotype 1a; and 27% had HCV genotype 1b.

The SVR rate for all subjects enrolled in the trial was 74%. A total of 352

(65%) subjects achieved eRVR and of those 322 (60%) were randomized to 24 weeks

(T12/PR24, n=162) or 48 weeks (T12/PR48, n=160) of treatment. The SVR rates were

similar at 92% (T12/PR24) and 90% (T12/PR48), respectively. Again, small numbers

of subjects were enrolled in some key subgroups:

• Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with

cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to

T12/PR48. The SVR rates were 67% (12/18) for the T12/PR24 group and 92% (11/12)

for the T12/PR48 group.

• Blacks/African Americans comprised 14% (73/540) of study subjects. Thirty-four

(47%) Black/African American subjects achieved an eRVR and were randomized to

T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 94% (16/17),

compared to 93% (246/265) for Caucasians.

Previously Treated Adults

Study C216 (REALIZE)

Study C216 was a randomized, double-blind, placebo-controlled, trial conducted

in subjects who did not achieve SVR with prior treatment with

Peg-IFN-alfa-2a/RBV or Peg IFN alfa-2b/RBV. The study enrolled prior relapsers

(subjects with HCV-RNA undetectable at end of treatment with a pegylated

interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment

follow-up) and prior non responders (subjects who did not have undetectable

HCV-RNA levels during or at the end of a prior course of at least 12 weeks of

treatment). The nonresponder population included 2 subgroups: prior partial

responders (greater than or equal to 2 log10 reduction in HCV-RNA at week 12,

but not achieving HCV RNA undetectable at end of treatment with peginterferon

alfa and ribavirin) and prior null responders (less than 2 log10 reduction in

HCV-RNA at week 12 of prior treatment with peginterferon alfa and ribavirin).

Subjects were randomized in a 2:2:1 ratio to one of two INCIVEK combination

treatment groups (with and without a Peg-IFN-alfa-2a/RBV lead in) or a control

group. The T12/PR48 group received INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks

(without a lead-in), followed by placebo and Peg-IFN-alfa-2a/RBV for 4 weeks,

followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The T12(DS)/PR48 group had a

lead-in (delayed start of INCIVEK) with placebo and Peg-IFN-alfa-2a/RBV for 4

weeks, followed by INCIVEK and Peg IFN alfa-2a/RBV for 12 weeks, followed by

Peg-IFN-alfa-2a/RBV for 32 weeks. The Pbo/PR48 group received placebo and

Peg-IFN-alfa-2a/RBV for 16 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks.

The 662 enrolled subjects had a median age of 51 years (range: 21 to 70); 70% of

the subjects were male; 26% had a body mass index greater than or equal to 30

kg/m2; 5% were Black; 11% were Hispanic or Latino; 89% had baseline HCV-RNA

levels greater than 800,000 IU/mL; 22% had bridging fibrosis; 26% had cirrhosis;

54% had HCV genotype 1a, and 46% had HCV genotype 1b. Null and partial

responders had higher baseline HCV-RNA levels and more advanced liver disease

(cirrhosis) than relapsers; other characteristics were similar across these

populations.

The lead-in and immediate start regimens produced comparable SVR and no SVR

rates, so data from these two groups were pooled (Table 11).

Table 11: Response Rates: Study C216

Treatment Outcome

All T12/PR48a

% (n/N)

Pbo/PR48

% (n/N)

SVR rate

Prior relapsers

86% (246/286)

22% (15/68)

Prior partial responders

59% (57/97)

15% (4/27)

Prior null responders

32% (47/147)

5% (2/37)

Treatment Outcomes for Subjects Without SVR

On-treatment virologic failureb

Prior relapsers

1% (3/286)

10% (7/68)

Prior partial responders

15% (15/97)

26% (7/27)

Prior null responders

50% (74/147)

22% (8/37)

Relapsec

Prior relapsers

3% (8/254)

63% (27/43)

Prior partial responders

20% (14/71)

0% (0/4)

Prior null responders

24% (15/62)

50% (2/4)

a Lead-in and immediate start T12/PR regimens pooled

b On-treatment virologic failure includes subjects who met a protocol-defined

virologic stopping rule or who had detectable HCV-RNA at the time of their last

dose of INCIVEK and subjects who had viral breakthrough on peginterferon

alfa/ribavirin.

c Relapse rates are calculated with a denominator of subjects with undetectable

HCV-RNA at the end of treatment.

Among prior relapsers, 76% (218/286) achieved an eRVR and of those 95% (208/218)

achieved an SVR. In an earlier, dose-finding clinical trial, 78% (52/67) of

prior relapsers achieved an eRVR and were treated with 24 weeks of peginterferon

alfa and ribavirin (T12/PR24); of those 94% (49/52) achieved an SVR.

For all populations in the study (prior relapsers, prior partial responders, and

prior null responders), SVR rates were higher for the T12/PR group than for the

Pbo/PR48 group across subgroups by sex, age, ethnicity, body mass index, HCV

genotype subtype, baseline HCV-RNA level, and extent of liver fibrosis.

Twenty-three percent of INCIVEK-treated subjects had cirrhosis at baseline. SVR

rates among cirrhotic subjects who received INCIVEK combination treatment

compared to Pbo/PR48 were: 87% (48/55) compared to 13% (2/15) for prior

relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and

14% (7/50) compared to 10% (1/10) for prior null responders.

Four percent (19/530) of treatment experienced subjects who received INCIVEK

combination treatment were Black/African Americans; the SVR rate for these

subjects was 63% (12/19) compared to 65% (328/503) for Caucasians.

CONTRAINDICATIONS

INCIVEK combination treatment is contraindicated in:

Pregnant women and men whose female partners are pregnant because of the risks

for birth defects and fetal death associated with ribavirin

INCIVEK is contraindicated when combined with drugs that are highly dependent on

CYP3A for clearance and for which elevated plasma concentrations are associated

with serious and/or life-threatening events (narrow therapeutic index). INCIVEK

is contraindicated when combined with drugs that strongly induce CYP3A and thus

may lead to lower exposure and loss of efficacy of INCIVEK. The contraindicated

medications include the following:

Alfuzosin

Rifampin

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Cisapride

St ’s wort (Hypericum perforatum)

Atorvastatin, lovastatin, simvastatin

Pimozide

Sildenafil (Revatio®) or tadalafil (Adcirca®) [for treatment of pulmonary

arterial hypertension]

WARNINGS AND PRECAUTIONS

The Warnings and Precautions for INCIVEK include drug interactions and the

following:

Pregnancy (Use with Ribavirin and Peginterferon Alfa)

Ribavirin may cause birth defects and fetal death; avoid pregnancy in female

patients and female partners of male patients. Patients must have a negative

pregnancy test prior to therapy and have monthly pregnancy test and for six

months after treatment ends. Hormonal contraceptives may not be reliable during

INCIVEK dosing and for up to two weeks following cessation of INCIVEK During

this time, female patients of childbearing potential should use 2 non-hormonal

methods of effective birth control. Examples of non-hormonal methods of

contraception include a male condom with spermicidal jelly OR female condom with

spermicidal jelly (a combination of a male condom and a female condom is not

suitable), a diaphragm with spermicidal jelly, a cervical cap with spermicidal

jelly, or an intrauterine device (IUD).

Serious Skin Reactions Serious skin reactions, including Drug Rash with

Eosinophilia and Systemic Symptoms (DRESS) and s- Syndrome (SJS)

were reported in less than 1% of subjects who received INCIVEK combination

treatment compared to none who received peginterferon alfa and ribavirin alone.

These serious skin reactions required hospitalization, and all patients

recovered. The presenting signs of DRESS may include rash, fever, facial edema,

and evidence of internal organ involvement (e.g., hepatitis, nephritis).

Eosinophilia may or may not be present. The presenting signs of SJS may include

fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae,

lips).

If a serious skin reaction occurs, all components of INCIVEK combination

treatment must be discontinued immediately and the patient should be promptly

referred for urgent medical care

Rash Rash developed in 56% of subjects who received INCIVEK combination

treatment [see Adverse Reactions (6.1)]. Severe rash (e.g., a generalized rash

or rash with vesicles or bullae or ulcerations other than SJS) was reported in

4% of subjects who received INCIVEK combination treatment compared to less than

1% who received peginterferon alfa and ribavirin alone. The severe rash may have

a prominent eczematous component.

Patients with mild to moderate rashes should be followed for progression of rash

or development of systemic symptoms. If rash progresses and becomes severe or if

systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa

and ribavirin may be continued. If improvement is not observed within 7 days of

INCIVEK discontinuation, sequential or simultaneous interruption or

discontinuation of ribavirin and/or peginterferon alfa should be considered. If

medically indicated, earlier interruption or discontinuation of ribavirin and

peginterferon alfa should be considered. Patients should be monitored until the

rash has resolved. INCIVEK must not be reduced or restarted if discontinued due

to rash. Treatment of rash with oral antihistamines and/or topical

corticosteroids may provide symptomatic relief but effectiveness of these

measures has not been established. Treatment of rash with systemic

corticosteroids is not recommended [see Drug Interactions (7)].

Anemia

Anemia has been reported with peginterferon alfa and ribavirin therapy. The

addition of INCIVEK to peginterferon alfa and ribavirin is associated with an

additional decrease in hemoglobin concentrations. Hemoglobin values less than or

equal to 10 g/dL were observed in 36% of subjects who received INCIVEK

combination treatment compared to 17% of subjects who received peginterferon

alfa and ribavirin. Hemoglobin values less than 8.5 g/dL were observed in 14% of

subjects who received INCIVEK combination treatment compared to 5% of subjects

receiving peginterferon alfa and ribavirin.

In subjects receiving INCIVEK combination treatment, 4% discontinued INCIVEK, 1%

discontinued INCIVEK combination treatment, and 32% underwent a ribavirin dose

modification (reduction, interruption or discontinuation) due to anemia. In

subjects treated with peginterferon alfa and ribavirin alone, there were two

discontinuations and 12% underwent ribavirin dose modification due to anemia.

Hemoglobin should be monitored prior to and at least every 4 weeks during

INCIVEK combination treatment. For the management of anemia, ribavirin dose

reductions should be used (refer to the prescribing information for ribavirin

for its dose reduction guidelines). If ribavirin dose reductions are inadequate,

discontinuation of INCIVEK should be considered. If ribavirin is permanently

discontinued for the management of anemia, INCIVEK must also be permanently

discontinued. Ribavirin may be restarted per the dosing modification guidelines

for ribavirin. The dose of INCIVEK must not be reduced and INCIVEK must not be

restarted if discontinued.

Laboratory Tests

HCV-RNA levels should be monitored at weeks 4 and 12 and as clinically

indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA

levels during treatment is recommended. The assay should have a lower limit of

HCV-RNA quantification equal to or less than 25 IU/mL and a limit of HCV-RNA

detection of approximately 10-15 IU/mL. For the purpose of assessing

response-guided therapy eligibility, an “undetectable” HCV-RNA result is

required; a confirmed “detectable but below limit of quantification” HCV-RNA

result should not be considered equivalent to an “undetectable” HCV-RNA result.

Hematology evaluations (including white cell differential count) are recommended

at weeks 2, 4, 8 and 12 or as clinically appropriate thereafter.

Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic

enzymes, bilirubin, and TSH) are recommended as frequently as the hematology

evaluations or as clinically indicated

General

INCIVEK must not be administered as monotherapy and must only be prescribed with

both peginterferon alfa and ribavirin. Therefore, the prescribing information

for peginterferon alfa and ribavirin must be consulted before starting treatment

with INCIVEK.

There are no clinical data on re-treating patients who have failed an HCV NS3/4A

protease inhibitor-based treatment, nor are there data on repeated courses of

INCIVEK [see Microbiology (12.4)].

Hepatic Impairment

INCIVEK is not recommended for patients with moderate or severe hepatic

impairment (Child-Pugh B or C, score greater than or equal to 7) or patients

with decompensated liver disease.

ADVERSE DRUG REACTIONS

The most commonly reported adverse reactions in adult subjects were rash,

fatigue, pruritus, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal

discomfort, dysgeusia and anal pruritis.

Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK

combination treatment compared to none of the subjects treated with

peginterferon alfa and ribavirin. The most frequent serious adverse events in

subjects treated with INCIVEK combination treatment were skin disorders (rash

and/or pruritus) and anemia. Fourteen percent of subjects discontinued INCIVEK

due to adverse drug reactions. Rash, anemia, fatigue, pruritus, nausea, and

vomiting were the most frequent adverse drug reactions leading to

discontinuation of INCIVEK

USE IN SPECIAL POPULATIONS

Hepatic Impairment: Safety and efficacy have not been established in patients

with Child-Pugh score greater than or equal to 7 (class B and C)

Co-infection: Safety and efficacy have not been established in HCV/HIV and

HCV/HBV co-infected patients.

Pediatrics: Safety and efficacy have not been established in pediatric patients.

Solid Organ Transplant: Safety and efficacy have not been established in

patients undergoing solid organ transplants

Ribavirin Pregnancy Registry available

Telaprevir is a product of Vertex Pharmaceuticals Incorporated.

The complete product label will be available soon on the FDA web site at

DrugsFDA (DOT)

Klein

Office of Special Health Issues

Food and Drug Administration

Struble

Division of Antiviral Drug Products

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May 23, 2011