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

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) 52 26 0.6%

Rash (SSC) 55 33 2.6%

Blood and lymphatic system disorders

Anemia (SSC) 32 15 0.9%

Gastrointestinal disorders

Nausea 39 29 <0.5

Diarrhea 26 19 <0.5

Hemorrhoids 12 3 <0.5

Anorectal discomfort 8 2 <0.5

Anal pruritus 6 1 <0.5

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.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 RGT BOC44/PR48 PR

SPRINT-2 (naïve)1 n=368 n=366 n=363

Anemia* 49 49 29

Dysgeusia* 37 43 18

Grade 3-4 neutropenia (500 to <750/mm3

and <500/mm3)29 33 18

RESPOND-2 (experienced)2 n=162 n=161 n=80

Anemia* 43 46 20

Dysgeusia* 43 45 11

Dry skin** 21 22 8

Grade 3-4 neutropenia (500 to <750/mm3

and <500/mm3)25 27 13

Rash‡ 17 14 5

1. Poordad F, et al. N Engl J Med 2011;364:1195–2062. 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;56:455-63

• Week 3

• Focal maculo-papular lesions of

the trunk (grade 1)

• Moderate pruritus

• No criteria of severity



Moderate: diffuse rash involving ≤50% of body surface area


• Week 6

• Maculo-papular rash

of the trunk and

limbs (grade 2)

• Moderate pruritus

• No criteria for

severity




Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment


Estimating body surface area (BSA)

9%

9%

Front18%

Back18% 9%

18% 18%

Hettiaratchy S, et al. BMJ 2004;329:101–3

Adult body BSA

Perineum 1%

Arm 9%

Head (front and back) 9%

Leg 18%

Chest 18%

Back 18%

Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase

>90% of all rash = mild/moderate

Inci

denc

e of

ras

h (%

)

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

Inci

denc

e of

ras

h (%

)

(n=1346) (n=764)

T12/PR arm






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


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


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

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


Drug considerations: severe rash and SCAR


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 requiredConsult with a dermatologist


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/dL Hemoglobin <8.5 g/dL

Pat

ien

ts (

%)

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

34

814

20

20

40

60

80

100

T12/PR Placebo/PR48

T12/PR Placebo/PR48

Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL

Pat

ien

ts (

%)

Hemoglobin shifts on telaprevir treatment: placebo-controlled Phase II and III studies

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

Number of patients

Week BL 4 8 12 16 20 24 28 36 48

T12/PR (750mg q8h) 1345 1291 1248 1209 1074 1040 1016 498 544 525

Placebo/PR48 764 742 721 677 625 584 565 459 399 379

160

150

140

130

120

110

Mea

n +

/– S

E

T12/PR (750mg q8h)Placebo/PR48

2 4 6 8 10 12 14 16 20 24 28 36 48 BL

Weeks

Management of anemia observed with telaprevir and boceprevir in clinical trials

Telaprevir Phase II/III placebo-controlled

trials1

Boceprevir trials2–4

Ribavirin dose reductions due to anemia

21.6% (telaprevir arms) vs 9.4% (control)

26% (boceprevir arms) vs 13% (control)

EPO use Not 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% vs0.5% controlAll 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 SmpC3. 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

SV

R (

%)

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

SV

R (

%)

No anemia Anemia

212/363 29/37 109/153 30/44n/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

PR

BOC+PR

BOC+PR

If Hb <10 g/dl: ↓RBV and not EPO allowed

If Hb < 10 G/dl: EPO useRVS

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/mm3) Grade 4 (<500/mm3) Grade 3/4

35 (25%)10 (7%)

45 (32%)

68 (17%)9 (2%)

77 (19%)Platelets Grade 3 (25,000 to <50,000/mm3) Grade 4 (<25,000/mm3) 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 findingsPatients, n (%) Telaprevir (n=176)

Serious AEs 90 (51)*

Discontinuation due to serious AE 21 (12)

Death 3 (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/mm3) Grade 4 (<500/mm3) 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 factorHézode C, et al, Hepdart 2011

CUPIC: Boceprevir – preliminary safety findingsPatients, n (%) Boceprevir (n=134)

Serious AEs 39 (29)*

Discontinuation due to serious AE 8 (6)

Death 1(1)

Rash Grade 3 SCAR

00

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/mm3) Grade 4 (<500/mm3) 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 factorHézode 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

Documents

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