Management of side effects

Rafael Esteban Liver Unit.

Hospital General Universitari Vall Hebron. Barcelona.

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% 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 Blood and lymphatic system disorders Anemia (SSC) 32 15 0.9%

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting Materials/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;364:1195–206 2. 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 AEs with DAAs: anemia

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

ient

s (%

)

Hemoglobin levels decline during the first 4 weeks of treatment and increase progressively after the end of Telaprevir (week 12) administration.

Summary of anemia data from Phase II and II telaprevir vs placebo controlled studies

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

ient

s (%

)

BOC44/ PR48

BOC RGT

Control BOC44/ PR48

Poordad F, et al. Hepatology 2010;52(Suppl.):402A

49% of patients in Boceprevir groups presented anemia vs 29% in the control group

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

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting Materials/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% 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 anemia Anemia

212/363

29/37

109/153

30/44 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

Trial design: EPO vs RBV dose reduction (DR) for managing anemia with boceprevir

After completion of 4-week Peg-

IFN/RBV lead-in, all patients

initiated boceprevir

Hemoglobin ≤10 g/dL

RBV DR by 200–400 mg/day*

EPO (40,000

IU/wk SC)

Hemoglobin ≤8.5g/dL:

Secondary strategy (EPO, RBV DR,

transfusion)

R

R = randomization

*Follow-up assessment at 2 weeks. If further DR was required, a second or third level of DR (by 200mg/day) could be used; SC: subcutaneously Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

Secondary anemia management was permitted when hemoglobin ≤8.5 g/dL; Discontinuation when hemoglobin ≤7.5 g/dL

Patients with hemoglobin >10 g/dL throughout the study remained in the pending randomization arm

Efficacy endpoints: EPO vs RBV dose reduction for managing anemia with boceprevir

*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort CI: confidence interval; EOT: end of treatment

Patie

nts

(%)

Δ (95% CI) –0.7% (–8.6, 7.2)*

178/249 178/251

Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

RBV DR EPO Secondary anemia management intervention was used in 18% of RBV DR patients

and in 37% of EPO patients

SVR according to use of a secondary anemia intervention (boceprevir anemia management trial)

Patie

nts

(%)

Secondary anemia intervention

141/204 37/45 107/158 71/93

Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

RBV DR EPO

Secondary anemia management intervention was used in 18% of RBV DR patients and in 37% of EPO patients

Specific adverse events with DAAs: rash

Optimal management

of dermatological reactions

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

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

Inci

denc

e of

rash

(%)

Telaprevir EU SmPC http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

(N=1346) (N=764)

Reported within a special search category

T12/PR arm

Incidence of rash events:* placebo-controlled Phase II and III studies

During telaprevir phase, by 4-week periods

During overall phase, by 12-week periods 100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

Pat

ient

s (%

)

Pat

ient

s (%

)

1–4 5–8 9–12

T12/PR (750mg q8h)

1–4 5–8 9–12

Placebo/PR48

1–12 13–24 25–36

T12/PR (750mg q8h)

37–48

Placebo/PR48

1–12 13–24 25–36 37–48

Cacoub et al. J Hepatol 2011; in press, accepted manuscript. DOI 10.1016/j.jhep.2011.08.006 *Reported within a special search category

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 Telaprevir EU SmPC

Estimating body surface area (BSA)

9%

9%

Front 18%

Back 18% 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%

Drug considerations: mild and moderate rash

Treating patients with mild or moderate rash Use 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

Rash

Mild

Moderate

Telaprevir discontinuation is generally NOT required

Telaprevir discontinuation is generally NOT required

For moderate rash that progresses, permanent discontinuation (do not dose-reduce) of telaprevir should be considered

If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted.

Peginterferon alfa may be continued unless interruption is medically indicated

*Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of telaprevir. This combination should be used with caution or alternatives should be considered Telaprevir EU SmPC

Mild rush (Grade 1 Dermatitis)

Mild rash is defined as localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)

Cacoub, P., Bourlière, M., Lübbe, J., Dupin, N., Buggisch, P., Dusheiko, G., Hézode, C.,Picard, O., Pujol, R., Segaert, S., Thio, B., Roujeau, J-C., Dermatological side effects of hepatitis c and its treatment: Patient management in the era of direct-acting antivirals, Journal of Hepatology (2011), doi: 10.1016/j.jhep. 2011.08.006. Grade 1 dermatitis,

Moderarte rush (Grade 2 Dermatitis)

Cacoub, P., Bourlière, M., Lübbe, J., Dupin, N., Buggisch, P., Dusheiko, G., Hézode, C.,Picard, O., Pujol, R., Segaert, S., Thio, B., Roujeau, J-C., Dermatological side effects of hepatitis c and its treatment: Patient management in the era of direct-acting antivirals, Journal of Hepatology (2011), doi: 10.1016/j.jhep. 2011.08.006. Grade 2 dermatitis,

Moderate rash is defined as Diffuse skin eruption involving up to approximately 50% of body surface area, with or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration

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)

TELAPREVIR must not be restarted if discontinued

Rash

Severe

SCAR?

Permanently discontinue telaprevir immediately. Consultation with a specialist in dermatology is recommended 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 specialist in dermatology

Telaprevir EU SmPC

Summary of rash data from Phase II and III placebo-controlled trials:* discontinuations

*During telaprevir treatment phase; analyzed within SSC

Improvement of rash occurs after telaprevir discontinuation Rashes may take weeks for complete resolution

Dis

cont

inua

tions

(%)

Dis

cont

inua

tions

(%) Telaprevir alone All treatment at the

same time

Telaprevir EU SmPC http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals

Patrice Cacoub et al. J Hepatol 2012

Proper skin care: - at least 15 min and should become a daily habit in order to become effective. - after a shower/bath - Emollient creams and lipid-rich lotions, rather than aqueous lotions or ointments, are effective and well-accepted by patients and should be prescribed as prophylactic baseline skin treatment If grade 1-2 dermatitis: - potent topical corticosteroids can be used (hands, feet, skin around the large joints, large skin surfaces)

Anorectal Symptoms

In telaprevir trials: – 29% of patients receiving triple therapy vs 7% of patients receiving

standard therapy

Most of these adverse events: - hemorrhoids, anorectal discomfort, anal pruritus, rectal burning However, most of them were mild to moderate, and < 1% resulted in

treatment discontinuation

Management: short-term topical corticosteroids, topical lidocaine-type agents, antihistamines before bedtime, and trying to control bowel movements with loperamide or diphenoxylate

and atropine.

is not believed to be related to levels of telaprevir, and the cause remains enigmatic

Summary and conclusions

Side effects remain a problem (Peg-IFN/RBV side effects dominant) Additional side effects with DAAs include

– Telaprevir:1–4 rash, anemia, anorectal itching – Boceprevir:5,6 anemia, dysgeusia, neutropenia

Rash:1–4,7 – Most rashes (>90%) are mild, responsive to treatment (compatible with

‘treating-through’) – Treat rash early and monitor patient closely – Few cases of severe cutaneous reactions (SJS, DRESS) (resolved with

treatment discontinuation) Anemia

– Increased with telaprevir and boceprevir (EPO use only allowed in boceprevir trials)

– Anemia with telaprevir is limited (12 weeks) – Strategies for treating anemia include EPO, RBV dose reduction and blood

transfusions 1. Jacobson IM, et al. N Engl J Med 2011;364:2405–16; 2. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A

3. Zeuzem S, et al. N Engl J Med 2011;364:2417–28; 4. Telaprevir EU SmPC 5. Poordad F, et al. N Engl J Med 2011;364:1195–206; 6. Bacon BR, et al. N Engl J Med 2011;364:1207–17

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

CUPIC: telaprevir – preliminary safety findings

Patients, 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 factor

CUPIC: Boceprevir – preliminary safety findings

Patients, n (%) Boceprevir (n=134)

Serious AEs 39 (29)*

Discontinuation due to serious AE 8 (6)

Death 1(1)

Rash Grade 3 SCAR

0 0

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 factor

Summary

Anemia is a common event associated with DAAs – Reducing the dose of RBV is considered the best initial approach

for managing anemia with DAAs

Most rash associated with telaprevir therapy is mild/moderate – Typically pruritic and eczematous, progression is infrequent (<10% of

cases)

Follow recommendations for treatment discontinuation and rash management – Mild/moderate rash can be treated with topical corticosteroids or systemic

antihistamines without discontinuation of DAA therapy

29