# Presentation: 708239

## Biologic License Supplement: Peginterferon α-2b and Ribavirin for Treatment of Chronic Hepatitis C

- Division of Clinical Trials Design and Analysis
- CBER, FDA

## Objectives of Presentation

- _Review of Study Design_
- Rationale for selection of peginterferon and ribavirin doses studied in phase 3
- Models for predicting sustained viral responses
- Power of dose ranging studies

## Objectives of Presentation

- _Summary of Efficacy_
- Treatment effects
- Virologic response in patient subgroups

## Objectives of Presentation

- _Summary of Safety_
- Safety profile of PEG/R compared to IFN/R

## Objectives of Presentation

- _Summary of Post-marketing Commitments_
- Optimal dosage of peginterferon and ribavirin
- Optimal duration of treatment in patient subgroups
- Treatment response in African Americans
- Effect of food on ribavirin absorption

## Phase 3 Combination Study(N= 1530) 

- Multi-center, randomized, open-label, active control, parallel group study with 48WK treatment and 24WK follow-up
- - PEG 1.5 g/kg QW, ribavirin 800 mg/day
- - PEG 1.50.5 g/kg QW, riba 1000-1200 mg/day
- - IFN 3x106 U TIW, ribavirin 1000-1200 mg/day
- Ribavirin absorption increased 70% in the presence of food. Protocol amended to require that ribavirin be taken with food.

## Selection of Peginterferon Dosage for Phase 3 Combination Study

**Phase 3 Peginterferon Monotherapy Study **

**Virologic Response**

## Selection of Ribavirin Dosage for Phase 3 Combination Study

**Phase 1 dose-ranging study (N=72)**
-  - PEG 0.35 g/kg/w and riba 600,  _800 mg/day_
-  - PEG 0.7 and riba 600, 800, _1000-1200 mg/day_
-  - PEG 1.4 and riba _600, 800, 1000-1200 mg/day_
**Viral response at 24 weeks of treatment**

## Primary Efficacy Outcome:Sustained Virologic Response

| Treatment Groups | HCV RNA Negative | Treatment Difference1 |
| --- | --- | --- |
| PEG 1.5/R | 264/511 (52%)
 | 6% (0.18, 11.6) |
| PEG 0.5/R | 239/514 (46%) | 1% (- 4.7, 6.5) |
| IFN/R
 | 231/505 (46%) |  |

**1**** vs. IFN/R**

## Efficacy Outcomes According to Subgroup Analyses

- _Pre-specified_
- 	- Viral genotype (1 vs. Non-1)
- 	- Cirrhosis
- _Post-hoc_
- 	- Viral titers (>2 x106/ml serum)
- 	- Age, gender, ethnicity
- 	- Geographic location
- 	- Body weight

## Treatment Response in Patients with Genotype 1

|  | High titer | Low titer |
| --- | --- | --- |
| I/R | 70/247 (28) | 42/96 (44) |
| PEG1.5/R | 75/256 (29) | 66/92 (72) |
| Treatmentdifference | 1% (-7,  8.8) | 28% (14, 42) |

## Treatment Response in Patients with Genotype 2-6

|  | High titer | Low titer |
| --- | --- | --- |
| I/R | 72/97 (74) | 47/65 (72) |
| PEG1.5/R | 68/95 (72) | 55/68 (81) |
| Treatmentdifference | -3% (-15,10) | 9% (-6,  22) |

## Treatment Response by Geographic Location

|                        TREATMENT  GROUP |  |  |
| --- | --- | --- |
| Study Center | PEG 1.5/R | I/R |
| US | 169/346 (49%) | 131/337 (39%) |
| Non-US | 95/165 (57%) | 100/168 (59%) |

## SUBGROUP ANALYSES

- Efficacy and Safety of Weight-adjusted Ribavirin Dosage

## Treatment Response Based on Ribavirin Weight-adjusted Dose

- Analysis is post-hoc
- True variable: body weight
- Hypothesis: BW is surrogate for ribavirin dosage (mg/kg)

## Treatment Response by Ribavirin Weight-adjusted Dose

- Differences in dosages across study arms

**  ****a**** mcg/kg/week/SC;****    b**** IU/week/SC;****  ****c ****mg/day/PO.**

## Treatment Response by Ribavirin Weight-adjusted Dose

- Non-randomized subgroups differ in:
- Numbers, body weights, ?other unknown factors
- Within-arm comparison suggestive
- Data too few and inconsistent
- Across-arm comparisons not appropriate

## Treatment Response by Ribavirin Dose

| Ribavirin Dose | PEG 1.5 Riba | PEG 0.5
Riba | IFN
Riba |
| --- | --- | --- | --- |
| <14.7a | 13/21 |  76/171 | 99/184 |
| >13.3 <14.7 | 25/38 | 91/174 | 75/170 |
| >10.7 <13.3 | 70/126 | 58/134 | 50/126 |
| <10.7 | 156/326 | 14/35 | 7/25 |
| Median (range) | 9.8(5-19) |  14(7-26) | 14(7-23) |

**a****dose quartiles, mg/kg/day**

## Treatment Response by Ribavirin Weight-adjusted Dose

| Body Weight
 |         Treatment Groups |  |
| --- | --- | --- |
|  | I/R  | PEG1.5/R |
|  < 75 kg | 94/178 (53)  | 108/185 (58) |
|  > 75 kg | 137/327 (42) | 156/326 (48) |
| Difference | 11% | 10% |

## Population PK and PD analysis

- Modeling for:
- Clearance
- Virologic response
- Safety (anemia)
- Remaining Issues
- Simulation of Safety and Efficacy  did not follow proposed dosing
- No data at 1400 mg/kg for BW >105 kg
- Ideal body weight
- Separation by gender

## SAFETY DATA SUMMARYPeginterferon and Ribavirin vs. Interferon and Ribavirin 

## Summary of Safety

- PEG/R compared to IFN/R associated with higher incidence of:
- dose-modifications
- serious and severe adverse events (*e.g* neutropenia, infections)
- certain AEs (fever, headache, application site reactions)

## Summary of Safety: Analyses by Ribavirin Weight-Adjusted Dose

- IFN and/or ribavirin dose-reduction due to adverse events
- Adverse events (both ribavirin- and interferon-associated)
- Dose threshold with steeper increase in ribavirin toxicity?

## Serious Infectious Adverse Events

|  | PEG1.5/R | PEG0.5/R | I/R |
| --- | --- | --- | --- |
| Abscess | 3 | 1 | 0 |
| Cellulitis | 5 | 1 | 1 |
| Infection | 3 | 0 | 0 |
| Sepsis | 0 | 1 | 0 |
| Appendicitis | 4 | 1 | 1 |
| Bronchitis | 0 | 1 | 0 |
| Pneumonia | 1 | 1 | 1 |
| Prostatitis | 1 | 0 | 0 |
| UTI | 0 | 1 | 1 |
| TOTAL | 17 | 7 | 3 |

## Modification of Dose (IFN or Ribavirin) in PEG1.5/R Arm

| Body Wt |  Ribavirin
 Dose |  All    
 Causes | Anemia |  Neutropenia |
| --- | --- | --- | --- | --- |
| kg  | mg/kg  | %  | % | % |
| 54 | >14.7 | 47 | 12 | 24 |
| 60-54 | >13.3 <14.7 | 61 | 16 | 20 |
| 60-75 | >10.7 <13.3 | 45
 | 10 | 22 |
| 75 | <10.7 | 38 | 7 | 16 |

## Incidence of Anemia and Neutro- penia in PEG 1.5/R Arm

|   Body   
  Wt |  Riba  
 Dose |    Anemia           
   All    Severe/LT |   Neutropenia     
 All   Severe/LT |
| --- | --- | --- | --- |
| kg | mg/kg |     %           % |      %          % |
| <54 | >14.7 |     18           0 |      47          24 |
| 60-54 | >13.3 <14.7 |     31           2  |      29          12 |
| 60-75 | >10.7 <13.3 |     13           0 |      31          12 |
| >75 | <10.7 |       8           0 |      23            9 |

## Conclusions (1)

- Peg-IFN + ribavirin (1.5 mcg/kg + 800 mg) is more effective than IFN + ribavirin (3x106 U + 1000-1200 mg) for inducing sustained HC viral response
- Most responders (95%) to  Peg-IFN + ribavirin did so by week 12

## Conclusions (2)

- Sustained response rates are higher in patients with genotypes 2 and 3, and lower with genotype 1
- Patients with genotype 1 and high viral loads have poorest response of all

## Conclusions (3)

-  Peg IFN + ribavirin is associated with a higher number of adverse events (*eg* infections, neutropenia and injection-site reactions) compared I/R
- Few safety or efficacy data exist for African Americans, a group known to have poor response to IFN

## Conclusions (4)

- Compared to patient with higher body weights, patients with lower body weight tended to have:
-  Higher response rates
-  Higher rates of toxicity

## Conclusions (5)

- A number of factors could account for this apparent effect of body weight on treatment response and toxicity
- Definitive conclusions about the safety and efficacy of Peg IFN+ribavirin as a weight-based regimen cannot be drawn

## Post-marketing Studies

- Safety and efficacy of Peg IFN + ribavirin as a weight-based regimen
- Safety and efficacy of shorter durations of Peg IFN + ribavirin in patients with high likelihood of response (genotypes 2-3, genotype-1 with low viral load)

## Optimization of Ribavirin Dose and Treatment Duration 

- Multi-center, randomized,open label trial in 4000 treatment-naïve patients with CHC
- _Arm A: fixed dose ribavirin_
- 	PEG1.5/Riba 800 mg for 24 or 48 wks
- _Arm B: weight-adjusted ribavirin_
-   PEG1.5/Riba 13_+_2 mg/kg for 24 or 48 wks
-   BW kg:        <65      65-85     85-105     >105
-   Riba mg:     800      1,000     1,200        1,400

## Optimization of  Peginterferon Dose

- Safety and efficacy of lower doses of Peg IFN when given with ribavirin
- Safety and efficacy of PEG/R in African Americans

## Peginterferon Dose Optimization 

- Multi-center randomized study comparing combination therapy with PEG1.5g/kg vs. PEG1.0 g/kg plus ribavirin in 1,000 patients with CHC genotype 1
- The dose regimen of ribavirin will be determined from in-treatment data in the ribavirin dose optimization study
- Evaluation of the effect of therapy in African Americans (n~100)

## In-treatment vs. Post-treatment Response

|  | In-treatm wk24 |  | Follow-up wk24 |  |
| --- | --- | --- | --- | --- |
|  | <75 kg | >75kg | <75 kg | >75 kg |
| I/R | 106/78 (60) | 172/327 (53) | 94/178 (53) | 137/327 (42) |
| PEG 0.5/R | 114/187 (61) | 176/327 (54) | 91/187 (49) | 148/327 (45) |
| PEG 1.5/R | 127/185 (69) | 202/326 (62) | 108/185 (59) | 156/326 (48) |

## Effect of Food on Ribavirin Absorption

- Relative bioavailability of ribavirin compared to the fasted state after:
- High fat meal
- Non-fat meal