# Presentation: 756261

## Pegasys® Copegus ®Hoffmann-La RocheBLA 125061

**Antiviral Drugs Advisory Committee**
**Bethesda, Maryland**
**November 14, 2002**

**Center for Biologics Evaluation and Research**** **

## Indications and Usage

**Pegasys****® Copegus® in Combination Are Indicated for the Treatment of Previously Untreated Patients With Chronic Hepatitis C Infection **

## Chronic Hepatitis C: SustainedTreatment Response (SVR)

**Interferon alfa-2a monotherapy ~ 15% **
**Peg-Interferon alfa-2a monotherapy ****~ 30****%**
**Interferon alfa-2b with ribavirin ****~ ****45%  **
**Peg-Interferon alfa-2b with ribavirin ****~ 50%**
**Response rate adversely affected by: **
**HCV genotype and viral load **
**Cirrhosis**
**Age, race**

## Study Drugs

**Hoffmann-La Roche**
**Interferon alfa-2a (Roferon A) IFN alfa-2a**
**Pegylated interferon alfa-2a (Pegasys) PEG-IFN **
**Ribavirin (Copegus) R **
**Schering Plough**
**Interferon alfa-2b (Intron A) IFN**
**Ribavirin (Rebetol) R **
**IFN alfa-2b/R combination (Rebetron)**

## Clinical Development 

_**Phase 1**_** **
** ****Pegasys (n=1393) Healthy subjects**
** ****Copegus(n=305)  Patients with CHC**
** ****PK  of PEG-IFN alfa-2a **
** ****Comparability of Copegus and Rebetol**
_**Phase 2**_
** ****PK study of Pegasys 180 ********g and Copegus 1000/1200 mg in 20 patients with CHC**

## Clinical Development: Phase 3

**NV15801: Randomized, partially blinded study comparing Pegasys/Copegus to IntronA/Rebetol (n=1121)**
**NV 15942: Randomized, double blinded, study of Pegasys/Copegus (n=1284)**
**Treatment duration (6 vs. 12 months)**
** ****Ribavirin dose (800 vs. 1000/1200 mg)**

## Rationale for Selection of Peginterferon and Ribavirin Dosages for Phase 3 Studies

## % SVR in Pegasys Monotherapy Studies

| 
Study n | IFN alfa2a | Peginterferon alfa-2a  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 45g | 90g | 135g | 180g | 270g |
| 1 (159) | 3% | 10% | 30% | -- | 31% | 24% |
| 2 (271) | 8% | -- | 15% | -- | 30% | -- |
| 3 (639) | 11% | -- | -- | 28% | 28% | -- |

## Rationale for Selection of Ribavirin Dose

**Similarity of PK data for Roche’s and Schering’s ribavirin **
**1000-1200mg recommended dosage for Schering’s ribavirin and IFN alfa-2b**
**800mg recommended dosage for Schering’s ribavirin and PEG-IFN alfa-2b**

## Analysis of Phase 3 Clinical Trials

## Phase 3 Protocols: Study Population 

_**Inclusion**_
**Men and women 18 yrs or older **
**Histologically proven CHC**
**Elevated ALT, detectable HCV RNA **
**Interferon-treatment naïve**
_**Exclusion**_
**Other forms of hepatitis, HIV co-infection**
**History of severe psychiatric, cardiac, neurologic, or ocular disorders**
_**International participation**_
**North/South America, Europe, Asia. **
**US patients 37% of total of both studies**

## Phase 3 Protocol: Assessment of Response

**Primary Endpoint at ****24 wk Post-therapy**** **
**Combined SVR and SBR for study 1**
**SVR alone for study 2**
**Futility Withdrawal at 24-weeks**** **
**Inadequate early viral response (HCV RNA **_****_**2 log drop) **_**OR  **_
**No biochemical response ( ALT remains elevated) **

## NV 15801 (Study 1) 

## NV 15801 Clinical Protocol 

**Study Design **
**n=1121 patients randomized 1:2:2 **
**PEGASYS alone, PEGASYS/COPEGUS, or REBETRON x 48 weeks **
**Dosing**
**PEGASYS  180 ****μg sc qw, INTRON A 3MIU tiw,  Ribavirin 1000/1200 mg po qd**
**Primary efficacy analysis **
**ITT population (all randomized)**
**Cochran-Mantel-Haenszel Test with stratification variables of country/genotype**
**Pegasys/Copegus vs. Rebetron**

## Population Characteristics

|  | All patients
n=1121 | U.S.
n = 460  | Non-US
n = 661 |
| --- | --- | --- | --- |
| Men | 800 (71%) | 333 (73%) | 467 (71%) |
| Whites | 943 (84%) | 385 (84%) | 558 (84%) |
| Age > 44yrs | 448(41%) | 225 (49%) | 232 (35%) |
| Weight > 85kg | 356 (32%) | 227 (50%) | 129 (22%) |

## Baseline Disease Characteristics

|  | Total
n = 1121 | U.S. 
N = 460  | Non-US
n = 661  |
| --- | --- | --- | --- |
| High Viral Load | 743(66%) | 313 (68%) | 430 (65%) |
| Genotype 1 | 728(65%) | 322 (70%) | 406 (61%) |
| Cirrhosis | 144(13%) | 72 (16%) | 72 (11%) |

## Principal Efficacy Outcomes

| Endpoint |  | PEG-IFN 
n=227 | PEG-IFN/R 
n=465 |  |  | IFN/R 
n=457 |
| --- | --- | --- | --- | --- | --- | --- |
| SVR/SBR |  | 55 (24%) |   210 (45%) |  |  | 180 (39%) |
|                                         
                                                       |  |  | p = 0.057 |  |  |  |
|  SVR |   62 (27%) |  |  | 234 (50%) | 190 (42%) |  |
|                                        
                                                       |  |  |  p = 0.001 |  |  |  |

## Percent SVR in Subgroups

|  | PEG-IFN/R | IFN/R | %Delta |
| --- | --- | --- | --- |
| All patients | 240/453 (53) | 195/444 (44) | 9 |
| Age:  <44 | 160/263 (61) | 136/272 (50) | 11 |
|          >45 | 78/190 (41) | 62/172 (36) | 5 |
| Race: White | 201/372 (54) | 177/385 (46) | 8 |
|           Black | 6/27 (22) | 3/13 (23) | -1 |
| Cirrhosis: Yes | 23/56 (41) | 19/54 (35) | 6 |
|                  No | 218/397 (55) | 179/390 (46) | 9 |
| Region: U.S. | 77/184 (42) | 84/183 (36) | 6 |
|             Non-U.S. | 164/269 (61) | 130/261 (50) | 11 |

## Histologic Responders in Patients with Paired Biopsies

| HAI >2 | PEG-IFN | PEG-IFN/R | IFN/R |
| --- | --- | --- | --- |
| Biopsies
Done | 28/39 (72%) | 64/80 (80%) | 60/79 (76%) |
| Planned | 65 | 110 | 110 |

## SVR by Genotype and Region

**Overlay Chart**

**0**

**20**

**40**

**60**

**80**

**All**

**Geno1**

**Geno**
** ****Non1**

**High**

**Low**

**PEG/R US**

**IFN/R US**

**PEG/R Non-US**

**IFN/R Non-US**

**Proportion of responders**

## Percent SVR by Genotype

**0**

**20**

**40**

**60**

**80**

**Percent Responders**

**all**

**Geno1**

**Geno**
**non1**

**High**
**titer**

**Low **
**Titer**

**PEG/R**

**IFN/R**

## SVR by Body Weight

**0**

**25**

**50**

**75**

**Percent Responders**

**PEG/R**
**1000-1200mg**

**IFN/R**
**1000-1200mg**

**Weight <85kg**

**Weight ******** 85kg**

## Adverse Events

|  | PEG | PEG/R | IFN/R |
| --- | --- | --- | --- |
| AE:    Severe | 28% | 29% | 29% |
|           Serious | 12% | 12% | 9% |
|           Death | 0.9% | 0 | 0.2% |
| Withdrawals | 7% | 10% | 11% |
| Dose mod: IFN 
                 R              | 27% | 32% | 18% |
|  | --- | 40% | 37% |

##  Percent Serious Adverse Events 

|  | PEG-IFN
N=224 | PEG/R
N=453 | IFN/R
N=444 |
| --- | --- | --- | --- |
| Totals |   12% |  12% |  9% |
| Neuro-Psychiatric | 2% | 4% | 3% |
| Infection | 3% | 3% | 2% |
| Gastrointestinal | 1% | 2% | 2% |

##  Number of Serious Infections

|  |  | PEG-IFN
n=227 | PEG/R
n=465 | IFN/R
     n=457 |
| --- | --- | --- | --- | --- |
| TOTAL | 7 (3.0%) |  | 16 (3.4%) | 8 (1.7%) |
|         Bacterial |  | 4 | 15 | 7 |
| PMN: <500 |  |  1 |  1 | 0 |
| Lymphocytes <500           |  | 1 | 2 | 1 |

## Neutropenia during Treatment and Follow-up

**0**

**10**

**20**

**30**

**40**

**50**

**60**

- Normal

- Grade1
- 1500-2000

- Grade2  1000-1500

- Grade3 500-1000

- Grade 4 <500

**PEG Mono**

**PEG/R **

**IFN/R**** **

## Lymphopenia During Treatment and Follow-up

**0**

**25**

**50**

**75**

- Normal

- Grade1
- 1500-1000

- Grade2
- 1000-500

- Grade 3
- <500

**PEG**** Mono**

**PEG/Combo**

**IFN****/Combo**

##  Patient Withdrawal Numbers

|  | PEG-IFN
n=223 |  |  | PEG-IFN/R
n=451 | IFN/R
n=443 |
| --- | --- | --- | --- | --- | --- |
| Total | 15 (7%) |  |  | 44 (10%) | 47 (11%) |
| AE: overall | 13 (6%) |  |  | 33 (8%) | 37 (9%) |
|   neuropsych |  | 5 |  | 16 | 20 |
|   general |  1 |  |  | 4 | 5 |
|   dermatol. |  2 |  |  | 3 | 5 |
| Lab: overall |  2 (1%) |  |  | 11 (2%) | 10 (2%) |
|    hematol | 2 |  |  | 6 | 4 |
|    thyroid/liver |  |  |    -- | 5 | 6 |

## Dose Modification 

|  | PEG-IFN |  | IFN | Copegus | Rebetol |
| --- | --- | --- | --- | --- | --- |
|  | Percentage of patients |  |  |  |  |
| AE | 11 |  | 11 | 21 | 22 |
| Lab Abn | 25 |  | 8 | 24 | 19 |
|       anemia | 1 |  | 3 | 22 | 19 |
|      neutropenia |  |  20 | 5 | 1 | <1 |
|      thrombocyt. |  |   4 | <1 | <1 | 0 |

## Serum Triglycerides

**0**

**25**

**50**

**75**

- <200

- 200-400

- 400-1000

- >1000

**PEG Mono**

**PEG/R **

**IFN/R **

## Laboratory Abnormalities by Weight

**0**

**25**

**50**

**75**

**Hemoglobin**
** ****<10g/dl**

**Neutropenia**
**Grade **_**>**_**3**

**PEG mono <65kg**

**PEG mono ******** 65kg**

**PEG/R <65kg**

**PEG/R ******** 65kg**

**IFN/R <65 kg**

**IFN/R ******** 65kg**

## Lab Abnormalities by BMI

**0**

**25**

**50**

**75**

**Percent involved**

**Hemoglobin**
**<10g/dl**

**Neutropenia**
******Grade 3**

**PEG/M <25BMI**

**PEG/M********25BMI**

**PEG/R <25BMI**

**PEG/R********25BMI**

**IFN/R <25BMI**

**IFN/R ********25BMI**

## Summary: Efficacy

**Peg-IFN alfa-2a 180********g /Ribavirin 1000-1200mg  higher SVR than IFN alfa-2b/Ribavirin 1000-1200mg   **
**Treatment difference 8%**
**Prognostic factors associated with lower response**
**HCV genotype 1/High viral titer (>2 million copies/ml)**
**Cirrhosis**
**Older age**
**Higher body weight**
**Response rates lower in US compared to Non-US**

## Summary: Safety

**Peg-IFN/R: higher observed incidence of certain adverse events compared to IFN/R **
**Serious adverse events (12% vs 9%)**
**Serious infections (3.4% vs 1.7%)**
**Grade 4 neutropenia (5% vs 1%)**
**Grade 3 thrombocytopenia (5% vs 0.2%)**
**Dose modifications (32% vs 18%)**
**Similar premature withdrawals (10% vs 11%)**
**Greater toxicity with lower body weight**

## NV 15942 (Study 2) 

## NV 15942 Clinical Protocol 

**Design: 1311 patients randomized by genotype and viral load  to 4 arms receiving ****Pegasys (180****μg) **
**Two treatment duration arms (24 vs. 48 weeks)**
**Two ribavirin dose arms (800 and1000-1200 mg) **
**Primary Efficacy Analysis **
**Sustained viral response in ITT population (all randomized receiving **_**>**_** 1dose)**
**Cochran-Mantel-Haenszel Test  with stratification variables of region, HCV genotype and titer, ribavirin dose **

## Randomization/Allocation

| STRATA | PEG/R
800x24w |  |  |  | PEG/R
1000x24 | PEG/R
800x48w | PEG/R
1000x48 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Geno-1 HVL |  |  |  1 |  |    1 |    4 | 4 |
| Geno-1 LVL |  |  |  | 1 |  1.5 |     1 | 1.5 |
| G non-1 HVL |  |  |  |  |  |  |  |
| G non-1 LVL |  |  |  |  |  |  |  |

## Population Characteristics

|  | All Patients
n= 1284 | U.S.
n=441 | Non-US
n=843  |
| --- | --- | --- | --- |
| Men | 838 (65%) | 277 (63%) | 561(67%) |
| White | 1146 (89%) | 404 (92%) | 742 (88%) |
| Age >44yrs | 509 (40%) | 229 (5%) | 280 (33%) |
| Weight >85kg | 390 (30%) | 206 (47%) | 184 (22%) |

## Baseline Disease Characteristics

| 
 | Total
n=1284 | U.S.
n=441  | Non-US
n=843  |
| --- | --- | --- | --- |
| High Titer | 819 (64%) | 288 (65%) | 531 (63%) |
| Genotype 1 | 740 (58%) | 270 (61%) | 470 (56%) |
| Cirrhosis | 321 (25%) | 127 (29%) | 194 (23%) |

## Pooled Sustained Virologic Response

|  | Treatment Duration |  | Ribavirin Dose |  |
| --- | --- | --- | --- | --- |
|  | 24 wk
n=487 | 48 wk
n=797 | 800mg
n=568 | 1000-1200 
n=716 |
| Odds ratio | 1.32 (1.01, 1.73) |  | 1.35 (1.05, 1.73) |  |
| p | 0.039 |  | 0.018 |  |

## %SVR by Strata, Treatment Duration and Ribavirin Dose

| STRATA | Treatment Duration |  |  | Ribavirin Dose |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 24 wk | 48wk | Delta | 800mg | 1000mg | Delta |
| Gen1HVL | 21 | 40 | 19 | 31 | 42 | 11 |
| Gen1LVL | 47 | 57 | 10 | 47 | 56 | 9 |
| G-non1H | 75 | 72 | -3 | 77 | 76 | -1 |
| G-non1L | 76 | 80 | 4 | 76 | 79 | 3 |

## SVR by Strata and Treatment Arm

## SVR by Body Weight

- 0

**25**

**50**

**75**

- Percent Responders

**PEG/R**
**800/24**

**PEG/R**
**1000/24**

**PEG/R**
**800/48**

**PEG/R**
**1000/48**

**Weight <85kg**

**Weight ******** 85kg**

## Pooled SVR in Patients with Cirrhosis

## Pooled SVR in Genotype 4

|  | Treatment Duration |  |  | Ribavirin Dose |  |
| --- | --- | --- | --- | --- | --- |
|  | 24wks |  | 48wks | 800mg | 1000mg |
| Genotype4 | 8/17(47) |  | 14/19(74) | 5/13(38) | 17/23(74) |
| High Titer |  |  0/2(0) | 1/3 (33) | 0/2(0) | 1/3(33) |
| Low Titer | 8/15(53) |  | 13/16(81) | 5/11(45) | 16/20(80) |

## Histologic Responders: Patients with Paired Biopsies

| 
HAI >2 | PEG/R
800 X 24w 
n=48 | PEG/R
1000X 24w 
n=51 | PEG/R
800X 48w
n=68 | PEG/RBV
1000X 48w
n=93 |
| --- | --- | --- | --- | --- |
| All | 35/48 (73) | 40/51 (78) | 52/68 (76) | 67/93 (72) |

## Percent with Adverse Events

|  | PEG/R
800 x24w | PEG/R
1000x24w | PEG/R
800 x 48w | PEG/R
1000x48w |
| --- | --- | --- | --- | --- |
| Severe | 22% | 23% | 32% | 32% |
| Serious | 3% | 7% | 9% | 10% |
| Death | 0 | 1(0.4) | 1(0.3) | 2(0.5) |
| Withdrawal | 5% | 5% | 16% | 15% |
| PEGdose | 30% | 26% | 33% | 36% |
| RBVdose | 19% | 27% | 28% | 38% |

## Serious Adverse Events

|  | PEG/R
800 x 24w | PEG/R
1000x24w | PEG/R
800 x48w | PEG/R
1000x48w |
| --- | --- | --- | --- | --- |
| Total | 4% | 7% | 10% | 11% |
| NeuroPsych | <1% | 3% | 2% | 3% |
| Infection | 1% | 1% | 1% | 3% |
| Inflam/auto | 1% | 1% | 1% | 1% |
| GI | <1% | 1% | 1% | 1% |

## Number of Serious Infections 

|  | PEG/R
800 mg x  24 w
N=207 |  | PEG/R
1000 x 24w N=280 | PEG/R
800mg x 48w
N=361 |  | PEG/R 1000 x 48w
N=436 |
| --- | --- | --- | --- | --- | --- | --- |
| Total |  | 2 (1.0%) | 3 (1.1%) | 5 (1.4%) | 12 (2.8%) |  |
| Bacterial |  | 1 | 3 | 5 |  | 10 |
| PMN 500 |  | 0 | 0 | 1 |  | 0 |
| Lymphs 500 |  | 0 | 0 | 1 |  | 2 |

## Case Report: Infection/Neutropenia

**68 yo man with difficulty swallowing and fever on study day 33**
**Day 47: Severe Neutropenia (ANC 400)**
** ****Study treatment PEG-IFN/ 1200mg R discontinued**
**Day 59: Hospital admission with severe throat pain, anemia, neutropenia and thrombocytopenia **
*** ******S. aureus *****epiglottitis diagnosed by laryngoscopy by smear**
*** ******S. aureus *****grown by urine culture**
**Day 60: Improvement**
** ****Response to multiple antibiotics and RBC transfusion**
** ****WBC reported to be near normal at time of discharge on this day.**

## Case Report: Infection/Neutropenia

**45 yo man with splinter injury to hand on study day 55  **
**Study treatment:PEG-IFN/800mg R **
**Day 58: splinter removed, wound cleansed, ANC 800**
**Wound infection**
**Day 60: wound check, refused antibiotics**
**Day 62-63: fever 39 C, agitation, oliguria**
**Septic shock, hospital admission **
**Day 64: ANC 2600 then 0 within 12 hr, Blood cultures: Gram pos cocci **
**Day 65:  expired**
**Autopsy: Disseminated abscesses, splenic lymphocyte depletion**

## Neutropenia during Treatment and Follow-up

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**Normal**

**Grade1**
**2000-1500**

**Grade2**
**1500-1000**

**Grade3**
**1000-500**

**Grade4**
**<500**

**PEG/R800x24**

**PEG/R1000x24**

**PEG/R800x48**

**PEG/R1000x48**

## Lymphopenia during Treatment and Follow-up

**0**

**25**

**50**

**75**

**Normal**

**Grade 1**
**1500-1000**

**Grade 2**
**1000-500**

**Grade 3**
**<500**

**PEG/R800x24**

**PEG/R1000x24**

**PEG/R800x48**

**PEG/R1000x48**

## Number of Patients Withdrawn

|  | PEG/800x24  | PEG/1000x24 | PEG/800x48  | PEG/1000x48 |
| --- | --- | --- | --- | --- |
| All Patients | 10 (5% | 13 (5%) | 59 (16%) | 67 (15%) |
| LAB | 1 | 1 | 2 | 4 |
|    Hematol | 1 | <1 | 2 | 2 |
|    Liver/Thyr | -- | <1 | 1 | 2 |
| AE | 4 | 4 | 14 | 12 |
|   Neuro-Psych | 3 | 1 | 4 | 5 |
|   General | <1 | <1 | 3 | 3 |
|   Derm | <1 | 1 | 2 | 1 |

## % Dose Modifications – 24 weeks

|  | PEG-IFN | PEG-IFN | R800 | R1000 |
| --- | --- | --- | --- | --- |
| AE | 7 | 9 | 12 | 18 |
| LAB | 23 | 20 | 8 | 12 |
|   Anemia | 0 | <1 | 8 | 11 |
|   PMN   | 20 | 16 | <1 | <1 |
|   PLT | 4 | 4 | <1 | 0 |

## % Dose Modifications - 48 weeks

|  | PEG-IFN  | PEG-IFN | R 800 | R1000 |
| --- | --- | --- | --- | --- |
| AE | 11 | 14 | 19 | 22 |
| LAB | 25 | 28 | 10 | 20 |
|   Anemia | <1 | <1 | 9 | 19 |
|    PMN | 22 | 24 | <1 | <1 |
|      PLT | 4 | 5 | <1 | <1 |

## Lab Abnormalities by Weight

**0**

**25**

**50**

**75**

**Hemoglobin**
**<10mg/dl**

**Neutropenia**
**Grade **_**>**_**3**

**R800x24 <65kg**

**R800x24 ******** 65kg**

**R1000x24<65kg**

**R1000x24********65kg**

**R800x48<65kg**

**R800x48********65kg**

**R1000x48<65kg**

**R1000x48********65kg**

## Lab Abnormalities by BMI

**0**

**25**

**50**

**75**

**Percent Incidence**

**Hemoglobin**
**<10g/dl**

**Neutropenia**
******Grade 3**

**R800x24 <25BMI**

**R800x24********25BMI**

**R1000x24<25BMI**

**R1000x24********25 BMI**

**R800x48<25BMI**

**R800x48********25BMI**

**R1000x48<25BMI**

**R1000x48********25BMI**

## Conclusions: Efficacy

**SVR in patients infected with genotype 1 **
**highest with Peg-IFN 180********g  qw / Ribavirin 1000-1200mg qd for 48 weeks **
**SVR in patients infected with genotype non-1 **
**similar in the four treatment regimens**
**SVR for genotype 4 **
**seems highest with combination therapy with 1000-1200mg ribavirin for 48 weeks**
**Response rates in US sites **
**lower compared to Non-US**
**Need for further assessment ?**

## Conclusions: Safety

**24-wk therapy with PEG-IFN 180********g and 800 or 1000/1200 mg ribavirin compared to 48-wk therapy: Lower incidence **
** ****severe or serious adverse events**
** ****withdrawal  **
**dose modification of either PEG-IFN or R**
**48 week/1000-1200mg ribavirin associated with higher: **
**serious infections **
**withdrawals for neutropenia**
**800 mg ribavirin compared to 1000/1200mg: Lower incidence **
**ribavirin dose modification **
**serious adverse events****	**
**Insufficient data to assess neutropenia and serious infections**
** ****Fatal infection on study associated with severe neutropenia **

## Conclusions: Risk-Benefit HCV Genotype Non-1

**Therapy with 800mg ribavirin for 24 weeks compared to 800 or 1000/1200 mg ribavirin for 48 weeks **
**less serious toxicity **
**similar sustained viral response**
**   **

## Unresolved Questions

**Many factors affect treatment response and toxicity**
**dose (PEG-IFN and R) and duration of treatment **
**HCV genotype and titers**
**demographic and other baseline characteristics (e.g. weight)**

## Need for Additional Studies

**Optimization of peginterferon and ribavirin dose and exposure **
**Weight based vs. fixed dosing **
**Confirm hypotheses raised by study 2 in patients with: **
**HCV genotype 1 and low viral titer**
**HCV genotype 4**