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Pilot Study, Hi-Dose Pegasys Induction- 37% SVR for IFN/RBV Nonresponders
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Reported by Jules Levin
This pilot study found that high-dose induction Pegasys therapy resulted in a better SVR than seen in previously reported studies of retreatment of IFN/RBV nonresponders with pegylated interferon plus RBV. Previous studies found 10% SVR in retreatment of IFN/RBV nonresponders using either Pegasys or PegIntron along with RBV. The authors of this pilot study concluded that Pegasys at high-dose of 360 ug/week during the first 12 weeks plus ribavirin produced the highest virologic response rates at weeks 12 & 72 (36%), and all doses were well tolerated. Roche is conducting the REPEAT Study to confirm the findings of this pilot study--which stands for "REtreatment with PEGASYS in pATients not responding to prior peginterferon alfa-2b/ribavirin combination therapy".
"PEGINTERFERON ALFA-2A (40KD) (PEGASYS) AND RIBAVIRIN (COPEGUS®) IN PATIENTS INFECTED WITH HCV GENOTYPE 1 WHO FAILED TO RESPOND TO INTERFERON AND RIBAVIRIN: FINAL RESULTS OF THE SPANISH HIGH-DOSE INDUCTION PILOT TRIAL'
Authors: M Diago, Hospital General de Valencia, Valencia, Spain; Manuel Romero-Gomez, Hospital Universitario De Valme, Seville, Spain; J Crespo, Hospital Marquez Valdecilla, Santander, Spain; A Olveira, Hospital La Paz, Madrid, Spain; R Perez, Hospital Central de Asturias, Asturias, Spain; R Barcena, Hospital Ramon y Cajal, Madrid, Spain; Jose M Sanchez-Tapias, Hospital Clinic i Provincial, Barcelona, Spain; M Munoz-Sanchez, Roche, Madrid, Spain
No effective treatment regimen has been established for patients who fail to respond to interferon/ribavirin. We aimed to determine the safety and efficacy of high-dose induction therapy with Pegasys during the first 12 weeks of Pegasys/Copegus combination therapy in this population.
Patients eligible for this, randomized, multicenter, open-label, pilot study were aged >=18 years, had detectable genotype 1 HCV RNA (>=600 IU/mL), had chronic hepatitis C without cirrhosis, as determined by liver biopsy, and had not responded to >=22 weeks of prior treatment with conventional interferon/ribavirin (i.e. were HCV RNA positive during treatment and follow-up). Patients were randomized to one of three Pegasys dosages (180, 270 or 360 μg/wk) with which they were treated for 12 weeks, followed by 180 μg/wk for 36 weeks. Copegus 1000/1200 mg/day was coadministered throughout the 48-week treatment period. Patients with detectable HCV RNA (>=50 IU/mL, COBAS AMPLICOR HCV Test, v2.0) at week 12 could discontinue treatment. Sustained virological response (SVR) was defined as undetectable HCV RNA (<50 IU/mL) at the end of a 24-week untreated follow-up phase.
Patients were stratified by baseline viral load (<800,000 or >800,000 IU/mL).
75% were male in study. Average age was 41-44. Weight: 75 kg in 180 7 270 dose regimen & 80 kg in 360 dose regimen. BMI was 26 & 26.7 in 180 7 270 regimens, respectively, and 27.2 in 360 dose.
Results
72 patients were randomized and 3 did not receive study medication; thus 72 patients were included in the ITT analysis. An induction dose-dependent increase in viral clearance was seen at week 12 and is reflected in SVR rates in the three groups (Table). The highest virological response among the 3 groups at week 12 and 72 was in patients treated with Pegasys 360 μg/wk for the first 12 weeks.
Viral response rates at week 12 (end of induction) and 72 (SVR) increased in proportion to the Pegasys dose given during the first 12 weeks. Viral response=undetectable HCV (<50 IU/ml). Sustained Viral Response (SVR) was 37.5% for high dose induction therapy regimen of 360 ug/week vs 30% for the 270 ug/week induction dose regimen and 17.9% for the 180 ug/week dose regimen.
Early virologic response rates were higher in patients with low HCV RNA <800,000 IU/ml than high HCV RNA at baseline; however, this trend is not apparent when SVR rates by baseline HCV RNA are considered. Consistent with the overall results, the highest viral response rates at week 12 and SVR rates at week 72 in patients with high & low viral loads were obtained in the highest induction dose group (360 ug/week).
WEEK 12 & 72 VIROLOGIC RESPONSE
Viral response=undetectable HCV (<50 IU/ml)
180 ug/week
12 wk: 21.4%
72 wk: 17.9%
270 ug/wk
12 wk: 35%
72 wk: 30%
360 ug/wk
12 week: 45%
72 wk: 37.5%
TOLERABILITY
The authors reported Pegasys was well tolerated across all 3 treatment groups. The mean weekly dose of Pegasys during the first 12 weeks was >=96% of the dose prescribed in the randomization scheme. Requirements for dose reductions did not increase in proportion to the dose of Pegasys. The incidence of adverse events, severe adverse events, and laboratory abnormalities including neutropenia and thrombocytopenia were similar among the 3 groups. Asthenia (50%), headache (38%), fever (35%), and myalgia (29%) were the most frequent adverse events overall. At week 12, grade 3 neutropenia (0.5 to 0.99 x 109 cells/L) was detected in 8 (29%), 5 (27.8%), and 3 (13%) patients treated with Pegasys 180 ug/week, 270 ug/week, and 360 ug/week, respectively. Although the use of hematopoietic growth factors was allowed under the study protocol, none were used during the study. No patients in any study group reported grade 4 neutropenia (<0.5 x 109 cells/L), or grade 3 (20 to 49.9 x 109 cells/L) or 4 (<20 x 109 cells/L) thrombocytopenia after 12 weeks of treatment. One patient in the high-dose group withdrew from the study because of an adverse event (depression).
DOSES OF PEGASYS ADMINISTERED DURING THE FIRST 12 WEEKS
| 180 ug/wk | 270 ug/wk | 360 ug/wk | | Mean (ug/week) | 172 | 263 | 349 | | Mean Total | 2141 | 3299 | 4368 | | Reductions for adverse events | 9(32%) | 2(10%) | 3(12.5%) |
ADVERSE EVENTS (AE) REPORTED DURING THE FIRST 12 WEEKS
| 180 ug/wk | 270 ug/wk | 360 ug/wk | | Patients w/AE | 25(89%) | 18(90%) | 22(92%) | | Pts w/severe AE | 7(25%) | 5(25%) | 6(25%) | | AE leading to withdrawal | - | - | 1(4%) |
The authors concluded that Pegasys plus Copegus can eradicate HCV RNA in patients infected with HCV genotype 1 who are non-responders to previous treatment with interferon/ribavirin. The combination was equally well-tolerated when Pegasys was given at doses of 180 to 360 μg/wk for the first 12 weeks of a 48 week regimen. Virological response rates at week 12 and 72 (SVR) increased in proportion to the induction dose given during the first 12 weeks. Regimens including an induction phase with a higher fixed dose of Pegasys may thus be of value in improving outcomes in prior non-responders.
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This is press release Roche distributed about this study at AASLD.
October 29th, 2004
Hepatitis C Non-Responders Have a Second Chance with PEGASYS(R)
BASEL, Switzerland, October 29 /PRNewswire/
--- Studies Show That Patients May be Re-treated Successfully
Hepatitis C (HCV) patients with difficult-to-treat disease, who do not respond to previous courses of therapy with either conventional interferon or peg-interferon alfa-2b[1] combination therapy, may now have an improved chance to be cured if they are re-treated with PEGASYS(R) plus COPEGUS(R). Two studies to be presented at the American Association for the Study of Liver Diseases meeting in Boston show that PEGASYS combination therapy is effective in non-responders to previous therapy.
Higher dose strategies for patients not responding to previous conventional interferon combination therapy
One study reports that more than one-third of hepatitis C genotype 1 patients who previously failed to respond to conventional interferon plus ribavirin achieved a sustained virological response (SVR) following re-treatment with a 12-week induction dose of PEGASYS.
Seventy-two patients were randomised into one of three arms where they received the standard dose of 180 microg or an increased dose of either 270 or 360 microg PEGASYS weekly for 12 weeks followed by a 180 microg dose of PEGASYS for the remaining 36 weeks. Throughout the trial, patients received either 1000 or 1200 mg of COPEGUS daily. There was a clear dose response with increasing doses of PEGASYS(R) with patients in the 360 microg induction dose arm achieving a 37.5% SVR. This is important as previous studies have reported SVRs of only around 10% in these difficult to treat patients. (i)
"These data show that a higher induction dose may be an effective treatment strategy for patients who are non-responders to previous therapy," said Dr. Moises Diago, Hepatologist at Hospital General Universitario, Valencia, Spain and lead author of the study. "The SVRs that were achieved in this study with PEGASYS and COPEGUS are encouraging and provide patients with a second chance to achieve viral eradication."
The second study suggests that the positive results seen in re-treating conventional interferon non-responders with PEGASYS and COPEGUS may also be achieved in patients not responding to previous peg-interferon alfa-2b combination therapy.
Pilot study provides look at effectiveness of PEGASYS in peginterferon alfa-2b non-responders
Dr. Norman Gitlin from Emory University in Atlanta, Georgia will present the results of a small single centre study examining the SVR that was achieved by giving PEGASYS plus COPEGUS to patients who failed to respond to a course of therapy with peg-interferon alfa-2b and ribavirin. In the 31 patients that Dr. Gitlin and colleague report on, 32% overall achieved an SVR and pre-existing cirrhosis did not preclude a successful response.
The trial studied patients who were not responsive to peg-interferon alfa-2b combination therapy at 12 to 24 weeks, who were then treated with a fixed 180 microg dose of PEGASYS per week and either 1000 or 1200 mg of COPEGUS daily. Cirrhosis was present in 32% of patients enrolled in the trial and 94% of all patients had genotype 1 HCV - the most difficult-to-treat form of the virus.
"Patients who do not respond to the current standards of care have few if any re-treatment options," said Dr. Gitlin. "The medical community has been skeptical of the value of re-treating patients who've already received a pegylated interferon, however, our experience suggests that the combination of PEGASYS and COPEGUS can provide higher SVRs than we've seen previously in this patient population, and that's good news for patients."
"Roche has encouraged physicians around the world to look at strategies that will give patients the best possible outcome," said Ciro Caravaggio, Hepatitis Franchise Leader at Roche. "The interim results of the high induction dose study were a significant factor in the design of our ongoing REPEAT study in peg-interferon alfa-2b non-responders, and Dr. Gitlin's study also gives us an interesting preview of the results we may achieve in REPEAT," he added.
Roche's ongoing commitment to finding solutions for patients who have not responded to earlier therapy
To support the growing patient population that is non-responsive to the earlier pegylated interferon treatment, Roche initiated a year ago the first global trial to study the efficacy of the new generation pegylated interferon combination therapy against the earlier one. This trial is known as REPEAT, which stands for "REtreatment with PEGASYS in pATients not responding to prior peginterferon alfa-2b/ribavirin combination therapy".
The REPEAT study will evaluate the efficacy and safety of the combination of PEGASYS and COPEGUS given for a longer, 72-week period, as well as examining the role of a 12-week induction regimen in this population.
Currently, 106 treatment sites in Belgium, Brazil, Canada, France, Germany, Greece, Italy, Portugal, Spain, Sweden, Switzerland, Turkey, UK and the USA are enrolling 900 patients for this trial and enrollment is expected to be completed by the beginning of next year. To enrol in REPEAT, patients must be diagnosed with chronic hepatitis C and have failed to achieve a response after at least 12 weeks of therapy with standard doses of peg-interferon alfa-2b and ribavirin.
In addition, there are nearly 50 other trials that have begun in 20 countries where PEGASYS and COPEGUS are being studied in patients who have failed to respond to other therapies.
About PEGASYS
PEGASYS, the market leader worldwide in hepatitis C therapy, provides significant benefit over conventional combination interferon therapy in HCV patients of all genotypes. The benefits of PEGASYS are derived from its large 40 kilodalton (KD) branched-chain polyethylene glycol (PEG) construction, which allows for sustained drug levels over the course of a full week. PEGASYS also distributes more readily to the liver (the primary site of infection) than conventional interferon. PEGASYS is the only pegylated interferon available as a ready-to-administer solution. Each weekly subcutaneous injection contains 180microg of pegylated interferon alfa-2a (40KD), which is the approved dose for all patients, regardless of body weight.
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-intensive healthcare groups. Its core businesses are pharmaceuticals and diagnostics. As a supplier of innovative products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is number one in the global diagnostics market, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2003, the Pharmaceuticals Division generated 19.8 billion Swiss francs in prescription drug sales, while the Diagnostics Division posted sales of 7.4 billion Swiss francs. Roche employs roughly 65,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai.
All trademarks used or mentioned in this release are legally protected.
(i) Shiffman, ML, et al. Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015-1023.
[1] PEG-Intron(R)
Roche
Sheila Gies, Roche, +1-973-687-0188 (mobile). Jo Galea, Axon Communications, +44-208-822-6779
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