Interim, 12-week analysis comparing Pegasys to Rebetron shows

• Similar antiviral efficacy with
• Significantly improved:
  • Quality-of-life measurements,
  • Tolerability,
  • And work productivity.

The interim, 12-week results of comparing peginterferon alfa 2a (Pegasys) monotherapy to standard Rebetron (interferon alfa 2b plus ribavirin, FDA-approved dosing) were presented by Robert P. Perrillo, MD of Ochsner Clinic in New Orleans, Louisiana. The randomized study of 412, treatment-naïve (no previous therapy) patients will continue for a full 48 weeks of treatment and an additional 24 weeks of observational follow-up to determine the sustained virologic response (SVR) rates. The dose of Pegasys is 180 micrograms injected once weekly. Rebetron dosing is interferon alfa 2b, 3 million international units injected 3-times weekly plus daily, oral ribavirin 1,000 (75 kg or less; 165 pounds or less) or 1,200 mg (at least 75 kg or 165 pounds).

(Editorial note; the purpose of this study is to compare efficacy, tolerability and safety for Pegasys monotherapy vs Rebetron (interferon alfa-2b 3 MIU+ribavirin 1000-1200 mg per day).

Baseline information included 27% women, 84% Caucasian, 75% with genotype 1 (the most difficult to treat), 56-60% with an HCV RNA greater than 6 log (1 million) "copies per milliliter," and 22-28% with cirrhosis or transition to cirrhosis on liver biopsy. The mean baseline ALT (alanine aminotransferase, liver enzyme) was 110 units per liter. All have completed 48 weeks of treatment and analyses are underway.

The interim results after 12 weeks were as follows. An undetectable HCV RNA (negative using Amplicor version 2.0) was achieved by 46.8% of the Pegasys arm and 50.3% of the Rebetron arm. (Note the standard test of virologic efficacy is the SVR 24 weeks after completing treatment.) The following adverse events were reported as more common among Rebetron patients than Pegasys patients: fatigue (68% Rebetron verses 66% in Pegasys); nausea (46% vs. 34%); itching ("pruritus," 20% vs. 7%); shortness of breath ("dyspnea," 18% vs. 10%) and anemia (here defined as reduction in hemoglobin greater than 4 grams per deciliter, 32% vs. 4%).

Several scales of quality-of-life measurements were reported. Using the "SF-36" scale at 4 and 12 weeks, the Rebetron arm had a significantly greater decline (worse outcomes) than the Pegasys arm in terms of physical functioning, general health, physical component summary and mental component summary (p<0.05 each component). Using the "Hepatitis Quality of Life Questionnaire" at 4 and 12 weeks, the Rebetron arm had a significantly greater decline (worse outcomes) than the Pegasys arm in terms of positive well-being and "hepatitis-specific limitations" (p<0.05 each component), and a significantly lesser improvement (smaller improvement, worse outcome) in "hepatitis-specific well-being" (p<0.05).

Using the Work Productivity and Activity Impairment survey at 4 and 12 weeks, patients in the Rebetron arm had higher percentages of impairment (15-20%) than patients in the Pegasys arm (5-10%), without statistical analysis. And, estimated work productivity at weeks 4 and 12 was less in the Rebetron arm (weekly wage loss $90-93) than in the Pegasys arm (weekly wage loss $30-44), without any statistical analysis.

The authors acknowledge that the results are merely interim and that a complete evaluation that compares the 2 study arms can only be undertaken 24 weeks after completion of the 48 treatment period. Certainly, adverse events rates, discontinuation rates, sustained virologic response rates, liver biopsy changes, and quality of life issues all must be taken into account. In addition, a comparison to a more current standard of care would be helpful, i.e. to peginterferon alfa plus ribavirin. The phase III study results of Pegasys plus ribavirin will be presented at DDW 2001 Conference that will take place in mid-May.

References
Perrillo RP and others. Therapy with pegylated interferon alfa-2a (Pegasys) demonstrates similar efficacy and significantly improved tolerability, quality of life, and work productivity compared with standard interferon alfa-2b/ribavirin (Rebetron) in patients with chronic hepatitis C. Abstract and poster presentation 452 (board 531) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic and Journal of Hepatology 2001 April;34(suppl 1):146.

Perrillo RP and others. An evaluation demonstrating continued efficacy and improved safety and tolerability in 17 patients switched to Pegasys after discontinuation from Rebetron for the treatment of chronic hepatitis C. Abstract and poster presentation 442 (board 532) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic and Journal of Hepatology 2001 April;34(suppl 1):146.

Switching to Pegasys after intolerance to Rebetron shows benefits for 17 patients (interim report).

Patients who have discontinued Rebetron (interferon alfa 2b plus ribavirin, standard dosing) due to drug intolerance showed significant benefits and many showed improved quality-of-life after switching to peginterferon alfa 2a (Pegasys). Robert P. Perrillo, MD of the Ochsner Clinic in New Orleans, Louisiana was the lead author of the poster presentation. The 17 patients were originally part of a 412-patient randomized trial comparing the efficacy of Rebetron to Pegasys. Those who discontinued Rebetron (after 1-36 weeks) that was "possibly related" to drug intolerance or clinically significant, therapy-related adverse events were offered the option of switching to the opposite arm's regimen of peginterferon alfa 2a, 180 micrograms injected once weekly. Another criterion for switching was having demonstrated at least a 1-log (10-fold) reduction of HCV RNA, using a Cobas Amplicor HCV test (version 2.0). The 17 patients who switched have now been followed for 24-36 weeks after the switch. Immediately prior to the switch, 47% of them achieved an undetectable HCV RNA. Specific baseline information about the 17 patients was not reported.

The results showed that 65% of the 17 patients achieved or maintained an undetectable HCV RNA (limit 50 international units per milliliter using Amplicor PCR test) after at least 24 weeks of follow-up. Also, 76% had a biochemical response, as determined by a normal ALT (alanine aminotransferase, liver enzyme). Six of 17 patients (35%) who, prior to switching, "had reported significantly decreased work productivity and activity" were able to return to work or "normal daily activity levels." One patient (6%) discontinued after switching to Pegasys due to persistent psoriasis (skin rash), an adverse event that started while taking Rebetron. There is an assumption that there were no other discontinuations. Other adverse events after switching to Pegasys were not reported.

The 17 patients had discontinued Rebetron due to: fatigue (71%), anemia (low red cell percentage or low hemoglobin, 47%), headache (47%), nausea (35%), depression (24%), and other reasons (41%), including appetite loss, anxiety, fever, nose bleed, syncope (fainting episode), mouth ulcers (sores) or rash.

For baseline information about the 412 patients initially randomized, see the previous report above.

The interim report of the 17 patients suggests that many of those who are intolerant to Rebetron can be switched to Pegasys, without compromising and even improving virological and biochemical responses. Additional follow-up of these patients is necessary to determine the overall benefits and adverse events. They will receive a total of 48 weeks of treatment with Pegasys, and 24 additional weeks of follow-up to determine the SVR rate.

Reference
Perrillo RP and others. An evaluation demonstrating continued efficacy and improved safety and tolerability in 17 patients switched to Pegasys after discontinuation from Rebetron for the treatment of chronic hepatitis C. Abstract and poster presentation 442 (board 532) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic and Journal of Hepatology 2001 April;34(suppl 1):146.

New Pegasys drug combinations show potential benefits (interim report).

A preliminary report of combining peginterferon alfa 2a (Pegasys) with one or two other drugs (antiviral and/or "immune modulating") was authored by Adrian M. Di Bisceglie, MD of St. Louis University in Louisiana. The interim analysis after 24 weeks of treatment showed a similar virologic response rate to standard interferon alfa 2b (Intron A) plus ribavirin (combination Rebetron, arm A) for each of the following 3 combinations: (arm B) Pegasys plus mycophenolate mofetil (CellCept, "immune modulator" FDA-approved to prevent transplant rejection, dose not stated); (arm C) Pegasys plus amantadine (FDA-approved to treat influenza virus, with some anti-HCV activity); and (arm D) Pegasys plus amantadine and ribavirin. Pegasys is dosed at 180 micrograms once weekly.

The 153 treatment-naïve (no previous therapy) patients (34% women) were randomized 3:3:1:1 to arms A-D, respectively. Randomization also occurred by genotype 1 (the most difficult to treat) and viral load (greater than or less than 1 million "international units per milliliter"). Baseline information included: genotype 1 (73%), mean ALT (liver enzyme) 109 units per liter, and high viral load (greater than 1 million "international units per milliliter") in 67%.

The interim, 24-week results exclude 7 patients (5%) who were initially randomized, but did not receive any study medications (160 total randomized with baseline information above excluding the 7 who dropped out before starting medications). By treatment arms, the undetectable viral load rates (limit 50 international units per milliliter) after 24 weeks were as follows: 58% (arm A); 53% (arm B); 67% (arm C); and 58% (arm D). When comparing weeks 12 to 24, arms A, B, and C demonstrated increased undetectability rates, while arm D showed a decrease. After 24 weeks, the percentages of each arm with a normal ALT were as follows: 71% (arm A); 50% (arm B); 43% (arm C); and 68% (arm D). When comparing weeks 12 to 24, only arm B demonstrated an increase in the percentage with a normal ALT, while the other 3 arms showed a decrease. Since these various results are interim data, no statistical analyses have been performed.

Dr. Di Biscegle reported that there were no unexpected side effects noted that were due to medications. Interim adverse events (AE) and AE rates were not reported. However, all treatment arms showed a "similar safety profile." There were 7% serious adverse events in total, but the rates by treatment arm were not reported. One patient died due to an "unrelated" accidental narcotic overdose. For those patients who took at least one dose of medications, 27% discontinued treatment (percentages by treatment arm were not reported). Discontinuation due to "expected adverse events" included 5% (not subdivided by treatment arm). Discontinuation due to "insufficient therapeutic response" represented 14% (not subdivided by treatment arm). The study is ongoing for a full 48 weeks of therapy, with an additional 24 weeks of follow-up.

The interim conclusions after only 24 weeks of observation indicated a similar virologic response for the 4 treatment arms (Rebetron; Pegasys + CellCept; Pegasys + amantadine; Pegasys + amantadine + ribavirin), with safety profiles reported to be similar. Also, the findings suggest that the new therapeutic combinations might represent different potential options for patients. In addition, the authors conclude that the interim results support using the combinations in larger phase III studies.

Reference
Di Bisceglie AM and others. Pegylated (40 kilodalton) interferon alfa-2a (Pegasys) in new combination therapies: a preliminary report of a randomized, multicenter efficacy and safety study. Abstract and poster presentation 408 (board 449) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic and Journal of Hepatology 2001 April;34(suppl 1):143.