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Consensus Interferon for Nonresponders- revisited
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Reported by Jules Levin
Last night I attended the Intermune DDW symposium where Consensus Interferon (CIFN) was discussed. The company is developing this drug for nonresponders. They are conducting phase III studies examining nonresponders to peginterferon/ribavirin. One of the studies is in the USA and is multi-center for I think 500 individuals. As well, they are studying CIFN in combination with gamma interferon (Actimune) with and without ribavirin for nonresponders. At the symposium, unpublished data was presented by Michael Gale (University of Texas Southwestern Medical Center, Dallas, Tx) on in vitro (test tube) research showing that CIFN suppresses IFN-a-2 "resistant" HCV RNA replication. Speakers said in vitro CIFN is more potent.
There were 3 abstracts presented at DDW on Consensus Interferon examining its utility in IFN/RBV & pegIFN/RBV nonresponders, and looking at CIFN in combination with IFN gamma, without RBV. Bear in mind when reading the study results from small pilot studies of CIFN for IFN/RBV & PegIFN/RBV nonresponders that previously reported studies of retreatment of IFN/RBV nonresponders report 6-12% SVR with PegIFN/RBV. Studies of double dose PegIntron or Pegasys plus RBV in IFN/RBV nonresponders suggest better viral clearance. 72 week results of PegIntron find no improvemt in SVR despite improved early viral clearance perhaps due to difficult in tolerating higher doses or due to relapse. The double dose Pegasys/RBV study only reported early data results and found better viral clearance. The Jacobson study found 50% relapse rates when treating IFN/RBV nonresponders with PegIntron/RBV.
You can read NATAP's real-time comprehensive coverage of key selected studies reported at this conference at this link on the NATAP website:
http://www.natap.org/2004/DDW/ddw.htm
At this DDW 2004 I've spoken with several researchers/doctors about their impressions of CIFN study results and as I've reported they are skeptical, to say the least. Nonetheless, perhaps we should remain open-minded as a number of leading thought leaders/researchers are investigators in phase III CIFN study in nonresponders. Some researchers emphatically expressed disbelief that CIFN is as effective as the data presented at this conference. Other researchers are investigators in the phase III studies of CIFN.
At the Intermune symposium speakers reviewed results from small pilot studies of CIFN in nonresponders. This Kaiser study (Kaiser et al AASLD 2003) examines IFN/RBV nonresponders and is a randomized, open-label single-center study in Germany. Patients received CIFN at daily doses of 18 mcg or 27 mcg for 4 weeks, followed by 9 mcg or 18 mcg, respectively, for 8 weeks, followed by CIFN 9 mcg plus RBV 1000/1200 mg/day. Demographics were 80% men, 47 yrs old, 93% genotype 1/4, 70% >850,000 IU HCV RNA, Ishak Score of 3.57-3.79, and 28% had cirrhosis. Week 72 SVR was 40% (11/27) with CIFN 18/9 mcg QD and 44% CIFN 27/18 QD.
Kaiser reported this data at DDW 2004. PegIFN/RBV nonresponders were randomized in open-label fashion to CIFN 27 mcg daily or CIFN 9 mcg daily for 4 weeks induction dosing, followed for 12 weeks of either CIFN 18 mcg QD plus RBV 11 mg/kg BW or CIFN 9 mcg daily (QD) plus RBV 11 mg/kg BW, respectively, followed by 32-72 weeks of CIFN 9 mcg QD plus RBV 11 mg/kg BW. Patients were treasted for 6 months with CIFN/RBV after achieving undetectable HCV RNA so duration of therapy varied by indivudual. There was 24 week followup period. Kaiser reported these results:
--Week 8: 20% & 27% HCV RNA negative in low (9 mcg CIFN/RBV) & high dose (27/18/9 mcg CIFN/RBV) arms
--week 24: 40% & 47% virus negative in low & high dose CIFN arms
--End of Treatment: 37% & 42% HCV RNA negative in low & high dose arms, respectively.
We should wait for SVR but even with 50% relapse rates SVR may be expected to be 18-21%, better than 10% seen in Jacobson study of IFN/RBV nonresponders treated with PegIntron/RBV.
Kaiser study presented at DDW 2004 reported End Of Treatment viral response of 37% and 43% for patients using low & high dose CIFN induction regimens, respectively (no significant differences). At week 8, viral negativity was 20% & 27%, respectively; at week 24, viral negativity was 40% & 47% in lo & hi dose regimens, respectively, for which Leevy suggested that since responses were better at week 24 perhaps for nonresponders the Early Viral Response rule should be 24, not 12, weeks.
LEEVY STUDY PRESENTED AT DDW 2004: Peg/RBV nonresponders at week 12 switched to CIFN 15 mcg daily/RBV
Leevy reported the end of treatment virological response and safety of CIFN and weight based ribavirin in HCV patients who were non-responders to PEG IFN a-2b and weight based ribavirin. This was a retrospective review of 137 consecutive PEG IFN a-2b/RBV non-responders re-treated with daily CIFN and RBV. All patients had previously received PEG IFN a-2b 1.5 mcg/kg once weekly and weight based dosed RBV, and did not have at least a 2 log decline in HCV RNA at week 12 of therapy (Null Responders).
With no washout period, patients were started on high dose CIFN at 15 mcg daily and RBV 1000-1200mg QD for 12 weeks, if they were HCV RNA negative the dose was reduced to 15 mcg 3 times weekly for the remainder of the 48 weeks, if they were not HCV RNA negative, no dose reduction was implemented.
The patients were 47 yrs, 58% men, 78 kg weight, 32% African-American, 94% genotype 1/4, viral load before PegIFN/RBV therapy was mean of 3.2 million copies/ml. Viral load before CIFN/RBV was mean 1.6 million copies/ml.
Leevy reported at the end of 12 and 24 weeks of therapy with daily IFN alfacon-1/RBV, the mean HCV RNA was 247,000 copies/ml and 189,902 copies/ml respectively, a significant reduction from the baseline (P<0.05 for both observations). By the end of therapy with CIFN/RBV (week 48) 59/137 (43%) of patients were HCV RNA negative. Therapy was well tolerated in all patients with flu-like symptom and fatigue reported in most patients, but no patients discontinued therapy. At week 12 23% of patients were virus negative & 60% had >2 log HCV RNA reduction. At week 24, 31% were negative & 69% had >2 log HCV RNA reduction, so Leevy suggested 24 weeks, not 12 weeks, should be Early Viral Response cutoff for consideration of stopping therapy in prior nonresponders.
Leevy also reported on patient responses to side effects of PegIFN vs daily CIFN/RBV at 8 weeks. Retrospectively, patients were asked to consider all of the following factors and then indicate which drug regimen they preferred; patients were surveyed without knowledge of their viral load: depression, injection site reactions, fatigue, joint & muscle aches, fever. Preferred drug regimen was Peg/IFN by 3% of patients, daily CIFN by 71%, and 24% said they were the same.
Leevy concluded patients will be monitored for HCV RNA response 6 months post treatment to determine the rate of SVR. These initial data are highly promising and warrant more study of CIFN/RBV in difficult to treat chronic Hepatitis C patients. Clearly, these data are from pilot studies and we should wait for results from phase III studies to reach conclusions.
INTERFERON GAMMA
Leevy discussed IFN g at the symposium. Chronic hepatitis C is a disease of T-cell hyporesponsiveness. Clearance of acute HCV infection requires a potent Th1 response mediated by production of IFN gamma (Thimme et al 2002). Clearance of HCV in chronic patients treated with IFN-a requires a shift from a dominant Th2 to Th1 response (mediated by IFN gamma). IFN gamma and IFN-a display synergistic antiviral activity (Blatt et al, Hepatology 2003,;38: 296a-7a).
Leevy reported at DDW 2004:
INTERIM RESULTS OF A PILOT STUDY OF THE COMBINATION OF CIFN AND IFN GAMMA INTERFERONS IN CHRONIC HEPATITIS C PATIENTS WHO HAVE FAILED TO RESPOND TO PEG-INTERFERON ALPHA 2 PLUS RIBAVIRIN
This is a pilot study in 32 Null Responders to Pegasys + ribavirin.
32 treatment-naïve patients received Pegasys plus RBV. After 12 weeks patients with early viral response (>2 log HCV RNA reduction or negative HCV RNA) continued treatment with Pegasys/RBV for 36 additional weeks. Patients with positive HCV RNA or <2 log HCV RNA reduction started CIFN 15 mcg daily plus IFN gamma 50 mcg three times weekly for 48 weeks.
At the end of 12 weeks of therapy, 12 of 32 (38%) of these Null Responder patients had undetectable HCV RNA (40% of genotype 1 patients (n=25) had negative HCV RNA at week 12), and a total of 20 of 32 (65%) of the patients had either a 2 log10 or greater decline in viral load or were HCV RNA negative. Assessment of the quantitative changes in HCV RNA from baseline demonstrated that these patients as a group had a significant reduction from a mean of 11.950,000 copies/mL at baseline to a mean of 87,000 copies/mL at week 12.
At week 24 47% (15/32) of all patients (n=32) had negative HCV RNA and 48% of genotype 1 patients (n=25) had negative HCV RNA.
All 32 patients had a reduction from baseline in serum ALT and by week 12, all patients had ALT values that were below the upper limit of normal.
Leevy reported all patients have had hemoglobin return to normal range while receiving CIFN and IFN gamma. No growth factors were used. 8 patients required filgrastim for neutropenia.
Leevy concluded patients will be treated for an additional 24 weeks and assessed for end of treatment response and SVR, and further study is warranted.
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