Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-10-09
2001-09-11
Woodward, Michael P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C530S399000
Reexamination Certificate
active
06288033
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of hepatitis B treatment.
BACKGROUND OF THE INVENTION
Chronic hepatitis B virus (HBV) infection is a serious global health problem affecting around 300 million individuals. Among them, approximately seventy-five percent are believed to be Asian. It also is estimated that 25-40% of these HBV carriers will die of cirrhosis or hepatocellular carcinoma.
In contrast to the course of the disease in Caucasians, the natural history of chronic HBV infection in Asians is characterized by an initial active viral replicative state with minimal liver damage (immune tolerance phase), followed by an active immune clearance phase with chronic active hepatitis, and later an inactive HBV non-replicative phase with the development of cirrhosis that may be complicated by hepatocellular carcinoma (HCC). In addition, a fourth phase, characterized by viremia and chronic active hepatitis in the absence of HBE antigenaemia may follow. The main aim of current treatment is to suppress HBV replication before there is any significant irreversible liver disease. As most of the liver damage occurs during the immune clearance phase (when HBV replication is being suppressed spontaneously), it would be ideal to suppress HBV replication in an earlier phase (immune tolerant phase).
So far, therapeutic trials have mainly been directed toward utilization of anti-viral agents, immunomodulators, immunosuppressives or certain specific combinations of these. At present, interferon-alpha is the only therapeutic approach that has had regulatory approval in a number of countries. However, interferon therapy has been reported to produce sustained clearance of hepatitis B e antigen (HBeAg) in 30-40% of North America and European patients, but only 25-65% of these patients ultimately cleared hepatitis B surface antigen (HBsAg). The response rate in Asian patients is lower: approximately 15-20% will clear HBeAg, of these only approximately 10% will clear HBsAg. One of the factors that affects the antiviral effects of these immunomodulatory agents is the high pretreatment HBV DNA level. Recently, second generation nucleoside analogs, such as lamivudine and famciclovir, have been shown to be effective in suppressing HBV replication with a good safety profile. However the nucleoside analogs have not been shown to maintain durable HBV DNA suppression once therapy is removed. Hence, the combination therapy goal is suppression and clearance.
There remains an urgent need in the art for effective anti-viral therapy against chronic HBV infection.
Thymosin alpha 1 (T&agr;1) initially isolated from Thymus Fraction 5 (TF5), has been sequenced and chemically synthesized. T&agr;1 is a 28 amino acid peptide with a molecular weight of 3108, which has shown activity similar to TF5 in modulating the maturation of T cells. T&agr;1 can influence immunoregulatory T cell function, promote interferon-alpha, interferon-gamma, and IL2 and IL3 production by normal human lymphocytes, and increase lymphocyte IL2 receptor expression.
There is evidence to suggest that T&agr;1 may influence recruitment of pre-NK cells, which would then become cytotoxic after exposure to interferon. T&agr;1 may also directly influence the lytic activity of mature NK cells. Recent investigations have shown that T&agr;1 enhances both allogenic and autologous human mixed lymphocyte reactions by activation of the T4 (helper/inducer)cells. This provides additional evidence that T4 cell may be the predominant target cell for the biological effect of T&agr;1.
Clinical trials of T&agr;1 as primary or adjunctive therapy for treatment of HBV infection indicate that it enhances immune responsiveness and augments specific lymphocyte parameters to significantly higher levels.
TF5 has been reported to decrease spontaneous cell-mediated lysis of hepatocytes using Peripheral Blood Mononuclear Cells (PBM) from patients with CHB. No effect on cytotoxicity was seen with TF5 treated control PBM. Additional studies showed that TF5 increased Con A-induced suppressor function in PBM from patients with CHB. T&agr;1 has been shown to enhance in vivo production of anti-HBs following Heptavax-B vaccination in previously non-reactive hemodialysis patients.
A controlled investigation was initiated in which 6 chronic woodchuck hepatitis virus (WHV)-carrier woodchucks were given twice weekly subcutaneous injections of T&agr;1 (10 &mgr;g/Kg) for 28 weeks. At the conclusion of the treatment, WHV DNA levels were undetectable in 4 of the treated animals, and were depressed 100-fold in the remaining 2 animals. Liver biopsy specimens obtained at the conclusion of treatment revealed a 50 to 300-fold decrease in the levels of WHV DNA replication intermediates in the 4 animals in which serum WHV DNA was undetectable-but only a small change from the pretreatment levels in the other 2 animals. No changes were identified in serum WHV DNA levels, or in tissue WHV DNA replication intermediates before or after treatment in any of the 6 untreated control animals.
In a US Phase II trial of Thymosin fraction 5 (TF5) and Thymosin alpha 1 (T&agr;1) in the treatment of CHB, 12 patients received TF5 or T&agr;1 and 8 patients received placebo twice weekly for six months. By the conclusion of the study (1 year), serum aminotransferase levels had improved significantly in the Thymosin e
1
-treated patients, but not in the placebo group. Nine (75%) of the Thymosin &agr;1-treated patients and 2 (25%) patients given placebo cleared serum HBV DNA (p<0.004, Fisher's exact test). Response to Thymosin al therapy was associated with significant improvements in peripheral blood lymphocyte, CD3 and CD4 counts, and in vitro production of interferon-gamma over initial values. No side effects were observed in patients given T&agr;1, and several patients given TF5 experienced induration and erythema at the injection sites. About 78% of the responders had a sustained remission with normal ALT levels and negative serum HBV DNA (using PCR) and HBeAg.
Subsequently a U.S. Phase III CHB multi center, placebo controlled, double-blind study was conducted in 99 patients that were serum HBV DNA and HBeAg positive. All patients were HbsAg(+) for at least 6 months with persistent ALT elevation. Following a 3 month screening period, 50 patients were randomized to receive T&agr;1 (1.6 mg, S.C. 2×/week) and 49 to receive placebo (mannitol, NaPO4; S.C. 2×/week) for 6 months and followed at month intervals for 6 months. Thirty eight T&agr;1 treated patients and 32 patients given placebo were followed after the 1 yr study for 23+7 (SD) months respectively. Two patients were removed from the study after randomization but prior to treatment. Results are presented for 49 patients in the T&agr;1 group and 48 patients in the placebo group. There were no statistically significant differences in ALT values, HBV DNA levels and histological findings between the two groups at inclusion. A complete response (CR) to treatment was defined as a sustained serum HBV DNA(−) status (2 negative results at least 3 months apart) during the 1 year study with negative HBV DNA and HBeAg at 12 months. A delayed response(DR) was determined as a sustained HBV DNA(−) status achieved after 12 months with a negative HBV DNA and HBeAg at last assessment. An incomplete response (IR) was characterized as a sustained HBV DNA(−) status during the study or post study period with continued presence of HBeAg. The response to treatment was as follows:
Group (n)
CR (%)
DR (%)
IR (%)
Tal(49)
7(14%)
5(10%)
0(0%)
Placebo(48)
2(4%)
4(8%)
2(4%)
p value
0.084
ns
ns
A total of 12 (25%) patients treated with T&agr;1 and 6(13%)patients given placebo (p<0.11) showed a sustained loss of HBV DNA with negative HBeAg during the 1yr study or post study follow up. Lamivudine is a reverse transcriptase inhibitor. As the activity of reverse transcriptase is necessary to transcribe the HBV-RNA pre-genome into HBV-DNA, a target for selective inhibition of viral replication is present. Selection of the
Moran Marjorie A.
Rothwell Figg Ernst & Manbeck
SciClone Pharmaceuticals Inc.
Woodward Michael P.
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