Drug Development for Antiretroviral Therapies

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[B]Hepatic C protease inhibitors[/B]


Similar to HIV, hepatitis C has a protease which is essential for viral replication. This protease differs from the HIV protease in that it is a serine protease which in hepatitis C has been ascribed to the NSV3 protein in concert with the NSV4 a co-factor. Several agents have been developed with activity against this protease which is a chemotrysin like serine protease with a shallow substrate binding region.

The most likely inhibitor to enter clinical studies in the future is the Boehringer Ingelheim compound 8, which has been tested in cell cultures with an EC50 of between 76 and 440 nanograms depending on the system used. This compound has a low potential for drug interactions having low inhibition of P450, but is heavily protein bound (97.6%). In studies in the rat model, an oral dose has shown a plasma bio-availability of only 5%. Due to the high plasma protein binding the volume of distribution is low.

[此贴子已经被作者于2003-9-30 9:15:26编辑过]

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[B]＊New analogues of ribavirin[/B]

Two new analogues of ribavirin were discussed. First of these levovirin is the L enantiomer of ribavirin which has a similar immunomodulatory activity as ribavirin, but without the associated toxicity. This drug has entered a phase I study at doses of between 200 and 1200mg and is well tolerated and orally absorbed.

The other compound viramidine is a prodrug of ribavirin, which is converted to the active drug by adenosine deaminase within the liver. Viramidine itself has no anti-HCV inhibitor but when converted to ribavirin shows similar antiviral activity against DNA and RNA viruses. Within a monkey model a dose of 600mg per kg had no significant hematological toxicity in males although it was associated with 10% reduction in red blood cells in the female. This compares with ribavirin which showed an 11-14% loss of red blood cells in males and 23-25% in females. Calculation showed that the therapeutic index for this drug was 6 times better than for ribavirin.

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[B]＊ Ribozymes[/B]

Ribozymes are catalytic RNA binders entailing a catalytic core with two binding arms which cleave target sequence allowing cell nucleases to destroy the viral RNA. Two ribozymes, one with activity against hepatitis B and one against hepatitis C were reported. Hep B zyme is targeted against the pregenomic RNA at the 31 terminus of the major transcript of hepatitis B. In cell systems their use led to a reduction in production of HBsAg and HBeAg. In a transgenic mouse model, doses of this ribozyme at between 30 and 300mg gave a viral load reduction of approximately 1.6-2.4 log compared with 3TC giving a reduction of approximately 2 log within this system.

Ribozymes against hepatitis C are associated with significant reduction in HCV RNA production in vitro, and have a synergistic effect with interferon with a dose response effect of the ribozyme. In addition, they allowed a 12% reduction of interferon without loss of efficacy suggesting that this drug is useful in allowing dose reduction of interferon. In the mouse model, delivery by the sub-cutaneous route led to active levels of ribozyme with little toxicity apart from injecting site reactions and basophilia, probably secondary to an accumulation of the ribozyme in renal tubular cells and lymph nodes. A phase I study has commenced with individuals receiving doses of between 3 and 90mg for up to 28 days. So far the drug has been well tolerated with no abnormalities in laboratory parameters and no major patient toxicity.

[此贴子已经被作者于2003-9-30 9:15:53编辑过]

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[B]＊MCC478[/B]

MCC478 is a nucleotide analogue which has entered phase I studies, and shown comparable efficacy to Epivir-HBV. In cell cultures it appears more potent than adefovir and up to 100 times more potent than Epivir-HBV. In mice, MCC478 was less efficacious than adefovir which may have been related to problems of exposure to the drug, although in infected ducks MCC478 had similar efficacy to Epivir-HBV and adefovir.

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[B]＊ L nucleoside analogues[/B]


The L nucleoside analogues are unnatural antiviral compounds which include Epivir-HBV. Other L nucleoside analogues have now been formulated including LdT, LdC and LdA, all of which are selective specific inhibitors of hepatitis B activity. They appear to be low in both mitochondrial and cellular toxicity and have good intracellular phosphorylation and activity in the wood chuck model. Pharmacokinetic studies of all these analogues would favor once daily therapy. LdC is not well absorbed and is presently being studied as a divaline ester.

Antiviral activity of LdT in adults with chronic hepatitis B has been investigated in a dose escalation study. Patients received either 25, 50, 100, 200 or 400mg of LdT, and had serum HBV DNA levels monitored weekly. After 4 weeks of treatment the mean reduction of HBV DNA was 2.4, 2.7, 3.1, 2.9 and 3.63 log10 copies/mL respectively. The HBV DNA levels were subjected to an analysis of first phase (during week 1) and second phase (during weeks 2-4) clearance. All doses of LdT were associated with similar falls in HBV DNA during the first week, but in the second phase of HBV clearance exhibited a dose associated effect. In addition, when therapy was stopped there was a quicker return to baseline in those individuals receiving lower doses of therapy.

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[B]＊ Adefovir [/B]


Adefovir has completed several studies showing anti-hepatitis B activity in individuals naïve to therapy and also in individuals who have previously been exposed to Epivir-HBV. Further data from study 437 was reported. This study evaluated the safety and efficacy of adefovir at two drug dose levels - 10mg and 30mg compared to placebo. A total of 515 individuals were randomized, 172 to adefovir 10mg daily, 173 to the 30mg arm daily and 170 to placebo. At week 48, 53% of the adefovir 10mg patients exhibited significant improvements in liver histology, with sero-conversion in 12% compared to 6% in the placebo arm. The median reduction serum HBV DNA in the 10mg arm was 3.52 log10 copies/mL compared with only 0.55 log10 copies/mL in the placebo arm.

Reduction in ALT was also greater in the adefovir arms. Although the 30mg arm had greater antiviral efficacy, this arm showed increased toxicity with dose reduction necessary in 25% of individuals compared with 3% in the 10mg arm. In addition, a greater than 0.5 g/dL rise in creatinine occurred in 8% of individuals in the 30mg arm. Interestingly there was no evidence of resistance in those failing adefovir, although it is unclear why indeed these patients did fail. Adefovir clearly has activity against hepatitis B and an expanded access program was reported to be starting by Gilead in the first quarter of 2002.

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[B]Entecavir [/B]


Entecavir is a cyclopentile guanosine nucleoside analogue with selective activity against hepatitis B viral DNA polymerase. It is orally bioavailable, and due to a long terminal elimination half life of approximately 110 hours is clearly suitable for once daily therapy.

Study 005 treated individuals who had active hepatitis B, both HBeAg positive and HbeAg negative, with well compensated liver disease. 136 individuals were randomized to receive entecavir at either 0.01, 0.1 or 0.5mg once daily, and a further group of 41 individuals received 3TC at the standard dose of 100mg daily. Over 50% of individuals in both groups were Asian. The median reduction in serum HBV DNA were 2.4, 4.3 and 4.7 log10 copies/mL with the 0.01, 0.1 and 0.5 mg doses, respectively, and a 3.4 log10 copy/mL drop with Epivir-HBV. The 0.1 and 0.5mg groups were significantly better in antiviral activity than the 0.01mg and the Epivir-HBV group. The 0.5mg arm performed significantly better than the 0.1mg arm. The other results of the study are summarized below. (Fig 5.)

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Study 014 is on going, with results available at 24 weeks. It studied individuals who had received and failed either greater than 24 weeks of Epivir-HBV or had the presence of the YMMD mutation. Individuals could be HBeAg positive or negative with compensated liver disease. Results of this study are summarized below. (Fig 6.)

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Phase III studies are presently recruiting, and clearly entecavir offers an important advance in therapeutic options for individuals with hepatitis B.

[此贴子已经被作者于2003-9-30 9:03:26编辑过]

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[B]Coviracil [/B]

Coviracil (FTC, emtricitabine) is an L nucleoside with potent selective activity against both HBV and HIV. In some studies, it appeared to have greater potency in vitro than Epivir-HBV.

Study 101 was a dose ranging study of hepatitis B infected individuals who received Coviracil at a dose of 25mg, 50mg, 100mg, 200mg or 300mg once daily for eight weeks. The antiviral activity was greater in all other arms compared with the 25mg arm.

A second study, 102, examined individuals, 88% of whom were Asian, who were randomized to receive Coviracil at a dose of 25mg, 100mg or 200mg for 48 weeks. Mean viral load at baseline ranged between 7.42 and 7.68 log10 copies/mL. Individuals could be HBeAg positive or negative with active viral replication. Individuals were stratified in this study by viral load and previous exposure to Coviracil in study 101. The results of this study are summarized below. (Fig 4.)

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Only 3 patients discontinued the study due to adverse events, one of whom developed Hoenoch-Schonlein purpura. Grade 3 and 4 toxicity was low, being 9% in the 25mg arm, 3% in the 100mg arm and 6% in the 200mg arm.

[此贴子已经被作者于2003-9-30 9:04:10编辑过]

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[B]Clevudine[/B]


Clevudine is biochemically similar to DFIAU, but does not appear to have the associated problems of mitochondrial toxicity and lactic acidosis production, at least in vitro. Experiments in the infected woodchuck model have shown this drug to be highly active at a dose of 10mg per kg once daily, producing a 9 log decrease in viral load with a dose dependent delay in the time to viral recrudescence.

An open label phase I / II dose escalation study is underway, with patients receiving either 10mg, 50mg or 100mg once daily for 28 days. 24 of 25 individuals have completed the study protocol Median DNA reduction at day 28 was 2.48, 2.74 and 2.95 log10 copies/mL respectively. Interestingly, 5 months after the end of treatment the median decrease in HBV DNA was 1.91 log10 copies/mL in the 10mg arm, and 2.07 log10 copies/mL among individuals receiving 50mg of clevudine. In individuals who received 100mg once daily, data was only available to week 8 (one month post therapy cessation) with 5 available patients demonstrating a continued HBV DNA fall greater than 3 log10 copies/mL.

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[B]ACH126443 [/B]


ACH126443 is an L nucleoside analogue which is highly potent against both HIV and hepatitis B. In vitro there is no mitochondrial toxicity. Due to its susceptibility to stomach acid, it must be dosed with an antacid, although an enteric coated preparation is now available. Due to the high levels of drug that may be potentiality achieved, it may be active against Epivir-resistant HBV and HIV.

Early results of a phase I b/ II clinical study are available, although it is important to realize that there are still placebo patients in each of the 3 arms therefore giving potential dilution of efficacy results. Results are available at day 14, and showed a drop in HBV DNA of 0.68, 1.43 and 1.74 log10 copies/mL in those receiving 1, 5 or 10mg, respectively. Clearly this drug does have activity against HBV, although much greater data needs to be made available before the manufacturers claims that this drug is "best in class" for both HIV and hepatitis B can be proven.