HCV-796, new HCV non-nucleoside- 14 day study

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HCV-796, new HCV non-nucleoside- 14 day study

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“Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-

796, in patients with chronic HCV: preliminary results from a

randomized, double-blind, placebo-controlled, ascending multiple dose

studyâ€

Reported by Jules Levin

DDW, May 21-24, 2006, Los Angeles (Digestive Disease Week)

Stephaen Villano from ViroPharma reported these study results at the

first oral presentation this morning at 8:30am at the opening session

at DDW.

PRECLINICAL

- chemical class: Benzofuran

- target: HCV NS5B RNA dependent RNA plymerase

- mechanism: non-compettitive allosteric inhibitor (non-nucleoside)

In vitro Antiviral Activity:

RdRp Enzyme activity:

- genotypes 1a & 1b: IC50= 0.01 - 0.16 uM

- genotypes 2, 3, 4: IC50 + 0.22 - 1.7 uM

Replicon Activity

- 1a replicon; EC50 = 4.5 +/- 2.0 nM

- 1b replicon: EC50 = 8.6 +/- 4.0 nM

In vivo Antiviral Activity:

- 2 log HCV RNA reduction in chimeric mice infected with HCV

STUDY DESIGN

Randomized, double-blind, placebo-controlled dose-ranging study.

Dosing: 6 ascending dose groups

- 50, 100, 250, 500, 1000, 1500 mg

- twice daily dosing

- 3:1 allocation (12 active, 4 placebo) per group

- 14 days of dosing

- 4 week post-treatment followup

- objectives; safety, PK, antiviral activity

Patients were treatment-naïve with chronic HCV; no other causes of

liver disease; no advanced or decompensated liver disease; plasma HCV

RNA >10,000 at screening; HIV-neg.; ALT <5x ULN.

Baseline HCV genotyping with TRUEGENE HCV'NC Genotyping Kit (Bayer

Healthcare); Roche Amplicor HCV Monitor. PK profiles on day I & 14.

DEMOGRAPHICS

There were about 12 in each dose group. Average age about 50 years.

About 25% female. Weight: 80-90 kg. In the 500-1500 mg dose groups

about 35% were Black, others White. Baseline HCV RNA: median 6.4 to

7.2.

725 were genotype 1.

PK

HCV-796 tmax is about 2-3 hours. Peak Cmax, AUC0-12, AUC

(day14/day1), and t1/2 occurred at the 1000 mg dose and declined with

the 1500 mg dose. With the 1000 mg dose:

Cmax: 2186 ng/mL;

AUC0-12 20048 ng hr/mL

T1/2: 54 hr

AUC day 14/day1: 4.2

Trough plasma concentrations (n=12) performed best with the 1000 mg

Q12 dose. They were well above target concentration based on

preclinical antiviral activity.

VIRAL LOAD REDUCTIONS

HCV-796 treatment resulted in reduced plasma HCV RNA levels. Maximal

antiviral effects were achieved at study day 4, with peak mean

reductions in HCV RNA across all doses ranging from 0.3 to 1.4 log10

(50% to 97%). In the 1000 mg cohort, the mean reduction in HCV RNA

was 1.4 log10 (96%) on day 4, 1.3 log10 (95%) on day 7, and 0.7 log10

(80%) on day 14. In this group, 83% of patients had reductions from

baseline > 1.0 log10 on day 4; 42% of these patients had reductions >

1.5 log10 and 33% had reductions > 2.0 log10. On day 14, 17% of

patients in the 1000 mg cohort had reductions from baseline > 2.0

log10. Antiviral activity appeared similar among patients infected

with HCV genotype 1 compared with those infected with other genotypes

of HCV. Trough Pk appeared to be related to viral load reduction in

the 1000mg dose group.

The speaker addressed the fact that peak viral load reduction of -1.4

log occurred on day 4 but viral load decline started to increase. The

issue of drug resistance was discussed by the speaker as a possible

reason and said that the resistance testing results analysis is

ongoing and will be presented later this year at another conference.

SAFETY

The drug was reported as generally well-tolerated. No dose-limiting

toxicities identified across the range of study doses. No serious

adverse events. Discontinuations due to AEs: placebo- 910 poorly

controlled hypertension (preexisting); 500 mg: (10 elevated TSH

level. 1500 mg: (1) elevated unconjugated bilirubin (3.7 mg/dL).

Most common AEs: headache 42%, constipation 17%; diarrhea: 25% in

1000 mg group; pruritis 17%; rash 25% in 100mg group. Across dose

groups there did not appear to be a trend in AEs except in 1000 mg

group 25% diarrhea, but 20% in placebo; and rash 25% in 1000 mg group

& 0% in placebo, and 4, 8, & 7% in 3 other dose groups, so there

appeared to perhaps be a rash issue.

Bilirubin (unconjugated)

Mean change in unconjugated bilirubin was +0.5 mg/dl during the

dosing period, occurred after a few days 7 then appeared to decline.

ALT

Mean ALT declined by 40 U/L in the 1000 mg group after 5 days on

therapy.

CONCLUSIONS by Authors

HCv-796 displays dose-related antiviral activity, across multiple HCV

genotypes; peak response achieved at the 500-1000 mg Q12 dose.

Exposure (PK) is less than dose-proportional with increasing dose,

with plateau at the 1000 mg Q12 dose. Genetic sequencing of HCV NS5B

is ongoing, with focus on subjects with 'breakthrough' virologic

response pattern. HCV-796 was well-tolerated: no dose-limiting

toxicities across the range of study doses; mild-moderate headache

was the most common AE; ALT decrease temporally associated with

antiviral activity. Study of combination therapy with peginterferon

ongoing.