Valopicitabine Adds Punch to Interferon's Attack on HCV

[Guest guest]

AASLD: Valopicitabine Adds Punch to Interferon's Attack on HCV

By Neil Osterweil, Senior Associate Editor, MedPage Today

Reviewed by Jasmer, MD; Associate Clinical Professor of Medicine,

University of California, San Francisco

October 30, 2006

T. Dieterich, M.D.

Mount Sinai Medical Ctr, NY

BOSTON, Oct. 30 -- A novel antiviral agent in development for hepatitis C

infections appears to have synergistic activity with Pegasys (pegylated

interferon & #945;-2a), reported researchers here.

Action Points

Explain to patients who ask that this study suggests that a new type of

antiviral agent known as a polymerase inhibitor shows promise as a therapy

against hepatitis C viral infections when used in combination with pegylated

interferon.

This study was published as an abstract and presented orally at a

conference. These data and conclusions should be considered to be

preliminary as they have not yet been reviewed and published in a

peer-reviewed publication

In a phase IIb trial, valopicitabine at a dose of 200 mg/day in combination

with Pegasys achieved marked reductions in HCV RNA at 24 weeks in

treatment-naïve patients with genotype-1, reported T. Dieterich,

M.D., of Mount Sinai in New York, and colleagues.

Although valopicitabine as monotherapy achieved less than a two-log

reduction in HCV DNA at 12 weeks (the standard interval for determining a

response in trials for HCV therapies), it appeared to enhance the activity

of pegylated interferon, said Dr. Dieterich in an interview at the American

Association for the Study of Liver Diseases meeting here.

The direct-acting antiviral -- a nucleoside-type HCV polymerase inhibitor --

has the potential to be an important part of a combined regimen for HCV,

along with other new agents such as protease inhibitors, he added.

In a five-arm trial comparing valopicitabine at varying doses in combination

with Pegasys, patients treated with the combination of 200 mg valopicitabine

and Pegasys had a mean 4.24 log10 reduction in HCV DNA.

In all, 23 of 34 patients on this combination had viral clearance at week

24, as determined by a standard assay's lower cutoff point of 20 IU/mL.

Dr. Dieterich presented the 24-week analysis from the ongoing 48-week phase

IIb trial.

Each arm of the five-arm trial involved various dosing regimens of

valopicitabine, given once-daily, in combination with Pegasys at 180 & #956;g

per week:

Pegasys beginning on day eight plus valopicitabine ramping from 400 mg to

800 mg beginning at day 29 to 32, followed by dosing at 800 mg (34

patients).

Valopicitabine at 200 mg beginning on day one plus pegylated interferon

beginning on day eight (34 patients).

Valopicitabine ramping from 400 mg to 800 mg from day one to six, followed

by dosing at 800 mg plus pegylated interferon beginning on day eight (34

patients).

Valopicitabine 800 mg beginning on day one plus pegylated interferon

beginning on day eight (36 patients)

Valopicitabine 800 mg plus pegylated interferon, both beginning on day one.

During the study the protocol was revised because of gastrointestinal

intolerance for some patients at the higher doses of valopicitabine, Dr.

Dieterich said.

In March 2006, patients who were assigned to the 800 mg doses and who had

HCV RNA at less than 600 IU/mL were randomly re-assigned to either the

200-mg or 400-mg groups, and 12 patients with HCV RNA at more than 600 IU/mL

were discontinued at the insistence of the FDA, he said.

At 24 weeks, 29 of the original 173 patients dropped out because of adverse

events, including three patients in the 200-mg arm.

Five serious adverse events were attributed to either valopicitabine or

valopicitabine with Pegasys during the first 24 weeks of treatment. Most of

these were GI-related, and four occurred in patients in one of the 800-mg

arms. Since the dose reduction, there have been no reported

valopicitabine-related gastrointestinal serious adverse events in either the

200- or 400-mg arms, Dr. Dieterich noted.

The investigators found that the most effective combination was that of

valopicitabine at 200 mg on day one with Pegasys beginning week two (day

eight). In all, 68% of patients in this group reached undetectable virus

levels at 24 weeks, compared with 58% in the pooled valopicitabine

800-mg/day arms.

Among the patients who required dose-reduction, two of 69 at 12 weeks

post-reduction still had detectable levels of HCV RNA, Dr. Dieterich said.

The investigators said they have started a drug-drug interaction study with

Rebetol (ribavirin), and if the combination proves safe they may proceed

with phase III trials investigating valopicitabine with Pegasys, with or

without Rebetol.

" The best thing for hepatits C is for two of these drugs [polymerase

inhibitors and protease inhibitors] to be approved, particularly for the

non-responding patients, " Dr. Dieterich said. " The take-home message here is

that is not a zero-sum game. When 3TC was approved [for HIV], AZT didn't go

away. "

Valopicitabine is being developed jointly by Idenix and Novartis. Dr.

Dieterich said that he no financial disclosures or conflicts of interest to

report.

Primary source: American Association for the Study of Liver Diseases

Source reference:

Lawitz E et al. " Valopicitabine (NM283) plus Peg-Interferon in

Treatment-Naïve Hepatitis C Patients with HCV Genotype-1 Infection: HCV RNA

Clearance During 24 Weeks of Treatment. " Abstract 93, presented Oct. 30.

http://www.medpagetoday.com/MeetingCoverage/AASLDMeeting/dh/4399

_________________________________________________________________

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[Guest guest]

AASLD: Valopicitabine Adds Punch to Interferon's Attack on HCV

By Neil Osterweil, Senior Associate Editor, MedPage Today

Reviewed by Jasmer, MD; Associate Clinical Professor of Medicine,

University of California, San Francisco

October 30, 2006

T. Dieterich, M.D.

Mount Sinai Medical Ctr, NY

BOSTON, Oct. 30 -- A novel antiviral agent in development for hepatitis C

infections appears to have synergistic activity with Pegasys (pegylated

interferon & #945;-2a), reported researchers here.

Action Points

Explain to patients who ask that this study suggests that a new type of

antiviral agent known as a polymerase inhibitor shows promise as a therapy

against hepatitis C viral infections when used in combination with pegylated

interferon.

This study was published as an abstract and presented orally at a

conference. These data and conclusions should be considered to be

preliminary as they have not yet been reviewed and published in a

peer-reviewed publication

In a phase IIb trial, valopicitabine at a dose of 200 mg/day in combination

with Pegasys achieved marked reductions in HCV RNA at 24 weeks in

treatment-naïve patients with genotype-1, reported T. Dieterich,

M.D., of Mount Sinai in New York, and colleagues.

Although valopicitabine as monotherapy achieved less than a two-log

reduction in HCV DNA at 12 weeks (the standard interval for determining a

response in trials for HCV therapies), it appeared to enhance the activity

of pegylated interferon, said Dr. Dieterich in an interview at the American

Association for the Study of Liver Diseases meeting here.

The direct-acting antiviral -- a nucleoside-type HCV polymerase inhibitor --

has the potential to be an important part of a combined regimen for HCV,

along with other new agents such as protease inhibitors, he added.

In a five-arm trial comparing valopicitabine at varying doses in combination

with Pegasys, patients treated with the combination of 200 mg valopicitabine

and Pegasys had a mean 4.24 log10 reduction in HCV DNA.

In all, 23 of 34 patients on this combination had viral clearance at week

24, as determined by a standard assay's lower cutoff point of 20 IU/mL.

Dr. Dieterich presented the 24-week analysis from the ongoing 48-week phase

IIb trial.

Each arm of the five-arm trial involved various dosing regimens of

valopicitabine, given once-daily, in combination with Pegasys at 180 & #956;g

per week:

Pegasys beginning on day eight plus valopicitabine ramping from 400 mg to

800 mg beginning at day 29 to 32, followed by dosing at 800 mg (34

patients).

Valopicitabine at 200 mg beginning on day one plus pegylated interferon

beginning on day eight (34 patients).

Valopicitabine ramping from 400 mg to 800 mg from day one to six, followed

by dosing at 800 mg plus pegylated interferon beginning on day eight (34

patients).

Valopicitabine 800 mg beginning on day one plus pegylated interferon

beginning on day eight (36 patients)

Valopicitabine 800 mg plus pegylated interferon, both beginning on day one.

During the study the protocol was revised because of gastrointestinal

intolerance for some patients at the higher doses of valopicitabine, Dr.

Dieterich said.

In March 2006, patients who were assigned to the 800 mg doses and who had

HCV RNA at less than 600 IU/mL were randomly re-assigned to either the

200-mg or 400-mg groups, and 12 patients with HCV RNA at more than 600 IU/mL

were discontinued at the insistence of the FDA, he said.

At 24 weeks, 29 of the original 173 patients dropped out because of adverse

events, including three patients in the 200-mg arm.

Five serious adverse events were attributed to either valopicitabine or

valopicitabine with Pegasys during the first 24 weeks of treatment. Most of

these were GI-related, and four occurred in patients in one of the 800-mg

arms. Since the dose reduction, there have been no reported

valopicitabine-related gastrointestinal serious adverse events in either the

200- or 400-mg arms, Dr. Dieterich noted.

The investigators found that the most effective combination was that of

valopicitabine at 200 mg on day one with Pegasys beginning week two (day

eight). In all, 68% of patients in this group reached undetectable virus

levels at 24 weeks, compared with 58% in the pooled valopicitabine

800-mg/day arms.

Among the patients who required dose-reduction, two of 69 at 12 weeks

post-reduction still had detectable levels of HCV RNA, Dr. Dieterich said.

The investigators said they have started a drug-drug interaction study with

Rebetol (ribavirin), and if the combination proves safe they may proceed

with phase III trials investigating valopicitabine with Pegasys, with or

without Rebetol.

" The best thing for hepatits C is for two of these drugs [polymerase

inhibitors and protease inhibitors] to be approved, particularly for the

non-responding patients, " Dr. Dieterich said. " The take-home message here is

that is not a zero-sum game. When 3TC was approved [for HIV], AZT didn't go

away. "

Valopicitabine is being developed jointly by Idenix and Novartis. Dr.

Dieterich said that he no financial disclosures or conflicts of interest to

report.

Primary source: American Association for the Study of Liver Diseases

Source reference:

Lawitz E et al. " Valopicitabine (NM283) plus Peg-Interferon in

Treatment-Naïve Hepatitis C Patients with HCV Genotype-1 Infection: HCV RNA

Clearance During 24 Weeks of Treatment. " Abstract 93, presented Oct. 30.

http://www.medpagetoday.com/MeetingCoverage/AASLDMeeting/dh/4399

_________________________________________________________________

Stay in touch with old friends and meet new ones with Windows Live Spaces

http://clk.atdmt.com/MSN/go/msnnkwsp0070000001msn/direct/01/?href=http://spaces.\

live.com/spacesapi.aspx?wx_action=create & wx_url=/friends.aspx & mkt=en-us