Pegasys + ribavirin (Edie)

[Guest guest]

Edie,

Here is one study, and although it is comprised of a very small group

of people, you have to admitt it is still pretty interesting! And no, this

isn't the study I was thinking was on relapsers, I believe these people had

never been treated.

Claudine

Treatment of HCV with Long-Acting " Pegylated " Alfa * Interferon Shows

Impressive Results

For 16 patients with genotype 1, end-of-treatment response rate is 63%;

for

4 patients with genotype 2, sustained response rate is 100%

by Harvey Bartnof, MD

There were several abstracts today that addressed the experimental

pegylated

forms of alfa * interferon. Pegylated means that the active drug is

encased

in a fat molecule called polyethylene glycol, or " peg " in an

abbreviated

acronym. This slows the metabolism significantly, allowing for a once

weekly

injection instead of the 3-times weekly approved dosing for the

non-pegylated form. The version from Hoffman-La Roche will be called

Pegasys

(pegylated interferon alfa-2a, while the version from Schering-Plough

will

be called Peg-Intron (pegylated interferon alfa-2b).

Hoffman-La Roche's Pegasys

A phase II, single arm, open-label study was presented that combined

Roche's

Pegasys with Rebetol (ribavirin) for the treatment of chronic infection

with

hepatitis C virus (HCV). The lead author was M. Sulkowski, MD, from The

s Hopkins University School of Medicine. Even though there were

only 20

patients, the results were impressive. Sixteen of the patients had

genotype

1, which is the most difficult to treat. The other four patients had

genotype 2, which is more responsive to treatment. All 20 patients had

chronic hepatitis C. This was defined as (1) a persistently elevated

blood

ALT (alanine aminotransferase, liver enzyme); (2) an HCV RNA viral load

greater than 2,000 copies per milliliter using the Amplicor Monitor

test;

and (3) an abnormal liver biopsy sample consistent with " compensated

non-cirrhotic liver disease. " All patients were therapy-naove (never

treated

for hepatitis C). Exclusion criteria included heart disease, kidney

disease,

pre-existing severe depression or other psychiatric disorders, seizure

disorder, retinopathy (eye disease), other liver diseases, and HIV

infection.

The dosage was once-weekly Pegasys (180 micrograms) injection under the

skin

plus oral Rebetol 1,000-1,200 mg daily. Since genotype 1 is more

refractory

to therapy, the duration of treatment for those patients was 48 weeks,

if

there was a normal ALT or undetectable HCV viral load at 24 weeks. For

those

with genotype 2, the treatment duration was 24 weeks. Those durations

reflect the standard guidelines based on genotype testing. The median

baseline HCV viral load was not stated.

The results showed that for those patients with genotype 1, the

end-of-treatment response was 63%. That means that 63% had an

undetectable

HCV viral load (limit 100 copies per milliliter) at the end of 48 weeks

of

therapy. (All results are reported using a stricter " intent-to-treat "

analysis, meaning that all enrolled patients are included.) Whereas,

for

those patients with genotype 2, the sustained response rate was 100%.

(Those

with genotype 2 received 24 weeks of therapy, followed by a 24-week

treatment-free follow-up period.) While the numbers of patients are

small,

these viral load undetectability rates are among the highest ever

reported

for patients treated for hepatitis C.

When the results of the entire 20 patients were analyzed together, at

the

48-week time point, the following were found: the percentage with a

normal

ALT was 60%, while those with an undetectable HCV viral load was 70%.

Interestingly, the percentage with an undetectable viral load at 12

weeks

was also approximately 70%.

Adverse events included lowered blood cell counts, which are known side

effects. The neutrophil (white blood cell) count and hemoglobin

(oxygen-carrying molecule in red blood cells, lowered in anemia)

stabilized

at week four. The decrease in blood platelets (for normal clotting)

stabilized by week 12. No patient withdrew from the study due to

abnormal

laboratory test results.

Two patients (10%) withdrew prematurely from the study. One had a

seizure

( " convulsion " or " fit " ), while another had bleeding in the back of the

eye

(retinal hemorrhage). Interferon has been associated with a lowered

seizure

threshold in past studies. The hemorrhage was not depicted further in

the

poster presentation. However, eight patients did have dosing changes,

due to

adverse events. Four changes were due to anemia and two were due to

neutropenia. Six other patients had a dose modification due to " other

adverse events. "

The patients will be followed for a longer period. The poster did not

state

whether liver biopsies would be performed at the end of the observation

period. The evaluation of a liver biopsy correlates much better with

long-term disease progression. HCV viral loads do not necessarily

correlate

with long-term outcome.

Even though these results are only interim, the authors conclude that

the

combination of Pegasys and Rebetol " appears to have acceptable

tolerability

and promising antiviral activity in the treatment of chronic hepatitis

C. "

It is quite possible that the sustained response rate for those with

genotype 1 will be lower than the end-of-treatment response (ETR) rate.

Often, this is the observed pattern. However, an ETR of 63% for

genotype 1

is higher than has been reported for any other therapy(ies) to date. It

appears that significant advances are being made in the treatment of

this

disease.

In a separate poster presentation, the half-life (amount of time for

half of

an original amount to be remaining) of Pegasys was found to be 77

hours,

while a standard interferon injection had a half-life of nine hours.

The

phase II dose-ranging study had 20 HCV negative volunteers. The

remainder of

the study evaluated pharmacokinetic and pharmacodynamic (metabolism

measurements) of Pegasys. The authors determined that the weekly

self-injected dose under the skin would be 180 micrograms. The lead

author

was N.E. Algranati, MD, from Hoffman-La Roche.

Schering Plough's PEG-Intron

Another poster addressed a different formulation of the same drug.

PEG-Intron (pegylated Intron, interferon alfa-2b, Schering-Plough)

injected

under the skin once weekly showed the same or better anti-HCV effects

as

standard Intron-A dosed at 3 million units injected 3-times weekly. The

pharmacokinetics and pharmacodynamics (metabolism measurements) of this

long

acting form of the drug were measured in a 24-week study of HCV

positive

patients. The half-life (time for an original amount to be reduced by

half)

of PEG-Intron was calculated to be 54 hours, compared to 8 hours for

standard Intron-A. No unexpected adverse effects occurred. Common

symptoms

include " flu " -like symptoms. Abnormal laboratory values included a low

white

cell count (neutropenia) and a low blood platelet count (for normal

blood

clotting, thrombocytopenia). The weekly dose will be 0.5 micrograms per

kilogram once weekly (weight in pounds X 0.454 = weight in kilograms).

The

lead author was Glue, MD, from Schering-Plough.

* Note that all generic versions use the spelling 'alfa' and not

'alpha.'

11/7/99

References:

Algranati NE and others. A branched methoxy 40 KD/ polyethylene glycol

(PEG)

moiety optimizes the pharmacokinetics (PK) of peg-interferon alpha-2a

(PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C

(CHC). Abstract and poster presentation 120 at the 50th Annual Meeting

of

the American Association for the Study of Liver Diseases. Dallas,

Texas;

November 5-9, 1999. Hepatology 30(4) Supp2, 190A. Glue P and others.

Peg-interferon-alpha-2b: pharmacokinetics, pharmacodynamics, safety and

preliminary efficacy data. Abstract and poster presentation 115 at the

50th

Annual Meeting of the American Association for the Study of Liver

Diseases.

Dallas, Texas; November 5-9, 1999. Hepatology 30(4) Supp2, 189A.

Sulkowski M

and others. Combination therapy with peginterferon alfa-2a (PEG-IFN)

and

ribavirin in the treatment of patients with chronic hepatitis C: a

phase II

open-label study. Abstract and poster presentation 145 at the 50th

Annual

Meeting of the American Association for the Study of Liver Diseases.

Dallas,

Texas; November 5-9, 1999. Hepatology 30(4) Supp2, 197A.

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