Maxamine for Hepatitis C Treatment

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NATAP

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Maxamine for Hepatitis C Treatment

By now, many of you may have heard of this new potential treatment in

development for the treatment of Hepatitis C. At two recent

conferences--EASL

in May (European Association for the Study of Liver Diseases) and the

Atlanta

CDC conference in April--Maxim Pharmaceuticals reported new but preliminary

data for Maxamine. This study is a phase II dosing regimen study of Maxamine

( Histamine Dihydrochloride) and Interferon alpha-2b in naïve chronic

hepatitis C patients. The data reported was from 12 and 24 week analysis,

but

this is a 72 week study. This study does not include people with cirrhosis.

From the two major previous studies of interferon+ribavirin combination

therapy for HCV, the overall week 24 end-of-treatment virologic responses

(HCV-RNA £100 copies/ml) were 53% and 57%, respectively. The

end-of-treatment

ALT (biochemical responses were 58%-71%. Of course, response rates differ

based on baseline genotype or HCV viral load. The end-of-treatment response

rather than the sustained response after 24 weeks follow-up is being used

for

comparison because the results reported from the Maxima study is 24 weeks

data.

How does Maxima work?

This explanation comes from Maxim Pharmaceuticals. Oxidative stress (free

radicals) in the liver causes irreversible damage to lymphocytes (CD4s and

other cells) which are essential for viral killing. Cytokines are less

effective activators of lymphocytes in such an environment. Maxamine

inhibits

phagocyte-derived oxidative stress and inflammation. Maxamine synergizes

with

cytokines such as interferon and IL-2. Maxamine potentiates immune therapies

(interferon is an immune therapy) by inhibiting the production and release

of

free radicals from phagocytes. This protects NK (natural killer) cells and

T-cells from free radical damage.

The activation of NK and T-cells by exogenous cytokines is irreversibly

blocked by the release of free radicals from phagocytes in virally infected

tissues. These free radicals induce apoptosis (cell programmed death) in NK

and T-cells. Maxima inhibits the production and release of free radicals;

thereby, creating a more favorable environment for the survival of activated

NK cells and T-cells.

The Study

The purpose of this study was to evaluate the safety and effective dose and

regimen of Maximine (4 different dose regimens) combined with interferon

alpha-2b (Intron-A) in treating patients with HCV. At 12 weeks,

non-responders discontinue therapy. At 12 weeks, responders continue therapy

for an additional 36 weeks for a total treatment of 48 weeks. At the end of

treatment (48 weeks) all patients discontinue therapy and are followed for a

total of 72 weeks (sustained response).

The study was a multi-center, international, randomized, phase II study

conducted in Belgium, Israel, Russia and the UK (not in the USA). Complete

response definitions were--

Virological complete response: loss of detectable HCV-RNA (Cobas Amplicor

HCV

Monitor Test 2.0, Roche Diagnostics; lower limit of detection 1000 HCV

copies/ml). The prior IFN+RBV studies discussed above used an undetectable

viral load level of 100 copies/ml.

Biochemical response: normalization of serum alanine transaminase (ALT)

levels.

There were four treatment arms:

IFN a-2b + Maxima (n=32) 3mg/week; IFN 3 MU TIW (3x/week) & Maxamine 1 mg

QD,

TIW, subcutaneous injection (QD is once daily)

IFN a-2b + Maxamine (n=35) 5 mg/week; IFN 3 MU TIW; Maxamine 1 mg QD,

5X/week, sc

IFN a-2b + Maxamine (n=29) 6 mg/week; IFN 3 MU TIW; Maxamine 1 mg BID, TIW,

sc

IFN a-2b + Maxamine (n=33) 10 mg/week; IFN 3 MU TIW; Maxamine 1 mg BID,

5x/week, sc

Baseline Characteristics

Patients had chronic HCV with compensated liver disease; mean age 30; mean

ALT (ULN--upper limit of normal) 4.5x; mean HCV-RNA 6.7 million copies/ml;

53% had 2 million copies/ml; 47% had Genotype 1; 49% had genotype 2 or 3.

Exclusions--Patients with hemoglobin <12 gm/dl were excluded, As well,

people

with HIV/HCV coinfection were excluded; advanced liver disease.

RESULTS

Week 24 (Overall Response Rates)

Complete Virologic Response Rates:

10 mg Maxamine arm-- 68%

6 mg Maxamine arm-- 69%

5 mg Maxamine arm-- 57%

3 mg Maxamine arm-- 63%

Complete Biochemical response (ALT) rates:

10 mg Maxamine arm-- 60%

6 mg Maxamine arm-- 73%

5 mg Maxamine arm-- 53%

3 mg Maxamine arm-- 44%

Week 24 Response By Genotype--

10 mg Maxamine arm--71% (genotype 2/3); 88% (genotype 1)

6 mg Maxamine arm-- 67% (genotype 2/3); 73% (genotype 1)

5 mg Maxamine arm-- 80% (genotype 2/3); 36% (genotype 1)

3 mg Maxamine arm-- 58% (genotype 2/3); 69% (genotype 1)

It's interesting that the genotype 1 individuals responded better than those

with genotype 2/3 in 3 of 4 dose regimens. Although this is a small study

limiting conclusions, if the improved response by genotype 1 turns out to be

real I think this may relate to the reasons why genotype 1 individuals

usually don't respond as well as genotype 2/3 individuals. It will be

interesting to me to see the response by cirrhotics to therapy including

Maxamine.

Week 24 Response by Viral Load--

10 mg Maxamine arm-- 70% (<2 million copies/ml); 67% ( 2 million copies/ml)

6 mg Maxamine arm-- 77% (<2 million copies/ml); 62% ( 2 million copies/ml)

5 mg Maxamine arm-- 62% (<2 million copies/ml); 41% ( 2 million copies/ml)

3 mg Maxamine arm-- 69% (<2 million copies/ml); 46% ( 2 million copies/ml)

Adverse Events

They reported that Maxamine administration resulted in mild transient side

effects: Maxamine induced a short-lasting flush in most patients, and a

short

lasting headache, hypotension, and tachycardia in some patients. Overall,

the

treatment has been well tolerated. At week 24, 5% were reported to

discontinue due to serious adverse events.

Comments by Jules Levin

This study is relatively small. The virological and biochemical response

rates were higher at 12 weeks than 24 weeks but I think that's to be

expected. The 47% of genotype 1 is relatively low compared to some other

studies (57% in European IFN+RBV study and 72% in US study). The mean age in

the Maxamine study was 30, but in the other two IFN+RBV studies the mean

ages

were 41 and 45 years, respectively. Increasing age can be associated with

reduced treatment outcome. However, the baseline HCV-RNAs were a little

lower

in the two IFN+RBV studies (4-4.5 million copies/ml and about 5 million

copies/ml, respectively) than in the Maxamine study (6.7 million copies/ml).

The lower limit of detection for HCV viral load was 1000 copies/ml in the

Maxamine study, but 100 copies/ml in the two IFN+RBV studies. The

percentages

of participants of women or African-Americans were not reported in the

Maxamine study. African-Americans generally appear to have genotype 1. Hard

to treat populations including cirrhotics need to be studied.

I think this Maxamine study suggests that Maxamine is promising. Further

studies are being discussed. Combining Maxamine with pegylated IFN and RBV

or

with pegylated IFN alone deserves attention.

________________________________________________________________________

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[Guest guest]

NATAP

<A HREF= " http://www.natap.org " >www.natap.org</A>

----------------

Maxamine for Hepatitis C Treatment

By now, many of you may have heard of this new potential treatment in

development for the treatment of Hepatitis C. At two recent

conferences--EASL

in May (European Association for the Study of Liver Diseases) and the

Atlanta

CDC conference in April--Maxim Pharmaceuticals reported new but preliminary

data for Maxamine. This study is a phase II dosing regimen study of Maxamine

( Histamine Dihydrochloride) and Interferon alpha-2b in naïve chronic

hepatitis C patients. The data reported was from 12 and 24 week analysis,

but

this is a 72 week study. This study does not include people with cirrhosis.

From the two major previous studies of interferon+ribavirin combination

therapy for HCV, the overall week 24 end-of-treatment virologic responses

(HCV-RNA £100 copies/ml) were 53% and 57%, respectively. The

end-of-treatment

ALT (biochemical responses were 58%-71%. Of course, response rates differ

based on baseline genotype or HCV viral load. The end-of-treatment response

rather than the sustained response after 24 weeks follow-up is being used

for

comparison because the results reported from the Maxima study is 24 weeks

data.

How does Maxima work?

This explanation comes from Maxim Pharmaceuticals. Oxidative stress (free

radicals) in the liver causes irreversible damage to lymphocytes (CD4s and

other cells) which are essential for viral killing. Cytokines are less

effective activators of lymphocytes in such an environment. Maxamine

inhibits

phagocyte-derived oxidative stress and inflammation. Maxamine synergizes

with

cytokines such as interferon and IL-2. Maxamine potentiates immune therapies

(interferon is an immune therapy) by inhibiting the production and release

of

free radicals from phagocytes. This protects NK (natural killer) cells and

T-cells from free radical damage.

The activation of NK and T-cells by exogenous cytokines is irreversibly

blocked by the release of free radicals from phagocytes in virally infected

tissues. These free radicals induce apoptosis (cell programmed death) in NK

and T-cells. Maxima inhibits the production and release of free radicals;

thereby, creating a more favorable environment for the survival of activated

NK cells and T-cells.

The Study

The purpose of this study was to evaluate the safety and effective dose and

regimen of Maximine (4 different dose regimens) combined with interferon

alpha-2b (Intron-A) in treating patients with HCV. At 12 weeks,

non-responders discontinue therapy. At 12 weeks, responders continue therapy

for an additional 36 weeks for a total treatment of 48 weeks. At the end of

treatment (48 weeks) all patients discontinue therapy and are followed for a

total of 72 weeks (sustained response).

The study was a multi-center, international, randomized, phase II study

conducted in Belgium, Israel, Russia and the UK (not in the USA). Complete

response definitions were--

Virological complete response: loss of detectable HCV-RNA (Cobas Amplicor

HCV

Monitor Test 2.0, Roche Diagnostics; lower limit of detection 1000 HCV

copies/ml). The prior IFN+RBV studies discussed above used an undetectable

viral load level of 100 copies/ml.

Biochemical response: normalization of serum alanine transaminase (ALT)

levels.

There were four treatment arms:

IFN a-2b + Maxima (n=32) 3mg/week; IFN 3 MU TIW (3x/week) & Maxamine 1 mg

QD,

TIW, subcutaneous injection (QD is once daily)

IFN a-2b + Maxamine (n=35) 5 mg/week; IFN 3 MU TIW; Maxamine 1 mg QD,

5X/week, sc

IFN a-2b + Maxamine (n=29) 6 mg/week; IFN 3 MU TIW; Maxamine 1 mg BID, TIW,

sc

IFN a-2b + Maxamine (n=33) 10 mg/week; IFN 3 MU TIW; Maxamine 1 mg BID,

5x/week, sc

Baseline Characteristics

Patients had chronic HCV with compensated liver disease; mean age 30; mean

ALT (ULN--upper limit of normal) 4.5x; mean HCV-RNA 6.7 million copies/ml;

53% had 2 million copies/ml; 47% had Genotype 1; 49% had genotype 2 or 3.

Exclusions--Patients with hemoglobin <12 gm/dl were excluded, As well,

people

with HIV/HCV coinfection were excluded; advanced liver disease.

RESULTS

Week 24 (Overall Response Rates)

Complete Virologic Response Rates:

10 mg Maxamine arm-- 68%

6 mg Maxamine arm-- 69%

5 mg Maxamine arm-- 57%

3 mg Maxamine arm-- 63%

Complete Biochemical response (ALT) rates:

10 mg Maxamine arm-- 60%

6 mg Maxamine arm-- 73%

5 mg Maxamine arm-- 53%

3 mg Maxamine arm-- 44%

Week 24 Response By Genotype--

10 mg Maxamine arm--71% (genotype 2/3); 88% (genotype 1)

6 mg Maxamine arm-- 67% (genotype 2/3); 73% (genotype 1)

5 mg Maxamine arm-- 80% (genotype 2/3); 36% (genotype 1)

3 mg Maxamine arm-- 58% (genotype 2/3); 69% (genotype 1)

It's interesting that the genotype 1 individuals responded better than those

with genotype 2/3 in 3 of 4 dose regimens. Although this is a small study

limiting conclusions, if the improved response by genotype 1 turns out to be

real I think this may relate to the reasons why genotype 1 individuals

usually don't respond as well as genotype 2/3 individuals. It will be

interesting to me to see the response by cirrhotics to therapy including

Maxamine.

Week 24 Response by Viral Load--

10 mg Maxamine arm-- 70% (<2 million copies/ml); 67% ( 2 million copies/ml)

6 mg Maxamine arm-- 77% (<2 million copies/ml); 62% ( 2 million copies/ml)

5 mg Maxamine arm-- 62% (<2 million copies/ml); 41% ( 2 million copies/ml)

3 mg Maxamine arm-- 69% (<2 million copies/ml); 46% ( 2 million copies/ml)

Adverse Events

They reported that Maxamine administration resulted in mild transient side

effects: Maxamine induced a short-lasting flush in most patients, and a

short

lasting headache, hypotension, and tachycardia in some patients. Overall,

the

treatment has been well tolerated. At week 24, 5% were reported to

discontinue due to serious adverse events.

Comments by Jules Levin

This study is relatively small. The virological and biochemical response

rates were higher at 12 weeks than 24 weeks but I think that's to be

expected. The 47% of genotype 1 is relatively low compared to some other

studies (57% in European IFN+RBV study and 72% in US study). The mean age in

the Maxamine study was 30, but in the other two IFN+RBV studies the mean

ages

were 41 and 45 years, respectively. Increasing age can be associated with

reduced treatment outcome. However, the baseline HCV-RNAs were a little

lower

in the two IFN+RBV studies (4-4.5 million copies/ml and about 5 million

copies/ml, respectively) than in the Maxamine study (6.7 million copies/ml).

The lower limit of detection for HCV viral load was 1000 copies/ml in the

Maxamine study, but 100 copies/ml in the two IFN+RBV studies. The

percentages

of participants of women or African-Americans were not reported in the

Maxamine study. African-Americans generally appear to have genotype 1. Hard

to treat populations including cirrhotics need to be studied.

I think this Maxamine study suggests that Maxamine is promising. Further

studies are being discussed. Combining Maxamine with pegylated IFN and RBV

or

with pegylated IFN alone deserves attention.

________________________________________________________________________

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