for Hepatitis C Treatment
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 naÔve 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.
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.
does Maxima work?
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
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.
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
study was a multi-center, international, randomized, phase II study conducted in
Belgium, Israel, Russia and the UK (not in the USA). Complete response
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
response: normalization of serum alanine transaminase (ALT) levels.
were four treatment arms:
a-2b + Maxima (n=32) 3mg/week; IFN 3 MU TIW (3x/week) & Maxamine 1 mg QD,
TIW, subcutaneous injection (QD is once daily)
a-2b + Maxamine (n=35) 5 mg/week; IFN 3 MU TIW; Maxamine 1 mg QD, 5X/week,
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,
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.
with hemoglobin <12 gm/dl were excluded, As well, people with HIV/HCV
coinfection were excluded; advanced liver disease.
(Overall Response Rates)
Virologic Response Rates:
mg Maxamine arm-- 68%
Maxamine arm-- 69%
Maxamine arm-- 57%
Maxamine arm-- 63%
Biochemical response (ALT) rates:
mg Maxamine arm-- 60%
Maxamine arm-- 73%
Maxamine arm-- 53%
Maxamine arm-- 44%
24 Response By Genotype--
mg Maxamine arm--71% (genotype 2/3); 88% (genotype 1)
Maxamine arm-- 67% (genotype
2/3); 73% (genotype 1)
Maxamine arm-- 80% (genotype
2/3); 36% (genotype 1)
Maxamine arm-- 58% (genotype
2/3); 69% (genotype 1)
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.
Week 24 Response by Viral Load--
10 mg Maxamine arm-- 70% (<2 million copies/ml); 67% („2 million copies/ml
Maxamine arm-- 77% (<2
million copies/ml); 62% („2
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)
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.
by Jules Levin
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 does suggest that Maxamine is promising. Further studies are being discussed. Combining Maxamine with pegylated IFN and RBV or with pegylated IFN alone deserves attention.