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 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.

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:

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:

Complete Biochemical response (ALT) rates:

Week 24 Response By Genotype--

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.

Week 24 Response by Viral Load--

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 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.