Hepatitis
B
Zadaxin Plus IFNα
Combination Therapy for Chronic Hepatitis B
| Although Zadaxin
is an effective monotherapy for CHB, a number of studies
suggest that Zadaxin can work in synergy with other immune
modulators or antiviral agents. |
| • |
In cell culture, Zadaxin
combined with IFNα enhanced
NK activity in human peripheral blood lymphocytes and
purified large granular lymphocytes to a greater extent
than that which would have resulted from an additive effect
alone (32) |
| • |
In animal studies, Zadaxin
in combination with IFNα
increased NK activity in immunosuppressed mice (28,29)
and had greater antiviral and antitumor activity than
that which would have resulted from an additive effect
alone (26,74,78,98) |
As discussed below, Zadaxin works in synergy with INFα
for treating hepatitis C. Therefore, human trials to improve
the effectiveness of other CHB monotherapies by the addition
of Zadaxin are being explored. Moreover, because of its excellent
safety profile, Zadaxin may be combined with other therapies
such as IFNα or nucleoside
analogs to enhance their efficacy without increasing their toxicity.
Phase 2 Italy trial (IFNα
plus Zadaxin)
This open label study tested the combination of low-dose lympho-blastoid
IFNα (L-IFNα)
and Zadaxin. (99)
| Patients and
protocol: |
| • |
15 patients with CHB |
| |
| – |
HBsAg positive |
| – |
HBV DNA positive |
| – |
ALT levels > 1.5
times normal |
|
| • |
11 treatment failures on
standard IFNα-2b therapy |
| • |
4 previously untreated
patients |
| • |
Zadaxin (1 mg) subcutaneously
on 4 consecutive days, L-IFNα
(3 MIU) intramuscularly on the fourth day |
| • |
Subsequently, Zadaxin and
L-IFNα biweekly for 26 weeks |
| • |
12-month follow-up |
| • |
Response defined as loss of HBV DNA
and normalization of ALT at 18 months. |
| Results: |
| • |
Overall sustained response
of 60% (9/15) |
| • |
Disease remission in 55%
(6/11) of previous IFNα-2b
treatment failures |
| • |
No reactivation of disease
in any sustained responders followed beyond follow-up
period |
It should be noted that in this trial, the dose of L-IFNα
(3 MIU BIW) was a fraction of the total standard dose (15-30
MIU) usually given in 3 to 6 injections per week. These data
suggest that responses of patients to the Zadaxin plus IFNα
combination may be higher than has been the general experience
with either Zadaxin
or IFNα monotherapy.
The results in patients who were previous interferon failures
are particularly striking, in light of the fact that historical
retreatment response rate with a second course of IFNα
would be expected to be no better than 10%. These results are
consistent with studies conducted in vitro and in animals (discussed
above) that suggest that Zadaxin acts in synergy with other
immune modulators.
Phase 2 Turkish trial (Zadaxin and IFNα-2b)
This trial compared IFNα-2b
monotherapy with Zadaxin plus IFNα-2b
combination therapy. (100)
| Patients and
protocol: |
| • |
31 patients with CHB |
| |
| – |
Treatment naïve |
| – |
Anti-HBe positive |
| – |
HBV DNA positive |
|
| • |
Group 1 |
| |
| – |
21 patients |
| – |
Weeks 1 to 26: 1.6
mg Zadaxin SC BIW + 10 MIU IFNα-2b
SC TIW |
| – |
Weeks 27 to 52: 10
MIU IFNα-2b
SC TIW |
| – |
26-week follow-up |
|
| • |
Group 2 |
| |
| – |
10 patients |
| – |
Weeks 1 to 52: 10
MIU IFNα-2b
SC TIW |
| – |
26-week follow-up |
|
| • |
Endpoints |
| |
| – |
Normalization of
ALT: weeks 52 and 78 |
| – |
HBV DNA negative:
weeks 52 and 78 |
| – |
Improved liver histology:
week 78 |
|
| Results: |
| • |
Response at week 52 |
| |
| – |
87.7% HBV DNA negative
with normal ALT: Zadaxin + IFNα-2b |
| – |
70% HBV DNA negative
with normal ALT: IFNα-2b
monotherapy |
|
| • |
Response at week 78 |
| |
| – |
76.2% sustained response:
Zadaxin + IFNα-2b |
| – |
40% sustained response:
IFNα-2b
monotherapy |
| – |
P = 0.002 |
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