Note: Descriptions are shown in the official language in which they were submitted.
w 095/23610 ~ ~ 6 0 2 4 ~ PCTAEPg5/00653
PHARMACEUTICAL COMPOSITION CONTAINING THYMOCTONAN AND AZT
This invention relates to the use of thymoctonan in
comhination with other compounds that inhibit retro-virus
replication in order to control immune system impairment in
the treatment of Acquired Immunodeficiency Syndrome (AIDS)
or ARC (AIDS related complex). Pharmaceutical compositions
and their preparations useful in such treatment are also
disclosed.
AIDS is caused by HIV, a human retrovirus of the
lentivirus group. The four recognized human retroviruses
belong to two distinct groups; the human T lymphotropic (or
leukaemia) retro-viruses, HTLV-I and HTLV-II, and the human
immunodeficiency viruses, HIV-1 and HIV-2. The former are
transforming viruses, and the latter are cytopathic
viruses. The most common cause of AIDS throughout the
world is HIV-1. HIV-2 has about 40 percent sequence
homology with HIV-1 and is more closely related to some
members of a group of simian immunodeficiency viruses
(SIV). HIV has the usual retroviral genes (env, qaq, and
~ol) and six extra genes involved in the replication and
other biologic activities of the virus.
The common denominator of AIDS is a profound
immunosuppression, predominantly of cell mediated immunity,
that leads to a variety of opportunistic diseases,
particularly certain infections and neoplasms. The main
cause of immune defect in AIDS is a quantitative and
qualitative deficiency in the subset of thymus-derived (T)
WO95/23610 PCT~P95/00653
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lymphocytes termed the T4 population. This subset of cells
is defined phenotypically by the presence of the CD4
surface cell molecule, which is the cellular receptor for
HIV. Although the T4 cell is the major cell type infected
with HIV, virtually any human cell that expresses the CD4
molecule on its surface is capable of binding to and being
infected with HIV. Of particular importance are cells of
monocyte-macrophage lineage.
The degree of relative contribution of each part of
the immune system to the host's ability to control HIV
infection is not yet clear. Nevertheless, attempts have
been made to augment the host's immune defense in HIV
infection with the hope of beneficially altering the
progress of the disease. An immunomodulatory intervention
is d'efined as a method or an agent believed to exert its
primary effect on the host's immune system but not to have
direct antiviral activity. In particular, an
immunomodulant like thymoctonan that has been shown to play
a major role in the differentiation and maturation of the
T-lymphocytes, and to reverse the depression of cell-
mediated immunity in severe viral infection, could exert a
regulatory effect with an enhancement of immune response,
leading to a decrease of viral burden and a slowing of
dlsease progression.
Thymoctonan is a synthetic octapeptide originally
isolated and characterized from fetal calf thymus, as
described in US patent No. 4,621,135.
WO95/23610 2 1 ~ ~ 2 ~ ~ PCT~P95/00653
The present invention provides products containingthymoctonan and an antiretroviral agent as a combined
preparation for simultaneous separate or sequential use in
the treatment of a retroviral disease. The products of the
invention may be used in particular to treat patients
infected with HIV, especially HIV-l.
The anti-retroviral agent used in the present
invention may be selected, for example, from reverse
transcriptase inhibitors (RT inhibitors) such as nucleoside
analogues or non-nucleoside inhibitors of HIV reverse
transcriptase (NNRTI's); protease inhibitors; agents which
block cell entry by HIV; nucleic acid-based therapeutics;
and Tat inhibitors (Tat is a regulatory protein required
for HIV replication in cultured cells and is a positive
transactivator which stimulates transcription: see, for
instance, B.M. Peterlin et al, Proc. Natl. Acad. Sci USA 83
9734 (1986)). These classes of anti-retroviral agent, with
particular reference to HIV, are discussed by Johnston and
Hoth in Science vol 260, 1286-1293, 28 May 1993.
Examples of RT inhibitors include AZT (3'-
azidothymidine, zidovudin, Retrovir); ddI (2',3'-
dideoxyinosine, Didanosine, Videx); ddC (2',3'-
dideoxycytidine, Zalcitabine, HIVID); 3TC (the (-)-
enantiomer of 2'-deoxy-3'-thiacytidine, Lamivadine); d4T
(didehydrothymidine, Stavidine); 3'-halo-dideoxypyridine
analogues such as FLT (3'-fluoro-thymidine); and PNEA (9-
(2-phosphonomethoxyethyl)-adenine, an acylic nucleotide).
WO95/23610 PCT~P95/00653
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Examples of non-nucleoside reverse transcriptase
inhibitors (NNRTI's) include tetrahydro-imidazo [4,5,1-
jk][1,4]-benzodiazepin-2(lH)-one; 11-cyclopropyl-7-methyl-
dipyrido-[2,3-b: 3'3'-f] 1,4-diazepin-6H-5-one (BI-RG-587,
nevirapine); and bis(heteroaryl)piperazines (BHAP's,
U-87201E, Alevidine Mesylate, ATV : see, for example, D.L.
Romero et al Proc. Natl. Acad. Sci USA 88 8806 (1991)).
There are currently 3 anti-retroviral agents approved
for HIV disease; 3'azidothymidine (AZT, Zidovudine),2',3',-
didoxyinosine (ddI, Didanosine) and 2',3'-dideoxycytidine
(ddC, Zalcitabine). Numerous others are in clinical
trials, such as for example rIFN-alpha, rIFN-betaSerl7 and
rIFN~ as cytokines, phosphonoformate as inhibitor of
reverse transcription, ribavirin, amphotericin B and
castanospermine with different modes of attack on the
retrovirus. Any of these may be employed as the anti-viral
agent in the present invention.
The combination comprising thymoctonan and anti-
retroviral agent is administered to a patient in an amount
sufficient to inhibit retro-viral replication; it is to be
noted that thymoctonan can also control or reduce the side
effects related to anti-retroviral agents such as AZT.
The invention also provides pharmaceutical
compositions containing thymoctonan, as an immunostimulant,
and an anti retro-viral agent. A pharmaceutically
acceptable carrier or diluent is typically also included in
the composition.
WOgS/23610 PCT/~5~00G53
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The results of the combined treatment showing a
positive and beneficial effect are reported below.
The combined therapy of the present invention
enhances the antiviral effect of the anti-retroviral agent
and thus yields the most effective and least toxic
treatment for ARC and AIDS.
A clinical study using an anti-retroviral agent in
combination with thymoctonan has demonstrated that
thymoctonan provides a synergistic complement in the
treatment of HIV infections including ARC and AIDS, itself
specifically. It was found that thymoctonan associated
with an anti-retroviral agent may prolong survival in HIV-
infected individuals.
The antiretroviral drugs preferred for use in the
present invention are AZT, ddI and ddC, alone or in
combination.
The amount of antiretroviral drug administered is
from 10 to 1500 mg/daily, preferably from 50 to 1000
mg/daily. For example, AZT is administered orally at a
dose from 600 to 1200 mg/daily and ddI at an oral dose of
from 500 to 750 mg/daily.
The amount of thymoctonan administered is from 0.25
to 1000 ~g/weekly, preferably from 0.5 to 100 ~g/weekly,
the route of administration being parenteral (i.m. or
s.c.).
More preferably the antiretroviral drug is
administered at conventional dosage, the thymoctonan at a
WO95/23610 PCT~P95/00653
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dosage of 0.5, 4 or 40 ~g by i.m. injection, once daily for
15 days (induction period); then twice weekly for at least
12 months.
Thymoctonan was administered in particular in
combination with AZT to a symptomatic HIV-infected
individuals with a CD4 count less than 500/~1, showing
suggestive evidence of a surprising favourable effect in
terms of viral load decrease in comparison with the single
treatment with AZT alone.
lo The combined administration, according to the present
invention, of thymoctonan and an antiretroviral agent
includes presentation in which both agents are administered
together as a therapeutic mixture, and also procedures in
which the two agents are administered separately, e.g.
thymoctonan through i.m. or s.c. injection and the anti-
retroviral agent by the oral route. Combined
administration further includes the separate administration
of the drugs in which one of the drugs is given first
followed shortly by the second.
Clinical data
As a part of a multicenter controlled double-blind,
clinical study we enrolled 12 patients (4 AIDS, 6CDC III
and 2 CDC II) that were treated for the first six months
with either 4 or 40 ~g of thymoctonan or placebo (2 times a
week by i.m. injection). After this period all the
patients voluntarily received the highest dose of active
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drug on open-label. Patients received since the beginning
of the treatment AZT 5000 mg/day orally, too.
For the evaluation of open-label treatment we chose a
case-control design. Patients in the control group were 24
(1:2 ratio) subjects, admitted in our service, who started
AZT treatment in the same period of time and matched
thymoctonan treated patients as to sex, age, CDC
classification of illness, number of CD4 + T-cells at
admission (median 117.5 vs 165 cells/~l) and previous
opportunistic infections. All cases and controls received
PCP prophylaxis whenever CD4 +T-cell count fell below
200/~l. The groups were homogeneous for all considered
entry variables.
They were followed for 19+5 months (cases) and 15+5
(controls). No case of death was observed in the
thymoctonan treated group, while 9 subjects (37.5%) died in
the control group (P=0.01 Fisher). No cases of disease
progression (in terms of CDC group shift for patients in II
or III stage) was observed in the thymoctonan group but in
4 out of 16 patients in the control group, 3 of whom died.
Four patients in the thymoctonan group and 11 in the
control group were hospitalized at least once during the
observation period and 3 vs 12 presented AZT intolerance.
In addition, in the thymoctonan group patients stayed
without AZT treatment or were in the hospital for a shorter
proportion of time (P<0.0001 Kruskal-Wallis).
