Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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RETINOID HEPATITIS THERAPY
Field of the Invention
This invention is drawn to a method of treating hepatitis comprising
administering to a subject in need of such treatment a therapeutically
effective
s amount of retinoid such as all- traps retinoic acid. In particular
embodiments, the
form of hepatitis is viral hepatitis caused by infection with A, B, C, D, E,
and G
and the treatment is with liposomal all- traps retinoic acid.
Background of the Invention
Hepatitis is an inflammatory liver disease. It is associated with toss of
so appetite, dark urine, fatigue, and, occasionally, fever. In particular
instances the
liver may become enlarged and jaundice may be present. Both chronic and acute
hepatitis is known. By definition, the acute form subsides, generally after
about
eight weeks. This form rarely results in liver failure. Chronic viral
hepatitis
patients often remain infectious. The chronic viral hepatitis group is at risk
of
i5 lasting liver disease, such as cirrhosis or hepatocellular carcinoma.
There are a number of causes and types of hepatitis, but hepatitis of viral
etiology is most common. Currently identified strains of viral hepatitis are
A, B,
C, D, E, and G. Note that the names have changed with increased knowledge
and more sophisticated tools. Type A was previously termed infectious
ao hepatitis. Type B was previously termed serum hepatitis, and Type C was non-
A, non-B hepatitis (with some exceptions). Type D was delta hepatitis.
Additional hepatitis viruses are regularly being identified and isolated.
Other
viruses have been known to exhibit hepatitis as a secondary effect. These
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viruses include Cytomegalovirus, Epstein-Barr virus, as well as Yellow Fever.
Hepatitis is also a secondary effect of certain parasites and bacteria
infections.
Non-viral hepatitis is also associated with autoimmune diseases, Wilson's
disease, hemochromatosis, and those diseases of toxic origin such as drug,
chemical, and alcoholic induced liver disease.
Particular attention is drawn to Hepatitis B and C. Hepatitis C was not
specifically identified by virus until 1988. Before that it was within the
class
termed non-A, non-B hepatitis, and, likely, comprising the vast majority of
non-A
non-B cases. Without being bound by any particular theory, it is believed that
an
io RNA virus of the type described as "Flavivirus" is the cause of Hepatitis
C. This
RNA virus has been described as a 40-50 nanometer linear single-strand RNA
(ribonucleic acid) virus with a lipid envelope. In native state, the lipid
envelope is
encased with glycoprotein polymers termed "spikes." Without being bound by
any particular theory, it is further believed that Hepatitis B is caused by a
double
i5 stranded DNA virus of the type known as Hepadnavirus. it is a 4~ nm
particle
containing ds DNA in a core associated with the polymerase, surrounded by a
capsule consisting of surface antigen.
Hitherto, there have been no satisfactory treatments for chronic viral
hepatitis, and particularly so for Hepatitis B or C. Interferon alpha is the
ao mainstay of therapy, together with specific antiviral compounds, such as
ribavirin and lamivudine. Unfortunately, response rates are rarely greater
than
50%. Prevention methodology has been suggested for hepatitis B, in the form
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of a vaccine. Hepatitis C vaccines have not proven effective. However, the
prevalence of both these chronic infections is in excess of 2 billion people.
Note, is made of the human enteroviruses. These are known to cause
numerous illnesses. Taxonomically, enterovirus is classified as a genus of the
family Picornaviridae. This genus is generally divided into five major groups.
These are (i) polioviruses, (ii) group A coxsackieviruses, (iii) group B
coxsackiviruses, (iv) echoviruses and (v) "newer" enteroviruses. Some recent
investigators exclude hepatitis A virus from the genus of enterovirus.
Enteroviruses are characterized by a high degree of genetic diversity at the
VP1
to locus. Particular reference is made to Echovirus 3, 4, 6, 7, 9 and 11, as
well as
Coxsackie A9, B2, B3, B5, and B9.
Note is also made of chronic diseases. These are illnesses that are
prolonged, do not resolve spontaneously, and are rarely cured completely.
Chronic diseases of viral origin such as Epstein-Barr are particularly noted
as is
hepatitis B and C.
Available treatments for enteroviral disease and chronic disease with a viral
component are unsatisfactory.
Summary of the Invention
This invention comprises a method of treating hepatitis comprising
ao administering to a subject in need of such treatment a therapeutically
effective
amount of all-traps retinoic acid, with particular reference to employing a
therapeutically effective amount of all-traps retinoic acid (interalia,
liposomal all-
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traps retinoic acid) of at least about 10mg at least about every other day. In
some embodiments therapeutically effective amounts of liposomal all- traps
retinoic acid are variously at least about 10 mg/m 2, at least about 15 mg/m2,
at
least about 50, at least about 65 mg/m 2 (particularly at least about 67.5
s mg/m2), at leasfi about 150 mg/m2 and further including at least about 100mg
at least about every other day. This method is particularly useful in
hepatitis
which is viral hepatitis including hepatitis A, B, C, D, E, or G.
This invention also comprises a method of treating hepatitis comprising
administering to a subject in need of such treatment a therapeutically
effective
io amount of retinoid. In a specific embodiment this includes retinoid in
liposomal
form, and further in therapeutically effective amount, optionally at least
about
every other day. Reference is made to amounts of at least about 10 mg/m 2, at
least about 15 mg/m2, at least about 50, at least about 65 mg/m Z
(particularly at
least about 67.5 mg/m2), at least about 150 mg/m2 and further including at
15 least about 100mg
This invention yet further comprises a method of treating enteroviral
infection in an infected subject comprising administering to said subject a
therapeutically effective amount of all- traps retinoic acid. In a specific
embodiment this includes retinoid in liposomal form, and further in
ao therapeutically effective amount, optionally at least about every other
day.
Reference is made to amounts of at least about 10 mg/m 2, at least about 15
mg/m2, at least about 50, at least about 65 mg/m 2 (particularly at least
about
67.5 mg/m~) at least about 150 mg/m2 and further including at least about
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100mg, and more. This method contemplates use of liposomal and free all- traps
retinoic acid. Specific enteroviral infections treated by the method are from
the
group consisting of (i) poliovirus, (ii) group A coxsackievirus, (iii) group B
coxsackivirus, (iv) echovirus or (v) "newer" enterovirus. Particular reference
is
5 made to Echovirus 3, 4, 6, 7, 9 or 11, and Coxsackie A9, B2, B3, B5, or B9.
In an additional embodiment this invention comprises a method of treating
chronic viral disease in a subject comprising administering to said subject a
therapeutically effective amount of retinoid., with particular reference to
retinoid
in liposomaf form. In particular subjects a therapeutically effective amount
of
to retinoid is at least about 50mg at least about every other day.
Detailed Description of the Invention
This invention will be better understood with resort to the following
definitions:
A. ATRA refers to all-traps retinoic acid, a retinoid. Retinoids in general
include traps-retinoic acid and all- traps-retinol. Other retinoids are
retinoic acid
is methyl ester, retinoic acid ethyl ester, phenyl analog of retinoic acid,
etretinate,
retinol, retinyl acetate, retinaldehyde, all-traps-retinoic acid, and 13-cis-
retinoic
acid. Non-liposomal retinoids, often suitable for oral administration, are
referred
to as "free." Particular reference is made to "free" ATRA. Some researchers
have suggested that the "free" or oral form of ATRA is largely bound to serum
2o proteins or other components after uptake and is not "free" in the sense of
in
solution and unbound. For convenience of terminology , as used herein, "free"
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is used with reference to the non-liposomal forms, without regard to the
eventual binding state in serum or other biological fluids.
B. Liposomal ATRA or retinoid shall be broadly understood to encompass
all lipid associated ATRA or retinoid forms. More narrowly defined,
"liposomes"
s are generally spherical structures comprising lipids, fatty acids, lipid
bilayer type
structures, unilamellar vesicles and amorphous lipid vesicles. Classically,
liposomes are completely closed lipid bilayer membranes containing an
entrapped
aqueous volume. Liposomes may be unilamellar vesicles (possessing a single
bilayer membrane) or multilamellar vesicles (onion-like structures
characterized
to by multiple membrane bilayers, each separated from the next by an aqueous
layer). The bilayer is composed of two lipid monolayers having a hydrophobic
"tail" region and a hydrophilic "head" region. The structure of the membrane
bilayer is such that the hydrophobic (nonpolar) "tails" of the lipid
monolayers
orient toward the center of the bilayer while the hydrophilic "head" orient
is towards the aqueous phase.
Liposomes are vesicles composed of one or more concentric phospholipid
bilayers and used medically especially to deliver a drug into the body. As
used
herein, and for convenience, drug:lipid aggregates will be included within the
terms liposome and liposomal. By way of example of such nonliposomal lipid
ao bearing forms, reference is made to U.S. Pat. 4,610,868 to Fountain, the
teachings of which are incorporated herein by reference.
Reference is made to liposomal-ATRA ("L-ATRA") and retinoids as
disclosed in US 5,811,119 "Formulation and Use of Carotenoids in the
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Treatment of Cancer" the teachings of which are incorporated herein by
reference
For convenience, the term "liposomal-ATRA" or "-retinoid" shall extend to
high ratio drug:lipid complexes that are not classically liposomes.
s C. Hepatitis shall be broadly construed in reference to inflammatory liver
disease associated with loss of appetite, dark urine, fatigue, and,
occasionally,
fever. Association liver enlargement and jaundice are common. Both chronic
and acute hepatitis is contemplated. While currently identified strains of
viral
hepatitis A, B, C, D, E, and G are noted, all known or later discovered
strains of
to viral hepatitis are also contemplated within this invention.
D. Therapeutically effective amount as to a drug dosage shall mean that
dosage that provides the specific pharmacological response for which the drug
is
administered in responding members of a population of subjects in need of such
treatment. As to free ATRA, a therapeutically effective amount shall include
z5 about 10, about 15, about 50 to about 150 mg/m Z and particularly about 65
mg/m2, and further about 90 mg/m 2. In particular embodiments a
therapeutically
effective amount is about 50 to about 150 mg administered at least about every
other day. As to L-ATRA, a therapeutically effective amount shall mean about
10, about 15, about 50 to about 150 mg/m 2 and particularly about 65 and 67.5
ao mg/m2. In particular embodiments, a therapeutically effective amount of L-
ATRA is about 50 to about 150 mg administered at least about every other day.
In particular instances, avoidance of toxic response or maintaining an
inhibitory
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concentration requires dosing more or less often. Smaller twice daily doses
are
contemplated.
Surprisingly, it has now been discovered that, beyond certain recognized
anti-cancer activities, retinoids, including ATRA act to reduce the viral load
in
s hepatitis patients, with particular reference to hepatitis B and C. In a
particular
embodiment, liposomal retinoid such as L-ATRA is effective.
Example 1
Liaosomal ATRA
A 24 year old female was diagnosed with APL and promptly enrolled in an
io L-ATRA (Atragen~, Aronex Pharmaceuticals, The Woodlands, TX) protocol and
began L-ATRA treatment. After 6 therapy doses, she developed nausea,
vomiting and headache and was diagnosed with Mallory-Weiss Syndrome and
upper gastrointestinal bleeding requiring endoscopy, i.v. medications and
blood
repositions. She continued receiving L-ATRA with no reduction in dose. After
the
15 7th dose, she developed ATRA Syndrome, requiring a 25 % dose reduction of
study drug. Her ATRA Syndrome resolved and she had received 21 doses of L-
ATRA, at which point she achieved first complete cancer remission.
Eighteen days later, she was admitted to initiate the first course of
consolidation therapy. During this admission, she presented with flu-like
~o symptoms and mild jaundice. Blood analysis disclosed a severe increase of
hepatic enzymes (SPGT and SGOT), hyperbilirubinemia and an increase of
alkaline phosphatase. Serological tests confirmed antibodies to hepatitis-C
positive, PCR determination of viral hepatitis-C positive.
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In compliance with the study protocol, the patient was removed from the
study due to of the development of hepatic disease. After removal from the
study, she began use of L-ATRA as single agent on a compassionate use basis
for up to 9 months. Her viral load on at the outset of this phase of treatment
was 427,174 copies/ml (blood). She began compassionate use treatment
receiving L-ATRA 3 times per week at 100mg or 67.5 mg/m 2 every other day
(QOD). About 3 weeks after treatment began, after 12 doses of L-ATRA, her
viral load was < 1,000 copies/ml. One month subsequent to this point her viral
load was < 1,000 copies/ml and her blood chemistry was normal as to hepatitis
to C (hepatic enzymes (SPGT and SGOT), bilirubin, and alkaline phosphatase).
Four months after beginning compassionate use of L-ATRA she was still in first
complete remission with PCR status negative and doing well.
Example 2
Free ATRA
A 34 year old female is diagnosed by serological tests as positive for
hepatitis-C.
She is promptly treated with free ATRA at about 1 OOmg or 67.5 mg/m ~
every other day (QOD). Her viral load on at the outset of treatment is about
300,00 copies/ml (blood). She receives free-ATRA (oral) 3 times per week.
ao About 3 weeks after treatment begins, after 12 doses of ATRA, her viral
load is
< 1,000 copies/ml. One month subsequent to this point her viral load is
< 1,000 copies/ml and her blood chemistry is normal as to hepatitis C (hepatic
enzymes (SPGT and SGOT), bilirubin, and alkaline phosphatase). Four months
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after beginning use of ATRA she is still in first complete remission with PCR
status negative.
Example 3
Free ATRA
s A 54 year old male is diagnosed by serological tests as positive for
hepatitis-A.
He is promptly treated with free ATRA at about 100mg or 67.5 mg/m 2
every other day (QOD). His viral load on at the outset of treatment is about
300,00 copies/ml (blood). He receives free-ATRA (oral) 3 times per week.
to About 3 weeks after treatment begins, after 12 doses of ATRA, his viral
load is
< 1,000 copies/ml. One month subsequent to this point his viral load is <
1,000
copies/ml and his blood chemistry is normal as to hepatitis A (hepatic enzymes
(SPGT and SGOT), bilirubin, and alkaline phosphatase). Four months after
beginning use of ATRA he is still in complete hepatitis remission with PCR
status
is negative.
Example 4
Liposomal ATRA in Hepatitis B
A 7-year-old Hispanic female with newly diagnosed/previously untreated
APL started to receive L-ATRA (ATRAGEN~) QOD at 90 mg/m 2. At baseline,
ao the medical history and serologic tests were consistent with HBV chronic
carrier
status of the patient (positive HBsAg, postive HBcAg and positive HBeAg)
though LFTs (liver function test) were within the normal limits.
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After 7 doses of L-ATRA, a grade I increase in liver transaminases was
observed which progressed to Grade III (including the LDH level ) after 12
doses
(3 weeks later). Serologic tests made 5 days later, the time when the patient
achieved hematologic complete remission (NCR), still showed positive HbsAg
s and HbcAg and HbeAg. Biopsy results on 6%2 weeks beginning treatment
showed Grade II chronic hepatitis and fibrosis.
Because of concerns that cytotoxic chemotherapy would further harm the
patient's hepatic condition, the patient was treated with L-ATRA monotherapy
as consolidation treatment. This was started on 10'/Z weeks after first
treatment
to at 67.5 mg/m2 TIW. L-ATRA was again withheld on 6'/2 later after the
patient
developed progressive moderate extoliative dermatitis assessed as related to
ATRAGEN and was restarted on one weele thereafter. The patient's LFT's
remained within the normal limits since that time (4- weeks thereafter).
All cited references and their teachings are incorporated herein by
is reference.
The compositions of this invention possess valuable pharmacological
properties. They inhibit virus proliferation with particular reference to
enteroviruses and hepatitis associated viruses in human and veterinary
medicine.
Administration is contemplated to include chronic, acute or intermittent
ao regimens.
The compositions are particularly useful in treating hepatitis A, B, C, D, E,
and G.
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In addition, the compositions can be used in in vitro methodologies,
including treating cell cultures of hepatic tissue to impede viral
proliferation in
cultures being grown for transplantation or autotransplantation, as well as in
r~
diagnostics or screening procedures (e.g., in an assay drawn to sensitive
hepatitis organisms). In some embodiments, tissues, cells or material treated
in
vitro or extra corporeally will, thereafter, be reintroduced into a subject
(which
need not be the source of origin of the tissue, cells or material). Compounds
of
the present invention can be employed in admixture with carriers, excipients
and
other drugs, and radiation therapy.
to The compositions of this invention are generally administered to animals,
including but not limited to mammals such as livestock, household pets,
humans, cattle, cats, dogs, poultry, etc. Enteral and parenteral
administration is
contemplated within this invention.
For parenteral application, particularly suitable are injectable, sterile
is solutions, preferably oily or aqueous solutions, as well as suspensions,
emulsions, or implants, including suppositories. Ampules are convenient unit
dosages. Subcutaneous and i.v. administration are particularly contemplated.
For parenteral application, particularly suitable are tablets, dragees,
liquids, drops, suppositories, or capsules. A syrup, elixir, or the like can
be used
~o wherein a sweetened vehicle is employed.
The pharmacologically active compositions of this invention can be
processed in accordance with conventional methods of Galenic pharmacy to
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produce medicinal agents for administration to patients, e.g., mammals
including
humans.
The compositions of this invention can be employed in admixture with
conventional excipients, i.e., pharmaceutically acceptable organic or
inorganic
s carrier substances suitable for parenteral, enteral (e.g., oral or
inhalation) or
topical application which do not deleteriously react with the active
compositions.
Suitable pharmaceutically acceptable carriers include but are not limited to
water, salt, sugar solutions, etc. The pharmaceutical preparations can be
sterilized and if desired mixed with auxiliary agents, e.g. They can also be
io combined where desired with other active agents, including radiation or
other
antiviral or antineoplastic therapy. Particular reference is made to combined
uses with antiviral drugs such as alpha interferon, ribavirin, amantadine,
ganciclovir, acyclovir, zidovudine, foscarnet, dideoxycytosine,
dideoxyinosine,
rimantadine, stavudine, famciclovir, and trifluridine.
15 In some embodiments of the present invention, dosage forms include
instructions for the use of such compositions.
For parenteral application, particularly suitable are injectable, sterile
solutions, preferably suspensions. Ampules are convenient unit dosages.
Sustained or directed release compositions can be formulated, e.g.,
20 liposomes or those wherein the active component is protected with
differentially
degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It
is
also possible to freeze-dry the new compositions and use the lyophilizates
obtained, for example, for the preparation of products for injection.
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Generally, the compositions of this invention are dispensed in unit dosage
form comprising liposomal ATRA of from 15 to 300 or more mg/m 2 and
particularly about 90 mg/m 2 ATRA, and from daily to about 5 out of 7 days to
about 3 out of 7 days per week.
It will be appreciated that the actual preferred amounts of active
compositions in a specific case will vary according to the specific
compositions
being utilized, the particular compositions formulated, the mode of
application,
and the particular situs and organism being treated. Dosages for a given
subject
can be determined using conventional considerations, e.g., by customary
so comparison of the differential activities of the subject compositions and
of a
known agent, e.g., by means of an appropriate, conventional pharmacological
protocol.
