U.S. patent application number 17/141763 was filed with the patent office on 2021-04-29 for minocycline compounds and methods of use thereof.
The applicant listed for this patent is Paratek Pharmaceuticals, Inc.. Invention is credited to Robert D. Arbeit, Thomas J. Bigger, Sean M. Johnston, Dennis P. Molnar, S. Ken Tanaka.
Application Number | 20210121483 17/141763 |
Document ID | / |
Family ID | 1000005329232 |
Filed Date | 2021-04-29 |
United States Patent
Application |
20210121483 |
Kind Code |
A1 |
Johnston; Sean M. ; et
al. |
April 29, 2021 |
MINOCYCLINE COMPOUNDS AND METHODS OF USE THEREOF
Abstract
Methods and compositions for using a tetracycline compound to
treat bacterial infections are described. In one embodiment, for
example, the invention provides a method of treating a subject for
an infection, comprising administering to said subject an effective
amount of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof, such that said subject is treated, wherein said
infection is selected from the group consisting of MSSA, MRSA,
B-streptococci, Viridans Streptococci, Enterococcus, or
combinations thereof.
Inventors: |
Johnston; Sean M.;
(Doylestown, PA) ; Arbeit; Robert D.; (W. Newton,
MA) ; Bigger; Thomas J.; (Norwell, MA) ;
Molnar; Dennis P.; (Hopkinton, MA) ; Tanaka; S.
Ken; (Bellevue, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Paratek Pharmaceuticals, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
1000005329232 |
Appl. No.: |
17/141763 |
Filed: |
January 5, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16745435 |
Jan 17, 2020 |
|
|
|
17141763 |
|
|
|
|
16157290 |
Oct 11, 2018 |
|
|
|
16745435 |
|
|
|
|
15637144 |
Jun 29, 2017 |
10124014 |
|
|
16157290 |
|
|
|
|
14995896 |
Feb 2, 2016 |
9724358 |
|
|
15637144 |
|
|
|
|
14258847 |
Apr 22, 2014 |
9265740 |
|
|
14995896 |
|
|
|
|
12398980 |
Mar 5, 2009 |
|
|
|
14258847 |
|
|
|
|
61068180 |
Mar 5, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 31/65 20130101 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61K 31/165 20060101 A61K031/165 |
Claims
1. A method of treating a subject for an infection, comprising
administering to said subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of MSSA, MRSA,
B-streptococci, Viridans Streptococci, Enterococcus, and
combinations thereof.
2. The method of claim 1, wherein said salt is a hydrochloride
salt.
3. The method of claim 1, wherein said salt is a tosylate salt.
4. The method of claim 1, wherein said subject is a human.
5. The method of claim 1, wherein said subject is suffering from
injury, abscess, ulcer, or cellulitis.
6. The method of claim 5, wherein said injury is a trauma, surgery,
bite, or burn.
7. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered orally.
8. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered intravenously.
9. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered orally at dose of about
100 mg to about 300 mg per day.
10. The method of claim 9, wherein said 9-[(2,2-dimethyl-propyl
amino minocycline is administered orally at a dose of about 200 mg
per day.
11. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered intravenously at a dose
of about 50 mg to about 150 mg per day.
12. The method of claim 11, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered intravenously at a dose
of about 100 mg per day.
13. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has a clinical success rate of treating
an infection of greater than about 93.2%.
14. The method of claim 1, wherein said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has a microbiologically evaluable
clinical success rate of treating an infection of greater than
about 93.7%.
15. A method of treating a subject for an infection, comprising
administering to said subject an oral dose of about 100 mg to about
300 mg per day of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, such that said
subject is treated, wherein said infection is selected from the
group consisting of MSSA, MRSA, B-streptococci, Viridans
Streptococci, Enterococcus, and combinations thereof, and further
wherein said subject is in need of treatment thereof.
16. A method of treating a subject for an infection, comprising
administering to said subject an intravenous dose of about 50 mg to
about 150 mg per day of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, such that said
subject is treated, wherein said infection is selected from the
group consisting of MSSA, MRSA, B-streptococci, Viridans
Streptococci, Enterococcus, and combinations thereof, and further
wherein said subject is in need of treatment thereof.
17. A pharmaceutical composition comprising from about 100 to about
300 mg of 94(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof and a pharmaceutically acceptable carrier for oral
administration.
18. The pharmaceutical composition of claim 17, wherein said
composition comprises about 200 mg of said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline.
19. A pharmaceutical composition comprising from about 50 to about
150 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof and a pharmaceutically acceptable carrier for
intravenous administration.
20. The pharmaceutical composition of claim 19, wherein said
composition comprises about 100 mg of said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/258,847, filed on Apr. 22, 2014 and
published as US 2015-0087711 A1; which is a continuation of U.S.
patent application Ser. No. 12/398,980, filed on Mar. 5, 2009, now
abandoned; which claims the benefit of the filing date under 35
U.S.C. 119(e) to U.S. Provisional Application Ser. No. 61/068,180,
filed on Mar. 5, 2008, entitled "Methods of Treating Infectious
Using Tetracycline Compounds." The entire contents of each of the
foregoing applications are incorporated herein by reference.
BACKGROUND
[0002] The development of the tetracycline antibiotics was the
direct result of a systematic screening of soil specimens collected
from many parts of the world for evidence of microorganisms capable
of producing bacteriocidal and/or bacteriostatic compositions. The
first of these novel compounds was introduced in 1948 under the
name chlortetracycline, Two years later, oxytetracycline became
available. The elucidation of the chemical structure of these
compounds confirmed their similarity and furnished the analytical
basis for the production of a third member of this group in 1952,
tetracycline. A new family of minocycline compounds, without the
ring-attached methyl group present in earlier tetracyclines, was
prepared in 1957 and became publicly available in 1967; and
minocycline was in use by 1972.
[0003] Recently, research efforts have focused on developing new
tetracycline antibiotic compositions effective under varying
therapeutic conditions and routes of administration. New
tetracycline analogues have also been investigated which may prove
to be equal to or more effective than the originally introduced
minocycline compounds. Examples include U.S. Pat. Nos. 2,980,584;
2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859;
3,957,980; 4,01.8,889; 4,024,272; and 4,126,680. These patents are
representative of the range of pharmaceutically active tetracycline
and tetracycline analogue compositions.
[0004] Historically, soon after their initial development and
introduction, the tetracyclines were found to be highly effective
pharmacologically against rickettsiae; a number of grain-positive
and gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, and
psittacosis. Hence, tetracyclines became known as "broad spectrum"
antibiotics. With the subsequent establishment of their in vitro
antimicrobial activity, effectiveness in experimental infections,
and pharmacological properties, the tetracyclines as a class
rapidly became widely used for therapeutic purposes. However, this
widespread use of tetracyclines for both major and minor illnesses
and diseases led directly to the emergence of resistance to these
antibiotics even among highly susceptible bacterial species both
commensal and pathogenic (e.g., pneumococci and Salmonella). The
rise of tetracycline-resistant organisms has resulted in a general
decline in use of tetracyclines and tetracycline analogue
compositions as antibiotics of choice. In addition, other
antibacterial agents have also been over used creating strains of
multiple drug resistant bacteria. Therefore, there is a need for
effective antibacterial agents for the treatment of bacterial
infections.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention pertains, at least in part,
to a method of treating a subject, comprising administering to the
subject an effective amount of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, wherein said
tetracycline compound has an efficacy greater than linezolid for
the treatment of bacterial infections.
[0006] In another embodiment, the invention also pertains, at least
in part, to a method of treating a subject for an infection, by
administering to the subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, wherein the tetracycline compound has a clinical success
rate of about 93.7% or greater for treating infections of
methicillin-susceptible Staphylococcus aureus (MSSA),
methicillin-resistant Staphylococcus aureus (MRSA), B-streptococci,
gram-negative bacteria (e.g., gram-negative rods (GNR)), Viridans
Streptococci, Enterococcus, gram-positive bacteria (e.g.,
gram-positive anaerobes), or combinations thereof.
[0007] In another embodiment, the invention also pertains to a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of MSSA, MRSA,
B-streptococci, Viridans Streptococci, Enterococcus, and
combinations thereof.
[0008] In another embodiment, said salt is a hydrochloride salt. In
another embodiment, said salt is a tosylate salt.
[0009] In another embodiment, said subject is a human. In another
embodiment, said subject is suffering from injury, abscess, ulcer,
or cellulitis. In another embodiment, said injury is a trauma,
surgery, bite, or burn.
[0010] In another embodiment, said 9-[(2,2-dimethyl-propyl
amino)-methyl]minocycline is administered orally. In another
embodiment, said 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline
is administered intravenously.
[0011] In another embodiment, said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered orally at dose of about
100 mg to about 300 mg per day. In another embodiment, said
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered
orally at a dose of about 200 mg per day. In another embodiment,
said 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is
administered intravenously at a dose of about 50 mg to about 150 mg
per day. In another embodiment, said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered intravenously at a dose
of about 100 mg per day.
[0012] In another embodiment, said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has a clinical success rate of treating
an infection of greater than about 93.2%. In another embodiment,
said 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has a
microbiologically evaluable clinical success rate of treating an
infection of greater than about 93.7%.
[0013] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an oral dose of about 100 mg to about
300 mg per day of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, such that said
subject is treated, wherein said infection is selected from the
group consisting of MSSA, MRSA, B-streptococci, Viridans
Streptococci, Enterococcus, and combinations thereof, and further
wherein said subject is in need of treatment thereof.
[0014] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an intravenous dose of about 50 mg to
about 150 mg per day of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, such that said
subject is treated, wherein said infection is selected from the
group consisting of MSSA, MRSA, B-streptococci, Viridans
Streptococci, Enterococcus, and combinations thereof, and further
wherein said subject is in need of treatment thereof.
[0015] In another embodiment, the present invention provides a
pharmaceutical composition comprising from about 100 to about 300
mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof and a pharmaceutically acceptable carrier for oral
administration. In another embodiment, said composition comprises
about 200 mg of said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline.
[0016] In another embodiment, the present invention provides a
pharmaceutical composition comprising from about 50 to about 150 mg
of 9-[(2,2-dimethyl-propyl amino) methyl]-minocycline or a salt
thereof and a pharmaceutically acceptable carrier for intravenous
administration. In another embodiment, said composition comprises
about 100 mg of said 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The invention pertains, at least in part, to the discovery
that 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is
effective to treat bacterial infections, including
methicillin-susceptible Staphylococcus aureus (MSSA),
methicillin-resistant Staphylococcus aureus (MRSA), B-streptococci,
gram-negative bacteria (e.g., gram-negative rods (GNR)), Viridans
Streptococci, Enterococcus, gram-positive bacteria (e.g.,
gram-positive anaerobes), or combinations thereof.
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline (compound 1) is
a potent antibiotic with a greater clinical success rate than
linezolid (e.g.,
N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]ac-
etamide, Zyvox.TM.). The structure of linezolid is:
##STR00001##
[0018] The invention pertains, at least in part, to a method of
treating a subject, comprising administering to said subject an
effective amount of compound 1 or a salt thereof, such that said
subject is treated, wherein the tetracycline compound has an
efficacy greater than linezolid.
[0019] The term "tetracycline compound" includes compounds with a
four-ring core structure similar to that of tetracycline and its
analogs (e.g., minocycline, sancycline, doxycycline, methacycline,
etc.). The tetracycline compound of the invention is a
9-aminomethyl tetracycline compound, e.g., a compound substituted
at the 9-position with an aminomethyl moiety (e.g.,
--CH.sub.2--NR'R'', wherein R' and R'' can each be hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl alkyl, etc.). The tetracycline
compound is 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline
(compound 1), or a salt thereof. The structure of compound 1
is:
##STR00002##
[0020] In a further embodiment, 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered orally as the free base
or as the tosylate salt. In another embodiment,
9[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered
intravenously as the hydrochloride salt.
[0021] The term "treating" or "treatment" refers to the
amelioration, eradication, or diminishment of one or more symptoms
of the disorder, e.g., a bacterial infection, to be treated. In
certain embodiments, the disorder term includes the eradication of
bacteria associated with the infection to be treated.
[0022] The term "prophylaxis" means to prevent or reduce the risk
of bacterial infection.
[0023] The term "resistance" or "resistant" refers to the
antibiotic/organism standards as defined by the Clinical and
Laboratories Standards Institute (CLSI) and/or the Food and Drug
Administration (FDA).
[0024] In a further embodiment, the infection may be an infection
caused by gram-positive pathogens (e.g., methicillin-susceptible
Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus
aureus (MRSA), Enterococcus faecalis, Enterococcus faecium,
vancomycin-resistant Enterococcus faecium (VRE), Streptococcus
pneumoniae, penicillin-resistant Streptococcus pneumoniae (PRSP),
Streptococcus pyogenes, Streptococcus agalactiae, etc.),
gram-negative pathogens (e.g., Haemophilus influenzae, Moraxella
catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Shigella
spp., Salmonella spp., Klebsiella pneumoniae, Enterobacter
aerogenes, Enterobacter cloacae, Serratia marcescens, Acinetobacter
baumannii, Stenotrophomonas maltophilia, etc.), anaerobic pathogens
(e.g., Bacteroides fragilis, Clostridium perfringens, etc.) and/or
atypical pathogens (e,g., Chlamydia pneumoniae, Legionella
pneumophila, etc.).
[0025] The infection may be resistant to other antibiotics, such as
penicillin or tetracycline. Examples of bacterial infections which
can be treated with the compounds of the invention include
infections of MSSA, methicillin-resistant Staphylococcus aureus
(MRSA) including both hospital-associated and community-associated
MRSA, streptococci (e.g., Streptococcus pneumoniae, Streptococcus
pneumoniae (PRSP), Streptococcus pyogenes, and Streptococcus
agalactiae), gram-negative bacteria (e.g., gram-negative rods
(GNR)), Viridans Streptococci, Enterococcus, gram-positive bacteria
(e.g., grain-positive anaerobes), or combinations thereof.
[0026] In another embodiment, the infection is a
hospital-associated MRSA infection. In another embodiment, the
infection is a community-associated MRSA infection.
[0027] In another embodiment, the infection is an acute bacterial
infection prompting or occurring during hospitalization.
[0028] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of MSSA, MRSA,
B-streptococci, Viridans Streptococci, Enterococcus, mixed
gram-positve cocci, mixed gram-positive cocci/gram-negative rods or
combinations thereof.
[0029] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of MSSA, MRSA,
B-streptococci, mixed gram-positive cocci, mixed gram-positive
cocci/gram-negative rods, or combinations thereof.
[0030] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of MSSA, MRSA,
B-streptococci, or combinations thereof.
[0031] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of
94(2,2-dimethyl-propyl amino)-methyl)-minocycline or a salt
thereof, such that said subject is treated, wherein said infection
is selected from the group consisting of hospital-associated MRSA
and community-associated MRSA.
[0032] In another further embodiment, the subject may be suffering
from complicated skin and skin structure infections (CSSSI). Such
CSSSI infections may result in hospitalization or occur during
hospitalization.
[0033] In another further embodiment, the subject may be suffering
from diabetic foot infections. Such diabetic foot infections may
result in hospitalization or occur during hospitalization.
[0034] in another further embodiment, the subject may be suffering
from community- or hospital-acquired pneumonia. Such community- or
hospital-acquired pneumonia may result in hospitalization or occur
during hospitalization.
[0035] In another further embodiment, the subject may be suffering
from intra-abdominal infection. Such an intra-abdominal infection
may result in hospitalization or occur during hospitalization.
[0036] In another further embodiment, the subject may be suffering
from an injury (e.g., trauma, surgery, bite, removal of foreign
body or burn), abscess (e.g., major or minor abscess), ulcer (e.g.,
lower or upper extremity ulcer), or cellulitis (which may be
accompanied by a co-morbidity, such as diabetes mellitus, hepatitis
C, substance abuse, cardiovascular disease (including coronary
artery disease or peripheral vascular disease), vascular
insufficiency, or immunosupressive therapy). Examples of major
abscesses includes those which require drainage or involve
subcutaneous or deeper tissues. An example of a burn includes a
burn over less than 5% of the subject's body,
[0037] The term "subject" includes animals capable of suffering
from a bacterial infection. Examples of subjects include animals
such as farm animals (e.g., cows, pigs, horses, goats, rabbits,
sheep, etc.), lab animals (mice, rats, etc.), pets (e.g., dogs,
cats, ferrets, etc.), and primates (e.g., monkeys, gorillas,
chimpanzees, and humans).
[0038] The tetracycline compound may be administered by any route
which allows the compound to perform its intended function, e.g.,
treat a bacterial infection. Examples of routes include orally,
intravenously, and topically. Preferably, the compound is
administered orally or intravenously.
[0039] The term "effective amount" includes the amount of the
tetracycline compound needed to treat a bacterial infection. For
example, an effective amount describes an efficacious level
sufficient to achieve the desired therapeutic effect through the
killing of bacteria and/or inhibition of bacterial growth.
Preferably, the bacterial infection is treated when the pathogen
(e.g., bacteria) is eradicated.
[0040] The term "evaluable clinical success" refers to a clinical
trial participant who: [0041] (1) did not meet any criteria for
evaluable clinical failure; [0042] (2)did not receive potentially
effective non-study antibiotics for any other reason; and [0043]
(3)the blinded evaluator indicated at the test of cure evaluation
that the infection had sufficiently resolved such that antibiotics
were not needed.
[0044] The term "evaluable clinical failure" refers to a clinical
trial participant who met any one of the following criteria: the
blinded evaluator discontinued study drug and indicated that the
infection had responded inadequately such that alternative
antibiotic(s) were needed; the blinded evaluator discontinued study
drug because of an adverse event that was assessed as probably or
possibly drug-related; the primary site of infection was surgically
removed; or the subject had no evaluation after the end of
intravenous treatment.
[0045] The term "clinical success rate" refers to the number of
evaluable clinical successes divided by the total number of
population in the trial.
[0046] The term "microbiologically evaluable clinical success rate"
refers to those who met the definition of evaluable clinical
success and had an infecting pathogen at baseline.
[0047] In one embodiment, the effective amount of the tetracycline
compound, e.g., 9[(2,2-dimethyl-propyl amino)-methyl]-minocycline,
when administered orally is from about 100 to about 300 mg, about
110 to about 290 mg, from about 120 to about 280 mg, from about 130
to about 270 mg, from about 140 to about 260 mg, from about 150 to
about 250 mg, from about 160 to about 240 mg, from about 170 mg to
about 230 mg, from about 180 mg to about 220 mg, from about 190 mg
to about 210 mg, or about 200 mg. The compound may be administered
as a salt (e.g., tosylate salt) or as a free base.
[0048] In another embodiment, the effective amount of the
tetracycline compound, e.g., 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline, when administered intravenously is from
about 50 to about 200 mg, from about 50 to about 150 mg, from about
60 to about 140 mg, from about 70 mg to about 130 mg, from about 80
mg to about 120 mg, from about 90 mg to about 110 mg, or about 100
mg.
[0049] It is to be understood that wherever values and ranges are
provided herein, e.g., in ages of subject populations, dosages, and
blood levels, all values and ranges encompassed by these values and
ranges, are meant to be encompassed within the scope of the present
invention. Moreover, all values in these values and ranges may also
be the upper or lower limits of a range.
[0050] In another embodiment, the tetracycline compound may be
administered once per day, either intravenously or orally.
[0051] In a further embodiment, the tetracycline compound has a
greater clinical success rate than linezolid (e.g.,
N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide-
), when the linezolid is administered at 600 mg orally or 600 mg
intravenously every 12 hours.
[0052] In a further embodiment, the compound of the invention has a
clinical success rate of greater than about 93.2%, greater than
about 95%, greater than about 96%, greater than about 97%, or
greater than about 98% when treating a bacterial infection. For
example, a clinical success rate of about 93.7% or greater. Such
bacterial infections include, e.g., MSSA, methicillin-resistant
Staphylococcus aureus (MRSA), B-streptococci, GNR, Viridans
Streptococci, Enterococcus, gram-positive anaerobes, or
combinations thereof. In contrast, linezolid was found to have a
clinical success rate of 93.7% when treating infections of these
bacteria.
[0053] In another further embodiment, the compound of the invention
has a microbiologically evaluable clinical success rate of greater
than about 93.7%, greater than about 95%, greater than about 96%,
greater than about 97%, or about 97.4% or greater, when treating a
bacterial infection. Such bacterial infections include, e.g., MSSA,
methicillin-resistant Staphylococcus aureus (MRSA), B.
streptococci, GNR, Viridans Streptococci, Enterococcus,
gram-positive anaerobes, or combinations thereof.
[0054] In a further embodiment, the invention pertains to a method
for treating a MSSA infection comprising administering an effective
amount of an antibiotic compound, wherein said compound has a
clinical success rate of greater than 91%. In a further embodiment,
the antibiotic compound is a tetracycline compound, e.g.,
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline. In contrast to
linezolid which has a clinical success rate of 91% against MSSA (as
determined in the trials described in the Exemplification of the
Invention), 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has
a clinical success rate of 93% against MSSA.
[0055] In another further embodiment, the invention pertains to a
method for treating MRSA infection comprising administering an
effective amount of an antibiotic compound, wherein said compound
has a clinical success rate of greater than 93%. In a further
embodiment, the antibiotic compound is a tetracycline compound,
e.g., 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline. In
contrast to linezolid which has a clinical success rate of 93%
against MRSA (as determined in the trials described in the
Exemplification of the Invention), 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has a clinical success rate of 100%
against MRSA.
[0056] In another further embodiment, the invention pertains to a
method for treating a B. streptococci infection comprising
administering an effective amount of an antibiotic compound,
wherein said compound has a clinical success rate of greater than
0%, greater than 10%, greater than 20%, greater than 30%, greater
than 50%, greater than 70%, greater than 80%, greater than 90%,
greater than 91%, greater than 92%, greater than about 93%, greater
than about 94%, greater than about 95%, greater than about 96%,
greater than about 97%, greater than about 98%, greater than about
99%, or about 100%. In a further embodiment, the antibiotic
compound is a tetracycline compound, e.g., 9[(2,2-dimethyl-propyl
amino)-methyl]-minocycline. In contrast to linezolid which has a
clinical success rate of 0% against B. streptococci (as determined
in the trials described in the Exemplification of the Invention),
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline has a clinical
success rate of 100% against B. streptococci.
[0057] In yet another further embodiment, the invention also
pertains to a method of treating a subject for an infection. The
method includes administering to the subject an effective amount of
9-[(2,2-dimethyl-propyl amino)-methyl]minocycline or salt thereof.
Advantageously, the 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has clinical success rate of about 93.7%
or greater for treating infections. Examples of infections which
can be treated using the methods of the invention include, but are
not limited to, MSSA, MRSA, B-streptococci, GNR, Viridans
Streptococci, Enterococcus, gram-positive anaerobes, or
combinations thereof.
[0058] In a further embodiment, the salt is a tosylate salt or a
free base when administered orally, or a hydrochloride salt when
administered intravenously.
[0059] The invention also pertains, at least in part, to a method
of treating a subject for an infection (e.g., a bacterial
infection), by orally administering to said subject about 200 mg of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, tosylate salt,
such that the subject is treated for the infection.
[0060] The invention also pertains, at least in part, to a method
of treating a subject for an infection (e.g., a bacterial
infection), by intravenously administering to the subject about 100
mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline,
hydrochloride salt, such that the subject is treated for the
infection.
[0061] In another embodiment, the invention also pertains to a
method of treating a subject for an infection (e.g., a bacterial
infection), by orally administering to the subject about 200 mg of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline, free base, such
that the subject is treated for the infection.
[0062] In one example, a subject is treated intravenously followed
by an oral step down. In another embodiment, the present invention
provides a method of treating a subject for an infection,
comprising administering to said subject an effective amount of
compound 1 or a salt thereof wherein said subject is initially
treated about 1 week or about 2 weeks or about 3 weeks
intravenously followed by about 1 week or about 2 weeks or about 3
weeks of oral treatment, such that said subject is treated.
[0063] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of compound 1 or
a salt thereof wherein said subject initially treated intravenously
has elevated compound 1 blood levels followed by reduced compound 1
blood levels with oral treatment, such that said subject is
treated.
[0064] In another embodiment, the present invention provides a
method of treating a subject for an infection, comprising
administering to said subject an effective amount of compound 1 or
a salt thereof for more than 28 days, up to and including about 28
days, up to and including about 21 days, up to and including about
14 days, up to and including about 10 days, up to and including
about 9 days, up to and including about 8 days, or up to and
including about 7 days, such that said subject is treated.
Pharmaceutical Compositions of the Invention
[0065] The invention also pertains to pharmaceutical compositions
comprising a therapeutically effective amount of a tetracycline
compound (e.g., a 9-aminomethyl tetracycline compound, e.g.,
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline) or a salt
thereof and, optionally, a pharmaceutically acceptable carrier.
[0066] In a further embodiment, the invention pertains to a
pharmaceutical composition comprising from about 100 to about 300
mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
there of and a pharmaceutically acceptable carrier. In a further
embodiment, the pharmaceutically acceptable carrier is acceptable
for oral administration. In another further embodiment, the
tetracycline compound is a free base or a tosylate salt.
[0067] In yet another further embodiment, the composition comprises
from about 110 to about 290 mg, from about 120 to about 280 mg,
from about 130 to about 270 mg, from about 140 to about 260 mg,
from about 150 to about 250 mg, from about 160 to about 240 mg,
from about 170 mg to about 230 mg, from about 180 mg to about 220
mg, from about 190 mg to about 210 mg, or about 200 mg of
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.
[0068] In another embodiment, the invention also pertains to a
pharmaceutical composition comprising from about 50 to about 150 mg
of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt
thereof (e.g., a hydrochloride salt) and a pharmaceutically
acceptable carrier suitable for intravenous administration.
[0069] In yet another further embodiment, the composition comprises
from about 50 to about 150 mg, from about 60 to about 140 mg, from
about 70 mg to about 130 mg, from about 80 mg to about 120 mg, from
about 90 mg to about 110 mg, or about 100 mg of
9[(2,2-dimethyl-propyl amino)-methyl]-minocycline.
[0070] The language "pharmaceutically acceptable carrier" includes
substances capable of being coadministered with the tetracycline
compound of the invention, e.g., 9-[(2,2-dimethyl-propyl
amino)-methyl]minocycline, and which allow the tetracycline
compound to perform its intended function, e.g., treat or prevent a
bacterial infection. Suitable pharmaceutically acceptable carriers
include but are not limited to water, salt solutions, alcohol,
vegetable oils, polyethylene glycols, gelatin, lactose, amylose,
magnesium stearate, talc, silicic acid, viscous paraffin, perfume
oil, fatty acid monoglycerides and diglycerides, petroethral fatty
acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
The pharmaceutical preparations can be sterilized and if desired
mixed with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds of the invention.
[0071] The tetracycline compounds of the invention that are basic
in nature are capable of forming a wide variety of salts with
various inorganic and organic acids. The acids that may be used to
prepare pharmaceutically acceptable acid addition salts of the
minocycline compounds of the invention that are basic in nature are
those that form nontoxic acid addition salts, i.e., salts
containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulthnate,
p-toluenesulfonate and palmoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., a mammal, it is often desirable in practice to
initially isolate a minocycline compound of the invention from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter flee base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. Preferably,
the tetracycline compound of the invention is administered as a
tosylate (e.g., p-toluenesulfonate) salt or as a freebase orally or
as a hydrochloride salt intravenously.
[0072] The tetracycline compounds of the invention and
pharmaceutically acceptable salts thereof can be administered via
either the oral, parenteral or topical routes. In general, these
compounds are most desirably administered in effective dosages,
depending upon the weight and condition of the subject being
treated and the particular route of administration chosen.
Variations may occur depending upon the species of the subject
being treated and its individual response to said medicament, as
well as on the type of pharmaceutical formulation chosen and the
time period and interval at which such administration is carried
out.
[0073] The pharmaceutical compositions of the invention may be
administered alone or in combination with other known compositions
for treating tetracycline responsive states in a subject, e.g., a
mammal. Mammals include pets (e.g., cats, dogs, ferrets, etc.),
farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals
(rats, mice, monkeys, etc.), and primates (chimpanzees, humans,
gorillas). The language "in combination with" a known composition
is intended to include simultaneous administration of the
composition of the invention and the known composition,
administration of the composition of the invention first, followed
by the known composition and administration of the known
composition first, followed by the composition of the invention.
Any of the therapeutically composition known in the art for
treating tetracycline responsive states can be used in the methods
of the invention.
[0074] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
diluents by any of the routes previously mentioned, and the
administration may be carried out in single or multiple doses. For
example, the novel therapeutic agents of this invention can be
administered advantageously in a wide variety of different dosage
forms, i.e., they may be combined with various pharmaceutically
acceptable inert carriers in the form of tablets, capsules,
lozenges, troches, hard candies, powders, sprays, creams, salves,
suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like.
Such carriers include solid diluents or fillers, sterile aqueous
media and various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective tetracycline
compounds of this invention are present in such dosage forms at
concentration levels ranging from about 5.0% to about 70% by
weight.
[0075] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols.
[0076] When aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient may be combined with various
sweetening or flavoring agents, coloring matter or dyes, and, if so
desired, emulsifying and/or suspending agents as well, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various like combinations thereof.
[0077] For parenteral administration (including intraperitoneal,
subcutaneous, intravenous, intradermal or intramuscular infection),
solutions of a therapeutic compound of the present invention in
either sesame or peanut oil or in aqueous propylene glycol may be
employed. The aqueous solutions should be suitably buffered
(preferably pH greater than 8) if necessary and the liquid diluent
first rendered isotonic.
[0078] These aqueous solutions are suitable for intravenous
injection purposes. The oily solutions are suitable for
intraarticular, intramuscular and subcutaneous injection purposes.
The preparation of all these solutions under sterile conditions is
readily accomplished by standard pharmaceutical techniques well
known to those skilled in the art. For parenteral application,
examples of suitable preparations include solutions, preferably
oily or aqueous solutions as well as suspensions, emulsions, or
implants, including suppositories. Therapeutic compounds may be
formulated in sterile form in multiple or single dose formats such
as being dispersed in a fluid carrier such as sterile physiological
saline or 5% saline dextrose solutions commonly used with
injectables.
[0079] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
[0080] In addition to treatment of human subjects, the therapeutic
methods of the invention also will have significant veterinary
applications, e.g., for treatment of livestock such as cattle,
sheep, goats, cows, swine and the like; poultry such as chickens,
ducks, geese, turkeys and the like; horses; and pets such as dogs
and cats. Also, the compounds of the invention may be used to treat
non-animal subjects, such as plants.
Exemplification of the Invention
EXAMPLE 1
Use of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline to treat
infections.
[0081] A randomized (1:1), controlled, evaluator-blinded Phase 2
study comparing 94(2,2-dimethyl-propyl amino)-methyl-minocycline
(compound 1) and linezolid (Zyvox.TM.) for the treatment of
complicated skin and skin structure infections (CSSSI) was
conducted. Patients with CSSSI who required initial intravenous
(IV) therapy and met inclusion and exclusion criteria were enrolled
at 11 centers in the US and were randomized to receive either
compound 1 (100 mg Q24 h IV with 200 mg Q24 h oral step-down) or
linezolid (600 mg Q12 h IV with 600 mg Q12 h oral step-down).
[0082] Study Evaluations
[0083] All subjects had four structured evaluations: at Enrollment
(Baseline); at End of IV Treatment; at End of Treatment; and at 10
to 17 days after last dose of treatment (test of cure (TOC)
evaluation). In addition, the blinded investigator saw each subject
daily while they were on IV therapy and at least every 3 days while
receiving oral treatment to determine whether to continue current
treatment, switch from IV to oral therapy, or discontinue
treatment.
[0084] At each of the four structured evaluations, the blinded
evaluator assessed the subject, with particular attention to
scoring the findings at the primary site of infection and obtaining
cultures. Clinical and microbiologic outcomes were determined using
these assessments, Primary evaluation criteria was safety and
tolerability compared with linezolid. Secondary evaluation criteria
was efficacy of compound 1 compared to linezolid, as well as
pharmacokinetics of compound 1.
[0085] Subjects were randomized on a 1:1 basis to receive either
compound 1 or linezolid. Random assignment of subjects avoids bias
and helps ensure that both known and unknown risk factors are
distributed evenly between treatment groups.
[0086] At each scheduled evaluation, the blinded evaluator examined
the primary site of infection; for patients with multiple
non-contiguous areas of infection, the blinded evaluator identified
the most severely affected portion at Enrollment and designated
that as the primary site of infection. The following information
was recorded for each patient: maximal linear dimension of area of
continuous involvement of infection; maximal linear dimension of
ulceration, if present; semi-qualitative (scale of 0 to 3; none,
mild, marked, severe) description of infection for the following
features: erythema, edema/induration, fluctuance, necrotic tissue,
purulence (including drainage), and tenderness/pain. In addition,
at the Enrollment Evaluation, the following were also recorded the
anatomical location of the primary site of infection; and the
clinical diagnosis of the type of the infection.
[0087] In addition, the patients in the study were monitored for
adverse events (AE). An adverse event is any untoward medical
occurrence temporally associated with the use of a medical product
in a subject, whether or not the event is considered causally
related to the medical product. An AE can be a new occurrence or an
existing process that increases significantly in intensity or
frequency.
[0088] Patient Inclusion/Exclusion Criteria
[0089] Patients were between 18 and 80 years of age. Patients were
on effective birth-control, or had no potential for childbearing.
Patients had a qualifying infection (see below). Patients with any
of the following conditions were not allowed in the trial: pregnant
or nursing; previously treated under this protocol; non-qualifying
skin/skin structure infection; allergy to study antibiotics;
received investigational drug within one month; history of chronic
liver cirrhosis; alanine aminotransferase (ALT) exceeding 2.times.
upper limit of normal (ULN) during week prior to enrollment; total
bilirubin exceeding ULN during week prior to enrollment; total body
weight <40 kg or >150 kg; known to be HIV positive and meets
CDC criteria for AIDS; life expectancy of less than 3 months;
required hemodialysis or peritoneal dialysis; creatine clearance
<30 mL/min; absolute neutrophil count <500/microliter;
hypotension (supine systolic BP <90 mmHg) or perfusion
abnormalities; required pressors to maintain blood pressure and/or
adequate tissue perfusion; received potentially effective systemic
antibiotic within 48 hrs; had an infecting pathogen know to be
intermediate or resistant to study antibiotics; had confirmed or
suspected non-infectious skin disorder that may potentially
interfere with evaluations; or any concomitant condition that would
interfere with evaluation or completion of the study.
[0090] Qualifying Infections
[0091] Examples of skin and soft tissue infections which were
qualified to have been treated in the study were: Infections
associated with trauma (e.g., traumatic injury (e.g., crush,
puncture, laceration, gunshot)); surgical incisions; animal or
human bites, providing the bite caused tissue damage; infections
associated with removable foreign body (e.g., suppurative phlebitis
associated with intravenous catheter sites, infected pacemaker
pocket, etc.), and burns, second-degree involving <5% body
surface), major abscesses (including carbuncles) which involve the
subcutaneous or deeper tissues and require incision and drainage
(or drained spontaneously), infected acute lower extremity ulcers
with co-morbidity, wherein the ulcer is acute i.e., has been
persistently present for less than three months, and is
accompagnied by at least one or the following diabetes mellitus
requiring an oral hypoglycemic agent or insulin, arterial vascular
insufficiency, or venous vascular insufficiency, or cellulitis with
co-morbidity such as diabetes mellitus requiring an oral
hypoglycemic agent or insulin, arterial vascular insufficiency;
venous vascular insufficiency, or immunosuppressive therapy during
the past 3 months.
[0092] Drug Administration
[0093] Both the investigational drug, compound 1, and the
comparator drug, Zyvox.TM. were administered intravenously and
orally. Patients randomized to linezolid may have received
aztreonam IV for suspected or documented gram-negative infection.
Subjects were initially treated with study drug IV and then
switched to oral therapy. The expected duration of IV treatment was
up to 7 days; the expected total duration of treatment (IV and
oral) was up to 14 days.
[0094] For IV administration, the HCl salt of compound 1 for
injection was given as 100 mg in 100 ml sterile saline infused over
30 minutes q24 h. For oral administration, compound 1 100 mg
capsules were taken fasting as 2 capsules with 8 oz. water q24 h.
No food was to be taken for 30 to 60 minutes after dosing and no
dairy products for 4 hours.
[0095] Linezolid (Zyvox.TM.) 600 mg tablets and pre-mixed 600 mg IV
infusion solution (300 ml volume) were obtained from commercial
sources. Linezolid 600 mg IV was administered as a 30 minute
infusion.
[0096] Patients randomized to linezolid may have received aztreonam
2 g IV q 12 h for suspected or documented gram-negative infection.
Aztreonam was obtained from commercial sources as a premixed
infusion solution (2 g in 50 ml) and administered over 30 minutes.
No other adjunct topical or systemic antibiotics were
permitted.
[0097] Efficacy Analysis
[0098] Efficacy analyses were performed on several populations of
subjects. Subjects were analyzed for efficacy according to
randomization, regardless of treatment administered.
[0099] The Intent-to-Treat (ITT) population includes all enrolled
subjects who received at least one dose of study medication.
[0100] The modified intent-to-Treat (mITT) population comprises all
subjects in the ITT population who have an Infecting Pathogen
isolated at prior to administration of the study compound.
[0101] The Clinically Evaluable (CE) population comprises all
subjects in the ITT population who meet specific criteria such that
the clinical outcome of their infection could be inferred to
reflect the effect of the study drug. The criteria include: have a
qualifying skin and skin structure infection; receive the correct
study drug (i.e., as randomized) for at least five calendar days,
have the necessary clinical evaluations performed, and did not
receive potentially confounding non-study antibiotics.
[0102] The Microbiologically Evaluable (ME) population includes all
subjects in the CE population who had an infecting pathogen at
baseline.
[0103] Subjects were considered to be an evaluable clinical failure
if they meet any one of the following criteria: the blinded
evaluator discontinued study drug and indicated that the infection
had responded inadequately such that alternative antibiotic(s) were
needed; the blinded evaluator discontinued study drug because of an
adverse event that was assessed as probably or possibly
drug-related; the primary site of infection was surgically removed;
or the subject had no evaluation after the end of IV treatment.
[0104] Subjects were considered to be an evaluable clinical success
if they meet all of the following: did not meet any criteria for
evaluable clinical failure; did not receive potentially effective
non-study antibiotics for any other reason; and at the test of cure
evaluation the blinded evaluator indicates that the infection had
sufficiently resolved such that antibiotics were not needed.
[0105] Pathogen Classification
[0106] An infecting pathogen was defined as an isolate derived from
the last positive culture taken from the site of infection under
study prior to and including day 1.
[0107] A persisting pathogen at the site of infection under study
was defined as an isolate that was the same genus and species as an
infecting pathogen; and was cultured at the Test-of-Cure evaluation
from the site of infection under study.
[0108] A superinfecting pathogen at the site of infection under
study is defined as a pathogen meeting all of the following
criteria: represented a genus and species not isolated during the
Enrollment evaluation, was cultured at any time from the day 3 of
treatment to the test of cure evaluation, inclusive; was cultured
from a patient who had at least one infecting pathogen; and was
cultured from a patient who represents a "clinical failure."
[0109] A superinfecting pathogen at a site other than the infection
under study is defined as a pathogen fleeting all of the following
criteria: represented a genus and species not isolated during the
baseline evaluation; was cultured at any time from day 3 of
treatment to the test of cure evaluation, inclusive; and was
cultured from a patient who has an AE of infection at or related to
the site from which the organism is cultured.
[0110] Microbiological Outcomes
[0111] Microbiological response to treatment was determined for
each infecting pathogen using the following classification:
documented eradication, presumed eradication, documented.
persistence, presumed persistence, or unknown.
[0112] Microbiological response to treatment was determined for
each subject using the following classification:
[0113] Microbiologic Success--all infecting pathogens isolated at
baseline were eradicated or presumed eradicated at the test-of-cure
evaluation and no superinfecting pathogen was isolated from the
site of infection under study.
[0114] Microbiological Failure--persistence or presumed persistence
of one or more infecting pathogens or isolation of a superinfecting
pathogen from the site of infection under study.
[0115] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures, embodiments, claims, and
examples described herein. Such equivalents are considered to be
within the scope of this invention and covered by the claims
appended hereto. The contents of all references, issued patents,
and published patent applications cited throughout this application
are hereby incorporated by reference.
[0116] Results
[0117] Enrollment: 234 patients over 11 sites. No discontinuations
due to elevated liver function tests (LFT)s. No serious adverse
events (SAE)s. Interim data and safety monitoring board
(DSMB)_review: no safety issues, blind not broken.
TABLE-US-00001 TABLE 1 Subpopulations. Subpopulations Compound 1
Linezolid All randomized 118 116 Randomized, treated 111 108
Intent-to-treat 111 (100%) 108 (100%) Modified ITT 82 (73.9%) 78
(72.2%) Clinically evaluable 100 (90.1%) 88 (81.5%)
Microbiologically Evaluable 75 (67.6%) 63 (58.3%) Safety Population
111 (100%) 108 (100%)
TABLE-US-00002 TABLE 2 Demographics. Demographic or Compound 1
Linezolid Parameter Measure (n = 111) (n = 108) Sex Female 45
(40.5%) 51 (47.2) Male 66 (59.5%) 57 (52.8%) Ethnicity Hispanic 38
(34.2%) 53 (49.1%) Non Hispanic 73 (65.8%) 55 (50.9%) Race
Caucasian 97 (87.4%) 99 (91.7%) Black 8 (7.2%) 6 (5.6%) Asian 4
(3.6%) 1 (0.9%) American Native 0 1 (0.9%) Other 2 (1.8%) 1 (0.9%)
Age (years) 18-44 51 (45.9%) 50 (46.3%) 45-64 50 (45.0%) 48 (44.4%)
>64 10 (9.0%) 10 (9.3%) Age Mean 44.9 45.8 SD 14.09 13.32 Min 19
19 Median 46 46 Max 81 76 Weight Mean 84.2 85.0 SD 21.95 20.22 Min
45 51 Median 80 80 Max 144 152 BMI (kg/m2) Mean 28.8 29.3 SD 6.89
6.80 Min 17 19 Median 28 28 Max 48 52
TABLE-US-00003 TABLE 3 Qualifying infections used in the study.
Category Compound 1 (n = 111) Linezolid (n = 108) Injury 21 17
Major Abscess 73 72 Lower extremity ulcer.sup.1 9 9 Cellulitis with
co-morbidity.sup.1 8 10 .sup.114/18 LE ulcers and 11/18 cellulitis
were in diabetics; most of the rest had venous insufficiency as
co-morbidity.
TABLE-US-00004 TABLE 4 Maximal dimensions of infections (ITT
population). Type of Infection Compound 1 (n = 111).sup.a Linezolid
(n = 108).sup.a Major Abscess.sup.b 10 (6-16) 7.8 (4.1-13) Infected
injury 10.5 (4-31) 7 (3-19.5) Cellulitis with co-morbidity 20
(12-31) 18 (3.3-33) .sup.aMedian (IQR) in centimeters
.sup.bIncludes surrounding cellulitis IQR = interquartile range
TABLE-US-00005 TABLE 5 Co-morbid conditions (ITT population).
Condition.sup.a Compound 1 (n = 111) Linezolid (n = 108) Hepatitis
C seropositive 46 (43%) 40 (37%) Substance abuse 41 (37%) 36 (33%)
Diabetes Mellitus 27 (24%) 20 (19%) Cardiovascular Disease.sup.b 35
(32%) 38 (35%) .sup.aHepatitis C seropositive confirmed by
serology; other conditions based on patient medical histories
.sup.bIncludes coronary artery or peripheral vascular disease
TABLE-US-00006 TABLE 6 Clinical findings. Compound 1 Linezolid
Characteristic Measure (n = 111) (n = 108) Erythema None 1 (0.9%) 2
(1.9%) Mild 10 (9.0%) 21 (19.4%) Moderate 65 (58.6%) 63 (58.3%)
Severe 35 (31.5%) 20 (18.5%) Edema/Induration None 2 (1.8%) 1
(0.9%) Mild 14 (12.6%) 23 (21.3%) Moderate 63 (56.8%) 57 (52.8%)
Severe 32 (28.8%) 25 (23.1%) Purulence None 32 (28.8%) 31 (28.7%)
Mild 43 (38.7%) 42 (38.9%) Moderate 28 (25.2%) 28 (25.9%) Severe 8
(7.2%) 5 (4.6%) Tenderness/Pain None 1 (0.9%) 0 Mild 8 (7.2%) 10
(9.3%) Moderate 41 (36.9%) 51 (47.2%) Severe 61 (55.0%) 45 (41.7%)
Fluctuance None 53 (47.7%) 53 (49.1%) Mild 28 (25.2%) 27 (25.0%)
Moderate 21 (18.9%) 18 (16.7%) Severe 9 (8.1%) 8 (7.4%) Necrotic
Tissue None 88 (79.3%) 87 (80.6%) Mild 12 (10.8%) 14 (13.0%)
Moderate 9 (8.1%) 5 (4.6%) Severe 2 (1.8%) 0
TABLE-US-00007 TABLE 7 Subject disposition. Compound 1 Linezolid
Subject subpopulation (n = 118) (n = 116) Intent-to-treat 111 108
Completed Therapy 106 (95.5%) 100 (92.6%) Premature Discontinuation
5 (4.5%) 8 (7.4%) Adverse Event 1 (0.9%) 2 (1.9%) Treatment Failure
1 (0.9%) 0 Lost to follow-up 3 (2.7%) 6 (5.5%)
TABLE-US-00008 TABLE 8 Duration of Treatment (ITT population).
Compound 1 Linezolid Route (n = 111).sup.1 (n = 108).sup.1 IV 4
(2-6) 3 (2-6) Total (IV plus oral) 10 (8-12) 10 (7-13) .sup.1Median
(IQR)
TABLE-US-00009 TABLE 9 Efficacy - ITT. Compound 1 Linezolid
Clinical Outcome (n = 111) (n = 108) Clinical Success 98 (88.3%) 82
(75.9%) Clinical Failure 13 (11.7%) 26 (24.1%) Failure 2 (1.8%) 6
(5.6%) Nonevaluable 11 (9.9%) 20 (18.5%)
TABLE-US-00010 TABLE 10 Efficacy - mITT. Compound 1 Linezolid
Clinical Outcome (n = 84) (n = 78) Clinical Success 75 (89.3%) 59
(75.6%) Clinical Failure 9 (10.7%) 19 (24.4%) Failure 2 (2.4%) 4
(5.1%) Nonevaluable 7 (8.3%) 15 (19.2%)
TABLE-US-00011 TABLE 11 Efficacy - clinically evaluable. Compound 1
Linezolid Clinical Outcome (n = 100) (n = 88) Clinical Success 98
(98.0%) 82 (93.2%) Clinical Failure 2 (2.0%) 6 (6.8%)
TABLE-US-00012 TABLE 12 Efficacy - microbiologically evaluable.
Contpound 1 Linezolid Clinical Outcome (n = 77) (n = 63) Clinical
Success 75 (97.4%) 59 (93.7%) Clinical Failure 2 (2.6%) 4
(6.3%)
TABLE-US-00013 TABLE 13 Microbiology - mITT population. Primary
Secondary Total Share of Bacteria Pathogen Pathogen Pathogens
Primary (%) MRSA 87 0 82 51 MSSA 59 1 60 37 Streptococci 8 13 21 5
(beta and other) Enterococci 5 2 7 3 Gram-negative 5 16 21 3 rods
Anaerobes 1 2 3 1 Total 160 34 194 100
TABLE-US-00014 TABLE 14 Distribution of baseline pathogen by
treatment (mITT population). Compound 1 Linezolid Bacteria (n = 84)
(n = 78) MRSA 44 (52.4%) 38 (48.7%) MSSA 31 (36.9%) 29 (37.2%)
B-hemolytie Streptococci 7 (8.3%) 2 (2.6%) Streptococci, other 4
(4.8%) 8 (10.3%) Enterococci 2 (2.4%) 5 (6.4%) Gram-positive, other
0 1 (1.3%) Gram-negative, other 13 (15.5%) 8 (10.3%) Anaerobes 0 3
(3.8%)
TABLE-US-00015 TABLE 15 Microbiology - clinical outcome (ME).
Compound 1 Linezolid Success Failure Success Failure Organism (n =
73) (n = 2) (n = 59) (n = 4) MSSA 27 2 21 2 MRSA 42 0 30 2 B-Strep
6 0 0 2 GNR 7 2 7 0 Viridans Strep 3 1 6 0 Enterococcus 1 1 3 0 G+
anaerobes 0 0 3 0 Mixed GPC 16 2 9 2 Mixed 12 2 10 0 GPC/GNR
TABLE-US-00016 TABLE 16 Microbiology outcome (ME). Compound 1
Linezolid Outcome.sup.1 (n = 75) (n = 63) Presumed Eradication 71
(94.7%) 58 (92.1%) Presumed Persistence 2 (2.7%) 4 (6.3%)
Persistence.sup.2 2 (2.7%) 1 (1.6%) .sup.1Presumed Eradication:
Clinical success, no pathogen at TOC Presumed Persistence: Clinical
failure, no pathogen at TOC Persistence: Clinical success,
enrollment pathogen isolated at TOC .sup.2MRSA persisted in all
three cases
TABLE-US-00017 TABLE 17 Safety and adverse events (AE) by patient.
Compound 1 Linezolid (n = 111) (n = 108) Drug Drug Organ System
Total Related.sup.a Total Related.sup.a Cardiac 4 0 4 3 Ear 0 0 2 1
Eye 2 0 1 1 GI 21 12 21 13.sup.b General 11 5 8 4 Heme 1 0 2 0
Infection 6 0 9 1 Injury 1 0 1 1 Investigations 7 3 11 8 Metabolism
9 1 7 2 Musculoskeletal 8 0 2 0 Neurologic 12 4 15 7 Psych 5 2 6 3
Renal 2 1 2 0 Reproductive 2 0 1 0 Respiratory 3 0 2 0 Skin 12 7 10
6.sup.c Vascular 3 0 1 1 None 65 (58.6%) -- 53 (49.1%) -- Total
Patients with 56 (41.4%) -- 55 (50.9%) -- 1 or more AE
.sup.aAssessed as probably or possibly drug-related by blinded
evaluator .sup.bIncludes 1 patient discontinued due to heartburn
.sup.cIncludes 1 patient discontinued due to rash
TABLE-US-00018 TABLE 18 Safety: ALT (max on treatment). ALT Level
Compound 1 Linezolid ALT within normal Within normal limits 84
(86.6%) 75 (78.9%) limits at enrollment 1x-2x 12 (12.4%) 14 (14.7%)
2x-3x 0 5 (5.3%) >3x 1 (1.0%) 1 (1.1%) ALT abnormal at Within
normal limits 1 (7.1%) 2 (16.7%) enrollment.sup.1 NS 11 (78.6%) 8
(66.7%) Increase 2 (14.3%) 2 (16.7%) .sup.1NS: >ULN and <2x
baseline. Increase: >2x ULN and 2x baseline NS = Not
significant
TABLE-US-00019 TABLE 19 Safety: ALT (EOT). ALT Level Compound 1
Linezolid ALT within normal Within normal limits 86 (93.5%) 79
(87.8%) limits at enrollment 1x-2x 6 (6.5%) 9 (10.0%) 2x-3x 0 1
(1.1%) >3x 0 1 (1.1%) ALT abnormal at Within normal limits 2
(15.4%) 4 (36.4%) enrollment.sup.1 NS 11 (84.6%) 7 (63.6%) Increase
0 0 .sup.1NS: >ULN and <2x baseline. Increase: >2x ULN and
2x baseline EOT = end of treatment
TABLE-US-00020 TABLE 20 Safety: ALT (TOC). ALT Level Compound 1
Linezolid ALT within normal Within normal limits 85 (94.4%) 75
(94.9%) limits at enrollment lx-2x 5 (5.6%) 4 (5.1%) 2x-3x 0 0
>3x 0 0 ALT abnormal at Within normal limits 3 (23.1%) 5 (41.7%)
enrollment.sup.1 NS 9 (69.2%) 6 (50,0%) Increase 1 (7.7%) 1 (8.3%)
.sup.1NS: >ULN and <2x baseline. Increase: >2x ULN and 2x
baseline
[0118] Total bilirubin was slightly elevated in 2 patients in each
group.
[0119] Summary of Results.
[0120] The ITT populations (111 received compound 1, 108 received
linezolid) were comparable in terms of enrollment criteria, disease
severity, co-morbidities, and demographics. Mean duration of total
treatment and of IV and oral therapy did not differ between
compound 1(9.9, 4.3, 5.6 days respectively) and linezolid (9.7,
4.3, 5.4 days, respectively). The efficacy (clinical success) of
compound 1 was 88.3% for the ITT population compared to 75.9% for
linezolid. In the clinically evaluable population, the clinical
success rates were 98% and 93.2% for compound 1 and linezolid,
respectively. Bacterial pathogens were cultured at baseline from
.about.74% of each treatment group; over 50% had MRSA. Among the
microbiologically evaluable patients, there were 2 failures in the
compound 1 group, none was associated with MRSA and 4 failures in
the linezolid group, 2 of which were associated with MRSA. Compound
1 was well tolerated. There were no discontinuations due to adverse
events (AEs) for compound 1 (vs 2 for linezolid) and no
drug-related serious AE in either group. In both treatment groups
the most common drug-related AEs were gastrointestinal (12 PTK vs
13 linezolid). GI events associated with compound 1 were observed
almost entirely during oral therapy, were mild, and did not result
in discontinuation of therapy. There were no observed differences
between the treatment groups in hematology or serum chemistry
parameters.
* * * * *