U.S. patent application number 14/509305 was filed with the patent office on 2015-09-24 for treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof.
The applicant listed for this patent is Forum Pharmaceuticals, Inc.. Invention is credited to Richard Chesworth, Gerhard Koenig, Gideon Shapiro.
Application Number | 20150265583 14/509305 |
Document ID | / |
Family ID | 41786120 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265583 |
Kind Code |
A1 |
Chesworth; Richard ; et
al. |
September 24, 2015 |
Treatment of Cognitive Disorders with
(R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide
and Pharmaceutically Acceptable Salts Thereof
Abstract
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
has been found to have procognitive effects in humans at
unexpectedly low doses. Thus,
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
and pharmaceutically acceptable salts thereof can be used at
unexpectedly low doses to improve cognition.
Inventors: |
Chesworth; Richard;
(Concord, MA) ; Shapiro; Gideon; (Gainesville,
FL) ; Koenig; Gerhard; (Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forum Pharmaceuticals, Inc. |
Watertown |
MA |
US |
|
|
Family ID: |
41786120 |
Appl. No.: |
14/509305 |
Filed: |
October 8, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14139178 |
Dec 23, 2013 |
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14509305 |
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13129782 |
Aug 9, 2011 |
8642638 |
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PCT/US2009/065173 |
Nov 19, 2009 |
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14139178 |
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61116106 |
Nov 19, 2008 |
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Current U.S.
Class: |
514/305 |
Current CPC
Class: |
A61K 31/439 20130101;
A61P 25/00 20180101 |
International
Class: |
A61K 31/439 20060101
A61K031/439 |
Claims
1. A method for improving cognition comprising administering to a
subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
2. The method of claim 1 wherein the daily dose is 1 mg or
less.
3. The method of claim 2 wherein the daily dose is 0.3 mg or
less.
4. A method for treating a cognitive disorder comprising
administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yObenzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
5. The method of claim 4 wherein the daily dose is 1 mg or
less.
6. The method of claim 5 wherein the daily dose is 0.3 mg or
less.
7. A method for treating a disorder selected from schizophrenia,
schizophreniform disorder, schizoaffective disorder, and delusional
disorder comprising administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
8. The method of claim 7 wherein the daily dose is 1 mg or
less.
9. The method of claim 8 wherein the daily dose is 0.3 mg or
less
10. A method for improving one or more of: learning, delayed
memory, working memory, visual learning, speed of processing,
vigilance, verbal learning, visual motor function, social
cognition, long term memory or executive function comprising
administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
11. The method of claim 10 wherein the daily dose is 1 mg or
less.
12. The method of claim 11 wherein the daily dose is 0.3 mg or
less.
13. A method for improving executive function comprising
administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yObenzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
14. The method of claim 13 wherein the daily dose is 1 mg or
less.
15. The method of claim 14 wherein the daily dose is 0.3 mg or
less.
16. A method for treating one or more symptoms of Alzheimer's
disease comprising administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
17. The method of claim 16 wherein the daily dose is 1 mg or
less.
18. The method of claim 17 wherein the daily dose is 0.3 mg or
less.
19. A method for improving one or more of: visual motor skills,
learning, executive function, and delayed memory in a subject, the
method comprising administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
20. The method of claim 19 wherein the daily dose is 1 mg or
less.
21. The method of claim 20 wherein the daily dose is 0.3 mg or
less.
22. A method for improving one or more of: attention, learning,
delayed memory, working memory, visual learning, speed of
processing, vigilance, verbal learning, visual motor function,
social cognition, long term memory or executive function comprising
administering to a subject
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof at a daily dose of less
than 3 mg.
23. The method of claim 10 wherein the daily dose is 1 mg or
less.
24. The method of claim 11 wherein the daily dose is 0.3 mg or
less.
25. The method of any of the forgoing claims wherein the subject is
suffering from anxiety or agitation.
26. A unit dose pharmaceutical composition comprising 0.3 to 3.0 mg
of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
27. A unit dose pharmaceutical composition comprising 0.3 to 1.5 mg
of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
28. A unit dose pharmaceutical composition comprising 1 mg of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/139,178, filed Dec. 23, 2013, which is a continuation of
U.S. application Ser. No. 13/129,782, filed Aug. 9, 2011, now U.S.
Pat. No. 8,642,638 granted Feb. 4, 2014, which is further a
National Phase application of International Application No.
PCT/US2009/065173, filed Nov. 19, 2009, which designated the United
States and published in English, and which further claims the
benefit of priority from U.S. Provisional Application No.
61/116,106, filed Nov. 19, 2008. The foregoing related
applications, in their entirety, are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Nicotinic acetylcholine receptors (nAChR) form a family of
ion channels activated by acetylcholine. Functional receptors
contain five subunits and there are numerous receptor subtypes.
Studies have shown that central nicotinic acetylcholine receptors
are involved in learning and memory. Nicotinic acetylcholine
receptors of the alpha7 subtype are prevalent in the hippocampus
and cerebral cortex.
[0003] WO 2003/055878 describes a variety of agonists of the alpha7
nAChR said to be useful for improving cognition. WO 2003/055878
suggests that certain agonists of the alpha7 nAChR are useful for
improving perception, concentration, learning or memory, especially
after cognitive impairments like those occurring for example in
situations/diseases/syndromes such as mild cognitive impairment,
age-associated learning and memory impairments, age-associated
memory loss, Alzheimer's disease, schizophrenia and certain other
cognitive disorders. Among the compounds described are
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
and pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
[0004] It has been found that
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
can have procognitive effects in humans at unexpectedly low doses.
Thus,
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
and pharmaceutically acceptable salts thereof can be used at
unexpectedly low doses to improve cognition in individuals
suffering from impaired cognition and in healthy individuals (i.e.,
individuals that are not suffering from an apparent cognitive
deficit). For example, it can be used to improve cognition in
patients suffering from Alzheimer's disease, schizophrenia and
other disorders such as other neurodegenerative diseases (e.g.,
Huntington's disease or Parkinson's disease) and attention deficit
disorder. It can be used treat certain disorders, e.g., Alzheimer's
disease, schizophrenia (e.g., paranoid type, disorganized type,
catatonic type, and undifferentiated type), schizophreniform
disorder, schizoaffective disorder, delusional disorder, positive
symptoms of schizophrenia, negative symptoms of schizophrenia at a
daily dose of 3 mg, 2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg, 1.50
mg, 1.25 mg, 1 mg, 0.7, 0.5, 0.3 mg or even 0.1 mg. The compound
can be used to improve one or more aspects of cognition, e.g., one
or more of: executive function, memory (e.g., working memory),
social cognition, visual learning, verbal learning and speed of
processing.
[0005] Described herein are methods for treating a patient by
administering a pharmaceutical composition that comprises
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or
pharmaceutically acceptable salt thereof at a daily dose of: 3 mg,
2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg, 1.50 mg, 1.25 mg, 1 mg,
0.7 mg, 0.5 mg, 0.3 mg, or 0.1 mg. The treatment can improve one or
more facets of cognition (e.g., visual motor skill, learning,
delayed memory, attention, working memory, visual learning, speed
of processing, vigilance, verbal learning, visual motor function,
social cognition, long term memory, executive function, etc.). The
methods can be used to treat: Alzheimer's disease, schizophrenia
(e.g., paranoid type, disorganized type, catatonic type, and
undifferentiated type), schizophreniform disorder, schizoaffective
disorder, delusional disorder, positive symptoms of schizophrenia
or negative symptoms of schizophrema.
[0006] "Dose" is the amount of active pharmaceutical ingredient
(API) administered to a patient. For example, 1 mg dose means 1 mg
of API was administered to each patient each day.
[0007] "Active Pharmaceutical Ingredient" is defined as either
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride,
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide,
(R)-7-chloro-N(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride monohydrate or
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride solvate.
[0008] Where solvate represents a stoichiometric ratio of 0.1 to 10
molecules of solvent compared to
(R)-7-chloro-N(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride or
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide.
Solvent molecules include but are not limited to water, methanol,
1,4 dioxane, ethanol, isopropanol or acetone. In some cases, water
is the preferred solvate.
[0009] "The test compound" is defined as
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride.
[0010] "EC.sub.ref" is the concentration of drug which elicits
equal response in oocytes transfected with cloned human alpha7
receptor at 50 .mu.M acetylcholine. Maximum stimulation of the
cloned human alpha7 receptor occurs at a concentration of >250
.mu.M of acetylcholine.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0011] FIG. 1 depicts the results of a study on the effect of the
test compound on P50 gating ratio. Specifically, FIG. 1A depicts
the baseline-adjusted average P50 gating ratio (T/C) as a function
of group assignment [F=1.16, P=0.36]. The standard errors of each
mean are noted in the legend. The bars (left to right) represent
placebo, 0.3 mg test compound, and 1.0 mg test compound. FIG. 1B
depicts the baseline-adjusted average P50 difference (C-T) as a
function of group assignment [F=3.97, P=0.07]. The standard errors
of each mean are noted in the legend. The bars left to right
represent placebo, 0.3 mg test compound, and 1.0 mg test
compound.
[0012] FIG. 2 depicts the results of a study on the effect of the
test compound on N100 gating ratio. Specifically, FIG. 2A depicts
baseline-adjusted average N100 gating ratio (T/C) as a function of
group assignment [F=3.04, P=0.10]. The standard errors of each mean
are noted in the legend. The bars left to right represent placebo,
0.3 mg test compound, and 1.0 mg test compound. FIG. 2B depicts
baseline-adjusted average N100 amplitude difference (C-T) as a
function of group assignment [F=1.02, P=0.38]. The standard errors
of each mean are noted in the legend. The bars left to right
represent placebo, 0.3 mg test compound, and 1.0 mg test
compound.
[0013] FIG. 3 depicts the results of a study on the effect of the
test compound on MMN amplitude and P300 amplitude. Specifically,
FIG. 3A depicts MMN as a function of group assignment [F=4.96,
P=0.02]. The standard errors of each mean are noted in the legend.
The bars left to right represent placebo, 0.3 mg test compound, and
1.0 mg test compound. FIG. 3B depicts P300 amplitude (in microvolts
relative to prestimulus voltage) measured at Pz scalp in response
evoked by a rare but unattended stimulus. Group assignment effect:
F=6.88, P=0.008. The standard errors of each mean are noted in the
legend. The bars left to right represent placebo, 0.3 mg test
compound, and 1.0 mg test compound.
DETAILED DESCRIPTION OF THE INVENTION
[0014] Described below are human clinical trials demonstrating that
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
elicits positive effects on cognition at an unexpectedly low daily
dose of 1 mg or less. The positive effects are observed in both
patients suffering from schizophrenia and in normal subjects. Also
described below are studies showing that the free concentration of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide in
humans administered at daily 1 mg dose (of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride) is at least an order of magnitude lower than that
expected to be required to exert a positive effect on cognitive
function, or can improve sensory electrophysiological responses
which correlate with improved cognitive and functional performance
in schizophrenia patients. Also described below are studies
demonstrating that that
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
has an unexpectedly long half-life in humans compared to that
expected based on pre-clinical studies in animals.
[0015] Because
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
can improve cognition at an unexpectedly low free plasma
concentration, it is less likely to elicit harmful side-effects on
its own and is less likely to exhibit harmful interactions with
other drugs. Due to the unexpectedly low free plasma concentration
required and the long half-life,
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is
expected to have special drug properties. These properties include
a high margin of safety and a favorable dosing regimen (e.g., once
daily dosing), both of which are highly advantageous for treating
patients with cognitive defects as well as patients that are
required to take additional medications.
Effect on Cognition in Schizophrenia Patients
[0016] The studies described below demonstrate that
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride can improve sensory electrophysiological responses
which correlate with improved cognitive and functional performance
in schizophrenia patients. These effects were observed at a daily
dose as low as 0.3 mg.
[0017] Impairment of the ability of the central nervous system to
inhibit irrelevant sensory information has long been used as a
model for understanding the deficits of attention seen in
schizophrenic patients. Two approaches to the measurement of this
ability have commonly been employed [see (Heinrichs, 2004; Potter
et al., 2006; Turetsky et al., 2007; Umbricht and Krljes, 2005) for
reviews and meta-analyses]: (1) the sensory gating paradigm in
which the presentation of one stimulus normally suppresses the
response elicited by a stimulus which rapidly follows it while
schizophrenic patients typically exhibit less suppression (gating)
of the second response; and (2) the oddball or orienting paradigm
in which a rare or unexpected event elicits a diminished response
in schizophrenic patients because attentional resources are
inappropriately focused on less salient aspects of the
environment.
[0018] Two responses are commonly used to assess brain activity:
(1) the auditory P50 response elicited by the second member of a
pair of clicks; and (2) the mismatch negativity (MMN) or N2
response evoked by a rarely occurring pure tone of no instructed
relevance to the patient. Abnormalities in both P50 gating and the
MMN have been reported in schizophrenic patients. Described below
are studies assessing both of these responses in patients treated
with
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride salt ("the test compound"). Also presented below are
studies assessing the influence of the test compound on the N100
and P300 components of the evoked response. These components emerge
after the P50 component and are as much related to attention to,
and memory for, task relevant stimuli as to the neural processes by
which task irrelevant stimuli are filtered (Turetsky et al., 2007;
and Sandman and Patterson, 2000).
[0019] The neurobiology of P50 sensory gating is well documented in
studies of human and animal subjects. Its regulation relies heavily
on the integrity of the hippocampus and pathways that provide input
to the hippocampus (Adler et al., 1998). For example, lesions of
the cholinergic pathway originating in the medial septal nucleus
disrupt the gating response, as do antagonists of low affinity
nicotinic receptors. Cholinergic agonists, including nicotine
itself (Adler et al., 1993; Duncan et al., 2001), have been shown
to enhance P50 gating (Freedman et al., 2001; Olincy et al.,
2006).
[0020] The neurobiology of the MMN is more complex. Imaging studies
suggest that the primary and secondary auditory cortices in the
temporal lobe are important for its generation (Naatanen and Alho,
1995). The dorsolateral prefrontal cortex also contributes (Schall
et al., 2003). The neurotransmitter systems underlying the MMN are
understudied and largely unknown. Yet, as is the case for P50,
nicotinic cholinergic systems appear important (Baldeweg et al.,
2006; Dunbar et al., 2007).
[0021] The sensitivity of P300 and N100 to cholinergic compounds
has been known for many years (Dierks et al., 1994; Kaga et al.,
1992). Various cholinergic antagonists--such as
scopolamine--profoundly reduce the amplitudes of these components.
In contrast, the components are markedly improved in amplitude by
cholinesterase inhibitors (Katada et al., 2003; Werber et al.,
2001) and other compounds that enhance cholinergic activity (Easton
and Bauer, 1997).
[0022] The test described above was used to study the effect of the
test compound on cognition in patients suffering from
schizophrenia. Prior to testing, the patients were dosed with: 1 mg
of the test compound daily, 0.3 mg of the test compound daily or
were administered a placebo for 20 days. Subjects were tested as
described below.
[0023] P50 waves were elicited by clicks, 1 msec in duration,
grouped in pairs in the classic S1-S2 sequence and presented
through earpieces inserted into the auditory canals. Click
intensity was adjusted individually to 50 dB above the hearing
threshold. The offset-to-onset time from S1 to S2 was fixed at 500
msec. The offset-to-onset time between click pairs was varied from
7-11 sec. A total of 30 pairs of clicks were presented during each
of 5 or more trial blocks with a one minute rest period interposed
between each block.
[0024] EEG responses to the clicks were amplified to a gain of 10K
and filtered (bandpass=3-30 Hz, 12 db roll-off). They were
collected from 63 tin electrodes positioned by an electrode cap
(Compumedics Neuroscan, Inc.). Additional electrodes of the same
type were applied to the mid-forehead (ground) and in a vertical
orientation above and below the left eye. Interelectrode impedances
were maintained below 10 kOhms. All recordings were made with the
subject sitting upright and relaxed but awake.
[0025] The EEG and eye movement signals were sampled by an
analog-to-converter programmed to retain EEG activity from 50 msec
preceding to 325 msec following click onset. The sampling rate was
1000 Hz. The digitized signals were stored in a database for
subsequent analysis.
[0026] The 150 sweeps of S1 and S2 responses were screened and
sweeps with voltage deviations greater than 100 microvolts in the
eye movement channels were rejected. The remaining accepted sweeps
were formed into time point averages. While blinded to group
assignment, the investigator visually examined the evoked potential
waveforms at the FCz electrode site. When possible, the
investigator identified a negative trough immediately prior to the
P50, the P50 itself, and the following N100 component. Admittedly,
a distinct P50 component could not be visually identified in all
patients at all time points. In those cases, the data was coded as
missing.
[0027] P50 response amplitude was calculated as the voltage
difference between the P50 peak and the preceding negative trough.
The P50 gating ratio was then calculated after (Olincy et al.,
2006) as the amplitude of the P50 response to the second (test)
stimulus divided by the amplitude of the P50 response to the first
(conditioning) stimulus. A small gating ratio is considered normal
or optimal. The P50 amplitude difference (Fuerst et al., 2007) was
also measured. It was the amplitude of the conditioning stimulus
P50 response minus the amplitude of the test stimulus P50 response.
A large P50 amplitude difference indicates normal gating.
[0028] N100 amplitude was calculated as the peak voltage of N100
minus the average voltage during the brief, 50 msec prestimulus
period. As was the case for P50, N100 responses to the conditioning
and test stimuli were calculated as ratios as well as
differences.
[0029] The MMN and P300 components were elicited during the
so-called oddball sequence. The stimulus sequence was a series of
lower (500 Hz) and higher (1000 Hz) pitched pure tones presented at
a rate of 1 tone per 0.6 sec. The tones were 50 msec in duration,
50 dB above hearing level, and randomly interspersed. The higher
pitched tone was the oddball event. Across the series of 600 tones,
it occurred at a probability of 0.2. The other tone occurred at the
complementary probability of 0.8. Patients were instructed to
ignore the tones and instead attend to a magazine held in the
lap.
[0030] During the task, EEG and EOG activity were digitized at a
rate of 500 Hz per channel for 50 msec preceding and 500 msec
following stimulus onset. Trials contaminated by eyeblinks or eye
movements were removed. An off-line program digitally filtered
(bandpass=0.1-30 Hz, 12 db roll-off) responses to the rare and
frequent events and constructed averaged event related responses
for each electrode. At the FCz electrode, the MMN was measured by
an automated algorithm that computed the summed amplitude, relative
to the prestimulus baseline, over a 100-200 msec time window
following the onsets of the rare (oddball) and frequent tones. MMN
was then recalculated as the voltage difference between these
responses. P300 amplitude was measured at the Pz electrode site as
the peak amplitude between 250 and 500 msec following stimulus
onset.
[0031] The plan for the analysis of the EEG measures was developed
prior to breaking of the blind. It was based on the study design
involving 3 groups (n=8 high dose, n=8 moderate dose, n=4 placebo)
and 4 time points (1 predrug+3 postdrug). The plan offered several
alternative strategies based upon the completeness and quality of
the recordings. Unfortunately, in the case of the P50/N100 gating
study, it was necessary to discard several patients and
post-treatment assignment time points from the analysis because, in
those instances, a P50 waveform was not identifiable and therefore
could not be measured. This problem has been acknowledged in the
literature, but has not been discussed as openly and frequently as
a skeptical scientist would like. For the analysis of P50 and N100,
we adopted strategy 1b: "If many postdrug data points are
missing/corrupted, then the remaining postdrug data points will be
averaged together to create a single postdrug data point." The
significant number of missing or unmeasurable P50's, unfortunately,
removed another of our analysis options, wherein we hoped to focus
on the subgroup of patients who showed the poorest sensory gating
at baseline and might show the strongest improvement in gating
after treatment. Of the 12 patients who provided valid and
measurable P50 responses, 2 were in the placebo group, and 5 were
in each of the two active dose groups.
[0032] FIGS. 1A and 1B present the results of simple analyses of
covariance wherein all time points during the treatment period with
valid data were averaged together to yield a single value. This
value was then adjusted by regressing it against the baseline value
and estimating a new value as if all patients possessed the same
baseline. Then, a simple F test was performed. In support of the
assumption of no significant differences between the treatment
groups at the baseline (i.e., before treatment), we conducted
simple ANOVAs evaluating the effect of treatment on all of the
evoked potential components discussed presently. In no case did
treatment significantly affect the baseline value. FIG. 1A shows a
non-significant [F=1.16, P=0.36] reduction (i.e., normalization) of
the P50 gating ratio among patients receiving the 1.0 mg dose of
the test compound. In contrast, FIG. 1B shows the P50 amplitude
difference score--a metric with superior reliability. It likewise
shows normalization at the high dose. However, in this case, the
change approaches statistical significance [F=3.97, P=0.07].
[0033] FIGS. 2A and 2B present an identical analysis of the N100
gating ratio and amplitude difference. Here, the gating ratio
demonstrates a more reliable effect of the medication [F=3.04,
P=0.10] than does the amplitude difference [F=1.02, P=0.38]. In
FIG. 2A, normalization is suggested by a lower score. In FIG. 2B,
normalization is indicated by the opposite direction of change.
[0034] MMN and P300 amplitude reflect activation of multiple
precortical and cortical pathways sensitive to stimulus novelty,
short term memory, and attention. MMN was calculated as the voltage
difference over 100-200 msec post-stimulus onset between the
responses to the rare and frequent stimuli. A more negative MMN
suggests normal cognitive function. P300 is not entirely
independent of MMN. P300 was calculated as the peak amplitude
relative to the average voltage of the waveform during the 50 msec
prestimulus period. A more positive P300 response is indicative of
improved cognitive function. P300 is maximal in amplitude when the
eliciting stimulus is both rare and task relevant (i.e., attended).
In the present study, the rare stimulus was not task relevant. In
fact, the patient was instructed to perform no task and to ignore
the stimuli. In the present study, therefore, P300 amplitude is
very small in comparison to amplitudes recorded under active task
conditions. The present P300 component is more similar to the
small, frontally-generated P300a described by Knight and colleagues
than the large, parietally-generated P300b described in most
studies of attentional dysfunction in schizophrenia.
[0035] In the analysis of P50 and N100 the baseline value was the
covariate and all values obtained during the treatment period were
averaged together. Data loss from unidentifiable MMN and P300
components was minimal. These analyses were conducted upon data
obtained from n=4 patients treated with placebo, n=7 patients
treated with 0.3 mg of the test compound, and n=8 patients treated
with 1.0 mg of the test compound.
[0036] FIGS. 3A and 3B show the results of the analysis of MMN and
P300 amplitudes during the oddball task. Both evoked potential
components were sensitive to the test compound in the predicted
direction: MMN [F=4.96, P=0.02]; P300 [F=6.88, P=0.008]. In a
dose-related manner, the test compound increased MMN and P300
amplitudes.
[0037] Despite the small number of patients enrolled in this trial,
the analysis revealed several significant or marginally significant
results. Both the 0.3 mg and 1.0 mg doses of the test compound
evoked significantly (p<0.05) larger P300 and MMN components
than were seen under the placebo condition. The effects of the test
compound on an earlier component of the evoked response component
(i.e., the P50) were limited to the highest, 1.0 mg, dose and were
technically not significant (p=0.1). These results indicate that
both the 0.3 mg dose and 1.0 mg dose of the test compound are
anticipated to be effective in treating schizophrenia.
[0038] The relative sensitivity or insensitivity of various evoked
response components to the test compound may be related to their
size and reliability of measurement. In addition, sensitivity
differences may relate to differences across the components in
their neural generators and innervation by cholinergic afferents.
Indeed, the two components (MMN and P300) which were most sensitive
to the test compound are generated or modulated by frontal cortical
pathways that receive input from brainstem cholinergic fibers. The
P50 is, in contrast, generated subcortically.
Effect on Cognition in Normal Subjects
[0039] The impact of the test compound on cognition in normal
subjects was assessed as described below. In these studies,
subjects were treated with the test compound dissolved in cranberry
juice.
[0040] The impact of the test compound on cognition in normal
subjects was assessed in a SAD (Single Ascending Dose) study with
the Digit Symbol Substitution Test (DSST). Utilizing this test, the
test compound was shown to have pro-cognitive effects at a daily
dose as low as 1 mg. This is unexpected since acetylcholine
esterase inhibitors, which indirectly activates the alpha7 receptor
by increasing acetylcholine levels, are not understood to exhibit
pro-cognitive effects in normal subject and, even in patients with
cognitive impairment, are not understood to exhibit pro-cognitive
effects after a single dose. The positive effects of the test
compound in the DSST indicate a beneficial effect on working memory
and executive function.
[0041] In the MAD (Multiple Ascending Dose) studies cognition was
assessed using tests from the CogState battery (cogstate.com).
Utilizing this test, the test compound was shown to have
pro-cognitive effects at daily a dose as low as 1 mg. The CogState
battery is a proprietary computerized cognitive battery of tests
measure various cognitive domains including: attention,
identification capability, working memory, visual memory, and
executive function. In these studies, the test compound was found
to have a positive impact on: visual motor skills, learning,
executive function, and delayed memory. The profile of the response
was unique insofar as the test compound had positive effects on
non-verbal learning and memory and executive function without
having a stimulatory effect on attention. The magnitude of the
effects were, in many cases, significant with effect sizes being
>0.4 (a threshold effect size which is commonly accepted as
having clinical significance). This therapeutic profile
(pro-cognitive effects on nonverbal learning and memory and
executive function without a central stimulatory effect) indicates
that the drug may be very beneficial in treating patients that
have, as a feature of their condition, symptoms of anxiety or
agitation.
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride Shows Effects at Unexpectedly Low Dose and Free
Plasma Concentration
[0042] The studies described above demonstrate that
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride administered at a daily dose of 1.0 mg or 0.3 mg can
improve cognition in patients suffering from schizophrenia and in
normal subjects.
[0043] The fact that a 0.3 mg or 1.0 mg dose of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride can elicit an effect in various measures of cognition
is surprising because at these dosages the concentration of free
drug is well below the K.sub.i of the compound to bind to the
alpha7 receptor.
[0044] In order for a small molecule to exert action at its target,
often a cell receptor, it must bind to its target. Thus, in
general, a small molecule drug is expected to exhibit activity when
the free drug concentration at the target (i.e., the concentration
of drug that is free and available to bind to the target)
approaches or exceeds the K.sub.i of the drug for target. Studies
have shown that in numerous cases the free drug concentration in a
particular tissue is about equal to the free drug concentration in
plasma (Mauer et al., 2005 and Trainor, 2007). For the brain, the
free plasma concentration is generally considered to represent the
maximum possible free drug concentration. The free drug
concentration in plasma ([free drug].sub.plasma) is determined by
measuring the total drug concentration in the plasma ([total
drug].sub.plasma) and the free fraction of the drug, i.e., the
fraction of the drug that is not bound to plasma protein
(fu.sub.plasma): [free drug].sub.plasma=[total
drug].sub.plasma.times.fu.sub.plasma. The total plasma drug
concentration and the fraction that binds to plasma protein can
both be measured using techniques known to those of skill in the
art.
[0045] Studies on
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
determined that the EC.sub.ref for human alpha7 receptor is
approximately 0.158 .mu.M and the K.sub.i (rat membrane) is
approximately 10 nM. Additional studies found the following values
for the free fraction of drug: Rat fu.sub.plasma=0.112, Dog
fu.sub.plasma=0.107, Human fu.sub.plasma=0.129.
[0046] Multiple ascending dose (MAD) human clinical trials were
conducted. The maximum plasma concentration was determined and used
to calculate the maximum free drug concentration which was used to
determine the maximum free drug concentration as a fraction of the
EC.sub.ref of the drug for human alpha7 receptor and the maximum
free drug concentration as a fraction of the K.sub.i of the drug
for rat brain alpha7 receptors. The EC.sub.ref, the concentration
of drug which elicits equal response in oocytes transfected with
cloned human alpha7 receptor at 50 .mu.M acetylcholine (the
endogenous receptor ligand), was determined to be 0.158 .mu.M. The
K.sub.i for rat brain alpha7 receptors was determined to be 10
nM.
TABLE-US-00001 TABLE 1 C.sub.max total C.sub.max free Fraction of
Fraction of .alpha.7 Study Day Dose C.sub.max (ng/mL) (nM) (nM)
.alpha.7 EC.sub.ref Binding K.sub.i SAD 1 1 mg 0.59 1.84 0.237
0.0015 0.0237 SAD 1 3.5 mg 2.06 6.42 0.828 0.0052 0.0828 MAD1 1 1
mg 0.63 1.96 0.252 0.0016 0.0252 MAD1 7 1 mg 2.12 6.61 0.853 0.0054
0.0853 MAD1 14 1 mg 2.64 8.23 1.06 0.0067 0.1060 MAD2 1 0.1 mg
0.055 0.172 0.022 0.0001 0.0022 MAD2 21 0.1 mg 0.232 0.724 0.093
0.0006 0.0093 MAD2 1 1 mg 0.623 1.943 0.251 0.0016 0.0251 MAD2 21 1
mg 2.42 7.547 0.974 0.0062 0.0974 MAD3 1 0.3 mg 0.182 0.568 0.073
0.0005 0.0073 MAD3 21 0.3 mg 0.704 2.195 0.283 0.0018 0.0283 MAD3 1
1 mg 0.547 1.71 0.221 0.0014 0.0221 MAD3 21 1 mg 1.99 6.20 0.800
0.0051 0.0800
[0047] In human single and multiple ascending dose clinical trials
in both healthy and schizophrenia patients, a 0.3 mg daily dose and
a 1.0 mg daily dose were shown to improve cognitive function or
correlates of cognitive function. As can been seen from Table 1
which presents an analysis of the free drug concentration, the 0.3
mg dose of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride produces a maximum free plasma concentration of
0.073-0.283 nM which is 0.005 to 0.0018 of the alpha7 EC.sub.ref
and 0.0073 to 0.0283 of the alpha7 K.sub.i. These values are
35-2000 times lower than would have anticipated if efficacy was to
be achieved when the free plasma concentration reached the K.sub.i
or the EC.sub.ref concentrations. When a similar calculation is
performed for the 1.0 mg doses (free plasma of 0.237-1.06 nM) these
fractional values of the K.sub.i and EC.sub.ref concentrations are
0.0015 to 0.0067 (EC.sub.ref) and 0.0237 to 0.106 (K.sub.i). These
values are 9.4-667 times lower than expected.
Half-Life of
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide in
Humans
[0048] Table 2 presents half-life (t.sub.1/2) data for
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
obtained from pre-clinical species as well as the half-life in
humans determined in clinical trials.
TABLE-US-00002 TABLE 2 Route of Species Administration Dose t
.sub.1/2 Mouse i.v. n/a * Rat i.v. 1 mg/kg 2.77 h Dog i.v. 0.5
mg/kg 5.39 Dog i.v. 3 mg/kg 13 Human p.o. 1 mg 50.1-70.1 *
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
was unstable in mouse plasma and as such a half-life (t.sub.1/2)
could not be accurately calculated.
[0049] The half-life determined in rat and dog suggested a human
half-life much shorter than the observed 60 hr half-life (initial
allometric scaling suggested a half-life of about 8 hours). The
unexpectedly long half-life in humans has several advantages. It
allows for once a day dosing. The drug will also have a very small
dynamic plasma range over the course of a day (about 15-20%). Thus,
if a patient misses a daily dose, the plasma level and the
consequent brain level will not be altered by a great degree. This
means that the beneficial effects of the drug will be less
dependent upon careful adherence to a specific dosing scheme.
Third, long half-life and slow elimination also mean that the final
dose will be lower than expected. This readily observed by looking
at the C.sub.max values on Day 1 versus Day 21. The C.sub.max
values on Day 21 are about 3.6-4.2 times higher than the Day 1
values. This ratio will translate into a dose that is 3.6-4.2 times
lower than would normally be expected due to this favorable
accumulation.
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