Note: Descriptions are shown in the official language in which they were submitted.
CYTISINICLINE IN THE TREATMENT OF SMOKING ADDICTION FOR
REFRACTORY SUBJECTS
FIELD OF THE INVENTION
The present invention relates to the use of cytisinicline (commonly referred
to as
cytisine) as a smoking cessation treatment, and in particular to a dosage
regimen for such
use.
BACKGROUND
Nicotine is an addictive substance that is rapidly absorbed during cigarette
smoking.
The drug distributes quickly and is thought to interact with neuronal
nicotinic acetylcholine
receptors (nAChRs) in the central nervous system (CNS). Nicotine addiction
results, at
least in part, from this interaction. Although many smokers attempt to cease
smoking, few
succeed without pharmacological supportive treatment.
Tobacco smoking contributes to some 7 million premature deaths each year
worldwide. Smoking is highly addictive, with more than 95% of unaided attempts
at
cessation failing to last 6 months. It has been estimated that for every year
that a person
delays stopping smoking beyond his or her mid-30s, that person loses 3 months
of life
expectancy. The World Health Organization's Framework Convention on Tobacco
Control identifies evidence-based approaches to promote smoking cessation,
which include
mass-media campaigns, tax increases on tobacco, and help for smokers wanting
to stop.
The pharmacotherapies currently available in the US and Western Europe to help
smokers stop include nicotine replacement therapy (NRT) and two non-nicotine
containing
medications: bupropion (Zybane, Glaxo-SmithKline) and varenicline
(Chantix /Champixe, Pfizer). NRT and bupropion appear to have about equal
efficacy.
Varenicline is more effective than single NRT and bupropion, although
combination NRT
is comparable in efficacy.
(-)-Cytisine (cytisinicline; commonly referred to simply as cytisine) is a
plant-based
alkaloid isolated from seeds of Cytisus laburnum L. (Golden chain). References
herein to
cytisine refer to (-)-cytisine, cytisinicline.
Cytisine's mechanism of action has assisted basic pharmacologists in
understanding the complex pharmacology of the various subtypes of the
nicotinic
acetylcholine receptor. These studies have shown that both nicotine and
cytisine bind
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strongly and preferentially to pre-synaptic a1pha4, beta2 (a4132) receptors
that mediate the
release of dopamine in the shell of the nucleus accumbens. This receptor
subtype has been
implicated in the development and maintenance of nicotine dependence and was
the
primary target for the drug varenicline, referred to above.
Tabex , containing the active substance cytisine, has been licensed and
marketed
in Central and Eastern Europe for several decades by Sopharma PLC (Sophia,
Bulgaria).
Tabex is supplied as a compressed film-coated tablet containing 1.5 mg
cytisine
tablets, the tablets to be taken orally with water in accordance with a
specified titration
schedule over a 25-day period. On days 1-3, six 1.5 mg cytisine tablets are
taken separately
at two-hourly intervals, giving a total dose of 9 mg of cytisine on each of
those days. On
days 4-12, five 1.5 mg cytisine tablets are taken separately at two and a half-
hourly
intervals, giving a total dose of 7.5 mg of cytisine on each of those days. On
days 13-16,
four 1.5 mg cytisine tablets are taken separately at three-hourly intervals,
giving a total
dose of 6 mg of cytisine on each of those days. On days 17-20, three 1.5 mg
cytisine tablets
are taken separately at four to five-hourly intervals, giving a total dose of
4.5 mg of cytisine
on each of those days. On days 21-24, two 1.5 mg cytisine tablets are taken
separately at
six-hourly intervals, giving a total dose of 3 mg of cytisine on each of those
days. Finally,
on day 25, a single 1.5 mg cytisine tablet is taken to complete the course of
treatment.
Despite its widespread use, cytisine has not been market-approved for use
outside
Central and Eastern Europe. However, two recent Phase 3 studies have been
conducted and
published in 2011 and 2014 in the New England Journal of Medicine. The overall
objectives in these trials were to confirm the efficacy and safety of cytisine
according to
current clinical development standards. Both studies were carried out using
the commercial
25-day titration schedule as described above.
The 2011 study (West R, Zatonski W, Cedzynska M, et al. Placebo-Controlled
Trial
of Cytisine for Smoking Cessation, New England Journal of Medicine
2011;365:1193-200)
describes a Phase 3 study with the primary outcome measure being sustained,
biochemically-verified smoking abstinence for 12 months after the end of
treatment. This
study showed an improved Relative Risk for substained abstinence for cytisine
compared
with placebo.
The 2014 study (Walker N, Howe C, Glover M, et al. Cytisine versus nicotine
for
smoking cessation, New England Journal of Medicine 2014;371:2353-62) describes
a
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Phase 3 study with the primary outcome measure being continuous self-reported
abstinence
from smoking one month after a quit date and a secondary outeome measure
including the
Relative Risk for continuous abstinence. This study showed that cytisine was
1.43 times
more likely than nicotine patches with gum or lozenges to help participants
stop smoking
and remain non-smokers for six months.
Thus, the efficacy of the 1.5 mg dose of cytisine using the 25-day titration
described
above in smoking cessation has been confirmed in these recent studies.
A need exists for nicotine addiction treatments with patient-friendly regimens
that
are less costly, more effective, have an improved safety profile, and/or can
more
successfully treat individuals who have failed to quit nicotine using the
known treatments.
SUMMARY
In one aspect, provided herein is the use of cytisine to address nicotine
addiction in
a subject, comprising providing cytisine in a unit dose of 3.0 mg cytisine
three times daily
to a subject in need thereof.
In some embodiments, the use of cytisine is over a 6 week duration. In some
embodiments, cytisine is provided for 12 weeks.
In some embodiments, the unit dose of cytisine comprises two tablets, each
tablet
containing 1.5 mg cytisine. In some embodiments, the unit dose of cytisine
comprises
single tablet containing 3.0 mg cytisine. In some embodiments, each unit dose
tablet is a
compressed, film coated tablet.
In another aspect, provided herein is the use of cytisine, or a method of
treating of
nicotine addiction in a subject, comprising administering cytisine to a
subject in need
thereof, wherein the subject is a refractory patient who has failed treatment
with one or
more nicotine addiction treatments.
In some embodiments, the subject is a refractory patient who has failed
treatment
with one or more nicotine addiction treatments. In some embodiments, the
subject is a
refractory patient who has failed treatment with two or more nicotine
addiction treatments.
In some embodiments, the nicotine addiction treatments are selected from
nicotine
replacement therapy (NRT), administration of bupropion, administration of
varenicline,
electronic cigarettes, vaping, and a combination thereof. In some embodiments,
the subject
smoked ten or more cigarettes per day prior to the use of cytisine. In some
embodiments,
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the subject has expired air CO concentration of about 10 ppm or greater prior
to the use of
cytisine.
In some embodiments, the use of cytisine or the method further comprises
providing
behavioral support to the subject.
DETAILED DESCRIPTION
In one aspect, provided herein is a method of treatment method of treating of
nicotine addiction in a subject, comprising administered cytisine provided in
a unit dose of
about 1.5 mg to about 5.0 mg cytisine three to six times daily to a subject in
need thereof.
In some embodiments of the methods disclosed herein, the unit dose is about
3.0 mg
administered three times daily. Administration of cytisine in accordance with
the methods
disclosed resulted in significantly better smoking cessation rate, as compared
with the
administration of the commercial 1.5 mg per unit dose titration schedule.
In some embodiments, the length of the administration is up to about 26 weeks.
In
certain embodiments the length of the administration is from about 6 weeks to
about 12
weeks, and in some embodiments, the cytisine is administered as described
above for about
6 weeks.
Compared with the commercial 25-day titration schedule with unit doses of 1.5
mg
cytisine, the percentage of smokers with continuous abstinence is surprisingly
higher in the
subjects treated according to the methods disclosed herein, as demonstrated,
for example,
in FIGURE 7.
Any suitable cytisine pharmaceutical composition or formulation can be used in
the
methods described herein. In some embodiments, cystisine can be formulated in
tablet
form, for example, as compressed film-coated tablets for oral administration.
The unit dose
can comprise a single tablet, such as a tablet containing 3.0 mg cytisine, or
it can comprise
two or more tablets which together contain the unit dose, e.g., 3.0 mg
cytisine. For
example, the unit dose of 3.0 mg can comprise two tablets, each containing 1.5
mg cytisine,
such as two Tabex tablets. Each Tabex tablet is typically formulated as a
compressed
film-coated tablet containing 1.5 mg cytisine in a single tablet together with
a number of
tablet- forming excipients (calcium sulfate, cellulose powder, colloidal
silica, magnesium
stearate) and coated with a coloured film-coat including polyvinyl alcohol,
titanium dioxide
and iron oxides.
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Alternatively, the cytisine may be formulated in a capsule or another vehicle
for
oral administration; or in a composition for nasal or topical administration.
The tablets and other dosage forms (hereinafter all referred to as
"compositions")
can contain one or more excipients, such as those common in the art.
Excipients that can
be employed in the compositions include, for example, fillers, disintegrants,
preserving
agents, lubricants, and wetting agents.
Examples of fillers that can be used include lactose (for example, either
anhydrous
or monohydrate), cellulose, starch (for example, corn and/or wheat starch),
calcium
phosphates, calcium sulfates, and mannitol.
Preserving agents prevent bacterial or fungal contamination of the formulation
and
include various antibacterial and antifungal agents such as parabens,
chlorobutanol, phenol,
and sorbic acid.
Suitable lubricants include stearic acid and its salts. One example of a
lubricant for
use in the compositions of the disclosure is magnesium stearate.
The pharmaceutical compositions can further comprise sweetening, flavoring, or
coloring agents.
A skilled in the art person will be well aware of suitable fillers, preserving
agents,
and lubricants other than those specifically mentioned above, as well as
suitable
sweetening, flavoring, and coloring agents, and other additives.
The pharmaceutical compositions of cytisine useful in the methods of the
disclosure
can comprise a coating, for example a film coating, and can be coated
according to any
method known in the art, for example, using collidone, shellac, gum arabic,
talc, titanium
dioxide, or sugar.
The pharmaceutical compositions comprising cytisine can be prepared by any
suitable method. For example, capsules can be prepared by mixing cytisine with
one or
more inert carriers such as lactose or sorbitol and packing into gelatin
capsules. Tablets can
be made by known compression methods.
In some embodiments of the methods, the subject is a refractory patient. As
used
herein, a "refractory patient" or "refractory subject" is a subject who has
failed treatment
with one or more known nicotine addiction treatments. The nicotine addiction
treatments
include both the regulatory agency-approved treatments and smoking cessation
methods
such as vaping and behavioral support, including web-based smoking cessation
programs
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and texting interventions. In some embodiments, the nicotine addiction
treatments include
FDA-approved, first-line smoking cessation medications such as nicotine
replacement
therapy (NRT), bupropion, and varenicline. Nicotine replacement therapy can be
the form
of patch, gum, lozenge, spray, and inhaler.
In some embodiments, the subject is a refractory patient who has failed
treatment
with two or more nicotine addiction treatments. In some embodiments, the
subject is a
refractory patient who has failed nicotine addiction treatments comprising
nicotine
replacement therapy (NRT), administration of bupropion, administration of
varenicline,
electronic cigarettes, vaping, or a combination thereof.
Any patient with nicotine addiction can be treated by the methods disclosed
herein.
In some embodiments, the subject is a smoker, for example, a smoker who smokes
about
3 or more cigarettes a day. In some embodiments, the subject is a smoker who
smokes
about 5 or more or about 10 or more cigarettes a day. In some embodiments, the
subject
has measurable expired air CO concentration of about 10 ppm or greater prior
to the
administration of cytisine.
Thus, in a second aspect, provided herein is a method of treating of nicotine
addiction in a subject, comprising administered cytisine to a subject in need
thereof,
wherein the subject is a refractory patient who has failed treatment with one
or more
nicotine addiction treatments. Doses, treatment regimens, and routes, of
administration
useful in the methods disclosed herein include those described above. Suitable
unit doses
include doses between about 1.0 mg and about 6 mg which can be administered
three to
six times daily, for example, at about equal intervals. For example, in some
embodiments,
the methods comprise administering cytisine provided in a unit dose of 3.0 mg
cytisine
three times daily to a refractory patient. Any suitable duration of
administration can be used
in the methods disclosed herein, for example, about 26 weeks, about 12 weeks,
or about 6
weeks. In some embodiments, the treatment is administered for about 6 weeks.
In some embodiments, the methods disclosed herein can further comprise
providing
behavioral support to the subject, for example, a refractory patient.
While each of the elements of the present invention is described herein as
containing multiple embodiments, it should be understood that, unless
indicated otherwise,
each of the embodiments of a given element of the present invention is capable
of being
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used with each of the embodiments of the other elements of the present
invention and each
such use is intended to form a distinct embodiment of the present invention.
The referenced patents, patent applications, and scientific literature
referred to
herein are hereby incorporated by reference in their entirety as if each
individual
publication, patent or patent application were specifically and individually
indicated to be
incorporated by reference. Any conflict between any reference cited herein and
the specific
teachings of this specification shall be resolved in favor of the latter.
Likewise, any conflict
between an art-understood definition of a word or phrase and a definition of
the word or
phrase as specifically taught in this specification shall be resolved in favor
of the latter.
As can be appreciated from the disclosure above, the present invention has a
wide
variety of applications. The invention is further illustrated by the following
examples,
which are only illustrative and are not intended to limit the definition and
scope of the
invention in any way.
EXAMPLES
Study Design
A six-arm, multi-center, double-blind, randomized, placebo-controlled study
conducted in male or female adults >18 years of age, smoking 10+ cigarettes
daily, and
willing to set a quit date that is 5-7 days after being randomized on the
study. The dosing
schedules were as shown in FIGURE 1.
The study was double-blinded to dose but not to the administration schedule,
and
the study arms were as shown in FIGURE 2. Study treatment started the day
after
randomization such that study treatment was initiated prior to the quit date,
as shown in
FIGURE 3.
Subjects were selected to meet all inclusion and exclusion criteria.
Percent reduction in in number of cigarettes smoked during treatment was
selected
as the primary outcome and was calculated as follows:
100 [ B __________________________________ x DX 1001%
where N = total number of cigarettes smoked, B = number of cigarettes smoked
at
baseline, and D = number of days of treatment.
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Quit Rates as confirmed by expired CO <10 ppm were the study's secondary
outcomes.
The subject demographics are summarized in FIGURE 4, and their smoking history
is shown in FIGURE 5.
Efficacy Conclusions
Smoking diary compliance, on which the primary analysis was based in part, was
high for all treatment arms. Study drug compliance was >94% for all treatment
arms with
slightly higher compliance with the tid schedule (>98%).
Results from the primary analyses demonstrated a significant reduction in
percentage of expected cigarettes smoked (cigarette score) in the both
commercial arms but
not in the tid arms. When pooling the placebo arms, the cigarette score was
significantly
reduced in both commercial arms, the 1.5 mg tid arm and approached
significance in the
3.0 mg tid arm. Subjects treated with 1.5 mg or 3 mg cytisine using the
commercial
schedule smoked approximately 14% to 16% fewer cigarettes than expected versus
pooled
placebo. Subjects treated with 1.5 mg or 3 mg cytisine on the tid schedule
smoked
approximately 9% to 12% fewer cigarettes than expected versus the pooled
placebo arm.
Although the decreases on the tid schedule were not as high as those seen on
the
commercial schedule, it should be noted that subjects in the placebo arm on
the tid schedule
reported a higher reduction in cigarettes smoked than subjects in the placebo
arm on the
commercial schedule. The tid placebo subjects smoked only one-third as many
cigarettes
as they normally would (LS mean: 35.30%) versus the commercial placebo
subjects at one-
half as many cigarettes smoked (LS mean: 47.10%), which possibly masked the
cytisine
treatment effect on the tid schedule.
Expired CO levels were measured during this study as an objective biochemical
marker for reduction in smoking. In all cytisine-treated arms, the reduction
in CO (55% to
62%) was consistent with reported reduction in cigarettes smoked (e.g. a range
of 25% to
32% as a cigarette scores represents a 75% to 68% reduction in cigarettes
smoking).
Conversely, in the placebo-treated arms, the reported reductions in the number
of cigarettes
smoked (e.g. 41% for cigarette score, representing a 59% reduction in
cigarettes smoked)
was not paralleled by a corresponding reduction in CO at only 29%. A similar
pattern for
plasma cotinine levels was observed with far greater reductions in cotinine
levels in the
cytisine arms compared to placebo arms.
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The changes in these objective markers suggest that, in general, placebo-
treated
subjects over-reported their reduction in cigarettes smoked. It also suggests
that the real
differences in cigarette scores between subjects treated with cytisine and
those treated with
placebo were greater than those actually observed.
Results for the initial quit rate at Week 4 demonstrated both arms of the tid
schedule
had high odds of success of quitting smoking compared with placebo; subjects
in the 3.0
mg cytisine arm had the best odds of success for quitting smoking: OR:
6.31(95% CI: 2.28,
18.45). The OR for the 1.5 mg cytisine arm on the tid schedule was 5.81 (95%
CI: 2.12,
16.87). On the commercial schedule, the ORs for the 1.5. and 3.0 mg cytisine
arms were
5.59 (95% CI: 2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively.
For the prolonged abstinence from Week 5 to Week 8 endpoint, both arms of the
tid schedule had higher odds of success for abstinence compared with placebo;
subjects in
the 3.0 mg cytisine arm had the best odds of success for abstinence from Weeks
5 to 8,
with an OR of 5.04 (95% CI: 1.42, 22.32). The OR for the 1.5 mg cytisine arm
on the tid
schedule was 4.33 (95% CI: 1.21, 19.30). On the commercial schedule, the ORs
for the 1.5
mg cytisine and 3.0 mg arms were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI:
0.55,
10.82), respectively.
Subjects in the cytisine arms on the tid schedule also had higher odds of
smoking
abstinence at the Week 6, 7, and 8 timepoints compared with subjects in the
corresponding
arms on the commercial schedule versus placebo, as demonstrated by higher ORs
at each
timepo int.
Discussion
This 6-arm, multicenter, double-blind, randomized study was designed to
evaluate
the effectiveness of 1.5 mg cytisine versus placebo using the commercial
titration schedule
approved in Central and Eastern Europe. The study also evaluated the
effectiveness of a
simplified tid dosing schedule for 1.5 mg and an increased dose of 3 mg (using
both the
commercial titration and simplified tid dosing schedules). The overall goal of
the study was
to obtain estimates of effect size for efficacy and safety endpoints that will
be used to
inform the design of future Phase 3 studies.
In total, 254 male or female adults >18 years of age who smoked >10cigarettes
daily
and were willing to set a quit date 5 to 7 days after randomization were
enrolled in the
study. Demographics and baseline characteristics were generally well balanced
across both
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schedules and treatment arms. Overall, the study population represented highly
addictive
smokers who on average were 48.4 years old and had been smoking for 32 years,
meaning
that most of them had started smoking in their adolescent years. In addition,
they had an
average of 4.5 prior quit attempts with the last quit attempt approximately
3.7 years prior
to entering the study and were currently smoking on average a pack of
cigarettes a day.
Analyses from the international EAGLES trial3 provided clear evidence that
smoking at a
young age and being of US origin was associated with lower success rates for
quitting. The
lower success rate in US smokers supports the view that smokers in the US may
have
reached a point in the tobacco epidemid such that those who continue to smoke,
despite
strong cultural pressures not to, have particular characteristics that make it
more difficult
for them to stop smoking.
Study drug compliance was high for all treatment arms with the tid schedule
better
(98.18%) than the commercial schedule (94.90%).
Results from the primary analyses demonstrated a significant reduction in
percentage of expected cigarettes smoked (cigarette score) in the both
commercial titration
arms. When pooling the placebo arms, the cigarette score was significantly
reduced in both
commercial arms, the 1.5mg tid arm and approached significance in the 3.0 mg
tid arm.
Subjects treated with 1.5 mg or 3 mg cytisine using the commercial schedule
smoked
approximately 14% to 16% fewer cigarettes than expected versus placebo.
Subjects treated
with 1.5 mg or 3 mg cytisine on the tid schedule smoked approximately 9% to
12% fewer
cigarettes than expected versus the placebo arm.
Expired CO levels were also measured during this study as an objective
biochemical marker for reduction in smoking. In all cytisine-treated arms, the
reduction in
CO (55% to 62% reduction) was consistent with the reported reduction in
cigarettes
smoked (e.g. a range of 25% to 32% as cigarette scores represents a 75% to 68%
reduction
in cigarettes smoking). Conversely, in the placebo-treated arms, the reported
reductions in
the number of cigarettes smoked (e.g. 41% as the cigarette score, representing
a 59%
reduction in cigarettes smoked) was not paralleled by a corresponding
reduction in CO at
only 29%. A similar pattern for plasma cotinine levels was observed with far
greater
reductions in cotinine levels in the cytisine arms compared to placebo arms.
The changes in these objective markers suggest that, in general, placebo-
treated
subjects over-reported their reduction in cigarettes smoked. It also suggests
that the real
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differences in cigarette scores between subjects treated with cytisine and
those treated with
placebo were greater than those actually observed.
Results for an initial quit rate at Week 4 for all cytisine-treated arms
demonstrated
significantly increased initial rates (50 to 54%) compared with pooled placebo
(16%), and
with ORs ranging from 5.38 to 6.31. Prolonged abstinence from weeks 5 to 8
(i.e., for 4
weeks off treatment) also demonstrated significantly increased prolonged quit
rates of 16-
to 30% in the cytisine-treated arms compared to 8% for pooled placebo and with
ORs
ranging from 3.23 to 5.04. Overall, the initial and prolonged quit rates were
highest for the
3 mg tid arm at 54% and 30%, respectively, and with the greatest ORs of 6.31
and 5.04,
respectively.
Overall, there were no safety concerns following dosing in the 1.5 mg cytisine
or
3.0 mg treatment arms on both schedules, and no new or unexpected AEs were
identified
during the study. TEAEs were experienced by approximately half the study
population in
all treatment arms. The tid dosing schedule had slightly fewer TEAEs overall.
Across both schedules, the SOCs with the highest incidence of TEAEs in any
treatment arm were infections and infestations, psychiatric disorders, and
gastrointestinal
disorders. Common TEAEs were AEs that had been previously reported in other
studies or
within the Investigator's Brochure.
All TEAEs were mild or moderate in severity on the commercial schedule and all
events except 2 were mild or moderate on the tid schedule: Subject 106-
131experienced a
severe head injury, and Subject 108-115 experienced a severe case of
influenza. Neither
event was considered related to study drug.
There were no relevant mean changes or shifts from baseline in laboratory
parameters over time or 12-lead ECG results. The overall incidence of
potentially clinically
significant changes in vital sign measurements was low, with the lowest
incidence
occurring on the tid schedule.
Overall, no new safety signals were observed during the conduct of this study.
The results are further summarized in FIGURES 5-10.
Overall Conclusions
Results from the primary analyses demonstrated a reduction in percentage of
expected cigarettes smoked in both schedules versus pooled placebo.
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Results for the initial quit rate endpoint demonstrated both cytisine arms of
the tid
schedule had high odds of success compared with placebo; subjects in the 3.0
mg cytisine
arm had the best odds of success for quitting smoking at Week 4.
For the prolonged abstinence from Week 5 to Week 8 endpoint, both arms of the
tid schedule had high odds of success compared with placebo; subjects in the
3.0 mg
cytisine arm had the best odds of success for abstinence from Weeks 5 to 8.
The study
demonstrated that cytisine is an effective aid to smoking cessation with an
advantageous
adverse event profile, and 3.0 mg tid dosing is more efficacious overall with
no increase in
adverse events.
Overall, there were no safety concerns following dosing in the 1.5 mg cytisine
or
3.0 mg arms on either schedule.
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