U.S. patent application number 16/762165 was filed with the patent office on 2021-01-28 for use of riluzole prodrugs to treat ataxias.
The applicant listed for this patent is BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD.. Invention is credited to Melissa Beiner, Robert Berman, Vladimir Coric, Gilbert L'Italien.
Application Number | 20210023061 16/762165 |
Document ID | / |
Family ID | 1000005165607 |
Filed Date | 2021-01-28 |
United States Patent
Application |
20210023061 |
Kind Code |
A1 |
Coric; Vladimir ; et
al. |
January 28, 2021 |
USE OF RILUZOLE PRODRUGS TO TREAT ATAXIAS
Abstract
Disclosed are methods of treating ataxia by administering to a
patient in need thereof a riluzole prodrug such as troriluzole.
Pharmaceutical compositions and kits including the riluzole
prodrugs are also disclosed.
Inventors: |
Coric; Vladimir; (Madison,
CT) ; Berman; Robert; (New Haven, CT) ;
Beiner; Melissa; (Madison, CT) ; L'Italien;
Gilbert; (Deep River, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD. |
New Haven |
CT |
US |
|
|
Family ID: |
1000005165607 |
Appl. No.: |
16/762165 |
Filed: |
November 11, 2018 |
PCT Filed: |
November 11, 2018 |
PCT NO: |
PCT/US2018/060232 |
371 Date: |
May 7, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62584856 |
Nov 12, 2017 |
|
|
|
62717948 |
Aug 13, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/20 20130101; A61P
25/00 20180101; A61K 31/428 20130101; A61K 9/48 20130101 |
International
Class: |
A61K 31/428 20060101
A61K031/428; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method of treating ataxia in a patient in need thereof,
comprising administering to the patient a therapeutically effective
amount of a riluzole prodrug.
2. The method of claim 1 wherein the ataxia is one or more of
Friedreichs ataxia, Ataxia telangiectasia, Autosomal recessive
ataxia with oculomotor apraxia type 1, Autosomal recessive ataxia
with oculomotor apraxia type 2, Spinocerebellar ataxia with axonal
neuropathy, Abetalipoproteinemia, Ataxia with isolated vitamin E
deficiency, Refsums disease and Cerebrotendinous xanthomatosis.
2. The method of claim 1 wherein the ataxia is Spinocerebellar
ataxia selected from SCA1, SCA2, SCA3, SCA6, SCA7, SCA8 and
SCA10.
3. The method of claim 2 wherein the ataxia is one or more of an
ataxia associated with translated GAG repeat expansions, an ataxia
associated with untranslated repeat expansions in non-coding
regions, or an ataxia associated with point-mutations.
4. The method of claim 1 wherein the ataxia is a multiple system
atrophy ataxia or a sporadic adult-onset ataxia.
5. The method of claim 1 wherein the riluzole prodrug has the
following formula: ##STR00006## and pharmaceutically acceptable
salts thereof, wherein: R.sub.23 is selected from the group
consisting H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CCH, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2OH, CH.sub.2OCH.sub.2Ph,
CH.sub.2CH.sub.2OCH.sub.2Ph, CH(OH)CH.sub.3, CH.sub.2Ph,
CH.sub.2(cyclohexyl), CH.sub.2(4-OH--Ph), (CH.sub.2).sub.4NH.sub.2,
(CH.sub.2).sub.3NHC(NH.sub.2)NH, CH.sub.2(3-indole),
CH.sub.2(5-imidazole), CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CONH.sub.2, and
CH.sub.2CH.sub.2CONH.sub.2.
6. The method of claim 5 wherein the riluzole prodrug has the
following formula: ##STR00007##
7. The method of claim 1 wherein the treatment provides an
improvement in the patient's total SARA score of at least 0.8, or
0.9, or 1.0, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5, or 1.6, or
1.7, or 1.8, or 1.9, or 2.0, or greater.
8. The method of claim 1 wherein the riluzole prodrug is
administered to the patient at a dosage of from about 17.5 to 200
mg per day.
9. The method of claim 8 wherein the riluzole prodrug is
administered to the patient at a dosage of about 17.5, or 35, or
70, or 100, or 140, or 200 mg per day.
10. The method of claim 9 wherein the riluzole prodrug is
administered to the patient at a dosage of 200 mg, once per
day.
11. The method of claim 9 wherein the riluzole prodrug is
administered to the patient at a dosage of 140 mg, once per
day.
12. The method of claim 1 wherein the riluzole prodrug is
administered to the patient once per day.
13. The method of claim 1 wherein the riluzole prodrug is
administered to the patient twice per day.
14. The method of claim 1 wherein the riluzole prodrug is
administered to the patient in the form of a capsule.
15. The method of claim 1 wherein the riluzole prodrug is
administered to the patient in the form of a tablet.
16. The method of claim 1 wherein the riluzole prodrug is
administered to the patient for a duration of from about 8 weeks to
48 weeks.
17. A kit for treating a patient afflicted with ataxia, the kit
comprising: (a) a riluzole prodrug; and (b) instructions for
administering the riluzole prodrug in the method of claim 1.
18. The kit of claim 17 wherein the prodrug has the following
formula: ##STR00008##
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the use of prodrugs of
riluzole to treat ataxias such as Spinocerebellar ataxia and
Friedreich ataxia.
BACKGROUND OF THE INVENTION
[0002] Ataxia is a disorder of the central nervous system wherein
the patient is unable to coordinate muscles for the execution of
voluntary movement, see, e.g., Klockgether, T., Ataxias,
Parkinsonism and Related Disorders, 13, S391-S394, 2007. Typical
symptoms of ataxia are gait dysfunctions, imbalance, impaired limb
coordination and altered speech. In many ataxia disorders, the
ataxia is due to degeneration of the cerebellar cortex and its
afferent or efferent fiber connections. Typical affected brain
regions are cerebellum, posterior column, pyramidal tracts and
basal ganglia. Ataxia may lead to a decreased motoneuron function.
Ataxia is typically classified into hereditary and non-hereditary
ataxias.
[0003] Hereditary ataxias are further classified into autosomal
recessive and autosornal dominant ataxias. Autosomal recessive
ataxias are, for example, Friedreichs ataxia ("FA"), Ataxia
telangiectasia ("AT"), Autosomal recessive ataxia with oculomotor
apraxia type 1, Autosomal recessive ataxia with oculomotor apraxia
type 2, Spinocerebellar ataxia with axonal neuropathy,
Abetalipoproteinemia, Ataxia with isolated vitamin E deficiency,
Refsums disease and Cerebrotendinous xanthomatosis. Autosomal
dominant ataxias include, for example, Spinocerebellar ataxia
("SCA"), which can be further classified into ataxias associated
with translated GAG repeat expansions (SCA 1, 2, 3, 6, 7 and 17),
ataxias associated with untranslated repeat expansions in
non-coding regions (SCAB, 10 and 12), ataxias associated with
point-mutations (SCA5, 13, 14 and 27). SCA3 is also known as
Machado-Joseph disease.
[0004] Non-hereditary ataxias can be further classified into
degenerative and acquired ataxias. Degenerative ataxias are, for
example, multiple system atrophy ataxia and sporadic adult-onset
ataxia. Acquired ataxias can be, for example, associated with
alcoholic/toxin-caused cerebellar degeneration or paraneoplastic
cerebellar degeneration.
[0005] There are currently no U.S. Food and Drug Administration
("FDA") approved medications for the treatment of SCAs. The
diagnosis of a spinocerebellar ataxia requires the exclusion of
acquired, non-genetic causes of ataxia, including alcoholism,
vitamin deficiencies, multiple sclerosis, vascular disease, tumors,
and paraneoplastic disease. A definitive diagnosis requires genetic
testing or occurrence within a kindred. Lifespan is often
significantly shortened due to complications related to neurologic
deficits.
[0006] Common features among the SCAs include being associated with
spinocerebellar degeneration, which is often observable on brain
imaging. In addition, symptom presentation among the SCA subtypes
share many common, prominent features: slowly progressive,
symmetrical, midline and appendicular ataxia with dysmetria, i.e.,
loss of accuracy; dysdiadochokinesis, i.e., loss of rhythm as in
difficulty performing alternating movements; decreased speed of eye
movements that affect eye gaze (including nystagmus and diplopia);
abnormalities of speech, i.e., dysarthria; difficulty swallowing;
hand/foot incoordination, i.e., limb ataxia; abnormal station; and,
abnormal gait. Notably, there can also be significant clinical
variation in the order and/or extent of symptom expression between
mutations, within a common mutation, and even within a kindred that
shares the same genotype. Non-cerebellar involvement may also occur
in many SCA subtypes (e.g., cognition, pyramidal, extrapyramidal,
motor neuron, peripheral nerve or macular involvement).
[0007] Signs and symptoms of SCA typically begin in early
adulthood, but can appear anytime from childhood to late adulthood;
SCAs are degenerative and progress over a number of years. The
severity of the disability and related mortality depends on type of
ataxia, the age of onset of symptoms, and other factors that are
poorly understood at this time. It is common for subsequent
generations to experience earlier onset and more extensive disease,
attributable to the phenomenon of "anticipation" whereby mutation
length, e.g., polyglutamine triplet expands over successive
generations.
[0008] The typical clinical course of SCAs may be described, for
example, as follows. Balance and coordination are often affected
first. Incoordination of hands, arms, and legs, and slurring of
speech are other common, early symptoms. Over time, individuals
with SCA may develop numbness, tingling, or pain in the arms and
legs, i.e., sensory neuropathy, uncontrolled muscle tensing, i.e.,
dystonia, muscle wasting, i.e., atrophy, and muscle twitches, i.e.,
fasciculations.
[0009] Walking often becomes difficult and is characterized by
walking with feet placed further apart to compensate for poor
balance. Impaired coordination of the arms and hands can affect the
ability to perform tasks requiring fine motor control such as
writing and eating. Rarely, rigidity, tremors, and involuntary
jerking movements, i.e., chorea, have been reported in people who
have been affected for many years.
[0010] Slow eye movements can be seen in some forms of ataxia,
including weakness in the muscles that control eye movement, i.e.,
ophthalmoplegia. As time goes on, ataxia can affect speech and
swallowing. Finally, individuals with SCA may also have difficulty
processing, learning, and remembering information, i.e., cognitive
impairment. With the production of abnormal proteins, the affected
nerve cells often eventually begin to function poorly and
ultimately degenerate. As SCA progresses, muscles can become
decreasingly coordinated, causing ataxia symptoms to become more
pronounced.
[0011] The most common SCAs include type 1, 2, 3, 6, 7, 8 and 10.
SCA1 often produces gait ataxia, limb ataxia, and dysarthria, with
brainstem involvement but little cognitive abnormality. SCA2 is
notable for the association of ataxia and dysarthria with slow
saccadic eye movements and polyneuropathy. SCA3 (Machado-Joseph
disease) is often accompanied by eyelid retraction, reduced
blinking, external ophthalmoplegia, dysarthria, dysphagia, and
sometimes parkinsonism or peripheral neuropathy. SCA6 is
comparatively less severe, typically progresses more slowly, is
more limited to cerebellar involvement than other SCAs, and has a
later age of onset. SCA7 is distinguished by retinal degeneration
leading to blindness, in addition to ataxia. Overall, there is
significant symptom overlap among these SCAs. The shared
symptomatic manifestations of the SCAs may reflect common pathology
affecting cerebellar purkinje cell fibers.
[0012] Glutamate is a predominant excitatory neurotransmitter
responsible for regulating signaling in normal brain function.
Riluzole (6-(trifluoromethoxy)benzothiazol-2-amine) is a glutamate
modulator which has been used for treatment of amyotrophic lateral
sclerosis (ALS).
[0013] Riluzole has been studied in patients with hereditary
cerebellar ataxias at doses of 50 milligrams ("mg") orally, twice
daily (see, Romano et al., Lancet Neurol 2015; 14: 985-91, and
ClinicalTrials.gov, number NCT01104649). On page 985 of the Romano
et al., publication, it is stated that: [0014] Our findings lend
support to the idea that riluzole could be a treatment for
cerebellar ataxia. Longer studies and disease-specific trials are
needed to confirm whether these findings can be applied in clinical
practice.
[0015] Accordingly, new methods are desired for the treatment of
ataxia which may provide benefits for patients afflicted with the
disease.
SUMMARY OF THE INVENTION
[0016] The present invention is directed to the treatment of
ataxia, e.g., SCA, with prodrugs of riluzole. By virtue of the
present invention, it may now be possible to provide more effective
ataxia treatments to patients. Patients may experience an improved
response in one or more areas including, for example, overall
survival, quality of life, overall response rate, duration of
response, delay of onset, or patient reported outcome.
[0017] In one aspect of the invention, there is provided a method
of treating ataxia in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of
a riluzole prodrug.
[0018] In one aspect, the ataxia is one or more of Friedreichs
ataxia ("FA"), Ataxia telangiectasia ("AT"), Autosomal recessive
ataxia with oculomotor apraxia type 1, Autosomal recessive ataxia
with oculomotor apraxia type 2, Spinocerebellar ataxia with axonal
neuropathy, Abetalipoproteinemia, Ataxia with isolated vitamin E
deficiency, Refsums disease and Cerebrotendinous xanthomatosis.
[0019] In one aspect, the ataxia is Spinocerebellar ataxia ("SCA")
selected from SCA1, SCA2, SCA3, SCA6, SCA7, SCA8 and SCA10.
[0020] In one aspect, the ataxia is one or more of an ataxia
associated with translated GAG repeat expansions (SCA 1, 2, 3, 6, 7
and 17), an ataxia associated with untranslated repeat expansions
in non-coding regions (SCAB, 10 and 12), or an ataxia associated
with point-mutations (SCA5, 13, 14 and 27).
[0021] In one aspect, the ataxia is a multiple system atrophy
ataxia or a sporadic adult-onset ataxia.
[0022] In one aspect, the riluzole prodrug has the following
formula:
##STR00001##
[0023] and pharmaceutically acceptable salts thereof, wherein:
[0024] R.sub.23 is selected from the group consisting H, CH.sub.3,
CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CCH,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2OH, CH.sub.2OCH.sub.2Ph,
CH.sub.2CH.sub.2OCH.sub.2Ph, CH(OH)CH.sub.3, CH.sub.2Ph,
CH.sub.2(cyclohexyl), CH.sub.2(4-OH--Ph), (CH.sub.2).sub.4NH.sub.2,
(CH.sub.2).sub.3NHC(NH.sub.2)NH, CH.sub.2(3-indole),
CH.sub.2(5-imidazole), CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CONH.sub.2, and
CH.sub.2CH.sub.2CONH.sub.2.
[0025] In one aspect, the riluzole prodrug has the following
formula:
##STR00002##
[0026] In one aspect, the treatment provides an improvement in the
patient's total SARA score of at least 0.8, or 0.9, or 1.0, or 1.1,
or 1.2, or 1.3, or 1.4, or 1.5, or 1.6, or 1.7, or 1.8, or 1.9, or
2.0, or greater.
[0027] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of from about 17.5 to 200 mg per day.
[0028] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of about 17.5, or 35, or 70, or 100, or 140, or
200 mg per day.
[0029] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of 200 mg, once per day.
[0030] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of 100 mg, twice per day.
[0031] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of 140 mg, once per day.
[0032] In one aspect, the riluzole prodrug is administered to the
patient at a dosage of 70 mg, twice per day.
[0033] In one aspect, the riluzole prodrug is administered to the
patient once per day.
[0034] In one aspect, the riluzole prodrug is administered to the
patient twice per day.
[0035] In one aspect, the riluzole prodrug is administered to the
patient in the form of a capsule.
[0036] In one aspect, the riluzole prodrug is administered to the
patient in the form of a tablet.
[0037] In one aspect, the riluzole prodrug is administered to the
patient for a duration of from about 8 weeks to 48 weeks.
[0038] In one aspect, the riluzole prodrug is administered to the
patient for a duration of from about 8 weeks to 16 weeks.
[0039] In one aspect of the invention, there is provided a method
for improving a response in a patient afflicted with ataxia
comprising administering to the patient in need thereof, an
effective amount of a riluzole prodrug.
[0040] In one aspect, the improved response is one or more of
overall survival, quality of life, overall response rate, duration
of response, delay of onset, or patient reported outcome.
[0041] In one aspect, the improved response is one or more of an
improvement of gait, balance, limb coordination or speech.
[0042] In one aspect, the improved response is an increased period
of time between episodes of ataxia.
[0043] In one aspect of the invention, there is provided a kit for
treating a patient afflicted with ataxia, the kit comprising:
[0044] (a) a riluzole prodrug; and
[0045] (b) instructions for administering the riluzole prodrug in
the method of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The following detailed description is provided to aid those
skilled in the art in practicing the present invention. Those of
ordinary skill in the art may make modifications and variations in
the embodiments described herein without departing from the spirit
or scope of the present disclosure. Unless otherwise defined, all
technical and scientific terms used herein have the same meaning as
commonly understood by one of ordinary skill in the art to which
this disclosure belongs. The terminology used in the description is
for describing particular embodiments only and is not intended to
be limiting.
[0047] As used in this application, except as otherwise expressly
provided herein, each of the following terms shall have the meaning
set forth below. Additional definitions are set forth throughout
the application. In instances where a term is not specifically
defined herein, that term is given an art-recognized meaning by
those of ordinary skill applying that term in context to its use in
describing the present invention.
[0048] The articles "a" and "an" refer to one or to more than one
(i.e., to at least one) of the grammatical object of the article
unless the context clearly indicates otherwise. By way of example,
"an element" means one element or more than one element.
[0049] The term "about" refers to a value or composition that is
within an acceptable error range for the particular value or
composition as determined by one of ordinary skill in the art,
which will depend in part on how the value or composition is
measured or determined, i.e., the limitations of the measurement
system. For example, "about" can mean within 1 or more than 1
standard deviation per the practice in the art. Alternatively,
"about" can mean a range of up to 10% or 20% (i.e., .+-.10% or
.+-.20%). For example, about 3 mg can include any number between
2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
Furthermore, particularly with respect to biological systems or
processes, the terms can mean up to an order of magnitude or up to
5-fold of a value. When particular values or compositions are
provided in the application and claims, unless otherwise stated,
the meaning of "about" should be assumed to be within an acceptable
error range for that particular value or composition.
[0050] The term "administering" refers to the physical introduction
of a composition comprising a therapeutic agent to a subject, using
any of the various methods and delivery systems known to those
skilled in the art. Typical routes of administration for riluzole
prodrugs include oral administration, e.g., by capsule or tablet.
Administering can also be performed, for example, once, a plurality
of times, and/or over one or more extended periods and can be a
therapeutically effective dose or a subtherapeutic dose.
[0051] The term "dosing frequency" refers to the frequency of
administering doses of a formulation disclosed herein in a given
time. Dosing frequency can be indicated as the number of doses per
a given time, e.g., once a week or once in two weeks.
[0052] The term "effective amount" refers to that amount which is
sufficient to effect an intended result. The effective amount will
vary depending on the subject and disease state being treated, the
severity of the affliction and the manner of administration, and
may be determined routinely by one of ordinary skill in the
art.
[0053] The terms "in combination with" and "in conjunction with"
refer to administration of one treatment modality in addition to
another treatment modality. As such, "in combination with" or "in
conjunction with" refers to administration of one treatment
modality before, during, or after administration of the other
treatment modality to the subject.
[0054] The term "pharmaceutically acceptable salt" refers to a salt
form of one or more of the compounds or prodrugs described herein
which are presented to increase the solubility of the compound in
the gastric or gastroenteric juices of the patient's
gastrointestinal tract in order to promote dissolution and the
bioavailability of the compounds. Pharmaceutically acceptable salts
include those derived from pharmaceutically acceptable inorganic or
organic bases and acids, where applicable. Suitable salts include
those derived from alkali metals such as potassium and sodium,
alkaline earth metals such as calcium, magnesium and ammonium
salts, among numerous other acids and bases well known in the
pharmaceutical art.
[0055] The term "prodrug" refers to a precursor of a drug which may
be administered in an altered or less active form. The prodrug may
be converted into the active drug form in physiological
environments by hydrolysis or other metabolic pathways. A
discussion of prodrugs is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design,
(1987) Edward B. Roche, ed., American Pharmaceutical Association
and Pergamon Press.
[0056] The terms "subject" and "patient" refer any human or
nonhuman animal. The term "nonhuman animal" includes, but is not
limited to, vertebrates such as nonhuman primates, sheep, dogs, and
rodents such as mice, rats and guinea pigs. In some embodiments,
the subject is a human. The terms, "subject" and "patient" are used
interchangeably herein.
[0057] The terms "therapeutically effective amount",
"therapeutically effective dosage" and "therapeutically effective
dose" of an agent (also sometimes referred to herein as a "drug")
refers to any amount of the active agent that, when used alone or
in combination with another agent, protects a subject against the
onset of a disease or promotes disease regression evidenced by a
decrease in severity of disease symptoms, an increase in frequency
and duration of disease symptom-free periods, or a prevention of
impairment or disability due to the disease affliction. The
therapeutically effective amount of an agent can be evaluated using
a variety of methods known to the skilled practitioner, such as in
human subjects during clinical trials, in animal model systems
predictive of efficacy in humans, or by assaying the activity of
the agent in in vitro assays.
[0058] The term "treatment" refers to any treatment of a condition
or disease in a subject and may include: (i) preventing the disease
or condition from occurring in the subject which may be predisposed
to the disease but has not yet been diagnosed as having it; (ii)
inhibiting the disease or condition, i.e., arresting its
development; relieving the disease or condition, i.e., causing
regression of the condition; or (iii) ameliorating or relieving the
conditions caused by the disease, i.e., symptoms of the disease.
Treatment could be used in combination with other standard
therapies or alone. Treatment or "therapy" of a subject also
includes any type of intervention or process performed on, or the
administration of an agent to, the subject with the objective of
reversing, alleviating, ameliorating, inhibiting, slowing down or
preventing the onset, progression, development, severity or
recurrence of a symptom, complication or condition, or biochemical
indicia associated with a disease.
[0059] Riluzole is currently available in the market as RILUTE.RTM.
(riluzole) is available from Sanofi-Aventis, Bridgewater, N.J. and
has the structure shown below.
##STR00003## [0060] 6-(trifluoromethoxy)benzothiazol-2-amine.
[0061] Certain preferred riluzole prodrugs have the structure:
##STR00004##
[0062] including enantiomers, diastereomers, hydrates, solvates,
pharmaceutically acceptable salts, and complexes thereof,
wherein:
[0063] R.sub.23 is selected from the group consisting H, CH.sub.3,
CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CCH,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2OH, CH.sub.2OCH.sub.2Ph,
CH.sub.2CH.sub.2OCH.sub.2Ph, CH(OH)CH.sub.3, CH.sub.2Ph,
CH.sub.2(cyclohexyl), CH.sub.2(4-OH--Ph), (CH.sub.2).sub.4NH.sub.2,
(CH.sub.2).sub.3NHC(NH.sub.2)NH, CH.sub.2(3-indole),
CH.sub.2(5-imidazole), CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CONH.sub.2, and
CH.sub.2CH.sub.2CONH.sub.2. Such agents may be useful as part of
the combination of the present invention.
[0064] One especially preferred riluzole prodrug, troriluzole (also
known as "trigriluzole"), has the following formula:
##STR00005##
[0065] Prodrugs of riluzole are described, for example, in U.S.
patent application Ser. No. 14/385,551, U.S. patent application
Ser. No. 14/410,647, PCT Application Serial No. PCT/US2016/019773
and PCT Application Serial No. PCT/US2016/019787.
[0066] The riluzole prodrugs may be present as isotopically labeled
forms of compounds detailed herein. Isotopically labeled compounds
have structures depicted by the formulas given herein except that
one or more atoms are replaced by an atom having a selected atomic
mass or mass number. Examples of isotopes that can be incorporated
into compounds of the disclosure include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such
as, but not limited to .sup.2H (deuterium, D), .sup.3H (tritium),
.sup.nC, .sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.31P,
.sup.32P, .sup.35S, Cl and I. Various isotopically labeled
compounds of the present disclosure, for example those into which
radioactive isotopes such as .sup.3H, .sup.13C and .sup.14C are
incorporated, are provided. Such isotopically labeled compounds may
be useful in metabolic studies, reaction kinetic studies, detection
or imaging techniques, such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT) including
drug or substrate tissue distribution assays or in radioactive
treatment of subjects (e.g. humans). Also provided for isotopically
labeled compounds described herein are any pharmaceutically
acceptable salts, or hydrates, as the case may be.
[0067] In some variations, the compounds disclosed herein may be
varied such that from 1 to "n" hydrogens attached to a carbon atom
is/are replaced by deuterium, in which "n" is the number of
hydrogens in the molecule. Such compounds may exhibit increased
resistance to metabolism and are thus useful for increasing the
half-life of the compound when administered to a subject. See, for
example, Foster, "Deuterium Isotope Effects in Studies of Drug
Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such
compounds are synthesized by means well known in the art, for
example by employing starting materials in which one or more
hydrogens have been replaced by deuterium.
[0068] Deuterium labeled or substituted therapeutic compounds of
the disclosure may have improved drug metabolism and
pharmacokinetics (DMPK) properties, relating to absorption,
distribution, metabolism and excretion (ADME). Substitution with
heavier isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life, reduced dosage requirements and/or an
improvement in therapeutic index. An .sup.18F labeled compound may
be useful for PET or SPECT studies. Isotopically labeled compounds
of this disclosure can generally be prepared by carrying out the
procedures known to those skilled in the art by substituting a
readily available isotopically labeled reagent for a
non-isotopically labeled reagent. It is understood that deuterium
in this context is regarded as a substituent in the compounds
provided herein.
[0069] The concentration of such a heavier isotope, specifically
deuterium, may be defined by an isotopic enrichment factor. In the
compounds of this disclosure any atom not specifically designated
as a particular isotope is meant to represent any stable isotope of
that atom. Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen", the position is understood to
have hydrogen at its natural abundance isotopic composition.
[0070] The riluzole prodrugs of the present invention may be given
orally, sublingually, intranasally, buccally, subcutaneously or in
any other suitable means of delivery.
[0071] The dose of the riluzole prodrug to be administered may
depend on the subject to be treated inclusive of the age, sex,
weight and general health condition thereof. In this regard,
precise amounts of the agent(s) for administration will depend on
the judgment of the practitioner. In determining the effective
amount of the riluzole prodrug to be administered in the treatment
or reducing of the conditions associated with the symptoms and
disorders, the physician may evaluate clinical factors including
symptoms severity or progression of the disorder. The effective
amount of the treatment will vary depending on the subject and
disease state being treated, the severity of the affliction and the
manner of administration, and may be determined routinely by one of
ordinary skill in the art.
[0072] The riluzole prodrug for treating ataxia or symptoms may be
dosed at or below about 400 mg/day, at or below about 300 mg/day,
at or below about 200 mg/day, at or below about 150 mg/day, at or
below about 100 mg/day, at or below about 70 mg/day, at or below
about 60 mg/day, at or below about 50 mg/day, at or below about
42.5 mg/day, at or below about 37.5 mg/day at or below about 35
mg/day, at or below about 20 mg/day, at or below about 17.5 mg/day,
at or below about 15 mg/day, at or below about 10 mg/day, at or
below about 5 mg/day, or at or below about 1 mg/day. In one aspect,
the riluzole prodrug is administered to the patient at a dosage of
from about 17.5 to 200 mg per day, preferably about 17.5, or 35, or
70, or 100, or 140, or 200 mg per day.
[0073] Typical dosing frequencies for the riluzole prodrugs include
once a day, twice a day, three times a day, four times a day, once
every other day, once a week, twice a week, three times a week,
four times a week, once every two weeks, once or twice monthly, and
the like. The dosing frequency is typically once per day, e.g., 140
mg per dose, or twice per day, e.g., 70 mg per dose, when
administered orally for ingestion.
[0074] The pharmaceutical compositions of the present invention
comprising the riluzole prodrug typically also include other
pharmaceutically acceptable carriers and/or excipients such as
binders, lubricants, diluents, coatings, disintegrants, barrier
layer components, glidants, coloring agents, solubility enhancers,
gelling agents, fillers, proteins, co-factors, emulsifiers,
solubilizing agents, suspending agents and mixtures thereof. A
skilled artisan in the art would know what other pharmaceutically
acceptable carriers and/or excipients could be included in the
formulations according to the invention. The choice of excipients
would depend on the characteristics of the compositions and on the
nature of other pharmacologically active compounds in the
formulation. Appropriate excipients are known to those skilled in
the art (see Handbook of Pharmaceutical Excipients, fifth edition,
2005 edited by Rowe et al., McGraw Hill) and have been utilized to
yield a novel sublingual formulation with unexpected
properties.
[0075] Examples of pharmaceutically acceptable carriers that may be
used in preparing the pharmaceutical compositions of the present
invention may include, but are not limited to, fillers such as
sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose,
polyvinyl-pyrrolidone (PVP), talc, calcium sulphate, vegetable
oils, synthetic oils, polyols, alginic acid, phosphate buffered
solutions, emulsifiers, isotonic saline, pyrogen-free water and
combinations thereof. If desired, disintegrating agents may be
combined as well, and exemplary disintegrating agents may be, but
not limited to, cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof such as sodium alginate. In general,
the pharmaceutical compositions of the present invention may be
manufactured using methods known in the art, for example, by means
of conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping, lyophilizing
processes and the like.
[0076] The pharmaceutical compositions of the present invention may
be administered in any suitable dosage form which can determined by
those skilled in the art. Typical dosage forms include tablets and
capsules for oral ingestion, orally dissolving or disintegrating
tablets or films for sublingual, buccal or other mucosal
administration, transdermal patches, and the like.
[0077] In one aspect of the invention, the riluzole prodrug is
provided in a form of an orally dissolving or disintegrating tablet
(ODT) for sublingual administration. In general, the excipients,
including mannitol and gelatin, are blended, solubilized with water
and deaerated before being mixed with the active pharmaceutical
ingredient (API), which has been milled separately. The particle
size of the API (D50) is less preferably than about 2 microns. The
mixture is lyophilized by flash freezing and then freeze-dried. The
effective amount of riluzole prodrug for the sublingual formulation
useful in the present invention to achieve a therapeutically
effective dose may be less than that of orally administered agent.
For example, the effective dose of the sublingual formulation of
the riluzole prodrug may be about 1 to 95%, preferably 50 to 90%,
more preferably 70 to 85% and most preferably about 80% of that of
the orally administered agent in a conventional tablet or capsule.
In one aspect of the invention, the pharmaceutical compositions are
prepared in an ODT form as described in U.S. Pat. No. 9,192,580,
issued Nov. 24, 2015. ODT dosage forms are further described by
Gregory et al., U.K. Patent No. 1,548,022 using fish gelatin as the
carrier. Fish gelatins suitable for use in the invention are
commercially available.
[0078] Typically, the ODT dosage form disintegrate or disperse
within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably
1 to 10 seconds and particularly 2 to 8 seconds, after being placed
in contact with a fluid. The fluid is preferably that found in the
oral cavity, i.e., saliva, as with oral administration.
[0079] The ODT compositions according to the invention can also
contain, in addition to the active ingredient arid fish gelatin
carrier, other matrix forming agents and secondary components.
Matrix forming agents suitable for use in the present invention
include materials derived from animal or vegetable proteins, such
as other gelatins, dextrins and soy, wheat and psyllium seed
proteins; gums such as acacia, guar, agar, and 10 xanthan;
polysaccharides; alginates; carboxymethylcelluloses; carrageenans;
dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone;
and polypeptide/protein or polysaccharide complexes such as
gelatin-acacia complexes.
[0080] Other materials which may also be incorporated into the ODT
compositions of the present invention include sugars such as
mannitol, dextrose, lactose, galactose, and trehalose; cyclic
sugars such as cyclodextrin; inorganic salts such as sodium
phosphate, sodium chloride and aluminum silicates; and amino acids
having from 2 to 12 carbon atoms such as glycine, L-alanine,
L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine,
L-leucine and L-phenylalanine. One or more matrix forming agents
may be incorporated into the solution or suspension prior to
solidification (freezing). The matrix forming agent may be present
in addition to a surfactant or to the exclusion of a surfactant. In
addition to forming the matrix, the matrix forming agent may aid in
maintaining the dispersion of any active ingredient within the
solution of suspension. This is especially helpful in the case of
active agents that are not sufficiently soluble in water and must,
therefore, be suspended rather than dissolved. Secondary components
such as preservatives, antioxidants, surfactants, viscosity
enhancers, coloring agents, flavoring agents, pH modifiers,
sweeteners or taste-masking agents may also be incorporated into
the fast-dissolving compositions. Suitable coloring agents include
red, black and yellow iron oxides and FD & C dyes such as
FD&C Blue No. 2 and FD&C Red No. 40 available from Ellis
& Everard. Suitable flavoring agents include mint, raspberry,
licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and
grape flavors and combinations of these. Suitable pH modifiers
include the edible acids and bases, such as citric acid, tartaric
acid, phosphoric acid, hydrochloric acid, maleic acid and sodium
hydroxide. Suitable sweeteners include, for example, sucralose,
aspartame, acesulfame K and thaumatin. Suitable taste-masking
agents include, for example, sodium bicarbonate, ion exchange
resins, cyclodextrin inclusion compounds, adsorbates or
microencapsulated actives.
[0081] In a preferred aspect of the invention, the ODT compositions
comprises from about 50-70 wt % riluzole prodrug, about 10-30 wt %
fish gelatin, about 10-20 wt % of one or more fillers, and 0.1-5.0
wt % of one or more flavorants.
[0082] Other methods of preparing ODTs may be used without
limitation, and detailed description of general methods thereof
have been disclosed, for example, in U.S. Pat. Nos. 5,631,023;
5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010;
6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626;
6,982,251; 7,282,217; 7,425,341; 7,939,105; 7,993,674; 8,048,449;
8,127,516; 8,158,152; 8,221,480; 8,256,233; and 8,313,768.
[0083] One measure for assessment of the methods of the present
invention is by using the Scale for the Assessment and Rating of
Ataxia ("SARA").
[0084] The SARA was developed as a clinician-administered
instrument to measure severity of symptoms in patients with SCA.
While there are multiple scales available, the SARA has been tested
in many patients with SCA. It has been demonstrated to have
excellent inter-rater reliability [i.e., intraclass correlations of
>0.95 (61, 62)], good test-retest reliability [intraclass
coefficient of 0.90 (61)], high internal consistency [Cronbach's
alpha of >0.94 (61, 62)], sensitivity to change over time in
populations with SCA (2, 63, 64) and able to detect treatment
effects (65). In addition, the SARA scores were highly correlated
with measures of activities of daily living, such as the Barthel
Index (typically used in stroke) and the Unified Huntingtons
Disease Rating Scale Part IV (typically used in Huntingtons
Disease). The SARA scores range from 0 (no ataxia) to 40 (severe).
The SARA takes approximately 15 minutes to administer. Assessed
items include: [0085] Gait (rated 0 to 8) [0086] Stance (0 to 6)
[0087] Sitting (0 to 4) [0088] Speech disturbance (0 to 6) [0089]
Finger chase (0 to 4) [0090] Nose-finger test (0 to 4) [0091] Fast
alternating hand movements (0 to 4) [0092] Heel-shin slide (0 to
4)
[0093] Once each of the 8 categories has been assessed, the total
score is calculated to determine the severity of ataxia. For motor
activities of the four extremities (items 5-8), assessments are
performed bilaterally and the mean values are used to obtain the
total score.
[0094] Other assessments that can be used to measure the
effectiveness of the methods of the present invention include the
following.
[0095] 8-Meter Walk Test
[0096] Advantages of performance-based measures include are that
metric outcomes are amenable to quantitative analysis; are
associated with high inter-rater reliability; and, these particular
tasks are not prone to learning/training effects. In addition,
these tests assess core functional deficits with ataxia, insofar as
fundamental symptoms involve deficits with lower (e.g., walking)
and upper extremity coordination (e.g., fine hand skills). The 8
Meter Walk Test (time in seconds to walk 8 meters at fastest speed
without personal assistance). This task is performed twice.
[0097] 9-Hole Peg Test
[0098] In this test, subjects place/remove pegs from the Rolyan
9-hole peg test apparatus for each hand separately. The task is
assessed twice for both the dominant and non-dominant hand. The
outcome measure is time (seconds).
[0099] The Inventory of Non-Ataxia Symptoms (INAS)
[0100] The INAS was designed for the purpose of assessing the
non-ataxia symptoms that are commonly associated with the inherited
cerebellar ataxias. This is a clinician administered scale that
consists of 30 items that assess 16 symptom domains: [0101]
Reflexes: biceps, patellar, Achilles, extensor plantar reflex;
[0102] Motor Symptoms: spasticity, paresis, muscle atrophy,
fasciculations, myoclonus, rigidity, chorea/dyskinesia, dystonia,
resting tremor; [0103] Sensory Symptoms: impaired vibration sense;
[0104] Ophthalmological findings: fixation/smooth pursuit, fast
saccades, visual acuity; [0105] Reported abnormalities: double
vision, dysphagia, urinary dysfunction, cognitive impairment
(examiner impression).
[0106] Unified Huntigton's Disease Rating Scale Part IV (functional
assessment)
[0107] The Unified Huntington's Disease Rating Scale (UHDRS) is a
clinical rating scale originally developed to assess multiple
domains in subjects with the neurodegenerative illness,
Huntington's Disease. One validated domain (UHDRS-IV) is the
Functional Assessment subscale and its use has been validated in
populations with ataxia (68) in general and SCA (61, 68, 69)
specifically. The UHDRS-IV assesses 25 instrumental and basic
activities of daily living.
[0108] Sheehan Disability Scale (SDS)
[0109] The Sheehan Disability Scale (SDS) is a patient-rated
measure of functional disability in domains of work, social and
family life. The SDS has demonstrated sensitivity to treatment
effects in numerous randomized controlled trials in populations
with varied diagnoses. The assessment is a three item questionnaire
measuring disease-related disruption of work, social life and
family life. Respondents evaluate impairment on an 11 point scale:
"not at all", three categories of "mild", three categories of
"moderate", three categories of "marked", and "extreme".
[0110] The EQ-5D
[0111] The EQ-5D is a patient self-report general health outcome
measure comprised of multiple domains. Sensitivity of symptom
improvement is uncertain. Domains of the EQ-5D include: [0112]
Mobility; [0113] Self-care; [0114] Usual daily activities; [0115]
Pain/Discomfort; [0116] Anxiety/Depression [0117] Visual Analog
Scale rating of overall health
[0118] Clinical Global Impression--Global Improvement (CGI-I)
[0119] This is a 7-point scale that requires the clinician to
assess how much the subject's illness has improved or worsened
relative to the baseline visit and it is rated as follows: [0120]
very much improved [0121] much improved [0122] minimally improved
[0123] no change [0124] minimally worse [0125] much worse [0126]
very much worse
[0127] Patient Global Impression of Change (PGI-C)
[0128] This is a patient self-reported global index scale that may
be used to rate the response of a condition to a therapy.
[0129] Cerebellar Neuropsychiatric Rating Scale (CNRS)
[0130] Based on an emerging understanding of the role of the
cerebellum in neuropsychiatric pathology, the Cerebellar
Neuropsychiatric Rating Scale (CNRS) was developed. This scale is
completed by the informant. Key symptom domains include attentional
control, emotional control, autism spectrum symptoms, psychosis
spectrum symptoms and social skill set. Each domain is assessed by
4 to 9 questions by a collateral informant. There are a total of 35
questions, each with 4 response categories (1-never, 2-sometimes,
3-often, and 4-almost always). Each domain receives a sub-score and
a total score is summed from all domains.
[0131] Cognitive Test Battery
[0132] The Cerebellar Cognitive Affective Schmahmann Syndrome Scale
(CCAS) is a clinician administered tool that assesses
neurocognitive functions that are considered mediated, at least
partially, by the cerebellum: executive function (planning,
set-shifting, abstract reasoning, working memory, and decreased
verbal fluency), linguistic function (dysprosodia, agrammatism and
mild anomia), spatial cognition (Visual spatial organization and
memory), and personality (affective range, disinhibition). The test
battery takes approximately 15 minutes to administer and includes
specific pencil and paper tests that have been shown to assess
deficits in subjects with cerebellar pathology.
[0133] Ophthalmological Assessments (SCA 7 ONLY)
[0134] Subjects with SCA7 can undergo quantitative ophthalmologic
assessments by either an ophthalmologist or qualified technician:
[0135] Best corrected visual acuity (right eye and left eye
measurements): Visual acuity is affected in SCA7 and is therefore
be measured longitudinally. This test is to be applied with the
ETDRS chart (either back-illuminated or projected) with the
patient's correction for distance. [0136] Color vision: SCA7 is
often characterized by cone-rod dystrophy affecting color vision.
Therefore, color vision is be assessed longitudinally, specifically
via a Farnsworth D15 Arrangement Test. Testers (i.e.,
ophthalmologists or qualified technicians) complete a score sheet,
which is used to generate a number of parameters, including Total
Error Score, Selectivity Index, and Confusion Index. [0137]
Multifocal Electroretinogram (mfERG): mfERG measures electrical
responses in the retina from different retinal locations. In SCA7,
mfERG commonly shows loss of photopic function suggestive of
diminished cone photoreceptors. Key parameters include P1 amplitude
and P1 timing in both the right and left eyes for each of the 5
measured rings. [0138] Tonometry: This test assesses intraocular
pressure at baseline. The preferred method utilizes applanation
tonometry.
[0139] Also, within the scope of the present invention are kits
comprising a riluzole prodrug (e.g., riluzole) for therapeutic
uses. Kits typically include a label indicating the intended use of
the contents of the kit and instructions for use. The term label
includes any writing, or recorded material supplied on or with the
kit, or which otherwise accompanies the kit.
EXAMPLES
[0140] The following examples illustrate the invention and are not
intended to limit the scope of the invention.
Example 1
[0141] A clinical study is conducted with the following parameters.
For additional information, refer to ClinicalTrials.gov Identifier
NCT02960893, www.clinicaltrials.gov.
Trial in Adult Subjects With Spinocerebellar Ataxia.
[0142] The purpose of this study is to compare the efficacy of
BHV-4157 versus placebo on ataxia symptoms in subjects with
spinocerebellar ataxia (SCA).
TABLE-US-00001 Condition Intervention Phase Spinocerebellar Ataxias
Drug: BHV-4157Drug: Phase 2 Spinocerebellar Ataxia Type 1 Placebo
Comparator Phase 3 Spinocerebellar Ataxia Type 2 Spinocerebellar
Ataxia Type 3 Spinocerebellar Ataxia Type 6 Spinocerebellar Ataxia
Type 7 Spinocerebellar Ataxia Type 8 Spinocerebellar Ataxia Type
10
[0143] Study Type: Interventional [0144] Study Design: Allocation:
Randomized [0145] Intervention Model: Parallel Assignment [0146]
Masking: Quadruple (Participant, Care Provider, Investigator,
Outcomes Assessor) [0147] Primary Purpose: Treatment [0148]
Official Title: A Phase IIb/III, Randomized, Double-blind,
Placebo-controlled Trial of BHV-4157 in Adult Subjects With
Spinocerebellar Ataxia
Primary Outcome Measures:
[0149] To measure the change in total score on the Scale for
Assessment and Rating of Ataxia (SARA) [ Time Frame: The change in
total score from baseline to week 8. ]
Secondary Outcome Measures:
[0150] To assess the safety and tolerability of BHV-4157 in
subjects with SCA by measuring the frequency and severity of
adverse events and discontinuations of adverse events. [ Time
Frame: Baseline to week 8. ] Measured by the frequency and severity
of adverse events and discontinuations of adverse events.
[0151] To compare efficacy of BHV-4157 with placebo on patient
impression of benefit via use of the PGI-C [ Time Frame: Baseline
to Week 8 ] Change in PGI-C score
Estimated Enrollment: 120
TABLE-US-00002 [0152] Arms Assigned Interventions Experimental:
BHV-4157 Drug: BHV-4157 140 mg QD 140 mg capsule QD Placebo
Comparator: Placebo Comparator Drug: Placebo Comparator matching
placebo capsule QD
Eligibility
TABLE-US-00003 [0153] Ages Eligible for Study: 18 Years to 75 Years
(Adult, Senior) Sexes Eligible for Study: All Accepts Healthy
Volunteers: No
Criteria
[0154] Inclusion Criteria:
[0155] Subjects with a known or suspected diagnosis of the
following specific hereditary ataxias: SCA1, SCA2, SCA3, SCA6,
SCA7, SCA8 and SCA10
[0156] Ability to ambulate 8 meters without assistance (canes and
other devices allowed)
[0157] Screening total SARA total score
[0158] Determined by the investigator to be medically stable at
baseline/randomization and must be physically able and expected to
complete the trial as designed
[0159] Subjects must have adequate hearing, vision, and language
skills to perform SARA ratings, 8 Meter Walk Test and other
neuropsychiatric testing and interviews as specified in the
protocol
Exclusion Criteria:
[0160] Any medical condition other than one of the hereditary
ataxias specified in the inclusion criteria that could
predominantly explain or contribute significantly to the subjects'
symptoms of ataxia
[0161] MMSE score <24
[0162] SARA total score of >30 points at screening
[0163] Clinical history of stroke
[0164] Active liver disease or a history of hepatic intolerance to
medications that in the investigator's judgment, is medically
significant
Additional Exploratory Objectives Include:
[0165] Exploratory Objectives [0166] To compare the efficacy of
BHV-4157 with placebo on non-ataxia symptoms in subjects with SCA
after 8 weeks of treatment, via assessment on the INAS [0167] To
assess pharmacokinetics of BHV-4157 and riluzole as well as assess
their correlations with clinical outcome measures [0168] To compare
efficacy of BHV-4157 with placebo on the 9-hole peg test [0169] To
compare the efficacy of BHV-4157 with placebo on disability as
measured by the Sheehan Disability Scale (SDS) [0170] To compare
efficacy of BHV-4157 with placebo on health outcomes via use of the
EQ-5D [0171] To compare efficacy of BHV-4157 with placebo on
patient impression of benefit via use of the PGI-C [0172] To
compare efficacy of BHV-4157 with placebo on clinician impression
of benefit via use of the CGI-I [0173] To compare efficacy of
BHV-4157 with placebo on activities of daily living, as assessed
via the UHDRS-IV (the functional subscale of the UHDRS) [0174] To
assess correlations of SCA Genotype with treatment effect [0175] In
the subgroup with SCA7, to provide preliminary assessments on
effects of BHV-4157 on ophthalmological assessments [0176] To
compare efficacy of BHV-4157 with placebo on the Cerebellar
Neuropsychiatric Ratings Scale (CNRS) and its subdomains [0177] To
compare efficacy of BHV-4157 with placebo on cognitive function, as
measured by the Cerebellar Cognitive Affective Schmahmann Syndrome
Scale (CCAS) [0178] To compare the effects of BHV-4157 with placebo
on changes in plasma BDNF and proBDNF levels [0179] To compare the
effects of BHV-4157 with placebo on the video-recorded assessment
of the gait item (Item 1) of the SARA, as assessed by a blinded
rater
The Study Design is as Follows:
[0180] The study is a Phase IIb/III, multicenter, randomized,
double-blind, 2-arm placebo-controlled parallel-group study
designed to assess safety, tolerability, and efficacy signals in a
population of patients with Spinocerebellar Ataxia (SCA). Subjects
will be randomized to receive placebo (QD) or BHV-4157 (140 mg QD),
stratified by diagnosis (genotype) and baseline severity (Gait Item
of the SARA of .ltoreq.4 and >4). Subjects with SCA3 genotype
will be limited to comprise up to approximately 10% of the total
population so that this most common type of SCA is not
over-represented.
[0181] Dosing will continue for 8 weeks. Subjects will return to
the clinic two weeks after discontinuing study medication for a
follow-up safety visit. In addition, subjects completing the
Randomization Phase will be offered 48 weeks of open-label
treatment as long as the PI believes open-label treatment offers an
acceptable risk-benefit profile. Subjects who agree to enter the
Extension Phase will not be required to wash-out of drug or
complete the follow-up safety visit, but instead should continue
dosing as specified in the extension phase.
[0182] Subjects entering the Extension Phase would have their first
Extension Visit four weeks after the Week 8 Randomization Phase
visit. If there is a delay of two weeks or more in dosing between
the Randomization Phase and the Extension Phase, subjects will be
required to complete an Extension Baseline Visit. Thereafter,
subjects will undergo visits every fourth week through Week 12 of
this phase. Then subjects will undergo visits every 12 weeks up to
Week 48 of this phase. All subjects will undergo a post study drug
termination visit two weeks after the last dose of study drug in
the Extension Phase.
[0183] Subjects will receive placebo (QD) or BHV-4157 (140 mg QD)
loose filled capsule. It is recommended that all patients ingest
this drug once every day in the morning (approximately at the same
time each day), without regard to meals. If subjects have
difficulty tolerating morning dosing (such as experiencing
sedation) then the investigator may permit the subject to switch to
night time dosing (and document this change).
[0184] Tables 1 to 7 below show data from Example 1.
TABLE-US-00004 TABLE 1 STABLE Subjects, defined by SCR-to-BLSARA
within 1 point.sup.# .DELTA. Btw Groups Response BHV-4157 Placebo
[95% CI] Definition BHV-4157 Placebo *p-value Total SARA -0.90
-0.50 -0.39 .gtoreq.3 points 24% 3.4% 0.03 STABLE (n = 34) (n = 29)
(-1.2-0.45) Total SARA -0.87 -1.49 0.62 .gtoreq.1 point 59% 41%
0.21 UNSTABLE (n = 28) (n = 38) (-0.61-1.85) STABLE NOT- STABLE
BHV-4157 Placebo BHV-4157 Placebo (n = 34) (n = 29) (n = 28) (n =
38) Total SARA -0.90 -0.50 -0.87 -1.49 Axial SARA [#1-4] -0.27 0.18
-0.46 -0.48 Appendicular SARA [4-8] -0.36 -0.44 -0.15 -0.69 Stable
baseline defined as Total SARA scores at screening and baseline
within the group median of 1 point, comprising 63 subjects (49% of
total sample) *fisher exact test without correction for multiple
comparisons .sup.#.ltoreq.1 point on Total SARA sore 1
TABLE-US-00005 TABLE 2 Population selected based on Experience of
Site/Raters Sites selected on the basis that the Principal
Investigator has over two decades of ataxia research and PIs are
raters, represents 72 subjects (55% of total sample) BHV-4157
Placebo .DELTA. Btw Groups (n = 37) (n = 35) [95% CI] Total SARA
-1.37 -0.97 -0.40 [-1.3-0.52] Gait [#1] -0.14 -0.06 -0.08
[-0.29-0.14] Axial Items [#1-4] -0.47 0.05 -0.52 [-1.1-0.07]
Appendicular [#5-8] -0.52 -0.68 0.16 [-0.39-0.72] Response
Definition BHV-4157 Placebo *p-value .gtoreq.3 points 21.6% 5.7%
0.09 .gtoreq.1 point 51.4% 31.4% 0.10 *, analytic model identical
to primary presenting LSmeans *, fisher exact test without
correction for multiple comparisons
TABLE-US-00006 TABLE 3 Population selected based on Experience of
Site/Raters BHV-4157 Placebo .DELTA. Btw Groups (n = 37) (n = 35)
[95% CI] Total SARA -4.37 -0.97 -0.40 [-1.3-0.52] Gait [#1] -0.14
-0.06 -0.08 [-0.29-0.14] Axial Items [#1-4] -0.47 0.05 -0.52
[-1.1-0.07] Appendicular [#5-8] -0.52 -0.68 0.16 [-0.39-0.72] *,
analytical model identical to primary, presenting LSmeans Assuming
true difference from data above, 500 subjects per arm would be
required to provide 90% power for a randomized controlled trial A
study this large is prohibitive for orphan indication and presents
challengesin detecting signals at 8-weeks Placebo effects may
extinguish over long-term Longitudinal cohort can be compared to
Natural History Cohort to demonstrate neuroprotective effects
TABLE-US-00007 TABLE 4 Exposure Proxy: Weight(lighter) BHV-4157
Placebo .DELTA. Btw Groups Lighter median (n = 27) (n = 39) [95%
CI] Total SARA* -1.38 -0.89 -0.50 [-1.8-0.60] Axial Items [1-4]
-0.85 -0.49 Appendicular Items [5-8] -0.69 -0.46 Change in Total
SARA Score Efficacy .DELTA. SARA Responder Analysis Sample BHV-4157
Placebo [95% CI] Responce Definition BHV-4157 Placebo P-value* All
Lighter -0.38 -0.89 -0. 0 .gtoreq.3 points in All 33% 18% 0.24
Subjects (n = 27) (n = 39) (-2.6-0. 0) Subjects (n = ) STABLE -1.18
-0.35 -0.83 .gtoreq.3 points at 26% 0 0.05 Subgroup (n = 29) (n =
17) Experience (n = 36) EXP Sites -1.64 -0. 1 -1.03 .gtoreq.3
points in Stable 3 % 5% 0.02 (n = 18) (n = 19) Subjects (n = )
*Sample divided by median weight (.ltoreq.76.4 vs >76.4 kg)
*Lighter median had crude prelimiminary estimate of 40% greater
exposure (using unmodeled data) and Phase 1 studies show
correlation of weight with exposure *fisher exact test without
correction for multiple comparisons indicates data missing or
illegible when filed
TABLE-US-00008 TABLE 5 Exposure Proxy: Weight Examination of PGIC
and CGI - no correlation or trend in general population or general
subpopulations Trends in lighter weight sample (from total subset
and among experienced sites) Sample BHV-4157 Placebo CGI Any
improvement Lighter 64% (n = 22) 45% (n = 29) Much improved '' 27%
7% Any Improvement Lighter at EXP sites 60% (n= 15) 33% (n = 12)
Much Improved '' 14% 3% PGI Any Improvement Lighter 34% (n = 23)
20% (n = 29) "Better and Definite '' 17% 0 improvement that has
made a real & worthwhile difference" Any Improvement Lighter at
EXP sites 45% (n = 16) 8% (n = 12) Better and Definite . . . '' 19%
0
TABLE-US-00009 TABLE 6 Gender as proxy for Exposure Females have
greater may have approximately 50% greater exposure based on Phase
1 data (c/w Rilutek USPI) Responder Analysis Change in Total SARA
Score Response Females BHV-4157 Placebo Definition BHV-4157 Placebo
All Subjects -1.08 -0.83 .gtoreq.3 points in 32% 17% (n = 31) (n =
36) All Subjects (n = 67) STABLE -1.33 -0.40 .gtoreq.3 points at
39% 0 Subgroup (n = 18) (n = 15) Experienced sites (n = 33)
Experience -1.15 -0.64 .gtoreq.3 points in 35% 6% of Sites (n = 20)
(n = 18) Stable Subjects (n = 38)
TABLE-US-00010 TABLE 7 Gender as proxy for Exposure Females
Subjects in Females Subjects in Stable Subgroup Experienced Site
Group Response BHV-4157 Placebo Response BHV-4157 Placebo
Definition (n = 18) (n = 15) Definition (n = 17) (n = 18) .gtoreq.3
points 39% 0 .gtoreq.3 points 41% 6% .gtoreq.1 point 67% 33%
.gtoreq.1 point 71% 28%
Example 2
[0185] This example describes a study entitled: Interim Extension
Phase Analyses of Study BHV4157-201: Phase IIb/III, Randomized,
Double-blind, Placebo-controlled Trial of Troriluzole (BHV-4157) in
Adult Subjects with Spinocerebellar Ataxia followed by 96-Week
Open-Label Extension Phase.
[0186] Introduction/Background:
[0187] Hereditary Spinocerebellar Ataxias (SCA) are progressive
neurodegenerative disorders that are characterized clinically by
progressive ataxia and are attributed to various autosomal dominant
genetic mutations. Currently, there are no FDA medications approved
for this debilitating disorder and treatment remains supportive.
The shared symptomatic manifestations of the SCAs may reflect
common pathology affecting cerebellar purkinje cell fibers. Prior
studies suggest that riluzole, via multiple mechanisms, including
glutamate modulation, may improve a range of genetically determined
ataxias, potentially by affecting Purkinje excitability.
Troriluzole (BHV-4157; formerly trigriluzole) is a novel pro-drug
of riluzole. An on-going Phase llb/Ill study, BHV4157-201, is
predicated on preclinical and clinical studies that implicate a
role for troriluzole in the potential treatment of SCA.
[0188] As previously reported, in the primary analysis from the
8-week Randomization Phase of the trial troriluzole showed
numerical improvement on the total score on the Scale for
Assessment and Rating of Ataxia (SARA) at Week 8 but did not meet
the study criteria in differentiating from placebo; however,
post-hoc analyses showed trends for therapeutic benefit in relevant
subgroups (e.g., those projected to have higher exposures, those
with stable pre-randomization baseline SARA scores). In addition,
data from the randomization phase of the trial suggested a
systematic difference in response between the appendicular items
and the axial SARA items. When the primary analytic method was
applied to the axial items and appendicular items separately, the
appendicular items appear particularly sensitive to a placebo
effect. To date, all subjects have had the chance to complete the
Week 24 visit from the long term, open-label extension phase of the
trial. In this presentation, results are presented on the course of
the population up to Week 48.
[0189] Study Design:
[0190] BHV4157-201 is an on-going Phase IIb/III, multicenter,
randomized, double-blind, 2-arm p lacebo-controlled parallel-group
study designed to assess safety, tolerability, and efficacy in a
population of patients with Spinocerebellar Ataxia (SCA). The study
is comprised of two periods: an 8-week randomization period,
followed by a 96-week open-label extension period. Regarding key
entry criteria, subjects were male and female outpatients between
the ages of 18-75 years, inclusive, with a known or suspected
diagnosis of the following hereditary ataxias: SCA1, SCA2, SCA3,
SCA6, SCA7, SCA8 and SCA10. All subjects completed genetic testing
to confirm the diagnosis of hereditary ataxias. The primary
objective of the study is to compare the efficacy of troriluzole
versus placebo on ataxia symptoms in patients with SCA as measured
by the total score on the Scale for the Assessment and Rating of
Ataxia (SARA). Secondary objectives include assessments of
functional disability, non-ataxia symptoms associated with SCA,
global functioning, performance-based measures of ataxia, and
neuropsychiatric and cognitive functioning.
[0191] During the 8-week Randomization Phase of the study, which
has been completed, 141 subjects were randomized, in a 1:1 ratio,
to receive either BHV-4157 (140 mg daily) or Placebo. Subjects
completing the Randomization Phase were offered approximately 96
weeks of open-label treatment, provided the investigator believed
open-label treatment offered an acceptable risk-benefit profile.
131 subjects entered the Extension Phase of the study, which is
currently on-going.
[0192] Results:
[0193] The ongoing, open-label, extension phase of BHV4157-201 has
high participation rates (99% of those completing the double-blind
randomization phase; N=131) and subjects who have completed up to
48 weeks of treatment demonstrate continued improvement from Week 8
and baseline. Interim analyses based on the design adaptations
described above show a consistent change in score for the axial
items of the SARA (modified SARA) for all treated patients at
various time points as compared to randomization baseline (Table
8). Notably, at week 24 and also week 48, subjects had a decrease
of -0.40 (STDV=1.17 and 1.08, respectively) in modified SARA
scores. Including analysis at 8 weeks and 36 weeks, these
improvements were slightly higher in patients with lower weight and
female gender. See also Tables 9-14 which show scores for various
subgroups.
TABLE-US-00011 TABLE 8 Modified SARA change from Randomization
Baseline - All Patients Mod SARA Time Period N change (SD) 8 weeks
126 -0.4 (1.50) 24 weeks 113 -0.3 (1.35) 36 weeks 102 -0.1 (1.30)
48 weeks 96 -0.0 (1.44)
TABLE-US-00012 TABLE 9 Modified SARA change from Randomization
Baseline - Low Weight Subgroup Mod SARA Time Period N change (SD) 8
weeks 63 -0.6 (1.56) 24 weeks 58 -0.5 (1.44) 36 weeks 54 -0.3
(1.34) 48 weeks 50 -0.2 (1.41)
TABLE-US-00013 TABLE 10 Modified SARA change from Randomization
Baseline - Female Subgroup Mod SARA Time Period N change (SD) 8
weeks 64 -0.3 (1.48) 24 weeks 59 -0.4 (1.32) 36 weeks 54 -0.1
(1.41) 48 weeks 50 -0.1 (1.50)
TABLE-US-00014 TABLE 11 Modified SARA change from Randomization
Baseline - by SCA1 & SCA2 Mod SARA Time Period N change (SD) 8
weeks 65 -0.5 (1.47) 24 weeks 60 -0.4 (1.45) 36 weeks 57 -0.1
(1.20) 48 weeks 54 -0.1 (1.44)
TABLE-US-00015 TABLE 14 Modified SARA change from Randomization
Baseline - by Non-SCA1 & SCA2 Mod SARA Time Period N change
(SD) 8 weeks 58 -0.3 (1.58) 24 weeks 53 -0.3 (1.24) 36 weeks 45
-0.1 (1.44) 48 weeks 42 -0.2 (1.44)
[0194] The observed changes provide consistent sustained
improvements or lack of decline in modified SARA scores at all time
periods and across sub-groups (the low-weight and female being
suggestive of a dose/weight response). This change also contrasts
with an increase of +0.99 (STDV =2.04) in axial SARA score as
described in the natural history study by Ashizawa et al at 1 year
(1). From the derived minimum clinically important difference
(MCID) of 0.75, these observed changes with troriluzole treatment
infer a benefit exceeding the MCID.
[0195] Conclusions:
[0196] Studies in SCA suggest a mechanistic role for the glutamate
modulator troriluzole in the treatment of patients with hereditary
spinocerebellar ataxia. Preliminary analyses, including data from
both the randomization phase and long-term extension phase of the
BHV4157-201 trial, suggest a sustained, clinically relevant disease
modifying treatment benefit of troriluzole relative to the natural
disease progression at all follow-up time periods. While the
natural history study by Ashizawa et al at 1 year shows an
approximately +1 point worsening in the axial SARA score of
patients with hereditary ataxias, the current ongoing trial shows a
-0.1 point improvement in the axial SARA score of study
participants at 6 months and no decline at 48 weeks. See, Ashizawa
T, Figueroa K, Perlman S, Gomez C, Wilmot G, Schmahmann J, Ying S,
Zesiewicz T, Paulson H, Shokkottai V, Bushara K, Kuo S, Geschwind
M, Xia G, Mazzoni P, Krischer J, Cuthbertson D, Holbert A, Ferguson
J, Pulst S, Subramony S. Clinical characteristics of patients with
spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective
observational study. Orphanet J Rare Dis. 2013; 8: 177. These
trends are consistent with results from two prior positive studies
using the active metabolite of troriluzole. See, Ristori G, Romano
S, Visconti A, Cannoni S, Spadaro M, Frontali M, Pontieri F E,
Vanacore N, Salvetti M. Riluzole in cerebellar ataxia: a
randomized, double-blind, placebo-controlled pilot trial.
Neurology. 2010;74(10):839-45; and Romano S, Coarelli G, Marcotulli
C, Leonardi L, Piccolo F, Spadaro M, Frontali M, Ferraldeschi M,
Vulpiani M C, Ponzelli F, Salvetti M, Orzi F, Petrucci A, Vanacore
N, Casali C, Ristori G. Riluzole in patients with hereditary
cerebellar ataxia: a randomized, double-blind, placebo-controlled
trial. Lancet Neurol. 2015;14(10):985-91. Epub 2015/09/01. doi:
10.1016/51474-4422(15)00201-x. PubMed PMID: 26321318. Based on the
totality of this data and the favorable tolerability profile of
troriluzole, the Applicant believes that troriluzole may offer
benefit to patients with SCA and is initiating further clinical
trials with this investigational agent. Study design improvements
will be incorporated into future trials based upon our Phase 2
trial experience including utilization of a modified SARA scale,
enhanced rater training procedures, enrichment of trial population
with particular genotypes and extension of study endpoints.
Example 3
[0197] This example describes a further analysis of the study of
Example 1. SASA scores were obtained and are reported in Table 15,
below. It can be seen that the Modified SARA attenuates the placebo
effect, and shifts the difference in favor of BHV-4157 ('all SCA').
The differences are slightly greater in SCA1&SCA2 but the
combination of stability and SCA1+2 subtype yields the largest
difference between BHV-4157 and placebo. Table 16 shows the eight
week change from baseline. For the enriched geneotypes, the stable
2 group showed a change in SARA score of 0.24 (-0.387--0.083) and
the stable group 1 showed a change in SARA score of 0.20
(-0.286--0.083).
TABLE-US-00016 TABLE 15 Modified SARA SCA1 and SCA2 Total SARA All
SCA Stable (-1 < diff < 1) Stable (-1 < diff < 1) Visit
BHV PBO BHV PBO BHV PBO BHV PBO BHV PBO May-18 Baseline n = 71 n =
68 4.127 4.426 2.177 2.268 n = 139 n = 139 14.230 4.426 4.465 2.212
week 8 n = 63 n = 68 n = 63 n = 68 n = 33 n = 36 n = 31 n = 27 n =
14 n = 12 .DELTA. Mean -0.810 -1.103 -0.429 -0.382 -0.424 -0.361
-0.387 -0.148 -0.286 -0.083 SD 1.765 2.282 0.946 1.305 1.062 1.457
0.955 1.134 0.914 1.379 StdChg 0.459 0.483 0.453 0.293 0.399 0.248
0.405 0.131 0.313 0.060 Sep-17 week 8 n = 63 n = 68 .DELTA. Mean
-0.810 -1.106 SD 1.765 2.322 StdChg 0.459 0.456
TABLE-US-00017 TABLE 16 8 WEEK CHANGE FROM BASELINE Enriched
Genotypes Total SARA. Mod SARA. Stable 2 Stable 1 Value - BHV5157
-0.81 -0.429 -0.387 -0.286 Value - Placebo -1.103 -0.382 -0.148
-0.083 STABLE 1 = 1 unit change between Baseline & Screening
total SARA STABLE 2 = 2 unit change between baseline and screening
total SARA
Example 4
[0198] A clinical study is conducted with the following parameters.
For additional information, refer to ClinicalTrials.gov Identifier
NCT03701399, www.clinicaltrials.gov.
BHV-4157 in Adult Subjects With Spinocerebellar Ataxia.
[0199] The purpose of this study is to compare the efficacy of
BHV-4157 (200 mg once daily) versus placebo after 48 weeks of
treatment in subjects with spinocerebellar ataxia (SCA).
TABLE-US-00018 Condition Intervention Phase Spinocerebellar Ataxias
Drug: troriluzole Phase 3 Spinocerebellar Ataxia Type 1 Drug:
Placebos Spinocerebellar Ataxia Type 2 Spinocerebellar Ataxia Type
3 Spinocerebellar Ataxia Type 6 Spinocerebellar Ataxia Type 7
Spinocerebellar Ataxia Type 8 Spinocerebellar Ataxia Type 10
[0200] Study Type: Interventional [0201] Study Design: Allocation:
Randomized [0202] Intervention Model: Parallel Assignment [0203]
Masking: Triple (Participant, Care Provider, Investigator) [0204]
Primary Purpose: Treatment [0205] Official Title: A Phase Ill, Long
Term, Randomized, Double-blind, Placebo-controlled Trial of
BHV-4157 in Adult Subjects With Spinocerebellar Ataxia
Primary Outcome Measures:
[0206] 1. Change in the total score of the Modified Scale for the
Assessment and Rating of Ataxia (SARA) BHV-4157 versus placebo on
ataxia symptoms in subjects with spinocerebellar ataxia (SCA) Type
1 and Type 2, after 48 weeks of treatment. [0207] An increase in
the total score indicates a worsening of symptoms. Change in the
total score of the Modified Scale for the Assessment and Rating of
Ataxia (SARA) BHV-4157 versus placebo on ataxia symptoms in
subjects with spinocerebellar ataxia (SCA) Type 1 and Type 2, after
48 weeks of treatment.
Secondary Outcome Measures:
[0208] 2. Change of total score as measured by the Modified Scale
for the Assessment and Rating of Ataxia of BHV-4157 versus placebo
on ataxia symptoms in subjects with spinocerebellar ataxia (SCA) of
any genotype after 48 weeks of treatment [0209] An increase in the
total score indicates a worsening of symptoms. Change of total
score as measured by the Modified Scale for the Assessment and
Rating of Ataxia of BHV-4157 versus placebo on ataxia symptoms in
subjects with spinocerebellar ataxia (SCA) of any genotype after 48
weeks of treatment. [Time Frame: Baseline to week 48]
[0210] 3. To assess of the safety and tolerability of BHV-4157 in
subjects with SCA by measuring the frequency and severity of
adverse events and discontinuations due to adverse events. [Time
Frame: Baseline to week 48]
[0211] 4. Measure the change in total score of BHV-4157 versus
placebo on patient impression of benefit via use of the Patient
Impression of Function and Activities of Daily Living Scale
(PIFAS). An increase in the total score indicates a worsening of
symptoms. Measure the change in total score of BHV-4157 versus
placebo on patient impression of benefit via use of the Patient
Impression of Function and Activities of Daily Living Scale
(PIFAS). [Time Frame: Baseline to week 48]
[0212] 5. Measure the change in the Neuro-QOL Fatigue Scale
comparing BHV-4157 versus placebo on daily fatigue and activities.
[0213] A decrease in the total score indicates a worsening of
symptoms. Measure the change in the Neuro-QOL Fatigue Scale
comparing BHV-4157 versus placebo on daily fatigue and activities.
[Time Frame: Baseline to week 48]
[0214] 6. To measure the change on upper extremity function and
activities as measured by the Neuro-QOL Upper Extremity Scale for
BHV-4157 versus placebo [0215] A decrease in the total score
indicates a worsening of symptoms. To measure the change on upper
extremity function and activities as measured by the Neuro-QOL
Upper Extremity Scale for BHV-4157 versus placebo. [Time Frame:
Baseline to week 48]
[0216] 7. To measure the change on lower extremity mobility and
activities as measured by the Neuro-QOL Lower extremity mobility
scale for cBHV-4157 versus placebo. [0217] A decrease in the total
score indicates a worsening of symptoms. To measure the change on
lower extremity mobility and activities as measured by the
Neuro-QOL Lower extremity mobility scale for cBHV-4157 versus
placebo. [Time Frame: Baseline to week 48]
[0218] 8. To measure the change over time comparing BHV-4157 versus
placebo on the clinician impression of global functioning via use
of the Clinical Global Impression-Global Improvement Scale (CGI-I)
[0219] An increase in the total score indicates a worsening of
symptoms. To measure the change over time comparing BHV-4157 versus
placebo on the clinician impression of global functioning via use
of the Clinical Global Impression-Global Improvement Scale (CGI-I).
[Time Frame: Baseline to week 48]
[0220] 9. To measure the change over time comparing BHV-4157 versus
placebo on patient impression of global functioning as measured by
the Patient Global Impression Scale (PGI) [0221] A decrease in the
total score indicates a worsening of symptoms. To measure the
change over time comparing BHV-4157 versus placebo on patient
impression of global functioning as measured by the Patient Global
Impression Scale (PGI). [Time Frame: Baseline to week 48]
[0222] 10. Compare the change of activities of daily living as
measured by the Activities of Daily Living Scale from the
Friedreich's Ataxia Rating Scale (FARS-ADL) for BHV-4157 versus
placebo [0223] An increase in the total score indicates a worsening
of symptoms. Compare the change of activities of daily living as
measured by the Activities of Daily Living Scale from the
Friedreich's Ataxia Rating Scale (FARS-ADL) for BHV-4157 versus
placebo. [Time Frame: Baseline to week 48]
[0224] 11. To measure the change on daily functioning using the
Functional Staging for Ataxia Scale from the Friedreich's Ataxia
Rating Scale (FARS-FUNC) for BHV-4157 versus placebo [0225] An
increase in the total score indicates a worsening of symptoms. To
measure the change on daily functioning using the Functional
Staging for Ataxia Scale from the Friedreich's Ataxia Rating Scale
(FARS-FUNC) for BHV-4157 versus placebo. [Time Frame: Baseline to
week 48] [0226] Estimated Enrollment: 230 participants [0227] Arms
Interventions/treatment
TABLE-US-00019 [0227] Experimental: Arm 1: BHV-4157 Drug:
troriluzole BHV-4157/troriluzole 200 mg PO 200 mg PO Placebo
Comparator: Arm 2: Placebo Drug: Placebos Placebo 200 mg PO 200 mg
PO
Eligibility
TABLE-US-00020 [0228] Ages Eligible for Study: 18 Years to 75 Years
(Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy
Volunteers: No
Criteria
[0229] Inclusion Criteria: [0230] a. Subjects with a known or
suspected diagnosis of the following specific hereditary ataxias:
SCA1, SCA2, SCA3, SCA6, SCA7, SCA8 and SCA10. [0231] i. A subject
has clinical evidence that supports diagnosis of one of the
aforementioned SCA genotypes but does not have producible test
results from a CLIA certified lab from either a family member or
for his or herself and the subject must be willing to undergo such
testing to confirm the SCA diagnosis (in this case, site must wait
for results of genotypic testing prior to randomization). b.
Ability to ambulate 8 meters without human assistance (canes and
other devices allowed). [0232] c. Screening total SARA score 8. d.
Determined by the investigator to be medically stable at
Baseline/randomization as assessed by medical history, physical
examination, laboratory test results, and electrocardiogram
testing. Subjects must be physically able and expected to complete
the trial as designed. [0233] e. Subjects must have adequate
hearing, vision, and language skills to perform SARA ratings and
other neuropsychiatric testing and interviews as specified in the
protocol.
Exclusion Criteria:
[0233] [0234] 1. MMSE score <24. [0235] 2. Any medical condition
other than one of the hereditary ataxias specified in the inclusion
criteria that could predominantly significantly to the subjects'
symptoms of ataxia (for example, alcoholism, vitamin deficiencies,
multiple sclerosis, vascular disease, tumors, paraneoplastic
disease, head injury, idiopathic late onset ataxia, multisystem
atrophy) or that can confound assessment of ataxia symptoms (for
example, stroke, arthritis). [0236] 3. SARA total score of >30
points at screening. [0237] 4. Clinical history of stroke. [0238]
5. Immunocompromised subjects. [0239] 6. Active liver disease or a
history of hepatic intolerance to medications that in the
investigator's judgment, is medically significant.
Study Design and Results
[0240] The study is conducted according to protocols which can be
developed by those skilled in the art. The study subjects are
treated in accordance with the protocols and their condition is
assessed in consideration of the primary and secondary outcome
measures according to medical practice procedures known to those
skilled in the art.
Example 5
[0241] A drug product in the dosage form of a hard gelatin capsule
for oral administration in a strength of 140 mg of BHV-4157 having
a composition as set forth below is prepared by techniques known to
those skilled in the art.
TABLE-US-00021 Component Function Content per Capsule Drug
Substance Active ingredient 140 mg Mannitol Binder/Filler 76.1 mg
Microcrystalline cellulose + Binder/Filler 30.08 mg dicalcium
phosphate Microcrystalline cellulose Binder/Filler 24.16 mg
Hydroxypropyl cellulose Binder/Filler 7.09 mg Crospovidone
Disintegrant 13.09 mg Colloidal silicon dioxide Glidant 1.94 mg
Magnesium stearate Lubricant 1.94 mg (vegetable grade)
[0242] Throughout this application, various publications are
referenced by author name and date, or by patent number or patent
publication number. The disclosures of these publications are
hereby incorporated in their entireties by reference into this
application in order to more fully describe the state of the art as
known to those skilled therein as of the date of the invention
described and claimed herein. However, the citation of a reference
herein should not be construed as an acknowledgement that such
reference is prior art to the present invention.
[0243] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the following claims. For example, it is
intended in accordance with the present invention that combination
therapy using a riluzole prodrug and other therapeutic agents can
be employed to treat ataxia and other associated diseases. Further,
riluzole prodrugs other than those specifically disclosed in the
description and Examples herein can be employed. Furthermore, it is
intended that specific items within lists of items, or subset
groups of items within larger groups of items, can be combined with
other specific items, subset groups of items or larger groups of
items whether or not there is a specific disclosure herein
identifying such a combination.
* * * * *
References