U.S. patent application number 15/966436 was filed with the patent office on 2019-01-10 for formulations, methods, kits, and dosage forms for treating atopic dermatitis and for improved stability of an active pharmaceutical ingredient.
The applicant listed for this patent is Asana BioSciences, LLC. Invention is credited to Louis Denis, Sandeep Gupta, Paras Jariwala, Wantanee Phuapradit, Aruna Railkar, Niranjan Rao, Helen Usansky, David Zammit.
Application Number | 20190008868 15/966436 |
Document ID | / |
Family ID | 63918777 |
Filed Date | 2019-01-10 |
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United States Patent
Application |
20190008868 |
Kind Code |
A1 |
Railkar; Aruna ; et
al. |
January 10, 2019 |
FORMULATIONS, METHODS, KITS, AND DOSAGE FORMS FOR TREATING ATOPIC
DERMATITIS AND FOR IMPROVED STABILITY OF AN ACTIVE PHARMACEUTICAL
INGREDIENT
Abstract
Embodiments of the disclosure relate generally to formulations,
methods of treatment, kits, and dosage forms for treating
inflammatory disorders, including atopic dermatitis, or cancer, the
formulations comprising an active pharmaceutical ingredient. The
formulation provided comprises granules, wherein the granules
comprise: micronized active ingredient; one or more granulation
binders; one or more fillers; one or more disintegrants; and one or
more antioxidants. In one embodiment, the methods of treatment
include orally administering the active ingredient to a subject
suffering from atopic dermatitis, where the active ingredient is in
an amount of about 20 mg to about 80 mg.
Inventors: |
Railkar; Aruna; (Wayne,
NJ) ; Jariwala; Paras; (Somerset, NJ) ;
Phuapradit; Wantanee; (Montville, NJ) ; Zammit;
David; (Fort Lee, NJ) ; Denis; Louis;
(Princeton, NJ) ; Rao; Niranjan; (Montgomery,
NJ) ; Usansky; Helen; (Hillsborough, NJ) ;
Gupta; Sandeep; (Plainsboro, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Asana BioSciences, LLC |
Lawrenceville |
NJ |
US |
|
|
Family ID: |
63918777 |
Appl. No.: |
15/966436 |
Filed: |
April 30, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62491655 |
Apr 28, 2017 |
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62514246 |
Jun 2, 2017 |
|
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62630392 |
Feb 14, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61P 17/00 20180101; A61K 9/2013 20130101; A61K 31/519 20130101;
A61K 9/2018 20130101; A61K 9/2054 20130101; A61P 37/00
20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/20 20060101 A61K009/20; A61P 17/00 20060101
A61P017/00 |
Claims
1. A pharmaceutical formulation for treating one or more diseases
characterized by the dysregulation of the Syk/JAK pathway,
comprising granules, wherein the granules comprise: micronized
active ingredient; one or more granulation binders; one or more
fillers; one or more disintegrants; and one or more antioxidants,
and the active ingredient is a compound of Formula (I) or a
pharmaceutically acceptable salt, enantiomer or prodrug thereof,
##STR00009## wherein R1 is a 6-membered ring of Formula (II):
##STR00010## wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to
C6) alkyl CN; and wherein R2 is a benzene ring of Formula (III):
##STR00011## wherein R4 is a 6-membered ring of Formula (IV):
##STR00012## wherein R5 is N or CH and R6 is a hydroxyl group,
methanol methyl group, or ethanol ethyl group, and wherein the
formulation has a total API degradation impurity level not above
about 0.6% of the total active ingredient amount after storage at 1
week at 40.degree. C./75% RH in an open container.
2. The formulation of claim 1, wherein the one or more antioxidants
comprise at least one of vitamin E or butylated hydroxytoluene.
3. The formulation of claim 2, wherein the one or more antioxidants
is vitamin E.
4. The formulation of claim 1, wherein the micronized granules have
a particle size of less than about 20 microns.
5. The formulation of claim 1, wherein the one or more fillers
comprise lactose monohydrate and the one or more distintegrants
comprise crospovidone.
6. The formulation of claim 1, wherein one or more granulation
binders are selected from the group consisting of
polyvinylpyrollidone and hydroxypropylcellulose.
7. The formulation of claim 6, wherein the one or more granulation
binders comprise polyvinylpyrollidone having a number average
molecular weight of about 30,000.
8. The formulation of claim 6, wherein the one or more granulation
binders comprise hydroxypropylcellulose having a viscosity at
25.degree. C. of 75-150 centipoise in a 5% w/w in aqueous
solution.
9. The formulation of claim 1, wherein the micronized granules have
an isopropyl alcohol content of less than about 5000 ppm.
10. The formulation of claim 1, wherein the granules are compressed
into a tablet.
11. The formulation of claim 1, further comprising one or more
extragranular components.
12. The formulation of claim 11, wherein the extragranular
components comprise one or more tableting fillers, one or more
disintegrants, one or more lubricants, and optionally one or more
surfactants.
13. The formulation of claim 12, wherein the one or more tableting
fillers comprise microcrystalline cellulose, the one or more
disintegrants comprise croscarmellose sodium, the one or more
surfactants comprise sodium lauryl sulfate, and the one or more
lubricants comprise magnesium stearate.
14. The formulation of claim 13, wherein the micronized granules
and extragranular components are compressed into a tablet.
15. The formulation of claim 14, wherein the micronized granules
have an isopropyl alcohol content of less than about 5000 ppm.
16. The formulation of claim 14, wherein the amount of active
ingredient per tablet is between about 5 to 50 mg.
17. The formulation of claim 14, wherein the amount of active
ingredient per tablet is between about 20 to 80 mg.
18. The formulation of claim 16, wherein the amount of active
ingredient per tablet is about 5 mg, about 20 mg, or about 50
mg.
19. The formulation of claim 17, wherein the amount of active
ingredient per tablet is about 20 mg, about 40 mg, or about 80
mg.
20. The formulation of claim 14, wherein the tablet has a hardness
of about 7 to 9 kP and a disintegration time of less than about 5
minutes in 0.1 N HCl, pH 6.8 and 50 mM phosphate buffer at
37.degree. C.
21. The formulation of claim 14, wherein the tablet comprises an
aesthetic coating.
22. The formulation of claim 21, wherein the coating is comprising
of hydroxypropylcellulose, titanium dioxide, talc and polyethylene
glycol.
23. The formulation of claim 14, wherein the active ingredient is
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
24. The formulation of claim 14, wherein the active ingredient is
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
25. The formulation of claim 1, wherein the disease comprises one
or more cancers.
26. The formulation of claim 1, wherein the disease comprises one
or more inflammatory disorders.
27. The formulation of claim 26, wherein the inflammatory disorders
comprise atopic dermatitis.
28. A kit comprising one or more dosage forms for treating one or
more diseases characterized by the dysregulation of the Syk/JAK
pathway and instructions for administering the dosage forms to a
subject, wherein the dosage forms comprise granules and
extragranular components compressed into a tablet, and wherein: the
micronized granules comprise: micronized active ingredient; one or
more granulation binders; one or more fillers; one or more
disintegrants; and one or more antioxidants; the extragranular
components comprise one or more tableting fillers, one or more
disintegrants, one or more lubricants, and optionally one or more
surfactants; the active ingredient is a compound of Formula (I) or
a pharmaceutically acceptable salt, enantiomer or prodrug thereof,
##STR00013## wherein R1 is a 6-membered ring of Formula (II):
##STR00014## wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to
C6) alkyl CN; and wherein R2 is a benzene ring of Formula (III):
##STR00015## wherein R4 is a 6-membered ring of Formula (IV):
##STR00016## wherein R5 is N or CH and R6 is a hydroxyl group,
methyl group, or ethyl group, and wherein the formulation has a
total API degradation impurity level not above about 0.6% of the
total active ingredient amount after storage at 1 week at
40.degree. C./75% RH in an open container.
29. The kit of claim 27, wherein the disease comprises one or more
cancers.
30. The kit of claim 27, wherein the disease comprises one or more
inflammatory disorders.
31. The kit of claim 30, wherein the inflammatory disorders
comprise atopic dermatitis.
32. The kit of claim 31, wherein the dosage form comprises the
active ingredient in a dose of about 20 mg to about 80 mg.
33. A dosage form for treating one or more diseases characterized
by the dysregulation of the Syk/JAK pathway, the dosage form
comprising micronized granules and extragranular components
compressed into a tablet, and wherein: the micronized granules
comprise: an active ingredient; one or more granulation binders;
one or more fillers; one or more disintegrants; and one or more
antioxidants; the extragranular components comprise one or more
tableting fillers, one or more disintegrants, one or more
lubricants, and optionally one or more surfactants; the active
ingredient is a compound of Formula (I) or a pharmaceutically
acceptable salt, enantiomer or prodrug thereof, ##STR00017##
wherein R1 is a 6-membered ring of Formula (II): ##STR00018##
wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
and wherein R2 is a benzene ring of Formula (III): ##STR00019##
wherein R4 is a 6-membered ring of Formula (IV): ##STR00020##
wherein R5 is N or CH and R6 is a hydroxyl group, methanol group,
or ethanol group, and wherein the formulation has a total API
degradation impurity level not above about 0.6% of the total active
ingredient amount after storage at 1 week at 40.degree. C./75% RH
in an open container.
34. The dosage form of claim 31, wherein the disease comprises or
one or more cancers.
35. The dosage form of claim 31, wherein the disease comprises one
or more inflammatory disorders.
36. The dosage form of claim 35, wherein the inflammatory disorders
comprise atopic dermatitis.
37. The dosage form of claim 36, wherein the active ingredient is
in an amount of about 20 mg to about 80 mg.
38. A method of stabilizing a pharmaceutical formulation, the
formulation being useful for treating one or more diseases
characterized by the dysregulation of the Syk/JAK pathway,
comprising: (a) mixing intragranular ingredients comprising an
active ingredient; one or more fillers; one or more disintegrants;
and one or more antioxidants; (b) granulating the mixed
intragranular ingredients while adding a solution of 10% w/w of one
or more granulation binders in 99% v/v isopropyl alcohol until
granules are formed; (c) drying and milling the granules to make
micronized granules; wherein the active ingredient comprises a
compound of Formula (I) or a pharmaceutically acceptable salt,
enantiomer or prodrug thereof: ##STR00021## wherein R1 is a
6-membered ring of Formula (II): ##STR00022## wherein R3 is H, OH,
C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN; and wherein R2 is a
benzene ring of Formula (III): ##STR00023## wherein R4 is a
6-membered ring of Formula (IV): ##STR00024## wherein R5 is N or CH
and R6 is a hydroxyl group, methyl group, or ethyl group, wherein
the formulation has a total API degradation impurity level not
above about 0.6% of the total active ingredient amount after
storage at 1 week at 40.degree. C./75% RH in an open container.
39. The method of claim 38, wherein the disease comprises one or
more cancers.
40. The method of claim 38, wherein the disease comprises one or
more inflammatory disorders.
41. The method of claim 40, wherein the inflammatory disorders
comprise atopic dermatitis.
42. The method of claim 41, wherein the active ingredient is in an
amount of about 20 mg to about 80 mg.
43. A method of preparing a compressed tablet pharmaceutical
formulation, the formulation used for treating one or more diseases
characterized by the dysregulation of the Syk/JAK pathway,
comprising: (a) mixing intragranular ingredients comprising an
active ingredient; one or more fillers; one or more disintegrants;
and one or more antioxidants; (b) granulating the mixed
intragranular ingredients while adding a solution of 10% w/w of one
or more granulation binders in 99% v/v isopropyl alcohol until
granules are formed; (c) drying and milling the granules to make
micronized granules; (d) mixing the micronized granules with
extragranular components, the extragranular components comprising
one or more tableting fillers, one or more disintegrants, one or
more lubricants, and optionally one or more surfactants; and
compressing the micronized granules with extragranular components
into a tablet, wherein the active ingredient comprises a compound
of Formula (I) or a pharmaceutically acceptable salt, enantiomer or
prodrug thereof: ##STR00025## wherein R1 is a 6-membered ring of
Formula (II): ##STR00026## wherein R3 is H, OH, C(O)OH, C1 to C6
alkyl or (C1 to C6) alkyl CN; and wherein R2 is a benzene ring of
Formula (III): ##STR00027## wherein R4 is a 6-membered ring of
Formula (IV): ##STR00028## wherein R5 is N or CH and R6 is a
hydroxyl group, methyl group, or ethyl group, and wherein the
formulation has a total API degradation impurity level not above
about 0.6% of the total active ingredient amount after storage at 1
week at 40.degree. C./75% RH in an open container.
44. The method of claim 43, wherein the disease comprises one or
more cancers.
45. The method of claim 43, wherein the disease comprises one or
more inflammatory disorders.
46. The method of claim 45, wherein the inflammatory disorders
comprise atopic dermatitis.
47. A method of treating one or more diseases characterized by the
dysregulation of the Syk/JAK pathway in a subject, comprising
administering to the subject a therapeutically effective amount of
an active ingredient in one or more dosage forms, wherein the
dosage forms comprise micronized granules and extragranular
components compressed into a tablet, and wherein: the micronized
granules comprise: an active ingredient; one or more granulation
binders; one or more fillers; one or more disintegrants; and one or
more antioxidants; the extragranular components comprise one or
more tableting fillers, one or more disintegrants, one or more
lubricants, and optionally one or more surfactants; and the active
ingredient is a compound of Formula (I) or a pharmaceutically
acceptable salt, enantiomer or prodrug thereof, ##STR00029##
wherein R1 is a 6-membered ring of Formula (II): ##STR00030##
wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
and wherein R2 is a benzene ring of Formula (III): ##STR00031##
wherein R4 is a 6-membered ring of Formula (IV): ##STR00032##
wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or
ethyl group, and wherein the formulation has a total API
degradation impurity level not above about 0.6% of the total active
ingredient amount after storage at 1 week at 40.degree. C./75% RH
in an open container.
48. The method of claim 47, wherein the disease comprises one or
more cancers.
49. The method of claim 47, wherein the disease comprises one or
more inflammatory disorders.
50. The method of claim 49, wherein the inflammatory disorders
comprise atopic dermatitis.
51. The method of claim 50 wherein the active ingredient is in an
amount of about 20 mg to about 80 mg.
52. A method of manufacturing a pharmaceutical formulation, the
formulation useful for treating one or more diseases characterized
by the dysregulation of the Syk/JAK pathway, comprising: (a) mixing
intragranular ingredients comprising an active ingredient; one or
more fillers; one or more disintegrants; and one or more
antioxidants; (b) granulating the mixed intragranular ingredients
while adding a solution of 10% w/w of one or more granulation
binders in 99% v/v isopropyl alcohol until granules are formed; (c)
drying and milling the granules to make micronized granules;
wherein the active ingredient comprises a compound of Formula (I)
or a pharmaceutically acceptable salt, enantiomer or prodrug
thereof: ##STR00033## wherein R1 is a 6-membered ring of Formula
(II): ##STR00034## wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or
(C1 to C6) alkyl CN; and wherein R2 is a benzene ring of Formula
(III): ##STR00035## wherein R4 is a 6-membered ring of Formula
(IV): ##STR00036## wherein R5 is N or CH and R6 is a hydroxyl
group, methyl group, or ethyl group, wherein the formulation has a
total API degradation impurity level not above about 0.6% of the
total active ingredient amount after storage at 1 week at
40.degree. C./75% RH in an open container.
53. The method of claim 52, wherein the disease comprises one or
more cancers.
54. The method of claim 52, wherein the disease comprises one or
more inflammatory disorders.
55. The method of claim 54, wherein the inflammatory disorders
comprise atopic dermatitis.
56. A compressed tablet comprising micronized granules and
extragranular components, wherein: the tablet has a total weight of
about 150 mg; the micronized granules comprise about 5 to 50 mg of
an active ingredient, about 118.6 to 736 mg of lactose monohydrate,
about 4.5 mg croscarmellose sodium, about 0.15 mg vitamin E and
about 4.5 mg granulation binder; and the extragranular components
comprise about 11.25 mg microcrystalline cellulose, about 4.5 mg
croscarmellose sodium and about 1.5 mg magnesium stearate, and
about 6 mg of an enteric coating; and the active ingredient is
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropy-
rimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
Description
TECHNICAL FIELD
[0001] Embodiments of the disclosure relate generally to
formulations, methods, kits, and dosage forms for treating atopic
dermatitis and for improved stability of an active pharmaceutical
ingredient. In one embodiment, the formulations, methods, kits and
dosage forms comprise administering the active pharmaceutical
ingredient with improved stability and can be used for the
treatment of inflammatory disorders or cancers, or for the
treatment of atopic dermatitis.
BACKGROUND
[0002] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within cells. Almost all kinases
contain a similar 250 to 300 amino acid catalytic domain. The
kinases can be categorized into families by the substrates they
phosphorylate.
[0003] JAK (Janus kinase, including JAK1, JAK2, JAK3 and TYK2) is a
family of intracellular non-receptor tyrosine kinases. JAK is
expressed in hematopoietic cells and abundantly in primary leukemic
cells from children with acute lymphoblastic leukemia. The
downstream substrates of JAK include the signal tranducer activator
of transcription (STAT) proteins. STAT proteins function both as
signaling molecules and transcription factors and ultimately bind
to specific DNA sequences present in the promoters of
cytokine-responsive genes. JAK/STAT signaling has been implicated
in the mediation of many abnormal immune responses such as
allergies, asthma, autoimmune diseases such as transplant
(allograft) rejection, rheumatoid arthritis, amyotrophic lateral
sclerosis and multiple sclerosis, as well as in solid and
hematologic malignancies such as leukemia and lymphomas.
[0004] Spleen tyrosine kinase (syk) is a member of the syk family
of protein tyrosine kinases and plays a crucial role in
inflammatory and allergic responses. Syk triggers IgE and IgG
receptor mediated signaling in mast cells, basophils, and
macrophages leading to degranulation and cytokine release.
[0005] Immunoreceptor tyrosine activation motif (ITAM)-mediated
signaling has emerged as a primary event in signaling pathways
responsible for human pathologies. ITAM-mediated signaling is
responsible for relaying activation signals initiated at classical
immune receptors such as T-cell receptors, B-cell receptors, and Fc
receptors in immune cells and at GPVI and Fc.gamma.RIIa in
platelets to downstream intracellular molecules such as Syk.
[0006] The binding of a ligand to an ITAM-containing receptor
triggers signaling events which allows for the recruitment of
proteins from a family of nonreceptor tyrosine kinases called the
Src family. These kinases phosphorylate tyrosine residues within
the ITAM sequence, a region with which the tandem SH2 domains on
either Syk or ZAP-70 interact. The interaction of Syk with
diphosphorylated ITAM sequences induces a conformation change in
the kinases that allows for tyrosine phosphorylation of the kinase
itself.
[0007] Not only do these kinases contribute to normal host defense,
they also play roles in the pathogenesis of diseases. Many diseases
are associated with abnormal cellular responses triggered by
protein kinase-mediated events. These diseases include autoimmune
diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies, asthma, Alzheimer's disease and
hormone-related diseases. As a consequence, there have been
substantial efforts in medicinal chemistry to find inhibitors of
protein kinases for use as therapeutic agents. There is a need in
the art for compounds that are dual inhibitors of Syk/JAK, as well
as for methods for treating conditions that can benefit from such
inhibition. There is also a need in the art for formulations of
compounds that are dual inhibitors of Syk/JAK, that may be utilized
in methods for treating conditions that can benefit from such
inhibition. Such formulations should optimize the efficacy of
Syk/JAK dual inhibitor compounds and should exhibit high levels of
stability.
[0008] Atopic dermatitis (AD) is a chronic inflammatory skin
disease. It is characterized by dry scaly skin, erythema, lesions
with oozing and crusting, excoriations due to itch, and
lichenification. The skin conditions are accompanied by intense
pruritus that poses a significant burden to subjects and their
quality of life. Up to 3% of adults have atopic dermatitis and
between 15-25% of children. Onset is in early childhood in
approximately 85% of cases but onset can occur later including
during adulthood.
[0009] Spleen tyrosine kinase (SYK) and Janus kinase (JAK) are
tyrosine kinases that play important roles in the pathogenesis of
various types of autoimmune and inflammatory diseases, including
atopic dermatitis. Deregulation of SYK has been implicated in
different human diseases such as B-cell malignancies, allergy,
asthma, and other inflammatory disorders. SYK binds to the
immune-receptor tyrosine-based activation motif (ITAM) present in
Fc.gamma.-activating receptors and integrins. Binding of SYK to the
ITAM activates downstream signaling events such as activation of
Bruton tyrosine kinase (BTK), eventually leading to increased
release of cytokines, lipid mediators and various proteases. These
mediators cause hyper-proliferation of B-cells, inflammation, and
tissue or cartilage damage. SYK also plays a critical role in
IL-17R signaling in keratinocytes. Therefore, inhibition of SYK
activity provides a potential approach for the treatment of various
types of lymphomas and inflammatory disorders.
[0010] The JAK kinases (JAK1, JAK2, JAK3 and TYK2) are required for
the physiologic signaling through the cytokines and growth factor
receptors that intrinsically lack kinase activity (12, 13). JAK
kinases, upon stimulation with factors such as erythropoietin,
granulocyte-macrophage colony stimulating factor, IL-3, IL-5,
thrombopoietin, and growth hormone, phosphorylate signal
transducers and activators of transcription (STAT1-5) family
proteins which are translocated to the nucleus and activate various
downstream target genes involved in cytokine and growth factor
response. JAK kinases play a role in inflammatory conditions,
particularly those driven by cytokines including atopic
dermatitis.
[0011] There is a need in the art for methods of treatment using
compounds that are dual inhibitors of Syk/JAK for treating
inflammatory disorders, such as atopic dermatitis.
SUMMARY
[0012] In one embodiment, the present disclosure relates to
formulations, methods, kits, and dosage forms for treating
conditions related to the inhibition of Syk/JAK, such as such as
inflammatory disorders or cancers, characterized by the presence of
solid tumors, particularly melanoma, colon cancer, non-small cell
lung cancer, bladder cancer and breast cancer and/or the following
cancers: prostate, head, neck, eye, mouth, throat, esophagus,
bronchus, larynx, pharynx, chest, bone, rectum, stomach, uterus,
cervix, ovaries, vagina, testicles, skin, thyroid, blood, lymph
nodes, kidney, liver, intestines, pancreas, brain, central nervous
system, adrenal gland, skin or a leukemia and/or lymphoma.
[0013] In one embodiment, the present disclosure relates to
formulations, methods, kits, and dosage forms for treating
conditions related to the inhibition of Syk/JAK, such as
inflammatory disorders including atopic dermatitis.
[0014] In an embodiment, the pharmaceutical formulations described
herein comprise granules, wherein the granules comprise a
micronized active ingredient, one or more granulation binders, one
or more fillers, one or more disintegrants and one or more
antioxidants. The formulations may further comprise extragranular
components. The active ingredient can be in the amount of about 20
mg to about 80 mg. The formulations described herein can be
administered to a subject once daily for a short-term or
long-term.
[0015] The active ingredient may comprise a compound of Formula (I)
shown below, or a pharmaceutically acceptable salt or prodrug
thereof,
##STR00001##
wherein R.sup.1 is a 6-membered ring of Formula (II):
##STR00002##
wherein R.sup.3 is H, OH, C(O)OH, C.sub.1 to C.sub.6 alkyl or
(C.sub.1 to C.sub.6) alkyl CN; and wherein R.sup.2 is a benzene
ring of Formula (III):
##STR00003##
wherein R.sub.4 is a 6-membered ring of Formula (IV):
##STR00004##
wherein R.sub.5 is N or CH and R.sub.6 is a hydroxyl group, methyl
group, or ethyl group, and wherein the formulation has a total API
degradation impurity level not above about 0.6% of the total active
ingredient amount after storage at 1 week at 40.degree. C./75% RH
in an open container.
[0016] In another embodiment, the present disclosure provides a
dosage form comprising a pharmaceutical formulation comprising an
active ingredient of formula (I) in a compressed tablet wherein the
active ingredient in the pharmaceutical formulation retains
stability after storage for a predetermined time and under
predetermined conditions, including in an open container. In some
embodiments, "storage in an open container" means that the
container was opened once or twice a day for a given period of
time, for example up to four weeks, but was otherwise left closed.
In one embodiment, the formulation can be used to treat atopic
dermatitis. In one embodiment, the active ingredient can be in an
amount of about 20 mg to about 80 mg.
[0017] In another embodiment, the present disclosure provides a
method of manufacturing or stabilizing a pharmaceutical
formulation. The formulation can be useful for the treatment of
atopic dermatitis. The method can comprise the steps of mixing
intragranular ingredients comprising an active ingredient; one or
more fillers; one or more disintegrants; and one or more
antioxidants; granulating the mixed intragranular ingredients while
adding a solution of 10% w/w of one or more granulation binders in
99% v/v isopropyl alcohol until granules are formed; and drying and
milling the granules to make micronized granules; wherein the
active ingredient comprises a compound of Formula (I) or a
pharmaceutically acceptable salt or prodrug thereof and wherein the
pharmaceutical formulation may further comprise extragranular
components. In said embodiment, the active ingredient in the
formulation retains stability and efficacy for a predetermined time
and under predetermined conditions, including conditions wherein
the container may be opened once or more than once. In one
embodiment, the formulation can comprise an active ingredient in an
amount of about 20 mg to about 80 mg.
[0018] In another embodiment, the present disclosure provides a kit
comprising one or more dosage forms and instructions for
administering the dosage forms to a subject, wherein the dosage
forms comprise a pharmaceutical formulation comprising an active
ingredient in substantially compressed tablet form optionally
combined with extragranular components, wherein the active
ingredient comprises a compound of the formula (I), wherein the
active ingredient in the pharmaceutical formulation retains
stability for a predetermined time and under predetermined
conditions.
[0019] In another embodiment, the present disclosure provides a
method of treating a condition characterized by dysregulation
(e.g., abnormality or impairment) of Syk/JAK pathways in a subject.
In one embodiment, the present disclosure provides a method of
treating a condition characterized by dysregulation (e.g.,
abnormality or impairment) of Syk/JAK2 pathways in a subject. In
another embodiment, the present disclosure provides methods for
treating atopic dermatitis. The methods can comprise administering
to the subject a therapeutically effective amount of an active
ingredient in one or more dosage forms, wherein the dosage forms
comprise a pharmaceutical formulation comprising an active
ingredient in granular form in a compressed tablet optionally
comprising one or more extragranular components, wherein the active
ingredient comprises a compound of formula (I), wherein the active
ingredient retains stability after storage of the pharmaceutical
formulation for a predetermined time and under predetermined
conditions. The dosage forms can comprise an active ingredient in
the amount of about 20 mg to about 80 mg and can be administered to
a subject once daily for a short-term period or a long-term
period.
[0020] In another embodiment, the present disclosure provides a
pharmaceutical formulation. The formulation can be useful for
treating atopic dermatitis. The formulation can comprise an active
ingredient in granular form in a compressed tablet optionally
comprising one or more extragranular components, wherein the active
ingredient comprises active ingredients of the formulations
described herein wherein the active ingredient comprises
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile (sometimes
referred to herein as "Compound 1"), or wherein the active
ingredient comprises
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. The
active ingredient can be in the amount of about 20 mg to about 80
mg.
BRIEF DESCRIPTION OF FIGURES
[0021] FIGS. 1A-1B provide a particle size distribution results
analysis report for the active ingredient prior to micronization.
FIG. 1A provides a graph showing the particle size distribution
results for the active ingredient prior to micronization. FIG. 1B
provides data for the particle size distribution results for the
active ingredient prior to micronization
[0022] FIGS. 2A-2B provide a particle size distribution results
analysis report for the active ingredient after micronization. FIG.
2A provides a graph showing the particle size distribution results
analysis report for the active ingredient after micronization. FIG.
2B provides data for the particle size distribution results
analysis report for the active ingredient after micronization.
[0023] FIG. 3 provides the 5-D Pruritus Scale.
[0024] FIG. 4 provides the Eczema Area and Severity Index (EASI)
assessment tool.
[0025] FIG. 5 is a graphical illustration of the study design of
Example 3.
[0026] FIG. 6 is a graphical illustration of the patient
demographics of Example 3.
[0027] FIG. 7A is a graph of the % of subjects to achieve EASI50
over time (Day 1 to Day 29) for a placebo and Compound 1 in the
doses of 20 mg, 40 mg and 80 mg, as demonstrated in Example 3.
[0028] FIG. 7B is a graph of the % of subjects to achieve EASI75
over time (Day 1 to Day 29) for a placebo and Compound 1 in the
doses of 20 mg, 40 mg and 80 mg, as demonstrated in Example 3.
[0029] FIG. 8A is a graph of the % CFB (percentage change from
baseline) for EASI (decrease) for the placebo and Compound 1 in the
doses of 20 mg, 40 mg and 80 mg, as demonstrated in Example 3.
[0030] FIG. 8B is a graph of the % CFB for IGA 0-1 (Investigator's
Global Assessment) for the placebo and Compound 1 in the doses of
20 mg, 40 mg and 80 mg, as demonstrated in Example 3.
[0031] FIG. 8C is a graph of the % CFB for BSA (body surface area)
(decrease) for the placebo and Compound 1 in the doses of 20 mg, 40
mg and 80 mg, as demonstrated in Example 3.
[0032] FIG. 9 is a graph of day 15 plasma concentration for
Compound 1 in the doses of 20 mg, 40 mg and 80 mg, as demonstrated
in Example 3.
[0033] FIG. 10 is a chart showing the inhibition of JAK and Syk
kinase activity by Compound 1, Tofacitinib, Upadacitinib, and
Baricitinib, as demonstrated in Example 3.
[0034] FIG. 11 is a chart showing Compound 1's inhibition of
JAK/STAT pathway in T cells stimulated with various cytokines, as
demonstrated in Example 3.
[0035] FIG. 12 is a chart showing Compound 1's inhibition of IL17
mediated CCL20 release in keratinocytes, as demonstrated in Example
3.
[0036] FIG. 13 is a graph showing average weekly change in pruritus
(NRS) for a placebo, and Compound 1 in the doses of 20 mg, 40 mg
and 80 mg, as demonstrated in Example 3.
[0037] FIG. 14A is a graph showing improvement in skin thickness
for Compound 1 in the doses of 20 mg, 40 mg and 80 mg.
[0038] FIG. 14B is a graph showing improvement in CD3+ cells for
Compound 1 in the doses of 20 mg, 40 mg and 80 mg.
[0039] FIG. 14C is a graph showing improvement in CD11c+ cells for
Compound 1 in the doses of 20 mg, 40 mg and 80 mg.
[0040] FIG. 15 is a chart showing Treatment-Emergent Adverse Events
(TEAE), as demonstrated in Example 3.
[0041] FIGS. 16A1-16G2 provide clinical activity, safety and
tolerability data for formulations of the present disclosure.
[0042] FIG. 16A1 provides background information and a summary of
methods, results and conclusions for formulations of the present
disclosure.
[0043] FIG. 16A2 provides preclinical study data for formulations
of the present disclosure.
[0044] FIG. 16A3 provides preclinical study data for formulations
of the present disclosure.
[0045] FIG. 16B provides dosing and patient parameters for clinical
trial data for formulations of the present disclosure.
[0046] FIG. 16C provides patient demographics and mean
pharmacokinetic parameters for clinical trial data for formulations
of the present disclosure.
[0047] FIG. 16D provides a graph of the mean plasma concentration
of a compound of the present disclosure over time in preclinical
models.
[0048] FIG. 16E provides a bar graph of inhibition of inflammation
biomarkers by formulations of the present disclosure.
[0049] FIG. 16F provides bar graphs showing duration of treatment
of formulations of the present disclosure for lymphoma subjects and
solid tumor subjects.
[0050] FIG. 16G1 provides a description of the efficacy and
safety/tolerability profile for a compound of the present
disclosure.
[0051] FIG. 16G2 provides a summary of the efficacy and
safety/tolerability profile for a compound of the present
disclosure.
DETAILED DESCRIPTION
[0052] The following detailed description is exemplary and
explanatory and is intended to provide further explanation of the
present disclosure described herein. Other advantages, and novel
features will be readily apparent to one of ordinary skill in the
art from the following detailed description of the present
disclosure.
[0053] The present disclosure provides one or more pharmaceutical
formulations comprising an active ingredient in granular form
compressed into a solid dosage form such as a tablet, methods of
manufacturing such formulations, kits, methods of treating, and
dosage forms wherein the active ingredient is configured to
regulate the Syk/JAK pathway so that such formulations are capable
of treating conditions associated with dysregulation in these
pathways, including but not limited to, cancers and inflammatory
disorders, for example atopic dermatitis.
[0054] The present disclosure comprises novel formulations
comprising pyrimido-pyridazinone compounds. The formulations
described herein are useful in treating cancer and inflammatory
disorders in patients, for example atopic dermatitis, by
administering one or more of the formulations to patients in need
thereof. The formulations described herein are particularly
desirable because of their unexpected superior stability profiles
over a predetermined amount of time and because of their
efficacy.
[0055] In an embodiment, the pharmaceutical formulations described
herein comprise micronized granules, wherein the granules comprise
an active ingredient, one or more granulation binders, one or more
fillers, one or more disintegrants and one or more antioxidants.
The formulations may further comprise extragranular components.
[0056] The active ingredient may comprise a compound of Formula (I)
shown below, or a pharmaceutically acceptable salt or prodrug
thereof,
##STR00005##
wherein R.sup.1 is a 6-membered ring of Formula (II):
##STR00006##
wherein R.sup.3 is H, OH, C(O)OH, C.sub.1 to C.sub.6 alkyl or
(C.sub.1 to C.sub.6) alkyl CN; and wherein R.sup.2 is a benzene
ring of Formula (III):
##STR00007##
wherein R.sub.4 is a 6-membered ring of Formula (IV):
##STR00008##
wherein R.sub.5 is N or CH and R.sub.6 is a hydroxyl group, methyl
group, or ethyl group, and wherein the formulation has a total API
degradation impurity level not above about 0.6% of the total active
ingredient amount after storage at 1 week at 40.degree. C./75% RH
in an open container.
[0057] Compounds of Formula (I) possess one or more chiral centers,
and it is specifically contemplated that each separate enantiomer
of compounds comprising an active ingredient of the disclosure, as
well as mixtures of the enantiomers, can be used in the present
formulations and methods. As disclosed herein, all chiral,
enantiomeric and racemic forms of a chemical structure are
intended, unless the specific stereochemistry is indicated. It is
well known in the art how to prepare optically active forms of the
compounds comprising active ingredients of the present formulations
and methods, such as by resolution of racemic forms or by synthesis
from optically active starting materials.
[0058] Active ingredients of the present disclosure can be
prepared, for example, according to the methods disclosed in U.S.
Pat. Nos. 8,729,079 and 9,382,277, the entire disclosures of which
are herein incorporated by reference. In some embodiments of the
disclosure, an active ingredient comprising the pharmaceutical
formulation of the disclosure can be present in at least about 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
98%, 99%, 99.5%, 99.9% or 100% w/w.
[0059] The active ingredient for use in the present formulations
and methods comprises compounds which regulate the Syk/JAK pathway.
The regulatory activity of the active ingredients of the disclosure
makes these compounds useful for manufacturing pharmaceutical
formulations, which can be used for treating conditions such as
inflammatory disorders, including atopic dermatitis, or cancers
characterized by the presence of solid tumors, particularly
melanoma, colon cancer, non-small cell lung cancer, bladder cancer
and breast cancer.
[0060] In certain embodiments, the active ingredient is
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. In other
embodiments, the active ingredient is
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
[0061] The present disclosure thus provides for stable or
stabilized pharmaceutical formulations comprising an active
ingredient of the disclosure as described herein, for example
stable or stabilized formulations comprising one or more compounds
of formula (I), or enantiomers, prodrugs, pharmaceutically
acceptable salts or free bases thereof. The stability of a
formulation according to the present disclosure can be determined,
for example, by measuring the physical state of the active
ingredient. In one embodiment, the active ingredient retains
stability and efficacy after storage for predetermined times and
under predetermined conditions.
[0062] As used herein, the term "substantially granular" means that
most of the active ingredient in the pharmaceutical compositions as
described herein, is in the form of granules, preferably micronized
granules, wherein such granules are compressed into a tablet. In
certain embodiments, substantially granular means that the granules
have a particle size of less than about 20 microns.
[0063] As discussed above, the active ingredient of the present
disclosure is maintained in substantially granular form by
combining the active ingredients with one or more stabilizing
components. Suitable stabilizing components for use according to
the present disclosure include one or more granulation binders; one
or more fillers; one or more disintegrants; and one or more
antioxidants, as further described herein.
[0064] The method by which the active ingredient and stabilizing
component is formulated can also affect stability. For example,
mixing intragranular ingredients comprising the active ingredient
with one or more fillers; one or more disintegrants; and one or
more antioxidants; granulating the mixed intragranular ingredients
while adding a solution of 10% w/w of one or more granulation
binders in 99% v/v isopropyl alcohol until granules are formed; and
then drying and milling the granules to make micronized granules
results in the formation of granules suitable for incorporating
into a compressed tablet and for maintaining stability of a
prolonged period.
[0065] In some embodiments, the formulations of the disclosure are
stable when subject to predetermined conditions for predetermined
times. For example, pharmaceutical formulations of the disclosure
can be stored at various predetermined temperatures and relative
humidities for defined or predetermined time periods, for example
in an open or closed container. In some embodiments, formulations
of the disclosure are stable upon storage at about 5, 25, 30, 37,
40 or 45 degrees Celsius and about 0%, 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or
100% relative humidity for a period of at least about 0.5, 1.5, 2,
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10,
10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 20, 25, 30, 35,
40, 45, 48, 50, 51, 52, 53, 55 or 60 hours 1 week, 2 weeks, 3 weeks
or 4 week; 1 month, 2 months, 3 months, 4 months, 5 months or 6
months.
[0066] In certain embodiments, formulations of the disclosure are
stable upon storage in an open or closed container at: about 30
degrees Celsius and about 90 percent relative humidity for a period
of at least about 20 hours; about 40 degrees Celsius and about 60
percent relative humidity for a period of at least about one week,
two weeks or three weeks; about 40 degrees Celsius and about 75
percent relative humidity for a period of at least about one week,
two weeks or three weeks; about 25 degrees Celsius and about 60
percent relative humidity for a period of at least about one month;
about 40 degrees Celsius and about 75 percent relative humidity for
a period of at least one month; about 25 degrees Celsius and about
75 percent relative humidity for a period of at least about 3
months; or 5 degrees Celsius at any relative humidity for a period
of at least about three months. In some embodiments, "storage in an
open container" means that the container was opened twice a day for
a given period of time, for example up to four weeks, but was
otherwise left closed.
[0067] In another embodiment, the formulation comprises the active
ingredient
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile or the active
ingredient
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile and
is stable upon storage in an open or closed container at: about 30
degrees Celsius and about 90 percent relative humidity for a period
of at least about 20 hours; about 40 degrees Celsius and about 60
percent relative humidity for a period of at least about one week,
two weeks or three weeks; about 40 degrees Celsius and about 75
percent relative humidity for a period of at least about one week,
two weeks or three weeks; about 25 degrees Celsius and about 60
percent relative humidity for a period of at least about one month;
about 40 degrees Celsius and about 75 percent relative humidity for
a period of at least one month; about 25 degrees Celsius and about
75 percent relative humidity for a period of at least about 3
months; or 5 degrees Celsius at any relative humidity for a period
of at least about three months.
[0068] The pharmaceutical formulations of the disclosure can also
be tested for other physical characteristics, for example by
evaluating the amount of active ingredient and/or impurity levels
of the formulations at the end of a predetermined time period after
they have been subjected to predetermined conditions, for example,
temperature and relative humidity in open and closed containers.
Suitable methods for measuring the impurity profile of the present
formulations are known in the art. Exemplary methods for measuring
the impurity profile of the present formulations may involve any
suitable chromatographic separation methods, such as high-pressure
liquid chromatography (HPLC) comprising the use of separation
column and gradient elution as are known to those of ordinary skill
in the art. An exemplary HPLC method for evaluating the amount of
active ingredient and/or impurity levels of the pharmaceutical
formulations of the present disclosure is described in Example 1
below. In addition, other methods may be utilized instead of or in
addition to HPLC separation methods, including capillary
electrophoresis, electron paramagnetic resonance, gas-liquid
chromatography, gravimetric analysis, solid-phase extraction
methods, liquid-liquid extraction method, ultraviolet spectrometry,
infrared spectroscopy, supercritical fluid extraction column
chromatography, mass spectrometry, nuclear magnetic resonance (NMR)
spectroscopy, and RAMAN spectroscopy.
[0069] In some embodiments, the impurity test comprises subjecting
the formulation to storage conditions at 40 degrees Celsius at 75%
relative humidity in open and closed containers. In another
embodiment, the impurity test comprises subjecting the formulation
to storage conditions under accelerated stress conditions at 60
degrees Celsius in closed containers. In another embodiment, the
formulations may be evaluated for impurity levels following storage
at 40 degrees Celsius at 75% relative humidity in open containers
for one week.
[0070] The pharmaceutical formulations of the disclosure can also
be tested for physical characteristics, such as Vitamin E content,
by use of any suitable analytical method, for example an HPLC
method comprising isocratic elution with water and acetonitrile as
the mobile phase and UV detection as described in Example 1
below.
[0071] Although exemplary amounts or ranges for the active
ingredient and other components are given, pharmaceutical
formulations of the disclosure can comprise any amount of these
components suitable for the purposes of obtaining the desirable
pharmacologic and stability properties as described herein. In
addition to the active ingredient, pharmaceutical compositions of
the disclosure can also comprise other pharmaceutically acceptable
excipients, for example adjuvants, antioxidants, binders, buffers,
coatings, coloring agents, compression aids, diluents,
disintegrants, emulsifiers, emollients, encapsulating materials,
fillers, flavoring agents, glidants, granulating agents,
lubricants, metal chelators, osmo-regulators, pH adjustors,
preservatives, solubilizers, sorbents, stabilizers, sweeteners,
surfactants, suspending agents, thickening agents, or viscosity
regulators. Suitable excipients for use in pharmaceutical
compositions of the disclosure are described, for example, in the
"Handbook of Pharmaceutical Excipients", 5th Edition, Eds.: Rowe,
Sheskey, and Owen, APhA Publications (Washington, D.C.), Dec. 14,
2005, the disclosure of which is incorporated herein by
reference.
[0072] In certain embodiments, pharmaceutical compositions of the
disclosure can be compacted into a unit dose form, e.g., tablet or
caplet, or added to unit dose form, e.g., a compressed tablet. In a
further embodiment, pharmaceutical compositions of the disclosure
can be formulated for administration as micronized granules or as a
suspension of micronized granules. A pharmaceutical formulation of
the disclosure which comprises micronized granules or a suspension
thereof can, for example, be sprinkled on or mixed with a
semi-solid carrier such as apple sauce or another food item for
administration to a subject. The which comprises micronized
granules or a suspension thereof can also, for example, be added to
a liquid carrier suitable for administration to subjects, such as a
solution of about 2% w/V hydroxypropyl cellulose and about 0.1% w/V
polysorbate 80 in water or about 0.2% hydroxypropylcellulose, and
0.1% Tween 80 in water, to form a suspension.
[0073] In one embodiment, the dosage form of the disclosure
comprises a compressed tablet, for example at about 25, 50, 75, 80
or 100 mg strengths. In another embodiment, the dosage form of the
disclosure comprises a capsule, for example at about 25, 50, 75, 80
or 100 mg strengths. In a further embodiment, the dosage form of
the disclosure is a tablet comprising micronized granules of the
active ingredient, for example at about 25, 50, 75, 80 or 100 mg
strengths. In another embodiment, the dosage form of the disclosure
is a capsule comprising micronized granules for example at about
25, 50, 75, 80 or 100 mg strengths. In one embodiment, the dosage
form of the disclosure is a capsule comprising micronized granules
for example at about 75 mg strength.
[0074] Suitable techniques for formulating pharmaceutical
compositions of the disclosure into tablets are well-known in the
art, and can comprise mixing the active ingredient and stabilizing
components with one or more pharmaceutically acceptable tableting
excipients and compressing the mixture into a tablet, for example
with a tableting press. The amount and nature of the tableting
excipients used can be readily chosen based on the desired
characteristics of the tablet, such as size, hardness, friability
and the like. Tablets comprising pharmaceutical compositions of the
disclosure can also be coated, for example with film coatings like
Opadry White.RTM., or with enteric coatings designed to prevent
dissolution of the tablets until the transit the stomach and/or
upper intestine. Suitable tablet coatings and methods for applying
them are well-known in the art.
[0075] Suitable techniques for formulating pharmaceutical
compositions of the disclosure into capsules are also well-known in
the art, and can comprise mixing the active ingredient and
stabilizing components with one or more pharmaceutically acceptable
capsule excipients and filling the mixture into a capsule. In one
embodiment, a pharmaceutical formulation of the disclosure (with or
without additional excipients) can be filled into a capsule, such
as a hard gelatin capsule. The hard gelatin capsule can be of any
appropriate size, for example size `0`, `0EL`, `3`, `4` and the
like. For example, in one embodiment a capsule of the disclosure
having a dosage strength of 25 mg of the active ingredient can be
filled into a hard gelatin capsule of size 4, where the target
capsule fill weight can comprise 100 mg. In another embodiment, a
capsule of the disclosure having a dosage strength of 100 mg of the
active ingredient can be filled into a hard gelatin capsule of size
0 el, where the target capsule fill weight can comprise 400 mg.
[0076] Also provided herein are kits comprising at least one dosage
form of the disclosure, for example a tablet or capsule, and
instructions for administering the at least one dosage form to a
subject. The kit can also comprise packaging or a container housing
the at least one dosage form of the disclosure, and can also
comprise instructions on storage, administration, dosing or the
like and/or an insert regarding the active ingredient. The kit can
also comprise instructions for monitoring circulating levels of the
active ingredient (or metabolites thereof) once administered, and
optionally materials for performing such assays including, e.g.,
reagents, well plates, containers, markers or labels, and the like.
Other suitable components to include in kits of the disclosure will
be readily apparent to one of skill in the art, taking into
consideration the desired indication, dosing regimen, storage
conditions and route of administration.
[0077] The pharmaceutical compositions of the disclosure can
formulated for administration as a single dose or as multiple doses
for continuous or periodic discontinuous administration. For
continuous administration, a kit can include the pharmaceutical
compositions of the disclosure in individual unit dosage forms
(e.g., tablet or capsule), and optionally instructions for
administering the individual unit dosage forms, for example, more
than once daily, twice a day (BID), four times a day (QID), daily,
weekly, or monthly, for a predetermined length of time or as
prescribed. When the pharmaceutical compositions of the disclosure
are to be delivered periodically in a discontinuous fashion, a kit
can include placebos during periods when the individual unit dosage
forms are not delivered. In some embodiments, formulations of the
present disclosure can be administered at a dose of about 10 mg
BID, about 20 mg BID, about 30 mg BID, about 40 mg BID, about 50 mg
BID, about 75 mg BID, about 100 mg BID, about 80 mg QID, or about
120 mg QID. In one embodiment, formulations of the present
disclosure can be administered at a dose of about 75 mg BID.
[0078] Suitable packages or containers are known in the art for
holding and dispensing pharmaceutical agents for periodic oral use.
In one embodiment, the package comprises indicators for each
administration period. In another embodiment, the package comprises
a labeled blister package, dial dispenser package, or bottle. The
kits of the disclosure can also comprise a means for containing any
type of packaging that houses the unit dosage forms, for example
bottles or vials, which can (for example) be held in close
confinement for commercial sale such as, e.g., injection or
blow-molded plastic containers into which the bottles or vials are
retained.
[0079] The pharmaceutical compositions, methods of treatment,
dosage forms and kits of the disclosure are useful in treating
conditions which are associated with dysregulation (e.g.,
abnormality or impairment) of the Syk/JAK pathway. In one
embodiment, the conditions are associated with dysregulation of the
Syk/JAK2 pathway. In one embodiment, a condition associated with
dysregulation of the Syk/JAK pathway comprises acute or chronic
inflammatory disorders, such as atopic dermatitis. In one
embodiment, a condition associated with dysregulation of the
Syk/JAK pathway comprises a disease that is associated with
abnormal cellular proliferation. The term "abnormal cellular
proliferation" refers to the uncontrolled growth of cells which are
naturally present in a mammalian body. In one embodiment, a disease
which is characterized by abnormal cellular proliferation is
cancer, for example cancer of the prostate, head, neck, eye, mouth,
throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,
colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries,
vagina, testicles, skin, thyroid, blood, lymph nodes, kidney,
liver, intestines, pancreas, brain, central nervous system, adrenal
gland, skin or a leukemia or lymphoma. In one embodiment, the
disease characterized by abnormal cellular proliferation is cancer
of the prostate. In another embodiment, the abnormal cellular
proliferation is associated with at least one solid tumor.
[0080] In one embodiment, the pharmaceutical compositions, methods
of treatment, dosage forms and kits of the disclosure are useful in
treating conditions including (without limitation) peripheral
T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL),
myelofibrosis (MF), for example primary myelofibrosis (PMF),
essential thrombocytopenia (ET), and polycythemia vera (PV), mature
B-cell neoplasms, for example diffuse large B-cell lymphoma
(DLBCL), both germinal B-cell (GCB) as activated B-cell (ABC)
subtypes, mantle cell lymphoma, high grade B-cell lymphoma (HGBL),
anaplastic large cell lymphoma, marginal zone lymphoma, hairy cell
leukemia, Waldenstrom macroglobulinemia, Monoclonal gammopathy of
undetermined significance (MGUS), plasma cell myeloma, Burkitt
lymphoma, Mature T and NK neoplasms, Hodgkin lymphoma,
posttransplant lymphoproliferative disorders (PTLD), histiocytic
and dendritic cell neoplasms, myeloid neoplasms, for example PV,
ET, primary myelofibrosis, chronic neutrophilic leukemia, chronic
myeloid leukemia, atypical chronic myeloid leukemia, juvenile
myelomonocytic leukemia, and acute myeloid leukemia, precursor
lymphoid neoplasm, for example, B-cell acute lymphoblastic leukemia
(B-ALL), Down Syndrome ALL, T-cell ALL (T-ALL), Mature lymphoid
neoplasms, for example, T-cell prolymphocytic leukemia, adult
T-cell leukemia/lymphoma (ATLL), Natural Killer/T-cell lymphoma
(NK/TCL), NK/T--Large Granular Lymphocytic Leukemia (NK/T-LGL),
primary mediastinal large B-cell lymphoma/Hodgkin lymphoma
(PBMCL/HL) and follicular lymphoma (FL), primary cutaneous lymphoma
(PCL), for example, mycosis fungoides/Sezary syndrome, and/or
peripheral T-cell lymphoma (PTCL). Further conditions include
(without limitation) acute and chronic graft-versus host Disease
(aGVHD and cGVHD) and treatment of immune mediated complications of
checkpoint inhibitors or other immune-oncology therapies. A list of
JAK or SYK driven hematologic malignancies is found in the 2016
revision of the World Health Organization (WHO) classification of
lymphoid neoplasms; Blood 2016 127:2375-2390, which is incorporated
by reference herein. A list of hemotologic malignancies with known
JAK mutations is found at Haematologica. 2015 October; 100(10):
1240-1253, which is incorporated by reference herein.
[0081] In another embodiment, a condition associated with
dysregulation of the Syk/JAK pathway comprises acute or chronic
inflammatory disorders, such as neutrophil-associated inflammation,
inflammatory arthritis, inflammation in peritonitis, inflammation
after myocardial infarction or bleomycin-induced pulmonary
fibrosis. Models for testing the ability of compounds to reduce
inflammation in inflammatory arthritis are known, e.g., as
described by Camps et al, Nature Med., 2005, 11, 936-943, which
also describes models useful in assessing the ability of compounds
to reduce inflammation in peritonitis; models for testing the
ability of compounds to reduce inflammation and/or improve healing
after myocardial infarction are described by Siragusa et al, Circ.
Res. (2010), 106, 757-768; and a model for testing the ability of
compounds to prevent bleomycin-induced pulmonary fibrosis is
described by Wei et al, Biochem Biophys Res Comm. 2010, 397:
311-317 and Brent et al, Toxicology, 2000, 147: 1-13, the entire
disclosures of which are incorporated herein by reference.
[0082] In one embodiment, the present disclosure provides
formulations, methods, kits, and dosage forms for broadly treating
all autoimmune diseases, including, for example (without
limitation), atopic dermatitis, alopecia areata, hand and foot
eczema, hidradenitis suppurativa, pemphigus vulgaris, psoriasis,
cutaneous lupus, vitiligo, inflammatory bowel disease (UC, CD),
rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus
erythematosus (SLE), psoriatic arthritis, and multiple sclerosis
(including other autoimmune diseases).
[0083] The disclosure thus provides a method of treating a disease
characterized by the dysregulation (e.g., abnormality or
impairment) of the Syk/JAK pathway in a subject, comprising
administering to the subject a therapeutically effective amount of
an active ingredient in one or more dosage forms, wherein the
dosage forms comprise a pharmaceutical formulation comprising an
active ingredient, wherein the active ingredient in the form of
micronized granules is formed into a compressed tablet, wherein the
active ingredient comprises a compound of the formula (I), and
wherein the active ingredient retains stability after storage of
the pharmaceutical formulation for a predetermined time and under
predetermined conditions.
[0084] As described herein, a therapeutically effective amount of
an active ingredient of the disclosure when used for the treatment
of cancer is, for example, an amount which may reduce the number of
cancer cells in fluids (e.g., blood, peripheral cells or lymphatic
fluids), reduce tumor size, inhibit metastasis, inhibit tumor
growth and/or ameliorate one or more of the symptoms of the cancer.
For cancer therapy, efficacy can be measured for example, by
assessing the time to disease progression and/or determining the
response rate, or measuring inhibition of tumor growth or
metastasis. In one embodiment, administration of the formulations
described herein can achieve inhibition of tumor growth in an
amount of 0% to 100%, preferably an amount of above about 50%.
[0085] As described herein, a therapeutically effective amount of
an active ingredient of the disclosure when used for the treatment
of an inflammatory disorder, such as atopic dermatitis, is an
amount which may delay the onset of or reduce the severity or
duration of an inflammatory response, or which mitigates one or
more symptoms of an inflammatory response. For treatment of an
inflammatory disorder, efficacy can be measured, for example, by a
reduction in physiologic signs of inflammation (e.g., redness,
swelling, heat, loss of function) or by measuring changes in the
levels of cells (e.g., monocytes, macrophages and other mononuclear
cells) or molecules (e.g., pro-inflammatory cytokines) associated
with inflammation. In one embodiment, treatment of atopic
dermatitis can be measured by evaluating a subject according to the
Investigators Global Assessment (IGA) scale, the 5-D Pruritus
Scale, the Pruritus Numeric Rating Scale or the Eczema Area and
Severity Index (EASI) assessment tool, as described, for example,
in FIGS. 3 and 4 and in Example 3 below.
[0086] The Syk/JAK pathways are known to be deregulated in various
cancers due to specific mutations in different members of each
pathway. For example aberrations in Syk/JAK pathways, such as those
caused by the recently identified JAK2.sup.V617F mutation and
translocations of the JAK2 gene, are underlying causes of leukemias
and other myeloproliferative disorders. Such mutations are easily
detected in tumor samples using methods known in the art Sarkar et
al (Diagn Mol Pathol. (1995) 4(4):266-73), the entire disclosure of
which is herein incorporated by reference.
[0087] Identifying a mammalian subject, e.g., a human patient, or a
population of such subjects who will respond positively to
treatment with pharmaceutical formulations of the disclosure prior
to initiation of treatment (also termed herein "predetermining" or
"selecting") can be accomplished by assaying a sample (for example
a tumor biopsy or blood sample comprising white blood cells when
the condition is cancer) from a patient to detect one or more of
the Syk/JAK mutations discussed above. Upon detection of a Syk/JAK
mutation, the subject may be treated with the pharmaceutical
formulations of the present disclosure, for example by
administering one or more pharmaceutical formulations of the
present disclosure which comprise a therapeutically effective
amount of an active ingredient as described herein.
[0088] A suitable sample may be obtained from the body of a subject
and may include, e.g., tissue samples, cells, extracellular matter,
or circulating cancer cells in blood or lymphatic fluid. Tissue
samples may be from any organ, including disease states of such
organs, such as the skin, the blood circulatory system, and any
circulating tumor cells. Tissue samples such as tumor biopsies may
be obtained using known procedures. Tissue specimens may also
include xenograft tumor samples, e.g., those from animals used in
drug dose or toxicology studies.
[0089] For example, a subject can be tested for the presence of a
JAK2.sup.V617F mutation. As discussed above, these mutations can be
detected using any suitable technique known in the art, including
fluorescence in situ hybridization, PCR-based sequencing of
relevant portions of a given gene, restriction fragment length
polymorphism analysis, or by monitoring expression levels of a
given gene product (e.g., protein or RNA. In one embodiment, a
method is provided for treating a condition treatable by inhibiting
the Syk/JAK pathway, comprising selecting a subject who has a
JAK2.sup.V617F mutation; and administering a therapeutically
effective amount of a pharmaceutical formulation of the disclosure.
In one embodiment, a method is provided for treating patients whose
cancers are characterized by the presence of the JAK2.sup.v617F
mutation and translocation of the JAK2 gene comprising the steps of
identifying patients having such mutation(s) and administering a
therapeutically effective amount of the formulation disclosed
herein.
[0090] In an embodiment, the present disclosure provides
pharmaceutical formulations comprising granules, wherein the
granules comprise: micronized active ingredient; one or more
granulation binders; one or more fillers; one or more
disintegrants; and one or more antioxidants, wherein the active
ingredient is a compound of Formula (I) or a pharmaceutically
acceptable salt or prodrug thereof, and wherein the formulation may
further comprise extragranular components. In an embodiment, the
active ingredient comprises
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. In another
embodiment, the active ingredient comprises
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
[0091] In an embodiment, the antioxidants of the formulations
described herein may include vitamin E or butylated hydroxytoluene;
the fillers may comprise lactose monohydrate; the distintegrants
may comprise crospovidone or croscarmellose sodium and the
granulation binders may comprise polyvinylpyrollidone or
hydroxypropylcellulose. In certain embodiments, the granulation
binders comprise hydroxypropylcellulose having a viscosity at
25.degree. C. of 75-150 centipoise in a 5% w/w in aqueous solution.
In certain embodiments, the granulation binders comprise
polyvinylpyrollidone having a number average molecular weight of
about 30,000. In an embodiment, the micronized granules of the
presently described formulation have a particle size of less than
about 20 microns. In an embodiment, the micronized granules have an
isopropyl alcohol content of less than about 5000 ppm.
[0092] In certain embodiments, the formulations may comprise one or
more extragranular components. The extragranular components may
comprise one or more tableting fillers, one or more disintegrants,
one or more lubricants, and optionally one or more surfactants. In
certain embodiments, the tableting fillers may comprise
microcrystalline cellulose, the disintegrants may comprise
croscarmellose sodium, the surfactants may comprise sodium lauryl
sulfate, and the lubricants may comprise magnesium stearate. In an
embodiment, the micronized granules and extragranular components
may be compressed into a tablet.
[0093] The formulations of the present disclosure may exist in any
embodiment known to one skilled in the art. In an embodiment, the
formulation may be present in the form of tablets, scored tablets,
compressed tablets, coated tablets, capsules, caplets, pills,
powder packets and modifications thereof. In an embodiment, the
formulation described herein comprises compressed tablets.
[0094] In an embodiment the micronized granules of the present
formulation have an isopropyl alcohol content of less than about
5000 ppm. The active ingredient in the embodiments described herein
may be between about 5 to 50 mg, 5 mg, about 20 mg, or about 50 mg.
Other aspects of the embodiments described herein may include a
tablet hardness of approximately 5-12 kP, or 7 to 9 kP and a
disintegration time of less than about 5 minutes in 0.1 N HCl, pH
6.8 and 50 mM phosphate buffer at 37.degree. C. In certain
embodiments the formulations may comprise a tablet having an
aesthetic coating; the coating may be comprised of
hydroxypropylcellulose, titanium dioxide, talc and polyethylene
glycol.
[0095] In an embodiment, the formulation described herein comprises
a compressed tablet having micronized granules and extragranular
components, wherein: the tablet has a total weight of about 150 mg;
the micronized granules comprise about 5 to 50 mg of an active
ingredient, about 75 to 900 mg, or 118.6 to 736 mg of lactose
monohydrate, about 1-20 mg, or 4.5 mg croscarmellose sodium, about
0.1-5 mg or 0.15 mg vitamin E, and about 1-10 mg, or 4.5 mg
granulation binder; furthermore, the extragranular components may
comprise about 5-20 mg, or 11.25 mg or microcrystalline cellulose,
about 1-10 mg or 4.5 mg croscarmellose sodium, about 1-10 mg or 1.5
mg magnesium stearate, and about 1-10 mg or 6 mg of an enteric
coating. The active ingredient in such an embodiment may comprise
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
[0096] In certain embodiments of such a compressed tablet,
granulation binders maybe selected from the group consisting of
polyvinylpyrollidone and hydroxypropylcellulose wherein
hydroxypropylcellulose has a viscosity at 25.degree. C. of 75-150
centipoise in a 5% w/w in aqueous solution. In certain embodiments,
the micronized granules comprise about 75-150 mg, or 117.1 mg to
about 72.1 mg of lactose monohydrate and the extragranular
components further comprise about 1-10 mg or 1.5 mg sodium lauryl
sulfate.
[0097] In certain embodiments, the micronized granules of a
compressed tablet as described herein may comprise about 5 mg of an
active ingredient and about 118.6 mg of lactose monohydrate, about
20 mg of an active ingredient and about 103.6 mg of lactose
monohydrate, or about 50 mg of an active ingredient and about 73.6
mg of lactose monohydrate.
[0098] Further included herein are embodiments comprising methods
of manufacturing the pharmaceutical formulation embodiments
described above. Also included are methods of preparing compressed
tablets and methods of stabilizing pharmaceutical formulations as
well as the preparation of dosage forms comprising micronized
granules and extragranular components compressed into a tablet. In
an embodiment, the methods, protocols and procedures regarding the
foregoing comprise the incorporation of an active ingredient
together with antioxidants including vitamin E or butylated
hydroxytoluene; fillers comprising lactose monohydrate;
distintegrants comprising crospovidone or croscarmellose sodium and
granulation binders comprising polyvinylpyrollidone or
hydroxypropylcellulose. In certain embodiments, the granulation
binders comprise hydroxypropylcellulose having a viscosity at
25.degree. C. of 75-150 centipoise in a 5% w/w in aqueous solution.
In certain embodiments, the granulation binders comprise
polyvinylpyrollidone having a number average molecular weight of
about 30,000. In an embodiment, the micronized granules of the
presently described embodiments have a particle size of less than
about 20 microns. In an embodiment, the micronized granules have an
isopropyl alcohol content of less than about 5000 ppm.
[0099] In an embodiment, the formulations may further comprise one
or more extragranular components. The extragranular components may
comprise one or more tableting fillers, one or more disintegrants,
one or more lubricants, and optionally one or more surfactants. In
certain embodiments, the tableting fillers may comprise
microcrystalline cellulose, the disintegrants may comprise
croscarmellose sodium, the surfactants may comprise sodium lauryl
sulfate, and the lubricants may comprise magnesium stearate. In an
embodiment, the micronized granules and extragranular components
may be compressed into a tablet.
[0100] In an embodiment, the active ingredient for the foregoing
may comprise
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. In
another embodiment, the active ingredient may comprise
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
[0101] In the above embodiments, the methods of manufacturing and
producing may comprise mixing intragranular ingredients comprising
an active ingredient; one or more fillers; one or more
disintegrants; and one or more antioxidants; granulating the mixed
intragranular ingredients while adding a solution of 10% w/w of one
or more granulation binders in 99% v/v isopropyl alcohol until
granules are formed; drying and milling the granules to make
micronized granules; wherein the active ingredient comprises a
compound of Formula (I) or a pharmaceutically acceptable salt or
prodrug thereof.
[0102] In a further embodiment, kits comprising one or more dosage
forms and instructions for administering the dosage forms to a
subject, wherein the dosage forms comprise granules and
extragranular components compressed into a tablet, are also
provided. In such embodiments, the formulation may comprise the
active ingredients comprising
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. In another
embodiment, the active ingredient may comprise
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dih-
ydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.
[0103] The above embodiments may be utilized in methods for
treating cancer or atopic dermatitis or inflammation in a subject,
comprising administering to the subject a therapeutically effective
amount of an active ingredient in one or more dosage forms, wherein
the dosage forms comprise micronized granules and extragranular
components compressed into a tablet.
[0104] Active ingredients of the present disclosure can be
prepared, for example, according to the methods disclosed in U.S.
Pat. Nos. 8,729,079 and 9,382,277, the entire disclosures of which
are herein incorporated by reference. In some embodiments of the
disclosure, an active ingredient comprising the pharmaceutical
formulation of the disclosure can be present in at least about 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
98%, 99%, 99.5%, 99.9% or 100% w/w.
[0105] The active ingredient for use in the present formulations
and methods comprises compounds which regulate the Syk/JAK pathway.
The regulatory activity of the active ingredients of the disclosure
makes these compounds useful for manufacturing pharmaceutical
formulations, which can be used for treating conditions such as
inflammatory disorders, including atopic dermatitis, or cancers
characterized by the presence of solid tumors, particularly
melanoma, colon cancer, non-small cell lung cancer, bladder cancer,
and breast cancer.
[0106] The therapeutically effective amount of a pharmaceutical
formulation of the disclosure provided to a subject will vary
depending upon the purpose of the administration, the state of the
patient, level of disease penetration and the like. As used herein,
"subject" includes any human or non-human animal in need of
treatment with the pharmaceutical formulations of the disclosure.
In one embodiment, a subject is any human in need of treatment with
the formulations of the disclosure (sometimes referred to herein as
a "patient"). A therapeutically effective amount of the active
ingredient in the pharmaceutical formulations of the disclosure can
be determined by an ordinarily skilled physician or medical
professional, taking into account certain variables, including the
specific condition and the size, age, weight, gender, disease
penetration, previous treatment and response pattern of the
patient.
[0107] In one embodiment, the pharmaceutical formulation is
administered orally, for example in capsule or tablet form. For
example, the present formulations can be provided as a unit dose,
for example as a compressed tablet, comprising a therapeutically
effective amount. In one embodiment, a unit dose comprising the
pharmaceutical formulation of the disclosure can be administered
once daily or multiple times daily, for example, 1 to 6 times in a
12 or 24 hour period. If multiple unit doses are administered in a
given time period, they can be administered at substantially even
time intervals. For example, if two unit doses are administered in
a 12 hour period, they can be given to the patient 6 hours apart.
Multiple unit doses are administered in a given time period can
also be administered at substantially uneven time intervals. In one
embodiment, a unit dose comprises a dosage form of the disclosure
in the form of a tablet or capsule for oral administration.
[0108] In some embodiments, the active ingredient in the
pharmaceutical formulations of the disclosure can comprise an
amount of about 0.5 to 100 percent by weight, for example about
0.5, 1, 1.5, 2, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99 or 100 percent by
weight. In another embodiment, the active ingredient comprises
about 3.5 percent or about 14 percent of the pharmaceutical
formulation by weight.
[0109] In some embodiments, formulations of the disclosure comprise
an active ingredient of the disclosure, formed into oral dosage
forms such as tablets, capsules, powders, suspensions, and the
like. In such dosage forms of the disclosure, the amount of active
ingredient comprising the dosage form can be any suitable amount,
for example about 0.5, 1, 1.5, 2, 2.5, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99 or
100 mg per unit dosage form. In certain embodiments, dosage forms
of the disclosure comprise about 20 to about 80 mg of the active
ingredient per dosage form.
[0110] In certain embodiments, formulations of the disclosure
comprise an active ingredient of the disclosure, formed into dosage
forms such as tablets, capsules, sachets, powders, suspensions,
suppositories and the like. In such dosage forms of the disclosure,
the amount of active ingredient comprising the dosage form can be
any suitable amount, for example about 0.5, 1, 1.5, 2, 2.5, 5, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, 99 or 100 mg per unit dosage form. In certain
embodiments, dosage forms of the disclosure comprise about 25, 50,
75, 80 or 100 mg of the active ingredient per dosage form. In one
embodiment, dosage forms of the disclosure comprise about 75 mg of
the active ingredient per dosage form.
[0111] A suitable daily (i.e. 24 hour time period) dose according
to methods of the disclosure, whether given all at once or in
multiple administrations, can depend on the specific method of
treatment and condition treated. In one embodiment, a suitable
daily dose, whether given all at once or in multiple
administrations, is between about 10 to 120 mg for oral
application, for example about 20 mg to 80 mg, 25 to 75 mg, 30 mg
to 70 mg, 35 mg to 65 mg, or 40 mg to 60 mg. In one embodiment, a
suitable daily dose is between about 40 mg to about 80 mg. In other
embodiments, a suitable daily dose is about 10 mg, 15 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg or 120 mg. In one
embodiment, a suitable daily dose is about 20 mg. In another
embodiment, a suitable daily dose is about 40 mg. In another
embodiment, a suitable daily dose is about 80 mg.
[0112] In another embodiment, a suitable daily (i.e. 24 hour time
period) dose according to methods of the disclosure, whether given
all at once or in multiple administrations, can depend on the
specific method of treatment and condition treated. In one
embodiment, a suitable daily dose, whether given all at once or in
multiple administrations, is between about 10 to 1000 mg for oral
application, for example about 20 to 500 mg, 50 mg to 250 mg or 75
mg to 100 mg. In other embodiments, a suitable daily dose is about
10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55
mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg,
200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900
mg or 1000 mg.
[0113] In another embodiment, a suitable daily dose, whether given
all at once or in multiple administrations, is about 0.1 mg/kg to
about 100 mg/kg, about 0.5 mg/kg to about 75 mg/kg, about 0.1
mg/kg, 1 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50
.mu.g/kg, 75 .mu.g/kg or 100 .mu.g/kg.
[0114] The therapeutically effective amounts may be provided on
regular schedule, i.e., daily, weekly, monthly, or yearly basis or
on an irregular schedule with varying administration days, weeks,
months, etc. Alternatively, the therapeutically effective amount to
be administered may vary. In one embodiment, the therapeutically
effective amount for the first dose is higher than the
therapeutically effective amount for one or more of the subsequent
doses. In another embodiment, the therapeutically effective amount
for the first dose is lower than the therapeutically effective
amount for one or more of the subsequent doses. Equivalent dosages
may be administered over various time periods including, but not
limited to, about every 2 hours, about every 6 hours, about every 8
hours, about every 12 hours, about every 24 hours, about every 36
hours, about every 48 hours, about every 72 hours, about every
week, about every two weeks, about every three weeks, about every
month, and about every two months. Alternatively, equivalent doses
may be administered over uneven intervals in accordance with the
recommended treatment of a health-care practitioner. The number and
frequency of dosages corresponding to a completed course of therapy
will be determined according to the judgment of a health-care
practitioner. The therapeutically effective amounts described
herein refer to total amounts administered for a given time period;
that is, if more than one active ingredient is administered, the
therapeutically effective amounts correspond to the total amount
administered.
[0115] In one embodiment, the pharmaceutical formulation is
administered orally once a day (QD). The administration can be
short-term or long-term. For example, short term administration can
comprise administration of the pharmaceutical formulation once a
day for about 1 week, 2 weeks, 3 weeks or 4 weeks, or any other
longer or shorter term. For example, long term administration can
comprise administration of the pharmaceutical formulation once a
day for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 30 days, 1
month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years,
or any other longer or shorter term.
[0116] The following examples are given to illustrate exemplary
embodiments of the present disclosure. It should be understood,
however, that the present disclosure is not to be limited to the
specific conditions or details described in these examples.
EXAMPLES
Example 1
Preformulation, Formulation and Analytical Data
[0117] Analytical studies for
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile are provided
below in Tables 1-3: Table 1 provides the results of an HCl pH
dependent solubility profile study, Table 2 provides the results of
an HCl solubility profile in organic solvents, and Table 3 provides
the results of an HCl stress study.
TABLE-US-00001 TABLE 1 pH 4.5 pH 5.5 pH 6.8 pH 7.5 0.1N Acetate
Acetate Phosphate Phosphate HCl Buffer Buffer Buffer Buffer Water
Initial N/A 4.50 5.52 6.80 7.55 N/A pH End pH 1.23 4.56 5.12 6.86
6.96 2.62 Solu- 10810 2.9 1.0 2.7 0.7 941 bility .mu.g/mL
TABLE-US-00002 TABLE 2 MeOH EtOH IPA Solubility .mu.g/mL 4437 4996
462
TABLE-US-00003 TABLE 3 1N 1N HCl NaOH 3% H2O2 rt, rt, rt,
80.degree. C. UV 24 hr 24 hr 30 hr 24 hr 23 hr % API based on
100.00% 99.54% 83.00% 99.93% 99.80% Peak Area %
[0118] Studies were conducted to evaluate excipient compatibility,
stability and disintegration comprising the use of Ac-Di-Sol and
Polyplasdone XL-10; PVP K-30 and Klucel LF and SLS. Water was
avoided as a granulating solved and IPA was used. The coating
comprised Opadry (IPA/water, 50/50) and tables were prepared in
5/20/50 mg strength, 150 mg weight (DT:<5 min in 0.1 N HCl, pH
6.8, 50 mM PO4 buffer). Details concerning ingredients and relative
weights for prototype formulation A and formulation B are provided
below in Table 4.
TABLE-US-00004 TABLE 4 Formulation A Batch Formulation B Batch
Ingredients mg/tab (g) mg/tab (g) Intragranular API 5/20/50 1.50 5
1.50 Lactose Monohydrate 117.25/lower 35.18 118.75 35.63 Primellose
4.5 1.35 0 0.00 Polyplasdone XL-10 0 0.00 4.5 1.35 Klucel LF/PVP
K-30 4.5 1.35 4.5 1.35 Extragranular Vivapur 101 11.25 3.38 11.25
3.38 Primellose 4.5 1.35 0 0.00 Polyplasdone XL-10 0 0.00 4.5 1.35
Magnesium Stearate 1.5 0.45 1.5 0.45 SLS 1.5 0.45 0 0.00 Total
weight 150 45 150 45.00 Coating: 4% w/w, Opadry White
[0119] In an additional study, residual solvent was evaluated in
the tables wherein IPA was used as a granulation solvent. The
results are provided below in Table 5.
TABLE-US-00005 TABLE 5 Sample Reported Sample ID Weight (mg)
Content (ppm) P14K080002A 108.84 387 P14K080002B 107.48 292
P14K080003A 100.35 1272 P14K080003B 102.15 470 P14K080004A 102.65
643 P14K080004B 102.90 164
[0120] The formulation screening strategy comprised a first batch
screening under accelerated storage conditions at 40 C/75% RH in
open and closed containers. Another batch was screened under
accelerated stress conditions at 60 C in closed containers.
Stability data is provided in Table 6.
TABLE-US-00006 TABLE 6 1 Week 40.degree. C./75% Initial RH Open 1
Week 60.degree. C. Sample Total Total Total Information Composition
Assay, % Impurity, % Assay, % Impurity, % Assay, % Impurity, %
P14K080001A PVP/AC-Di-Sol/SLS 98.6 0.436 98.9 0.602 90.6 2.157
P14K080001B PVP/Polyplasdone XL 101.4 0.334 94.1 2.673 101.1 2.629
10 P14K080001C PVP/AC-Di-Sol 103.0 0.275 104.5 0.476 102.4 1.156
P14K080001D PVP/Polyplasdone XL 107.6 0.370 104.2 1.002 107.6 2.082
10/SLS P14K080002A KlucelLF/AC-Di- 106.9 0.222 107.8 0.210 105.0
1.653 Sol/SLS P14K080002B KlucelLF/ 104.6 0.364 104.4 0.143 104.7
2.100 Polyplasdone XL10 P14K080002C KlucelLF/AC-Di-Sol 104.6 0.330
96.7 2.480 105.8 0.259 P14K080002D Klucel LF/ 98.4 0.334 93.4 3.759
97.6 2.230 Polyplasdone XL 10/SLS
[0121] The analytical procedures for determination of content
uniformity, blend uniformity, amount of active ingredient and
related impurities (including degradation compounds) in
pharmaceutical formulations of the present disclosure comprising
active ingredient-containing tablets (5 mg, 20 mg and 50 mg
strengths) comprised the use of an HPLC method. The column used for
separation has USP L1 packing and dimensions of 4.6.times.150 mm,
with a 3.5 micron particle size. The HPLC method uses gradient
elution where the mobile phase was a buffer solution of 1 mM
ammonium formate, pH 3.2, and 0.1% formic acid in acetonitrile, and
eluted fractions were subject to UV detection at 275 nm. Detailed
analytical results for prototype formulations at 1 week, 40 C/75%
RH in an open container are provided in Table 7.
TABLE-US-00007 TABLE 7 1 WK, 40.degree. C./75% RH, Open Batch # Wt
of Tablets (g) Impurities Retention Time, min RRT Peak Area %
Recover P14K080002A 1.60316 Unknown-1 7.105 0.67 1258 0.002
Unknown-2 7.399 0.70 2125 0.004 Unknown-8 9.79 0.93 5716 0.011
Unknown-10 10.315 0.98 7262 0.014 ASN002 10.559 1.00 40910752 N/A
Unknown-12 11.303 1.07 29691 0.051 Unknown-13 11.593 1.10 21378
0.043 Unknown-14 11.835 1.12 2951 0.005 Unknown-15 12.187 1.15 4399
0.009 Unknown-16 12.428 1.18 1716 0.003 Unknown-17 12.771 1.21 5924
0.012 Unknown-21 13.721 1.30 12305 0.025 Unknown-25 14.568 1.38
2464 0.005 Unknown-26 14.86 1.41 1345 0.002 Unknown-27 15.166 1.44
2264 0.004 Unknown-36 18.288 1.73 4677 0.009 % Total Impurity 0.210
P14K080002B 1.58841 Unknown-2 7.388 0.70 2690 0.005 Unknown-7 9.344
0.88 13003 0.026 Unknown-8 9.769 0.93 8669 0.017 Unknown-9 10.085
0.96 2400 0.004 Unknown-10 10.294 0.97 14157 0.019 ASN002 10.56
1.00 27284322 N/A Unknown-11 10.891 1.03 13904 0.049 Unknown-12
11.302 1.07 402914 0.828 Unknown-13 11.595 1.10 18407 0.037
Unknown-14 11.841 1.12 2100 0.004 Unknown-15 12.201 1.16 6897 0.014
Unknown-16 12.432 1.18 3066 0.006 Unknown-17 12.798 1.21 10370
0.021 Unknown-18 13.078 1.24 5544 0.011 Unknown-20 13.567 1.29
15836 0.032 Unknown-25 14.628 1.39 6789 0.013 Unknown-27 15.171
1.44 2786 0.005 Unknown-30 16.521 1.56 1719 0.003 Unknown-31 16.757
1.59 2345 0.004 Unknown-35 18.071 1.71 5593 0.011 Unknown-36 18.259
1.73 9928 0.020 Unknown-38 19.189 1.82 2262 0.004 % Total Impurity
1.143
[0122] The formulation batches described above were prepared by
micronizing the active, ingredient, combining the active ingredient
with intragranular and extragranular components to form a tablet,
and finally coating the tablet.
[0123] Micronization:
[0124] The general procedure for micronizing the active ingredient
comprised the use of a Micronizer 4'' SDM and batches of
approximately 500-550 g were micronized. The micronization
parameters consisted of the following:
[0125] Inlet Air-100 PSI
[0126] Grinding Chamber Air-40 PSI
[0127] Feeder Nozzle-20 PSI
[0128] Number of Passes #1
[0129] In an embodiment, 512 g of material was added to the feeding
chamber and the weight of the material obtained after micronization
was 452 g.
[0130] The table below provides particle size measurement in hexane
for the active ingredient as described herein.
TABLE-US-00008 TABLE 8A Active Ingredient D (0.1) D (0.5) D (0.9)
As is API 3.752 12.354 32.411 Micronized API 1.675 7.036 13.530
[0131] FIG. 1 provides a particle size distribution results
analysis report for the active ingredient prior to micronization,
and FIG. 2 provides a particle size distribution results analysis
report for the active ingredient after micronization.
[0132] Formulation Configuration:
[0133] The formulations were configured into two tablet
formulations, 20 mg, and 50 mg. Table 8b provides the evaluation of
residual solvent levels (isopropyl alcohol or "IPA") for the 20 mg
tablet, and Table 8c provides PVP K30-IPA evaluation of IPA
residual solvent levels for the 50 mg tablet. The general procedure
for making the formulations comprised weighing the required
intragranular material and mixing it, titurating the powder mixer
in a mortar and pestle, slowing adding IPA-PVP K30 10% w/w solution
to the powder while continuingly mixing (adding additional IPA 99%
until granules are formed if required), drying the wet mass in an
oven at 40 C for 30 minutes, passing the dried mass through
Fitzmill (Hammer Forward, Screen #0040, Speed #2500 RPM), weighing
and measuring the required extragranular materials and adding them
in following order Vivapur 101, Primellose/Polyplasone XL-10 and
SLS, mixing for 3-5 minutes in a tubular mixer, adding magnesium
stearate and mixing for 1 minute in a tubular mixer, tableting the
formulation in F-Press keeping target at 150 mg and hardness at 9
KPa.
[0134] The coating formula is provided below in Table 8d:
TABLE-US-00009 TABLE 8d # Mg per Dose % w/w Ingredients Theoretical
(g) 1 150 n/a API tablets 300 2 6 4 Opadry White 03F180004 12 3 n/a
n/a Purified Water 54 4 n/a n/a Isopropyl Alcoholo 99% 54
[0135] Stability data was generated and collected for eight
prototype formulations. Details of the study results are proved
below in Table 9a (40 degrees Celsius/75 RH) and Table 9b (60
degrees Celsius). Formulations 1A, 1C, 2A and 2C displayed superior
stability results.
[0136] Formulations 1A, 1C, 2A and 2C were further evaluated to
test the effect of antioxidants.
[0137] As shown in Tables 10a and 10b, certain prototype
formulations were evaluated for determination of
DL-.alpha.-Tocopherol (Vitamin E) content comprising an HPLC
method. The column used for separation has a USP L1 packing,
4.6.times.150 mm, with a 3.5 micron particle size, and method uses
isocratic elution with water and acetonitrile (97:3 v/v) as the
mobile phase and UV detection at 294 nm.
[0138] Further analysis was conducted to evaluate excipient
compatibility, stability and disintegration at the 5 mg strength:
Ac-Di-Sol and Polyplasdone XL-10; PVP K-30 and Klucel LF; and SLS.
In addition, higher strength tablets were evaluated for stability
and tablet properties, the effect of antioxidants (5 mg strength),
and polymorphs. Formulations A, B, C, and D provided in Table 11
below were selected for further evaluation.
[0139] Following additional analysis, the following formulations
(Table 12) were selected as lead candidates:
Immediate-Release Formulations
[0140] Immediate-release formulations of the disclosure containing
a micronized hydrochloride salt of the active ingredient described
herein were prepared in 2 dosage strengths (5 mg and 20 mg) for use
in clinical studies. Table 13 provides component composition and
amounts for 5 mg and 20 mg strength tablets.
TABLE-US-00010 TABLE 13 Amount per Tablet (mg) Component 5 mg 20 mg
Compound 1 HCl (micronized) 5.396** 21.584** Lactose Monohydrate,
NF (Modified Spray Dried 116.704 100.516 Fast Hydroxypropyl
Cellulose, NF (Klucel ELF 4.500 4.500 Pharm) Croscarmellose Sodium,
NF (Ac-Di-Sol) 9.000 9.00 Vitamin E, USP (dl-.alpha.-Tocopherol)
0.150 0.150 Microcrystalline Cellulose, NF (Vivapur Type 11.250
11.250 101) Sodium lauryl sulfate, NF (Kolliphor SLS fine) 1.500
1.500 Magnesium Stearate, NF (Ligamed MF-2-K) 1.500 1.500 Isopropyl
Alcohol, USP* -- -- Core Tablet 150.00 150.00 Opadry White
03F180004 6.000 6.000 Purified Water* -- -- Isopropyl alcohol* --
-- Total Weight (mg) 156.00 156.00 USP = United States
Pharmacopeia; NF = National Formulary *Evaporates during the
process **Weights of Compound 1 hydrochloride include correction
factors for purity and hydrogen chloride content of API such that
the weights of Compound 1 free base in 5 mg and 20 mg tablets are 5
mg and 20 mg per tablet, respectively.
[0141] The formulations provided in Table 13 further comprise
inactive ingredients as provided below in Table 14. Each excipient
is within the potency limits listed for an oral route of
administration in the most current FDA Inactive Ingredient Guide
(IIG) as applicable. Table 15 provides the quantitative composition
of Opadry White 03F180004.
TABLE-US-00011 TABLE 14 Amount per Tablet (mg) IIG limits Component
Components 5 mg 20 mg (Mg) Function Lactose Monohydrate, 116.704
100.516 587.44 Diluent NF (Modified Spray dried fast Flo)
Hydroxypropyl 4.50 4.50 240 Binder Cellulose, NF (Klucel ELF Pharm)
Croscarmellose Sodium, 9.00 9.00 180 Disintegrant NF (AC-DI-SOL)
Vitamin E, USP (dl-.alpha.- 0.15 0.15 1.34 Antioxidant Tocopherol)
Microcrystalline 11.25 11.25 234.6 Diluent Cellulose, NF (Vivapur
Type 101) Sodium Lauryl Sulfate, 1.50 1.50 51.69 Wetting NF
(Kolliphor SLS fine) agent Magnesium Stearate, NF 1.50 1.50 400.748
Lubricant (Ligamed MF-2-K) Isopropyl Alcohol, USP* -- -- --
Granulation solvent Opadry White 6.00 6.00 See Table 3 Aesthetic
03F180004 for the break Coating down system Purified Water * -- --
-- Coating solvent Isopropyl Alcohol, USP* -- -- -- Coating
solvent
TABLE-US-00012 TABLE 15 Blend Amount Ingredients/ IIG limits
formula (mg/tablet) Compendial Reference (mg) (% w/w) 5 mg 20 mg
HPMC 2910/Hypromellose 92.794 60.00 3.6 3.6 (USP, PhEur, JP)
Titanium Dioxide 35.7 20.00 1.2 1.2 (USP, FCC, PhEur, JP) Talc
(USP, FCC, PhEur, JP) 220.4 10.00 0.6 0.6 Macrogol/PEG (NF, FCC,
450 10.00 0.6 0.6 JECFA, Ph. Eur) MW 6000 Total weight of Opadry
White 03F180004 per tablet 6 mg 6 mg
[0142] The above-described tablets are packaged into high density
polyethylene (HDPE) bottles with induction seals and packed with 1
g silica gel desiccant canisters, closed with child-resistant
polypropylene screw caps.
Example 3
Evaluation of Clinical Activity, Safety and Tolerability of
Compound 1, a Dual SYK/JAK Inhibitor, in Patients with Moderate to
Severe Atopic Dermatitis
[0143] Example 3 evaluates the safety, tolerability and efficacy of
Compound 1 in subjects with moderate to severe atopic dermatitis,
as well as the pharmacokinetic (PK) profile of Compound 1 and
pharmacodyncamic/biomarkers for evidence of drug activity.
Methods and Study Design:
[0144] The study conducted was a randomized, double-blind,
placebo-controlled, multicenter, sequential dose escalation study
in subjects with moderate-to severe atopic dermatitis. The study
included a screening period (up to 30 days) and a treatment period
for 4 weeks with a 14 day follow up period that concluded with an
end-of-study visit. Three sequential cohorts of 20, 40 and 80 mg QD
were evaluated. At each dose level a total of 12 subjects were
enrolled with 9 subjects receiving Compound 1, and 3 subjects
receiving matching placebos.
[0145] A total of approximately 36 subjects were randomized at
approximately 10 study sites in the U.S. and Canada. Dose
escalation occurred after a review of the blinded safety data by a
Safety Review Committee (SRC). Dose escalation continues until the
Maximum Tolerated Dose (MTD) is defined. The dose at which study
drug related adverse events within the same organ class results in
treatment discontinuation in .gtoreq.2 of the subjects (or
.gtoreq.3 subjects in any system organ class), is considered to
exceed the Maximum Tolerated Dose (MTD).
[0146] The dose level immediately below is considered the MTD. All
data up to and including the assessments at the end of the 28-day
treatment period (Day 29) of the current cohort were included in
the review. The SRC reviews the blinded safety data and recommends
initiation of the next dose cohort or halting dose escalation.
Lower or intermediate dose levels and alternate dosing schedules
other than those proposed, may be explored as supported by the
clinical data of the previous cohort(s) in an effort to better
define the MTD. Higher dose levels may be evaluated as supported by
the emerging clinical data.
[0147] Upon signing the informed consent, the each subject
underwent screening assessments from Day -30 to Day -1 prior to
study drug administration. On Day 1 (baseline), eligible subjects
were randomized, subjected to the Day 1/baseline assessments and
received Compound 1 at 20, 40 or 80 mg or placebo, dependent on
cohort and randomization schedule. At this visit, PK/PD samples
were collected at predose and up to 8 hours (or up to 12 hours at
selected sites). Subjects were monitored in clinic for 2 hours
following the first study drug administration. Subjects returned to
the clinic on Day 2 for PK and PD samples (24 hours post dose).
[0148] Pre-dose PK and PD samples were collected on Days 8 and 29
(last day of treatment). On Day 15, PK/PD samples were also
collected at pre-dose and up to 8 hours post-dose and subjects
returned on Day 16 for PK and PD samples (24 hours post dose).
Subjects came in for additional safety assessments on Days 8, 22
and 29, as well as at the end of the follow up period (Day 43).
Disease assessments were conducted on Days 1, Day 15 and Day
29.
[0149] FIG. 5 is a graphical illustration of the study design,
including the treatment period, safety follow-up period, starting
doses and number of subjects. In the study design shown in FIG. 5,
9 active and 3 placebo subjects were randomized in each Cohort.
FIG. 6 is a graphical illustration of the patient demographics. In
the demographics shown in FIG. 6, there were no use of topical or
systemic steroids, and emollient use was required with consistent
application (once daily or twice daily).
Diagnosis and Subject Inclusion/Exclusion Criteria:
[0150] Inclusion Criteria: [0151] 1. Ability to provide written
informed consent obtained prior to any study-related procedure
being performed. [0152] 2. Male or female, 18.ltoreq.years and
.ltoreq.75 years of age. [0153] 3. Chronic AD diagnosed by the
Hanifin and Rajka criteria that has been present for at least 6
months before the screening visit (information obtained from
medical chart or patient history). [0154] 4. Eczema Area and
Severity Index (EASI) score .gtoreq.16 at baseline visits. [0155]
5. Investigator's Global Assessment (IGA) score .gtoreq.3 at the
baseline visits. [0156] 6. At least 10% body surface area (BSA) of
AD involvement at the baseline visits. [0157] 7. Subject has a body
mass index (BMI).ltoreq.35 kg/m.sup.2. [0158] 8. History of
inadequate response to topical corticosteroids or calcineurin
inhibitors as treatment for AD within 1 year before the screening
visit (information obtained from medical chart or patient history).
[0159] 9. Subjects must apply stable doses of an Investigator
approved, basic bland emollient once or twice-daily for at least 7
days before the baseline visit. [0160] 10. Subjects must be willing
to use medically effective methods of birth control, if of
reproductive potential* and sexually active (unless they are
exclusively sexually active with same-sex partners). Adequate birth
control is defined as agreement to consistently practice an
effective and accepted method of contraception from at least 4
weeks prior to baseline (Day 1) throughout the duration of the
study and for 4 weeks after last dose of study drug: [0161] a. For
females, adequate birth control methods are defined as: hormonal
contraceptives, intrauterine device (IUD), vasectomized partner or
double barrier contraception (i.e., condom+diaphragm, condom or
diaphragm+spermicidal gel or foam). [0162] b. For males, adequate
birth control methods are defined as: vasectomy, double barrier
contraception (i.e., condom+diaphragm, condom or
diaphragm+spermicidal gel or foam) or used by the sole partner of a
hormonal contraceptive or IUD. [0163] For females, menopause is
defined as 24 months without menses; if in question, a
follicle-stimulating hormone confirming the nonchildbearing
potential (refer to laboratory reference ranges for confirmatory
level) must be documented prior to baseline visit. Hysterectomy,
bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal
ligation must be documented, as applicable. [0164] 11. Females of
reproductive potential must have a negative serum pregnancy test at
screening and negative urine pregnancy test at baseline (Day 0).
[0165] 12. Subjects must be willing and able to comply with clinic
visits and study-related procedures
[0166] Exclusion Criteria: [0167] 1. Subjects have clinically
infected atopic dermatitis. [0168] 2. Presence of any of the
following laboratory abnormalities at the screening visit: [0169]
a. Hemoglobin <11 g/dL [0170] b. White blood cell
(WBC)<3.0.times.10.sup.3/L [0171] c. Platelet count
<125.times.10.sup.3/L [0172] d. Neutrophils
<2.50.times.10.sup.3/L [0173] e. Lymphocytes
.ltoreq.1.2.times.10.sup.3/L [0174] f. Aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) >1.5.times. the upper limit
of normal (ULN) [0175] g. Total bilirubin >ULN (except for
elevated indirect bilirubin secondary to Gilbert's syndrome) [0176]
h. Creatinine >ULN. [0177] 3. Subjects with uncontrolled
hypertension within the last 1 month prior to screening or blood
pressure at screening of systolic blood pressure >140 mm Hg or
diastolic BP >90 mm Hg, confirmed by repeat assessments. [0178]
4. Positive QuantiFERON.RTM.-TB test indicating possible
tuberculosis infection, unless there is documented evidence of a
completed adequate treatment course for latent TB. [0179] 5.
History of latent or active tuberculosis or exposure to endemic
areas within 8 weeks. [0180] 6. Availability of chest radiograph at
screening or within 3 months before the screening visit (radiology
report must be available) with results consistent with prior TB
infection (including but not limited to apical scarring, apical
fibrosis, or multiple calcified granuloma). This does not include
non-caseating granulomata. Screening chest radiography is not
mandatory if no clinical signs or symptoms indicating active TB
infection, unless history of latent or active tuberculosis or
exposure to endemic areas within the last 12 months. [0181] 7.
Positive hepatitis B core antigen, positive hepatitis B surface
antigen, positive hepatitis C antibody, and/or positive human
immunodeficiency virus at the screening visit. [0182] 8. Subject
has used hydroxyzine or diphenhydramine within 1 week prior to
baseline (Day 1). [0183] 9. Subject has used topical products
containing urea within 1 week prior to baseline (Day 1). [0184] 10.
Subject has used systemic antibiotics within 2 weeks or topical
antibiotics within 1 week prior to baseline (Day 1). [0185] 11.
Subject has used any topical medicated treatment for atopic
dermatitis within 2 weeks prior to baseline (Day 1), including, but
not limited to, topical corticosteroids, calcineurin inhibitors,
tars, bleach, antimicrobials, medical devices, and bleach baths.
[0186] 12. Subject has used systemic treatments (other than
biologics) that could affect atopic dermatitis less than 4 weeks
prior to baseline (Day 1) (e.g., retinoids, calcineurin inhibitors,
methotrexate, cyclosporine, hydroxycarbamide [hydroxyurea],
azathioprine, oral/injectable corticosteroids). Note: Intranasal
corticosteroids, eye drops containing corticosteroids, and inhaled
corticosteroids for stable medical conditions are allowed if
subject has been on a stable dose for at least 4 weeks prior to
baseline (Day 1) and will continue usage at the same dose for the
duration of the study. [0187] 13. Subject has received any marketed
or investigational biological agent within 12 weeks or 5 half-lives
(whichever is longer) prior to baseline (Day 1). [0188] 14. Subject
is currently receiving a non-biological investigational product or
device or has received one within 4 weeks prior to baseline (Day
1). [0189] 15. Subject has excessive sun exposure, is planning a
trip to a sunny climate, or has used tanning booths within 4 weeks
prior to baseline (Day 1), or is not willing to minimize natural
and artificial sunlight exposure during the study. Use of sunscreen
products and protective apparel are recommended when exposure
cannot be avoided. [0190] 16. Subject has received a live
attenuated vaccine within 4 weeks prior to baseline (Day 1) or
plans to receive a live attenuated vaccine during the study and up
to 4 weeks or 5 half-lives (of the study product), whichever is
longer, after the last study product administration. [0191] 17.
Subject is known to have immune deficiency or is immunocompromised.
[0192] 18. History of malignancy within 5 years before the baseline
visit, with the following exceptions: [0193] a. subjects with a
history of completely treated carcinoma in situ of cervix, and
non-metastatic squamous or basal cell carcinoma of the skin are
allowed. [0194] 19. Planned major surgical procedure during the
length of the patient's participation in this study. [0195] 20.
History of congestive heart failure New York Heart Association
(NYHA) class III or IV [0196] 21. 12-Lead electrocardiogram (ECG)
abnormalities considered by the investigator to be clinically
significant or QTc F.gtoreq.450 milliseconds, regardless of
clinical significance, at screening. Abnormal ECG may be confirmed
with one repeat assessment. For subjects with QTcF.gtoreq.450 msec
on initial ECG, the mean of the two QTc F assessments will
determine eligibility. [0197] 22. Myocardial infarction,
angioplasty, or cardiac stent placement within the last 6 months.
[0198] 23. A medical condition requiring the therapeutic use of
anticoagulants NSAID (Nonsteroidal Antiinflammatory Drugs) and
low-dose aspirin will be not considered antiplatelets. [0199] 24.
History of hypertrophic scarring or keloid formation in scars or
suture sites. [0200] 25. Has difficulty swallowing medications, or
known history of malabsorption syndrome. [0201] 26. History of
recurrent GERD (Gastroesophageal reflux disease) requiring the use
of proton pump inhibitors within the last month. [0202] 27. Known
history of diverticulitis. [0203] 28. Uncontrolled diabetes. [0204]
29. Any medical or psychiatric condition which, in the opinion of
the investigator or the sponsor's medical monitor, would place the
patient at risk, interfere with participation in the study, or
interfere with the interpretation of study results. [0205] 30.
Pregnant or breast-feeding women. [0206] 31. Known hypersensitivity
to Compound 1 or its excipients. [0207] 32. Prior treatment with
SYK or JAK inhibitors for which the subject received no clinical
benefit, or the subject relapsed whilst on therapy.
Investigational Product, Dosage and Mode of Administration:
[0208] Compound 1 was administered orally at doses of 20, 40 and 80
mg qd. Compound 1 was made available in 5-mg, 20-mg, and 50-mg
strength tablets.
Duration of Study:
[0209] The total treatment period for each patient was 4 weeks (to
day 29) and the total follow-up period for each patient was 14 days
(to day 43).
Criteria for Evaluation:
[0210] Assessment of safety: Safety was assessed by AEs, vital
signs, 12-lead ECG, physical examination, and laboratory safety
assessments.
[0211] Assessment of PK variables: The following PK parameters for
Compound 1 were derived from the concentration-time data of
Compound 1 after the first and Day 15 dose administration in the
fasted state, as data allowed: Cmax, tmax, AUC0-.infin., AUC0-t,
AUC-24, .lamda.z, t1/2, CL/F and Vd/F
[0212] Assessment of efficacy variables: Preliminary efficacy was
assessed by changes in the following assessments between Day 1
(baseline) and Days 15 and 29: IGA, EASI, 5-D Pruritus scale,
Pruritus Numeric Rating Scale, % BSA involvement of AD, and skin
microbiome analysis
[0213] Assessment of Pharmacodynamics/Biomarker Parameters: [0214]
1. Change from baseline in inflammatory markers in serum (including
immune markers and CRP) [0215] 2. Change from baseline in molecular
skin biomarkers (inflammatory and barrier) [0216] 3. Change from
baseline in cellular markers (including reduction in inflammatory
cells) [0217] 4. Change from baseline in epidermal thickness and
barrier markers in skin biopsies.
Assessments of Efficacy
Investigator's Global Assessment
[0218] The IGA is an assessment scale used in clinical studies to
determine severity of AD and clinical response to treatment based
on a 5-point scale ranging from 0 (clear) to 4 (severe) (18). The
IGA score was assessed at screening, day 1/baseline (pre-dose), and
days 15, 29, 43 or early termination.
TABLE-US-00013 TABLE 16 IGA assessment scale Score Category
Definition 0 Clear Minor, residual discoloration; no erythema or
induration/papulation; no oozing/crusting 1 Almost Trace, faint
pink erythema with almost no induration/ clear papulation; no
oozing/crusting 2 Mild Faint pink erythema with mild
induration/papulation; disease no oozing/crusting 3 Moderate
Pink-red erythema with moderate induration/ disease papulation;
there may be some oozing/crusting 4 Severe Deep/bright red erythema
with severe induration/ disease papulation; with
oozing/crusting
5-D Pruritus Scale:
[0219] The 5-D Pruritus Scale is a 1-page, 5-question, validated
questionnaire used in clinical trials to assess 5 dimensions of
background itch: degree, duration, direction, disability, and
distribution (19). Each question corresponds to 1 of the 5
dimensions of itch; subjects rate their symptoms over the preceding
2-week period as "present" or on a 1 to 5 scale, with 5 being the
most affected. Subjects were subjected to this assessment at the
following visits: day 1/baseline (pre-dose), and days 15, 29, 43 or
early termination. The 5-D Pruritus Scale is provided in FIG.
3.
Pruritus Numeric Rating Scale:
[0220] The Pruritus NRS is a single-question assessment tool that
is used to assess the patient's worst itch as a result of AD in the
previous 12 hours. Subjects complete the patient recorded outcome
once daily. Patient compliance on the pruritus NRS is followed at
each clinic visit. Subjects were instructed on daily reporting at
the Baseline visit and are queried for compliance at every clinic
visit. Subjects completed the rating scale daily through the last
study visit using the scale provided below.
Eczema Area and Severity Index:
[0221] The Eczema Area and Severity Index (EASI) is a validated
measure used in clinical practice and clinical trials to assess the
severity and extent of AD. Four AD disease characteristics are
assessed for severity by the investigator or designee on a scale of
"0" (None) through "3" (severe). In addition, the area of AD
involvement is assessed as a percentage by body area of head,
trunk, upper and lower extremities and converted to a score of 0 to
6. Subjects were subjected to this assessment at the following
visits: screening, day 1/baseline (pre-dose), and days 15, 29, 43
or early termination. The EASI assessment tool is provided in FIG.
4.
Body Surface Area Involvement of Atopic Dermatitis
[0222] Body surface area affected by AD was assessed for each major
section of the body (head, trunk, arms, and legs) and is reported
as a percentage of all major body sections combined. Subjects were
subjected to this assessment at the following visits: screening,
day1/baseline (pre-dose), and days 15, 29, 43 or early
termination.
Skin Microbiome Analysis
[0223] Collection of skin microbiome samples is a non-invasive
procedure where a swab is passed along the lesional surface of the
area of worst eczema involvement, and another swab is passed along
a non-lesional area of skin within 5 cm of the lesional site.
Samples were collected from the same lesional and non-lesional
areas at day 1/baseline (pre-dose) and days 29, 43 or early
termination.
Assessment of Pharmacodynamic and Exploratory Biomarkers
Assessment of Exploratory Markers
Skin Biopsies:
[0224] For each subject, a maximum of four skin biopsies were
collected during this study.
[0225] Two punch biopsy samples (one from lesional skin and one
from non-lesional skin) were collected at Day 1 and one punch
biopsy was collected from the same lesional skin (outside the scar
of the previous biopsies) at Day 15 (optional for subjects) and Day
29.
Other Biomarkers:
[0226] A panel of biological markers were assessed to determine the
effect of Compound 1 on the disease process. These may include, but
are not limited to: [0227] Serum cytokines and inflammatory markers
[0228] Molecular skin biomarkers (inflammatory and barrier) [0229]
Circulating and tissue resident cellular phenotyping [0230]
Epidermal thickness and barrier markers from skin biopsies [0231]
Other biomarkers related autoimmune or inflammatory diseases
Results:
[0232] FIG. 7A is a graph of the % of subjects to achieve EASI50
over time (Day 1 to Day 29) for a placebo and Compound 1 in the
doses of 20 mg, 40 mg and 80 mg. FIG. 7B is a graph of the % of
subjects to achieve EASI75 over time (Day 1 to Day 29) for a
placebo and Compound 1 in the doses of 20 mg, 40 mg and 80 mg. 3
subjects reached EASI90, 2 subjects with 100% clearance. FIGS.
8A-8C shows the improvement in EASI, IGA & BSA after 4 weeks
for a placebo, and Compound 1 in the doses of 20 mg, 40 mg and 80
mg. FIG. 8A is a graph of the % CFB (percentage change from
baseline) for EASI (decrease) for the placebo and Compound 1 in the
doses of 20 mg, 40 mg and 80 mg. FIG. 8B is a graph of the % CFB
for BSA (body surface area) (decrease) for the placebo and Compound
1 in the doses of 20 mg, 40 mg and 80 mg. FIG. 8C is a graph of the
% CFB for IGA 0-1 (Investigator's Global Assessment) for the
placebo and Compound 1 in the doses of 20 mg, 40 mg and 80 mg. FIG.
9 is a graph of day 15 plasma concentration for Compound 1 in the
doses of 20 mg, 40 mg and 80 mg. FIG. 9 shows dose-dependent
C.sub.max and AUC, rapid oral absorption (T.sub.max 2-4 hrs) and
moderate rate of elimination, T.sub.1/2 of 10-14 hrs, and low
inter- and intra-individual variability. FIG. 10 is a chart showing
the inhibition of JAK and Syk kinase activity by Compound 1,
Tofacitinib, Upadacitinib, and Baricitinib. In FIG. 10, the
IC.sub.50 values were determined in biochemical kinase assays using
purified partial or full length enzymes. FIG. 11 is a chart showing
inhibition of Compound 1 in JAK/STAT pathway in T cells stimulated
with various cytokines. As shown in FIG. 11, Compound 1 showed
strong inhibition of JAK/STAT pathway in T cells (primary)
stimulated by various cytokines.
[0233] FIG. 12 is a chart showing Compound 1's inhibition of IL17
mediated CCL20 release in keratinocytes. As shown in FIG. 12,
unlike Tamatinib and Tofacitinib, Compound 1 inhibits IL-17-SYK
mediated CCL20 release, from human keratinocytes, at levels similar
to IL17 neutralizing antibodies (*p<0.05; *** p<0.001
compared to IL17+DMSO control (One-way ANOVA with Dunnett's
multiple comparison test), and % is percent decrease from IL17+DMSO
control). In FIG. 12, each bar represents mean and SEM for 3
replicates (n=3) of a single donor. FIG. 13 is a graph showing
average weekly change in pruritus (NRS) for a placebo, and Compound
1 in the doses of 20 mg, 40 mg and 80 mg. As demonstrated in FIG.
13, Compound 1 shows early decrease in pruritis.
[0234] FIGS. 14A-C are graphs showing improvements in epidermal
hyperplasia and cellular infiltrates observed as early as Day 15
for Compound 1 in the doses of 20 mg, 40 mg and 80 mg. FIG. 14A is
a graph showing improvement in skin thickness for Compound 1 in the
doses of 20 mg, 40 mg and 80 mg. Reductions in total skin thickness
can be observed as early as Day 15. FIG. 14B is a graph showing
improvement in CD3+ cells for Compound 1 in the doses of 20 mg, 40
mg and 80 mg. T cell infiltration into all layers of the skin is
reduced with 40 and 80 mg ASN002 at Day 29. FIG. 14C is a graph
showing improvement in CD11c+ cells for Compound 1 in the doses of
20 mg, 40 mg and 80 mg. Myeloid DC infiltration into all layers of
the skin is reduced with 40 and 80 mg ASN002 as early as Day 15.
FIG. 15 is a chart showing Treatment-Emergent Adverse Events
(TEAE), as demonstrated in Example 3.
Conclusion
[0235] Compound 1 showed clear efficacy in moderate to severe AD
patients. Compound 1 results in rapid symptom
improvement--significant reduction in patient reported itch was
observed as early as 2nd day of treatment with Compound 1. Compound
1 was well tolerated in patients with moderate to severe atopic
dermatitis. Compound 1 once daily demonstrated predictable
pharmacokinetics as evidenced by dose-dependent exposure, minimum
individual variability and accumulation. Compound 1 treatment down
regulates inflammatory pathways, showing improvements in epidermal
hyperplasia and cellular infiltrates as early as Day 15.
[0236] The most common adverse events were headache and nausea
predominantly reported on Day 1 associated with fasting and also
reported from placebo patients. No serious infections or
thromboembolic events occurred. No clinically significant changes
in chemistry lab parameters except asymptomatic, mild-to-moderate
transient elevations of CPK were observed. No changes in lipid
profile were observed. No clinically significant changes in
hematologic lab parameters including platelets, neutrophils and
lymphocytes were observed. Subjects in the Compound 1 treatment
arms showed rapid onset and dose-related declines after 4 weeks in
EASI50 of 29%, 100% and 88% and EASI75 of 0%, 63% and 50% for the
20, 40 and 80 mg cohorts respectively. Baseline EASI scores were
29.0, 21.3 and 29.0, respectively. The average decreases in EASI
and in Pruritis Numeric Rating Scale (NRS) at week 4 for the 20, 40
and 80 mg cohorts were 21%, 79% and 70% and 15%, 47% and 71%
respectively. In the 80 mg cohort, reduction in itch was seen as
early as Day 2, (.about.45%) and improvements were also observed in
the 40 and 80 mg cohorts in IGA assessments (up to 38% reaching
0-1). These clinical improvements were also associated with
reversal of cutaneous biomarkers (cellular infiltrates, immune and
hyperplasia markers) particularly in the mid and high dose.
Abstract for Example 3
[0237] Background:
[0238] Dysregulation of Th2 and Th22 cytokine pathways are
implicated in the pathogenesis of atopic dermatitis (AD). Compound
1 is a novel oral inhibitor of JAK and SYK signaling (including
Tyk2), that diminishes production of Th2 and Th22 cytokines. Syk
also regulates IL17R signaling in keratinocytes and keratinocyte
differentiation. Objectives: Efficacy, Safety and Pharmacology of
Compound 1 was evaluated in moderate-to-severe AD patients in a
Phase 1b randomized, double-blind, placebo-controlled study
(NCT03139981).
[0239] Methods:
[0240] Patients were randomized 1:3 placebo or Compound 1 at 20, 40
or 80 mg once daily for 4 weeks (n=36). Inclusion criteria were
Eczema Area and Severity Index (EASI) .gtoreq.16, body surface area
(BSA) involvement .gtoreq.10% and an Investigator's Global
Assessment (IGA) of .gtoreq.3 at baseline visit. Study objectives
included safety/tolerability, efficacy and pharmacokinetic
measurements. No concomitant administration of topical
corticosteroids or other immunosuppressants was permitted during or
prior to study.
[0241] Results: Compound 1 was very well tolerated at all dose
levels. The most common adverse events were transient, mild
headache and nausea, mostly restricted to Day 1 of dosing. Subjects
in the Compound 1 treatment arms showed rapid onset and
dose-related declines after 4 weeks in EASI50 of 29%, 100% and 88%
and EASI75 of 0%, 63% and 50% for the 20, 40 and 80 mg cohorts
respectively. Baseline EASI scores were 29.0, 21.3 and 29.0,
respectively. The average decreases in EASI and in Itch Numeric
Rating Scale (NRS) at week 4 for the 20, 40 and 80 mg cohorts were
21%, 79% and 70% and 15%, 47% and 71% respectively. In the 80 mg
cohort, reduction in itch was seen as early as Day 2, (.about.45%)
and improvements were also observed in the 40 and 80 mg cohorts in
IGA assessments (up to 38% reaching 0-1). These clinical
improvements were also associated with reversal of cutaneous
biomarkers (cellular infiltrates, immune and hyperplasia markers)
particularly in the mid and high dose.
Conclusion
[0242] This is a clinical report on safety, efficacy and effect on
the pathologic lesional skin phenotype with oral JAK/SYK inhibitor
Compound 1 in moderate-to-severe AD. Compound 1 was very well
tolerated and demonstrated early improvements in pruritus and
robust activity in EASI after 4 weeks with associated reversal of
cutaneous biomarkers of inflammation.
Example 4
Clinical Activity, Safety and Tolerability of Compound 1, a Dual
SYK/JAK Inhibitor, in Patients with Non-Hodgkin's Lymphoma
(NHL)
[0243] A formulation of the disclosure comprising
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrim-
ido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile comprises a
potent inhibitor of Spleen Tyrosine Kinase (SYK) and Janus Kinases
(JAK). Pre-clinical studies indicate that the formulation has low
nM IC50s against SYK and JAK, decreases proliferation in
ibrutinib-resistant cell lines, and suppresses tumor growth in
rodent xenograft models of NHL and other hematologic
malignancies.
[0244] Methods:
[0245] Phase 1/2 clinical trial in patients with solid tumors and
hematologic malignancies evaluates escalating oral doses of the
formulation disclosed herein at 10, 20, 30, 40, 50, 75 and 100 mg
BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 allows patients
with solid tumors or hematologic malignancies; Phase 2 allows only
patients with diffuse large B-Cell lymphoma (DLBCL), follicular
lymphoma (FL) or mantle cell lymphoma (MCL). Endpoints include
safety, tolerability, pharmacokinetics, serum markers of
inflammation, and response using RECIST or Lugano Classification
System,
[0246] Results:
[0247] Thirty-eight patients have enrolled in the DLT phase at
doses of 10 mg-100 mg BID and at 80-120 mg QD. All patients had
multiple prior lines of treatment (range: 2-8). The present
formulation was well tolerated. No dose limiting adverse events
have been reported at these dose levels. Most drug-related adverse
events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic
exposure was high (C.sub.max, AUC (0-12 h) and T.sub.1/2 at 40 mg
BID were 0.7 .mu.M, 6.3 .mu.Mh and 18 h, respectively). High
systemic exposure was also observed at 80 mg QD. Robust reduction
of CRP, IL-18, MIP1.beta., VCAM-1, TNFR2 was observed at all doses.
About 50% reduction in target lesions at 3 months in a FL patient
(Lugano, 6 prior lines) and stable disease and reduction of
pruritus in a peripheral T-Cell lymphoma patient after 2 months
(Lugano, 2 prior lines) of treatment were observed. Treatment using
the present formulation continues in both lymphoma patients.
Formulation-induced lymphocytosis, indicative of
recompartmentalization, has been observed in two recently enrolled
patients. Accrual of patients continues. FIGS. 16A-16G provide
clinical activity, safety and tolerability data for formulations of
the present disclosure.
Conclusion
[0248] The present formulation was safe and well tolerated.
Encouraging preliminary evidence of efficacy in NHL patients was
observed. MTD has not been reached and dose escalation
continues.
[0249] While the present disclosure has been discussed in terms of
certain embodiments, it should be appreciated that the present
disclosure is not so limited. The embodiments are explained herein
by way of example, and there are numerous modifications, variations
and other embodiments that can be employed that would still be
within the scope of the present disclosure.
* * * * *