Search

EP-3953395-B1 - PLASMA KALLIKREIN INHIBITORS AND METHODS OF USE THEREOF IN OCULAR DISORDERS

EP3953395B1EP 3953395 B1EP3953395 B1EP 3953395B1EP-3953395-B1

Inventors

  • BABU, YARLAGADDA
  • KANSARA, Viral
  • MCELHENY, RICK

Dates

Publication Date
20260506
Application Date
20200408

Claims (11)

  1. A drug composition comprising an effective amount of a plasma kallikrein inhibitor of formula IB for use in the treatment of an ocular disease, wherein the plasma kallikrein inhibitor is a compound of the formula IB, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the plasma kallikrein inhibitor of formula IB is the sole therapeutic agent present in the drug composition, and wherein the plasma kallikrein inhibitor of formula IB is non-surgically administered to a suprachoroidal space (SCS) of an eye of the subject: wherein X is CH or N; Y is CH or N; R is -CH=CH-R 2 , -C=C-R 2 , -C(R 2 )=CH 2 , -CH=CH 2 , -C(R 2 )=C(R 3 ), -CH=NR 2 or -C(R 2 )=N-R 3 ; R 1 is -H, -R, -NO 2 , -CN, -halo, -N 3 , -C 1-8 alkyl, -(CH 2 ) n CO 2 R 2 , -C 2-8 alkenyl-CO 2 R 2 , -C 2-4 alkoxy, -O(CH 2 ) n CO 2 R 2 , -C(O)NR 2 R 3 , -NR 2 R 3 , -(CH 2 ) n OR 2 , -C(O)OH, -O-C 1 -C 3 alkyl, -OCH 3 , N(R 2 )C(O)R 3 , or -(CHR 2 ) n ; V is independently selected from R 1 ; R 10 is -(CH 2 )-cyclopropyl or -isobutyl; R 11 is hydrogen or =O; R 2 is H, -halo, -alkyl, -haloalkyl, -CO(CHR 1 ) n -OR 1 , -(CHR 1 ) n -NH-CO-R 1 , -(CHR 1 ) n -NH-SO 2 R 1 , -(CHR 1 ) n -C(O)(CHR 1 )-NHR 1 , -(CHR 1 ) n -C(S)(CHR 1 )-NHR 1 , -(CH 2 ) n O(CH 2 ) n CH 3 , - CF 3 , -C 2-5 acyl, -(CHR 1 ) n OH, -(CHR 1 ) n CO 2 R 1 , -(CHR 1 ) n -O-alkyl, -O(CHR 1 ) n -O-(CH 2 ) n -O-alkyl, -(CHR 1 ) n -S-alkyl, -(CHR 1 ) n -S(O)-alkyl, -(CHR 1 ) n -S(O 2 )-alkyl, -(CHR 1 ) n -S(O2)-NHR 3 , -(CHR 3 ) n -N 3 , -(CHR 3 ) n NHR 4 , 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds or substituted or unsubstituted-(CHR 3 ) n cycloalkyl which may be saturated or unsaturated; R 3 is -H, -OH, -CN, substituted alkyl, -C 2-8 alkenyl, -(CH 2 ) n -cycloalkyl, substituted or unsubstituted cycloalkyl, -N(R 1 )R 2 , or 5-6 membered saturated substituted or unsubstituted heterocyclyl ring; and n is an integer from 0 to 4.
  2. The drug composition for use of claim 1, wherein said drug composition is administered 1 to 12 times per year, 2 to 6 times per year or 2 or 3 times per year.
  3. The drug composition for use of claim 1 or claim 2, wherein the effective amount of the plasma kallikrein inhibitor in the drug composition ranges from about 0.01 mg to about 20 mg, or wherein the effective amount of the plasma kallikrein inhibitor in the drug composition ranges from about 0.1 mg to about 10 mg, or wherein the effective amount of the plasma kallikrein inhibitor in the drug composition ranges from about 0.1 mg to about 1 mg.
  4. The drug composition Z for use of any one of claims 1 to 3, wherein the ocular disease or condition affects a posterior segment of the eye.
  5. The drug composition for use of any one of claims 1 to 3, wherein the ocular disease or condition is selected from the group consisting of: a diabetic eye disease, diabetic retinopathy, diabetic macular edema, retinopathy, hypersensitive retinopathy, sickle cell retinopathy, retinopathy of prematurity, or central serous retinopathy, macular degeneration, age related macular degeneration, dry age related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy, occult with no classic choroidal neovascularization in age-related macular degeneration, subfoveal wet age-related macular degeneration, uveitis, macular edema, diabetic macular edema, scleritis, retinitis, choroiditis, Stargardt's disease, vitreomacular adhesion associated with neovascular age related macular degeneration, a neovascular condition, aberrant ocular angiogenesis, ocular neovascularization, choroidal neovascularization, and polypoidal choroidal vasculopathy.
  6. The drug composition for use of any one of claims 1 to 3, wherein the ocular disease or condition is selected from the group consisting of: macular degeneration, diabetic retinopathy, and diabetic macular edema.
  7. The drug composition for use of any one of claims 1 to 6, wherein the drug composition is configured to be administered to the SCS of the eye via a hollow microneedle.
  8. The drug composition for use of any one of claims 1 to 7, wherein R is -CH=CH 2 , V is - C(O)OH, Y is N, R 10 is -(CH 2 )-cyclopropyl, R 11 is =O, X is CH, and R 1 is -OCH 3 .
  9. The drug composition for use of any one of claims 1 to 7, wherein R is -CH=CH 2 , V is - C(O)OH, Y is N, R 10 is -(CH 2 )-cyclopropyl, R 11 is =O, X is CH, and R 1 is H.
  10. The drug composition for use of any one of claims 1 to 7, wherein R is -CH=CH 2 , V is - C(O)OH, Y is N, R 10 is -isobutyl, R 11 is =O, X is CH, and R 1 is H.
  11. The drug composition for use of any one of claims 1 to 7, wherein R is -CH=CH 2 , V is - C(O)OH, Y is CH, R 10 is -isobutyl, R 11 is H, X is N, and R 1 is H.

Description

BACKGROUND OF THE DISCLOSURE The anterior region of the eye refers to the front portion of the eye (i.e., the portion of the eye in front of, and including, the lens), and includes structures in front of the vitreous humor such as the cornea, iris, ciliary body and lens. The posterior segment of the eye refers to the back portion of the eye (i.e., the portion of the eye behind the lens), and includes the vitreous humor, the sclera, the choroid, the Bruch's membrane, the retinal pigment epithelium, the subretinal space, the retina, the macula, the optic disk, the optic nerve, the ciliary body, and/or the trabecular meshwork. The sclera (a.k.a., the white of the eye) is an opaque, fibrous, protective outer layer of the eye. The sclera includes connective tissue that maintains the shape of the eye by offering resistance to internal and external forces. The suprachoroidal space is the area between the sclera and choroid in the posterior segment of the eye. The delivery of drugs to the eye is extremely difficult, particularly to the posterior segment of the eye. Many inflammatory and proliferative diseases in the posterior segment of the eye require long term pharmacological treatment. Examples of such diseases include macular degeneration, diabetic macular degeneration, diabetic retinopathy, and others. The current long term pharmacological treatments of such disorders can result in various adverse effects and adverse clinical manifestations, both locally in the eye and systemically. Although there are known methods of delivery of drugs into the posterior segment of the eye, it is often difficult to deliver effective doses of a drug to the posterior segment of the eye using conventional delivery methods and drug formulations. Delivery methods for drug formulations to the eye include topical application, intravitreal administration (IVT), intracameral administration, systemic administration, and administration to the suprachoroidal space. While each of these methods offers clinical utility for the treatment of certain diseases and conditions, not all of these methods are suitable for delivery of a drug to the posterior segment of the eye. Topical applications, such as eye drops, are useful in treating conditions affecting the exterior surface of the eye or tissues at the front of the eye, however, eye drops are often not sufficiently conveyed to the posterior segment of the eye. Due to the limited half-life of many compounds in the vitreous, IVT administration generally requires multiple injections which increases the risk of cataract, retinal detachment, elevated intraocular pressure, hemorrhage and endophthalmitis. The delivery of drug formulations to the posterior segment of the eye through systemic administration is limited by the outer and inner blood-retinal barriers and reduced therapeutic potency due to the dilution and degradation of the drug before reaching the posterior segment of the eye. Delivery to the suprachoroidal presents an attractive delivery methods for drugs to the posterior segment of the eye. However, even for this mode of administration the half-life of many drugs is such that repeated injections are required (for example every 1 to 2 months) and the concentration of the drug is below the levels needed for effective treatment. US2016/310417 discloses a fluid formulation comprising inter alia kallikrein inhibitor ecallantide (peptide) for the administration to a suprachoroidal space (SCS) of an eye via a hollow microneedle to a patient to treat eye diseases, such as macular edema, a posterior ocular disorder or choroidal malady. It would be desirable to provide better, safer, more effective therapies for the treatment of various eye diseases and conditions, including diseases and conditions of the posterior segment of the eye. The present disclosure addresses these and other needs. SUMMARY OF THE DISCLOSURE The invention is defined by the appended claims. Any subject-matter falling outside the scope of the claims is provided for information purposes, only. The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy. The present invention relates to a drug composition comprising an effective amount of a plasma kallikrein inhibitor of formula IB for use in the treatment of an ocular disease, wherein the plasma kallikrein inhibitor is a compound of the formula IB, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the plasma kallikrein inhibitor of formula IB is the sole therapeutic agent present in the drug composition, and wherein the plasma kallikrein inhibitor of formula IB is non-surgically administered to a suprachoroidal space (SCS) of an eye of the subject. The compounds of the disclosure are plasma kallikrein inhibitors. In some embodiments, the compound of the disc