COMPOSITIONS AND COMBINATIONS FOR THE TREATMENT OF ANGIOGENESIS DISEASES AND DISORDERS

Abstract

The present invention relates to compositions, combinations and methods for treating, reducing, ameliorating, alleviating, or inhibiting the progression of, angiogenesis diseases and disorders in a patient in need thereof (such as for example AMD), utilizing Te-containing compounds.

Claims

1. A combination comprising at least one Te-containing compound having the formula I or II: ##STR00016## wherein: each of t, u and v is independently 0 or 1; each of m and n is independently 0, 1, 2 or 3; Y is selected from the group consisting of ammonium, phsophonium, potassium, sodium and lithium; X is a halogen atom; and each of R.sub.1-R.sub.18 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl; alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido; and at least one angiogenesis inhibitor.

2. A combination according to claim 1, wherein said at least one Te-containing compound is a compound of formula L wherein t, u and v are each 0 and wherein each of R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is hydrogen, wherein X is chloro and wherein Y is ammonium.

3. (canceled)

4. A combination according to claim 1, wherein said at least one Te-containing compound is a compound of formula II, wherein each of m and n is 0 and wherein each of R.sub.11, R.sub.14, R.sub.15 and R.sub.18 is hydrogen.

5. (canceled)

6. A combination according to claim 1, wherein said at least one angiogenesis inhibitor is selected from Ranibizumab, Aflibercept, Bevacizumab or any combinations thereof.

7. A combination according to claim 1, wherein said at least one Te-containing compound is formulated for oral administration.

8. A combination according to claim 1, wherein said at least one Te-containing compound is formulated for topical administration.

9. A combination according to claim 1, wherein said at least one Te-containing compound is formulated for intraocular administration.

10. A combination according to claim 1, wherein said at least one Te-containing compound is formulated for targeted in-situ administration.

11. A combination according to claim 1, wherein said at least one Te-containing compound is formulated for parenteral administration.

12-24. (canceled)

25. A method of treating an angiogenesis related condition, disease or disorder comprising administering to a patient in need thereof at least one Te-containing compound selected from ##STR00017## wherein: each of t, u and v is independently 0 or 1; each of in and n is independently 0, 1, 2 or 3; Y is selected from the group consisting of ammonium, phsophonium, potassium, sodium and lithium; X is a halogen atom; and each of R.sub.1-R.sub.18 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido; wherein said patient has been previously treated with at least one angiogenesis inhibitor (i.e. prior to the administration of said Te-containing compound).

26. A method of treating an angiogenesis related condition, disease or disorder comprising administering to a patient in need thereof at least one Te-containing compound selected from ##STR00018## wherein: each of t, u and v is independently 0 or 1; each of m and n is independently 0, 1, 2 or 3; Y is selected from the group consisting of ammonium, phsophonium, potassium, sodium and lithium; X is a halogen atom; and each of R.sub.1-R.sub.18 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido; wherein said patient is being treated with at least one angiogenesis inhibitor (i.e. during the administration of said Te-containing compound).

27. A method of claim 25, wherein said angiogenesis related condition is AMID, said method further comprising the steps of administering to said subject a combination of at least one anti VEGF agent and at least one Te-containing compound of formula I or II.

28-32. (canceled)

33. The method of claim 25, wherein said at least one Te-containing compound is administered orally.

34. The method of claim 25, wherein said at least one Te-containing compound is administered daily to said subject,

35. The method of claim 25, wherein said at least one anti VEGF agent is administered once a month.

36. The method of claim 25, wherein said at least one anti VEGF agent is administered on an on demand regimen.

37-38. (canceled)

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0147] Clinical Study

[0148] Patients were orally administered with AS101/Formula I in conjunction with intraocular injections of intra vitreal anti VEGF. None of these two patients responded well to intra vitreal anti VEGF injections alone and were in danger of vision loss. A special compassionate approval has been given by the local committee of ethics in Meir medical center, Kfar Saba, and the Ministry of Health in Israel to treat these two patients with orally taken AS101.

[0149] Case 1

[0150] The patient was a 63 year old woman was first examined on May 2, 2011, due to metamorphopsia in her right eye. Visual acuity was 20/30 in the right eye and 20/15 in the left eye. The anterior segment and media examinations were unremarkable. Fundus examination revealed large drusen in both eyes. OCT examination showed a juxta foveal PED and sub foveal sub retinal fluid in the right eye, and drusen in the left eye. Patient underwent 3 intra-vitreal Lucentis (Ranibizumab) injections in one month intervals, resulting in the resolution of the subretinal fluid. Four month after the 3rd injection, the patient experienced again metamorphopsia in the right eye and OCT examination showed a new large PED and minimal sub retinal fluid. Patient underwent an additional intra-vitreal Lucentis injection and from this point examination continued every month with treatment in PRN mode. Until Jul. 26, 2012 the patient underwent 9 intra-vitreal Lucentis injections. On January 2013 treatment was switched to Aflibercept (Eylea) and the patient received 3 montly injection and an additional injection on Jun. 18, 2013. During the follow up period, visual acuity ranged between 20/25 and 20/30.

[0151] One year after the first injection to the right eye, on May 1, 2012, visual acuity dropped in the left eye to 20/40, subretinal fluid appeared in OCT and the patient began to receive Lucentis injections to the left eye. After the second injection the visual acuity dropped to 20/150 and a large central PED appeared with subretinal fluid over the peak of the PED and over its slope. The patient received an intravitreal triancinolon acetonid injection followed by the 3rd lucentis one week later. A month later, visual acuity improved to 20/25 and the size of the PED decreased significantly, but the subretinal fluid did not resolve. The patient received 2 additional Lucentis injections and on Nov. 27, 2012 treatment was switched to Eylea when it became available in Israel. The patient received 8 monthly Eylea injections, the last one on Jun. 18, 2013. The amount of the subretinal fluid did not change over the peak of the PED as well as at the slope. A posterior sub capsular cataract developed in the left eye and we decide to inject again Lucentis with triamcinilon acetonide prior the cataract surgery.

[0152] On Jul. 7, 2013, the patient started to receive 12 drops of AS101 every day orally. On Aug. 13, 2013 the patient received the Lucentis with triamcinilon acetonide injections and OCT one month later showed a decrease of the amount of the subretinal fluid at the base of the PED.

[0153] On Sep. 16, 2013 the patient underwent the cataract surgery in the left eye. On the next 3 monthly OCT tests the subretinal fluid at the slope of the PED absorbed for the first time since it appeared and no additional injections were needed in the left eye for 8 months until the discontinuation of the AS101 in Mar. 24, 2014.

[0154] In the right eye the patient underwent cataract surgery on Mar. 17, 2014. No intravitreal injections were needed in the right for 10 months, until the discontinuation of the AS101.

[0155] In Mar. 24, 2014, AS101 was discontinued. 3 weeks later, on Apr. 13, 2014, OCT test was performed due to new symptom of metamorphopsia showed a development of new subretinal fluid in both eyes.

[0156] In another observation found during the compassionate treatment was that drusens/dry AMD did not developed to Wet AMD, suggesting that the treatment of the present application can also prevent or delay the progression of dry AMD to Wet AMD.

[0157] Case 2

[0158] The patient was a 77 years old man was diagnosed with decreased vision in his left eye. Visual acuity was 20/30 in the right eye and 20/200 in the left eye. Anterior segment and media were normal accept mild nuclear sclerosis in the lens of the right eye and posterior vitreous separation in both eyes. Retina examination revealed in the right eye multiple mid size drusen in the macula, and in the left macula large drusen, central PED and macular hemorrhages. OCT of right eye showed small drusen and in the left eye a central PED and sub retinal fluid at the slope of the PED. Patient received 3 monthly injections of intra vitreal Avastin continued by additional Avastin injections in a PRN mode. When Avastin stopped to respond, treatment was changed to Lucentis injections. During 20 months the patient received 9 Avastin injections and 6 Lucentis injections (total of 15 injections in 20 months). Except for one occasion of a 5 month interval between 2 injections, the patient received an injection every month. His visual acuity ranged between 20/100 and 20/50. Four days after the last Lucentis injection, on 13 Aug. 2013 the patient started to take 12 drops of AS101 orally.

[0159] The patient continued to receive Lucentis injections PRN on the following dates: Nov. 8, 2013, Feb. 2, 2014, May 2, 2014, Jul. 3, 2014. On examination on Nov. 11, 2014 there was no need for injection. And in all follow on examinations until January 2016 (no further data is available) The total number of injections during AS101 treatment was 4 in 27 months.

[0160] The last visual acuity in Nov. 11, 2014 was 20/30 in the right eye and 20/50 in the left eye. No adverse events were reported in this patient.

TABLE-US-00001 TABLE 1 Summary of patients treated with a combination of the invention Angiogenesis Angiogenesis inhibitor injections Duration of inhibitor injections prior to treatment treatment with the during treatment according to the combination of the according to the invention invention invention Patient RE: 15 injections 9 months RE: 0 injections in #1 (Lucentis or Eylea) 9 months in 20 months LE: 1 injection in 9 LE: 14 injections months (Lucentis or Eylea) in 20 months Patient 15 injections 27 months Te- 4 injections in 27 #2 (Lucentis or containing months Avastin) during 20 compound: AS 101; (maximal time months Angiogenesis interval between inhibitor: Lucentis) injections: 14 months)