# US 9,872,854 B2 · Methods for the treatment of psoriatic arthritis using apremilast

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- Number: US 9,872,854 B2
- Document ID: US9872854B2
- Status: Granted
- Kind: B2
- Application number: 14/209,874
- Filed: 2014-03-13
- Published: 2014-10-09
- Granted: 2018-01-23
- Earliest claimed: 2013-03-14
- Assignees: Celgene Corporation
- Applicants: Celgene Corporation
- Inventors: Robert Day
- Web page: https://patentgrep.com/patent/US9872854B2

## CPC

- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Methods of treating, managing or preventing psoriatic arthritis are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with a second active agent.

## Claims

### Claim 1

A method of treating psoriatic arthritis, which comprises orally administering to a patient having psoriatic arthritis escalating doses of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable polymorph, salt or solvate thereof, wherein the method consists of the following dosing schedule:
(i) 10 mg in the morning on the first day of administration;
(ii) 10 mg in the morning and 10 mg after noon on the second day of administration;
(iii) 10 mg in the morning and 20 mg after noon on the third day of administration;
(iv) 20 mg in the morning and 20 mg after noon on the fourth day of administration;
(v) 20 mg in the morning and 30 mg after noon on the fifth day of administration; and
(vi) 30 mg in the morning and 30 mg after noon on the sixth and every subsequent day of administration.

### Claim 2 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 90% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 3 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 95% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 4 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 96% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 5 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 97% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 6 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 98% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 7 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione comprises greater than about 99% by weight of (+) isomer based on the total weight percent of the compound.

### Claim 8 (depends on 1)

The method of claim 1, wherein the stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione is administered in tablet form.

### Claim 9 (depends on 8)

The method of claim 8, wherein the tablet comprises a 10 mg, 20 mg or 30 mg dose of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 10 (depends on 9)

The method of claim 9, wherein the tablet comprises a 10 mg dose of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 11 (depends on 9)

The method of claim 9, wherein the tablet comprises a 20 mg dose of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 12 (depends on 9)

The method of claim 9, wherein the tablet comprises a 30 mg dose of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 13 (depends on 1)

The method of claim 1, further comprising administering to the patient a therapeutically effective amount of one or more second active agents.

### Claim 14 (depends on 13)

The method of claim 13, wherein the one or more second active agents are selected from the group consisting of a nonsteroidal anti-inflammatory drug, an immnunosuppressant, a topical steroid, a glucocorticoid, a calcineurin inhibitor, a Cox-2 inhibitor, a TNF-alpha inhibitor, an antirheumatic, an antipsoriatic, an interleukin inhibitor, a narcotic analgesic combination, a salicylate, a glucocorticoid and a topical rubefacient.

### Claim 15 (depends on 13)

The method of claim 13, wherein the second active agent is a nonsteroidal anti-inflammatory agent.

### Claim 16 (depends on 13)

The method of claim 13, wherein second active agent is a disease-modifying antirheumatic agent.

### Claim 17 (depends on 13)

The method of claim 13, wherein the one or more second active agents are selected from the group consisting of abatacept, acetaminophen, acetaminophen/hydrocodone, acetaminophen/tramadol, acitretin, adalimumab, alclometasone, alefacept, alemtuzumab, aloe vera, aluminum hydroxide/aspirin/calcium carbonate/magnesium hydroxide, amcinonide, ammonium lactate/urea, ammonium lactate/halobetasol, anakinra, anthralin, aspirin, auranofin, aurothioglucose, atorvastatin, azathioprine, benzocaine/pyrilamine/zinc oxide, betamethasone, betamethasone/calcipotriene, calcipotriene, celecoxib, certolizumab, chondroitin, clobetasol, clocortolone, coal tar, coal tar/salicylic acid, corticotropin, cortisone, cyclophosphamide, cyclosporine, daclizumab, desonide, desoximetasone, dexamethasone, diclofenac, diclofenac/misoprostol, diflorasone, diflunisal, doxycycline, esomeprazole, esomeprazole/naproxen, etanercept, etodolac, famotidine, famotidine/ibuprofen, fenoprofen, fluocinonide, flurandrenolide, flurbiprofen, fostamatinib, glucosamine, gold sodium thiomalate, golimumab, halcinonide, halobetasol, hydrocortisone, hydrocortisone/pramoxine, hydroxyurea, hydroxychloroquine, ibuprofen, indomethacin, infliximab, interferon, interferon gamma-1b, ibrutinib, ketoprofen, lansoprazole, lansoprazole/naproxen, leflunomide, lenalidomide, levamisole, meclofenamate, meloxicam, methotrexate, methoxsalen, methylprednisone, methylprednisolone, methyl salicylate, minocycline, mometasone, mycophenolate mofetil, nabumetone, naproxen, oxaprozin, penicillamine, phenytoin, piroxicam, pomalidomide, pramoxine, prednisone, prednisolone, prednicarbate, primrose oil, resorcinol, rituximab, rofecoxib, salsalate, sulindac, sulfasalazine, tazarotene, tetracycline, tocilizumab, tofacitinib, tolmetin, tramadol, triamcinolone, trolamine salicylate, ustekinumab, valdecoxib, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

### Claim 18 (depends on 13)

The method of claim 13, wherein the second active agent is methotrexate.

### Claim 19 (depends on 13)

The method of claim 13, wherein the second active agent is sulfasalazine.

### Claim 20 (depends on 13)

The method of claim 13, wherein the second active agent is lefunomide.

### Claim 21 (depends on 13)

The method of claim 13, wherein the second active agent is etanercept.

### Claim 22 (depends on 13)

The method of claim 13, wherein the second active agent is an oral corticosteroid.

### Claim 23 (depends on 22)

The method of claim 22, wherein the second active agent is prednisone.

### Claim 24 (depends on 1)

The method of claim 1, wherein the patient has received prior treatment for psoriatic arthritis.

### Claim 25 (depends on 24)

The method of claim 24, wherein the prior treatment is with a disease-modifying antirheumatic drug.

### Claim 26 (depends on 24)

The method of claim 24, wherein the psoriatic arthritis is refractory to the prior treatment.

### Claim 27 (depends on 1)

The method of claim 1, wherein psoriatic arthritis is symmetric polyarthritis, asymmetric oligoarthritis, distal interphalangeal joint arthritis, arthritis mutilans, or predominant spondylitis.

### Claim 28 (depends on 1)

The method of claim 1, which comprises administering stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of any salt or solvate forms of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 29 (depends on 1)

The method of claim 1, which comprises administering a pharmaceutically acceptable salt of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

### Claim 30 (depends on 1)

The method of claim 1, which comprises administering a pharmaceutically acceptable solvate of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.