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Use of CTLA4 compound for achieving drug-free remission in subjects with early RA

一种受试者、无药物的技术，应用在类风湿性关节炎,早期类风湿性关节炎领域，能够解决没有证实等问题

Inactive Publication Date: 2017-02-22
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Previous studies have examined multiple treatment withdrawal paradigms with many biologic agents, but have not demonstrated durable remission following rapid withdrawal of all RA treatments (Huizinga, T. et al., “Clinical and radiographic outcomes at two years and the effect of tocilizumab discontinuation following sustained remission in the second year of the ACT-RAY study”, Ann. Rheum. Dis. , 72(Suppl 3):63(2013); Quinn, M.A. et al., “Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained fliximab raw” af , Arthritis Rheum. , 52:27-35 (2005); vanden Broek, M. et al., “Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoidarthritis and disease activity score-steered therapy”, Ann. Rheum. Dis. , 70:1389-1394 (2011); Villeneuve, E. et al., “Preliminary results of a multicentre randomized controlled trial of etanercept and methotrexate to induce emission in patients with newly diagnosed inflammatory arthritis”, Arthritis Rheum. , 63:S960-S961 (2011))

Method used

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  • Use of CTLA4 compound for achieving drug-free remission in subjects with early RA
  • Use of CTLA4 compound for achieving drug-free remission in subjects with early RA
  • Use of CTLA4 compound for achieving drug-free remission in subjects with early RA

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0134] The lyophilized CTLA4Ig (250mg / vial) drug product is a sterile, nonpyrogenic lyophile suitable for intravenous (IV) administration. Each single-use vial contains 250 mg of CTLA4Ig, which is constituted with USP Sterile Water for Injection and further diluted with USP 0.9% Sodium Chloride Injection at the time of use.

[0135] The batch recipe for the 115 liter batch size is described in Table 4 below.

[0136] Table 4

[0137] batch recipe

[0138] components Quantity (kg) CTLA4Ig drug substance a

4.6 Maltose monohydrate 9.2 hydrochloric acid Adjust to pH 7.5 sodium hydroxide Adjust to pH 7.5 Water for Injection Appropriate amount to 119.6 b

[0139] a CTLA4Ig drug substance: protein concentration 50 mg / ml, 25 mM sodium phosphate, 50 mM sodium chloride, pH 7.5, < 5% HMW substance.

[0140] b Prepared bulk solution density = approximately 1.04 g / ml.

[0141] Add the desired amount of CTLA4Ig drug substance t...

Embodiment II

[0159] CTLA4Ig SC, 125 mg / ml (125 mg / vial) drug product is formulated as a sterile, pyrogen-free ready-to-use solution suitable for subcutaneous administration. A batch of CTLA4Ig SC, 125 mg / ml (125 mg / vial) drug product was manufactured at 5-L scale (3,500 vials). The batch formulation is described in Table 7 below.

[0160] Table 7

[0161] batch recipe

[0162] components Quantity (gm) CTLA4Ig drug substance a

625 sucrose 850 Poloxamer 188 40 Sodium dihydrogen phosphate, monohydrate 0.715 Disodium hydrogen phosphate, anhydrous 4.86 Water for Injection Appropriate amount to 5.0 L Total batch size (L) 5.0

[0163] a CTLA4Ig drug substance: protein concentration 50 mg / ml, 25 mM sodium phosphate, 50 mM sodium chloride, pH 7.5, < 5% HMW substance.

[0164] As described above in Example I, the manufacturing process for the CTLA4Ig SC, 125 mg / ml (125 mg / vial) drug product included bulk drug substance from 25 mM so...

Embodiment III

[0171] Evaluating Very Early Rheumatoid Arthritis Therapy (AVERT) is a Phase 3b, randomized, active-controlled 24-month trial with a 12-month double-blind treatment period.

[0172] Research design

[0173] The study design is described graphically in the figure 2 middle.

[0174] include standard

[0175] ●Willing to participate in the study and provided signed informed consent

[0176] Active clinical synovitis in ≥2 joints (including ≥1 facet joint and excluding the distal interphalangeal joint) for ≥8 weeks at Screening

[0177] Onset of persistent symptoms ≤ 2 years prior to screening

[0178]Disease Activity Score 28 (DAS28) C-reactive protein (CRP) ≥ 3.2 at Screening

[0179] ●Anti-cyclic citrullinated peptide-2 positive

[0180] Methotrexate (MTX) naïve or MTX ≤10 mg / kg for ≤4 weeks and dosed less than 1 month prior to screening

[0181] ●Biologically primitive

[0182] Withhold chloroquine, hydroxychloroquine, and sulfasalazine for ≥28 days (if accepted)

...

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Abstract

The present invention is directed to methods and compositions for achieving drug-free remission in subjects with early RA by administering to a subject in need thereof an effective amount of soluble CTLA4 molecule until Disease Activity Score Calculator for Rheumatoid Arthritis (DAS)-defined remission is achieved and then withdrawing the RA therapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 61 / 984,287, filed April 25, 2014; the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates generally to the field of rheumatoid arthritis (RA), such as early rheumatoid arthritis. In particular, the present invention relates to methods and compositions for achieving drug-free remission in a subject with early RA, wherein an effective amount of a soluble CTLA4 molecule is administered to the subject in need thereof until rheumatoid arthritis is achieved A Disease Activity Score (DAS) calculator defined remission, and then RA therapy was withdrawn. Background technique [0004] Rheumatoid arthritis (RA) is the most common inflammatory arthritis, affecting approximately 1% of the world population (Wolfe, F., “The epidemiology of drug treatment failure in rheumatoidarthritis”, Baillie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61P19/02A61P29/00G01N33/68
CPCA61K38/1777G01N33/6893G01N2800/102G01N2800/52C07K14/70521A61K38/1774A61P19/02A61P29/00A61P37/06A61P43/00C07K14/00A61K9/0019C07K14/70503C07K2319/30G01N33/564
Inventor C.卡耶卡
Owner BRISTOL MYERS SQUIBB CO
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