REDUCING IMMUNOGENICITY TO PEGLOTICASE
The disclosure provides methods of treating gout in patients comprising administering a PEGylated uricase. Also provided are methods of treating gout in patients comprising co-administering a PEGylated uricase and methotrexate (MTX). Also provided are methods of reducing immunogenicity of a PEGylated uricase and prolonging the urate lowering effect comprising co-administration of the PEGylated uricase and MTX.
1 . A method of treating gout in a patient having a serum uric acid (SUA) level of ≥6 mg/dL comprising:
administering methotrexate (MTX) to said patient at a dose of about 5 mg to about 50 mg per week for a period of 4 weeks prior to a first administration of a PEGylated uricase; and
co-administering the PEGylated uricase and MTX to said patient using a dosage regimen comprising a dose of about 0.5 mg to about 24 mg of the PEGylated uricase intravenously every 2 weeks for a total of 26 doses, and a dose of about 5 to about 50 mg of MTX per week, wherein the co-administered MTX is administered concurrently with each administration of the PEGylated uricase.
2 . (canceled)
3 . The method of claim 1 , wherein the PEGylated uricase is administered at a dose of 8 mg and MTX is administered at a dose of 15 mg.
4 . The method of claim 1 , further comprising administering folic acid to said patient at a dosage of 1 mg per day.
5 . The method of claim 1 , further comprising an altered dosage of MTX, wherein the altered dosage comprises:
administering folic acid to said patient at a dosage of about 2 mg per day; or
administering MTX to said patient at a dosage of about 7.5 mg twice per day; or
administering MTX to said patient at a dosage of about 10 mg, wherein the altered dosage of MTX is based on laboratory findings.
6 . The method of claim 5 , wherein the altered dosage of MTX comprises a temporary stop for laboratory parameters selected from the group consisting of WBC levels of less than about 3.0×10 9 /L, platelet levels of less than about 50×10 9 /L, hematocrit levels of less than about 27%, AST/ALT levels of greater than about 2× upper limit of normal (ULN), and eGFR levels of less than 30 mL/min/1.73 m 2 , wherein the altered dosage of MTX comprises a reduction in the dosage of MTX to 10 mg per week for laboratory parameters selected from the group consisting of: WBC levels of from about 3.0×10 9 /L to about 3.5×10 9 /L and AST/ALT levels of between about 1.5 and about 2×ULN.
7 . The method of claim 1 , further comprising a prophylactic regimen of colchicine for a period of at least 2 weeks prior to the first administration of the PEGylated uricase.
8 . The method of claim 1 , wherein the SUA levels of the patient are determined prior to each dose of the PEGylated uricase.
9 . The method of claim 1 , further comprising measuring one or more of trough PEGylated uricase levels, anti-PEGylated uricase antibody levels, and anti-PEG antibody levels, prior to each dose of the PEGylated uricase after the first dose.
10 . (canceled)
11 . (canceled)
12 . The method of claim 1 , wherein the SUA level is reduced to less than 6 mg/dL as a result of co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
13 . The method of claim 1 , wherein the SUA level is reduced to less than 5 mg/dL as a result of co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
14 . The method of claim 1 , wherein the SUA level is reduced to less than 2 mg/dL as a result of co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
15 . The method of claim 1 , wherein the incidence of infusion reaction, gout flare, or anaphylaxis is reduced as a result of co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
16 . The method of claim 1 , wherein the level of MTX metabolite is increased relative to a patient not receiving co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
17 . The method of claim 1 , further comprising measuring one or more of peripheral joint urate deposition volume and inflammatory volume via any advanced imaging technique.
18 . The method of claim 17 , wherein peripheral joint urate deposition volume is reduced in the patient relative to a patient not receiving co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
19 . The method of claim 18 , wherein peripheral joint urate deposition volume is determined by dual-energy computed tomography (DECT) scanning.
20 . The method of claim 19 , wherein peripheral joint urate deposition volume is determined by ultrasound.
21 . The method of claim 17 , wherein inflammatory volume is reduced in the patient relative to a patient not receiving co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
22 . The method of claim 21 , wherein inflammatory volume is determined by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), or MRI without contrast, or both.
23 . The method of claim 1 , wherein the mean titer of anti-PEGylated uricase antibodies is less than or equal to 1:6000 as a result of co-administration of the PEGylated uricase and MTX immunosuppressive therapy.
24 . The method of claim 1 , wherein the serum uric acid level is normalized by week 12 after co-administration of PEGylated uricase and MTX treatment begins.