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 MMF. Also provided are methods of reducing intolerance to a PEGylated uricase and prolonging the urate lowering effect comprising co-administration of the PEGylated uricase and MMF.
1 . A method of treating gout in a patient having a serum uric acid level of ≥6 mg/dL comprising:
administering mycophenolate mofetil (MMF) to said patient at a dose of 500 mg twice per day orally for a period of 2 weeks prior to the first administration of a PEGylated uricase;
co-administering a PEGylated uricase and MMF to said patient using a dosage regimen comprising a dose of 8 mg of the PEGylated uricase intravenously every 2 weeks for a total of 12 doses; and a dose of 1000 mg MMF twice per day orally, wherein the co-administered MMF is administered concurrently with each administration of the PEGylated uricase;
administering 8 mg of the PEGylated uricase at a dosage of 8 mg intravenously every 2 weeks for a total of 12 doses.
2 . A method of reducing or preventing loss of response to a PEGylated uricase and prolonging the urate lowering effect comprising co-administration of the PEGylated uricase at a dosage of 8 mg intravenously every 2 weeks and mycophenolate mofetil (MMF) at a dosage of 1000 mg twice per day orally to a patient having a serum uric acid level of ≥6 mg/dL prior to PEGylated uricase treatment initiation;
wherein the co-administration of the PEGylated uricase and MMF result in the serum uric acid level being normalized relative to a patient not receiving co-administration of the PEGylated uricase and MMF immunosuppressive therapy.
3 . The method of claim 1 or 2 , further comprising a prophylactic regimen of colchicine for a period of at least 2 weeks prior to the first administration of the PEGylated uricase.
4 . The method of any of claims 1 to 3 , wherein the SUA levels of the patient are determined prior to each dose of the PEGylated uricase.
5 . The method of any of claims 1 to 3 , further comprising measuring one or more of trough PEGylated uricase levels, anti-PEGylated uricase antibody levels, and anti-monomethoxypoly(ethylene glycol) (PEG) antibody levels, prior to each dose of the PEGylated uricase after the first dose.
6 . The method of claim 2 , further comprising measuring hematology and liver function on a weekly basis or every 2 weeks during treatment.
7 . The method of any of claims 2 to 6 , wherein said co-administration of the PEGylated uricase and MMF results in normalization of the serum uric acid level in the patient relative to a patient not receiving co-administration of the PEGylated uricase and MMF.
8 . The method of any of claims 1 to 7 , wherein the serum uric acid level is reduced to less than 6 mg/dL as a result of co-administration of the PEGylated uricase and MMF.
9 . The method of any of claims 1 to 8 , wherein the serum uric acid level is reduced to less than 5 mg/dL as a result of co-administration of the PEGylated uricase and MMF.
10 . The method of any of claims 1 to 9 , wherein the serum uric acid level is reduced to less than 2 mg/dL as a result of co-administration of the PEGylated uricase and MMF.
11 . The method of any of claims 1 to 10 , wherein the incidence of infusion reaction, gout flare, or anaphylaxis is reduced as a result of co-administration of the PEGylated uricase and MMF.
12 . The method of any of claims 1 to 11 , wherein the level of MMF metabolite is increased relative to a patient not receiving co-administration of the PEGylated uricase and MMF.
13 . The method of claim 1 or 2 , further comprising measuring one or more of peripheral joint urate deposition volume and inflammatory volume.
14 . The method of claim 13 , wherein peripheral joint urate deposition volume is reduced in the patient relative to a patient not receiving co-administration of the PEGylated uricase and MMF treatment.
15 . The method of claim 14 , wherein peripheral joint urate deposition volume is determined by dual-energy computed tomography (DECT) scanning.
16 . The method of claim 13 , wherein inflammatory volume is reduced in the patient relative to a patient not receiving co-administration of the PEGylated uricase and MMF treatment.
17 . The method of claim 16 , wherein inflammatory volume is determined by Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) or MRI without contrast, or both.
18 . The method of any of claims 1 to 17 , wherein:
the mean titer of anti-PEGylated uricase antibodies is less than or equal to 1:7000 as a result of the PEGylated uricase and MMF treatment.
19 . The method of any of claims 1 to 18 , wherein the serum uric acid level is normalized by week 12 after the PEGylated uricase and MMF treatment begins.