Dimethyl Fumarate and Vaccination Regimens

Abstract

Provided herein is a method of treating or preventing a disease or disorder (e.g., MS) in a subject in need thereof, comprising (a) administering to the subject a first dose of a pharmaceutical composition comprising a fumarate agent (e.g., DMF) for a first dosing period; (b) administering a vaccine; and (c) administering to the subject a second dose of the pharmaceutical composition for a second dosing period.

What is claimed is: 
     
         1 . A method of treating or preventing multiple sclerosis in a subject in need thereof, comprising
 (a) administering to the subject a first dose of a pharmaceutical composition for a first dosing period, wherein the pharmaceutical composition comprises a fumarate agent selected from the group consisting of monomethyl fumarate, a compound that metabolizes into monomethyl fumarate in vivo, a deuterated analog thereof, a pharmaceutically acceptable salt thereof, and a combination thereof;   (b) administering a vaccine to the subject; and   (c) administering to the subject a second dose of the pharmaceutical composition for a second dosing period, wherein the second dosing period is after the first dosing period.   
     
     
         2 . The method of  claim 1 , wherein the fumarate agent is monomethyl fumarate, dimethyl fumarate, or a combination thereof. 
     
     
         3 . The method of  claim 1  or  2 , wherein the fumarate agent is dimethyl fumarate. 
     
     
         4 . The method of  claim 3 , wherein the first dose is a daily amount of about 480 mg dimethyl fumarate. 
     
     
         5 . The method of any of  claims 1 - 4 , wherein the second dose is lower than the first dose. 
     
     
         6 . The method of any of  claims 1 - 5 , wherein the second dose is 0 mg fumarate agent. 
     
     
         7 . The method of any of  claims 1 - 6 , further comprising administering a titration dose of the pharmaceutical composition prior to the first dosing period. 
     
     
         8 . The method of  claim 7 , wherein the fumarate agent is dimethyl fumarate and the titration dose is a daily amount of about 240 mg dimethyl fumarate. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein the first and second doses of the fumarate agent are in a form of microtablets, micropellets, granules, capsules, or tablets. 
     
     
         10 . The method of any of  claims 1 - 9 , wherein the dimethyl fumarate is in a form of microtablets, and wherein the microtablets are enterically coated. 
     
     
         11 . The method of any of  claims 1 - 10 , wherein the step of administering the vaccine occurs before or during the first dosing period. 
     
     
         12 . The method of any of  claims 1 - 11 , wherein the vaccine induces a T cell-dependent immune response. 
     
     
         13 . The method of  claim 12 , wherein the vaccine induces a T cell-dependent anamnestic humoral immune response. 
     
     
         14 . The method of  claim 12 , wherein the vaccine induces a T cell-dependent neoantigen immune response. 
     
     
         15 . The method of any of  claims 1 - 11 , wherein the vaccine induces a T cell-independent immune response. 
     
     
         16 . The method of any of  claims 1 - 15 , wherein serum antibody level induced by the vaccine in the subject is lower compared to average serum antibody level observed in subjects administered with the vaccine but not the fumarate agent, and the second dose is less than the first dose. 
     
     
         17 . The method of any of  claims 1 - 15 , wherein serum antibody level induced by the vaccine in the subject increases less than 4-fold from pre-vaccination to 4 weeks after vaccination, and the second dose is less than the first dose. 
     
     
         18 . The method of any of  claims 1 - 17 , wherein the vaccine is a live or inactive vaccine. 
     
     
         19 . The method of  claim 18 , wherein the vaccine is an inactive vaccine. 
     
     
         20 . The method of any of  claims 1 - 17 , wherein the vaccine is a vaccine selected from the group consisting of tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof. 
     
     
         21 . The method of any of  claims 1 - 17 , wherein the vaccine is tetanus diphtheria toxoids vaccine. 
     
     
         22 . The method of any of  claims 1 - 17 , wherein the vaccine is keyhole limpet hemocyanin vaccine. 
     
     
         23 . The method of  claims 1 - 17 , wherein the vaccine is pneumovax-23 vaccine. 
     
     
         24 . The method of any of  claims 1 - 23 , wherein the second dose is 0 mg fumarate agent. 
     
     
         25 . A method of treating or preventing a neurological disease or disorder in a subject in need thereof, comprising
 (a) administering to the subject a first dose of a pharmaceutical composition for a first dosing period, wherein the pharmaceutical composition comprises a fumarate agent selected from the group consisting of monomethyl fumarate, a compound that metabolizes into monomethyl fumarate in vivo, a deuterated analog thereof, a pharmaceutically acceptable salt thereof, and a combination thereof, wherein the subject receives a vaccine;   (b) determining an immune response of the subject to the vaccine before the end of the first dosing period; and   (c) administering to the subject a second dose of the pharmaceutical composition for a second dosing period, wherein the second dose is equal to or less than the first dose.   
     
     
         26 . The method of  claim 25 , wherein the neurological disease or disorder is multiple sclerosis. 
     
     
         27 . The method of  claim 25  or  26 , wherein the fumarate agent is monomethyl fumarate, dimethyl fumarate, or a combination thereof. 
     
     
         28 . The method of any of  claims 25 - 27 , wherein the fumarate agent is dimethyl fumarate. 
     
     
         29 . The method of  claim 28 , wherein the first dose is a daily amount of about 480 mg dimethyl fumarate. 
     
     
         30 . The method of any of  claims 25 - 29 , wherein the second dose is 0 mg fumarate agent. 
     
     
         31 . The method of any of  claims 25 - 30 , further comprising administering a titration dose of the pharmaceutical composition prior to the first dosing period. 
     
     
         32 . The method of  claim 31 , wherein the fumarate agent is dimethyl fumarate and the titration dose is a daily amount of about 240 mg dimethyl fumarate. 
     
     
         33 . The method of any of  claims 25 - 32 , wherein the first and second doses of the fumarate agent are in a form of microtablets, micropellets, granules, capsules, or tablets. 
     
     
         34 . The method of any of  claims 25 - 33 , wherein the dimethyl fumarate is in a form of microtablets, and wherein the microtablets are enterically coated. 
     
     
         35 . The method of any of  claims 25 - 34 , wherein the subject receives the vaccine about 2 to 4 weeks before the start of the first dosing period, or during the first dosing period. 
     
     
         36 . The method of any of  claims 25 - 35 , wherein the subject receives the second dose of the fumarate agent following the end of the first dosing period. 
     
     
         37 . The method of any of  claims 25 - 36 , wherein the vaccine induces a T-cell dependent immune response. 
     
     
         38 . The method of any of  claims 25 - 37 , wherein the vaccine induces a T-cell independent immune response. 
     
     
         39 . The method of any of  claims 25 - 38 , wherein the immune response of the subject to the vaccine is characterized in that the serum antibody level induced by the vaccine in the subject increases less than 4-fold from pre-vaccination to 4 weeks after vaccination, and the second dose is less than the first dose. 
     
     
         40 . The method of any of  claims 25 - 39 , wherein the immune response of the subject to the vaccine is characterized in that the serum antibody level induced by the vaccine in the subject increases at least 2-fold from pre-vaccination to 4 weeks after vaccination, wherein the second dose is the same as the first dose. 
     
     
         41 . The method of any of  claims 25 - 40 , wherein the immune response of the subject to the vaccine is characterized in that the scrum antibody level induced by the vaccine in the subject is lower compared to average serum antibody level induced by the vaccine in subjects administered with the vaccine but no fumarate agent, and the second dose is less than the first dose. 
     
     
         42 . The method of any of  claims 25 - 41 , wherein the vaccine is a live or inactive vaccine. 
     
     
         43 . The method of  claim 42 , wherein the vaccine is an inactive vaccine. 
     
     
         44 . The method of any of  claims 25 - 41 , wherein the vaccine is a vaccine selected from the group consisting of tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof. 
     
     
         45 . The method of any of  claims 25 - 41 , wherein the vaccine is tetanus diphtheria toxoids vaccine. 
     
     
         46 . The method of any of  claims 25 - 41 , wherein the vaccine is keyhole limpet hemocyanin vaccine. 
     
     
         47 . The method of  claims 25 - 41 , wherein the vaccine is pneumovax-23 vaccine. 
     
     
         48 . A method of treating or preventing a neurological disease or disorder in a subject who receives a vaccine, comprising:
 (a) screening a plurality of doses of a pharmaceutical composition comprising a fumarate agent selected from the group consisting of monomethyl fumarate, a compound that metabolizes into monomethyl fumarate in vivo, a deuterated analog thereof, a pharmaceutically acceptable salt thereof, and a combination thereof, by   (1) identifying a first group of subjects and at least a second group of subjects, wherein both the first and second groups of subjects receive the vaccine while treated with the fumarate agent, wherein the first group of subjects is treated with a first dose of the fumarate agent, and the second group of subjects is treated with a second dose of the fumarate agent;   (2) determining a lower risk dose; and   (b) administering the lower risk dose of the pharmaceutical composition to the subject.   
     
     
         49 . The method of  claim 48 , wherein the neurological disease or disorder is multiple sclerosis. 
     
     
         50 . The method of  claim 48  or  49 , wherein the fumarate agent is dimethyl fumarate. 
     
     
         51 . The method of  claim 50 , wherein the first dose is a daily amount of about 480 mg dimethyl fumarate. 
     
     
         52 . The method of any of  claims 48 - 51 , wherein the second dose is 0 mg fumarate agent. 
     
     
         53 . The method of any of  claims 48 - 52 , further comprising administering a titration dose of the pharmaceutical composition to the subject. 
     
     
         54 . The method of any of  claims 48 - 53 , wherein the fumarate agent is dimethyl fumarate and the titration dose is a daily amount of about 240 mg dimethyl fumarate. 
     
     
         55 . The method of  claims 48 - 54 , wherein the group of subjects treated with the lower risk dose have higher proportion of subjects with at least 2-fold increase in serum antibody levels induced by the vaccine from pre-vaccination to 4 weeks after vaccination. 
     
     
         56 . The method of  claims 48 - 54 , wherein the group of subjects treated with the lower risk dose have higher proportion of subjects having serum antibody levels induced by the vaccine not less than average scrum antibody level observed in subjects administered with the vaccine but no fumarate agent at 4 weeks after vaccination. 
     
     
         57 . The method of any of  claims 48 - 56 , wherein the vaccine is a live or inactive vaccine. 
     
     
         58 . The method of  claim 57 , wherein the vaccine is an inactive vaccine. 
     
     
         59 . The method of any of  claims 48 - 56 , wherein the vaccine is a vaccine selected from the group consisting of tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof. 
     
     
         60 . The method of any of  claims 48 - 56 , wherein the vaccine is tetanus diphtheria toxoids vaccine. 
     
     
         61 . The method of any of  claims 48 - 56 , wherein the vaccine is keyhole limpet hemocyanin vaccine. 
     
     
         62 . The method of  claims 48 - 56 , wherein the vaccine is pneumovax-23 vaccine. 
     
     
         63 . The method of any of  claims 48 - 62 , wherein the lower risk dose is the second dose, wherein the second dose is less than the first dose. 
     
     
         64 . A method of treating or preventing multiple sclerosis in a subject in need thereof, comprising
 (a) determining a subject's baseline lymphocyte count prior to treatment;   (b) administering to the subject a first dose of a pharmaceutical composition for a first dosing period, wherein the pharmaceutical composition comprises a fumarate agent selected from the group consisting of monomethyl fumarate, a compound that metabolizes into monomethyl fumarate in vivo, a deuterated analog thereof, a pharmaceutically acceptable salt thereof, and a combination thereof;   (c) determining a subject's total lymphocyte count after the first dosing period; and   (d) if the lymphocyte count after the first dosing period is about 90% of the baseline lymphocyte count or lower, do not administer tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine, pneumovax-23 vaccine, or any combinations thereof.   
     
     
         65 . The method of  claim 64 , wherein the subject's lymphocyte count is 70% of the baseline lymphocyte count or lower. 
     
     
         66 . The method of  claim 64 , wherein the subject's lymphocyte count is 50% of the baseline lymphocyte count or lower. 
     
     
         67 . The method of any of  claims 64 - 66 , wherein the fumarate agent is monomethyl fumarate, dimethyl fumarate, or a combination thereof. 
     
     
         68 . The method of  claims 64 - 66 , wherein the fumarate agent is dimethyl fumarate. 
     
     
         69 . The method of  claim 67 , wherein the first dose is a daily amount of about 480 mg dimethyl fumarate. 
     
     
         70 . The method of any of  claims 64 - 69 , further comprising administering to the subject a second dose for a second dosing period. 
     
     
         71 . The method of  claim 70 , wherein the second dose is lower than the first dose. 
     
     
         72 . The method of  claim 71 , wherein the second dose is 0 mg fumarate agent. 
     
     
         73 . The method of any of  claims 64 - 72 , further comprising administering a titration dose of the pharmaceutical composition prior to the first dosing period. 
     
     
         74 . The method of  claim 73 , wherein the fumarate agent is dimethyl fumarate and the titration dose is a daily amount of about 240 mg dimethyl fumarate. 
     
     
         75 . The method of any of  claims 70 - 74 , wherein the first and second doses of the fumarate agent are in a form of microtablets, micropellets, granules, capsules, or tablets. 
     
     
         76 . The method of any of  claims 64 - 75 , wherein the dimethyl fumarate is in a form of microtablets, and wherein the microtablets are enterically coated. 
     
     
         77 . The method of any of  claims 64 - 76 , further comprising administering a vaccine, wherein the step of administering the vaccine occurs before or during the first dosing period. 
     
     
         78 . The method of  claim 77 , wherein the vaccine induces a T cell-dependent immune response. 
     
     
         79 . The method of  claim 77 , wherein the vaccine induces a T cell-dependent anamnestic humoral immune response. 
     
     
         80 . The method of  claim 77 , wherein the vaccine induces a T cell-dependent neoantigen immune response. 
     
     
         81 . The method of  claim 77 , wherein the vaccine induces a T cell-independent immune response. 
     
     
         82 . The method of any of  claims 77 - 81 , wherein serum antibody level induced by the vaccine in the subject is lower compared to average serum antibody level observed in subjects administered with the vaccine but not the fumarate agent, and the second dose is less than the first dose. 
     
     
         83 . The method of any of  claims 77 - 81 , wherein scrum antibody level induced by the vaccine in the subject increases less than 4-fold from pre-vaccination to 4 weeks after vaccination, and the second dose is less than the first dose. 
     
     
         84 . The method of any of  claims 77 - 81 , wherein the vaccine is a live or inactive vaccine. 
     
     
         85 . The method of  claim 84 , wherein the vaccine is an inactive vaccine. 
     
     
         86 . The method of any of  claims 77 - 85 , wherein the vaccine is a vaccine selected from the group consisting of tetanus diphtheria toxoids vaccine, keyhole limpet hemocyanin vaccine, pneumovax-23 vaccine, and any combinations thereof. 
     
     
         87 . The method of  claim 86 , wherein the vaccine is tetanus diphtheria toxoids vaccine. 
     
     
         88 . The method of  claim 86 , wherein the vaccine is keyhole limpet hemocyanin vaccine. 
     
     
         89 . The method of  claim 86 , wherein the vaccine is pneumovax-23 vaccine. 
     
     
         90 . The method of any of  claims 70 - 89 , wherein the second dose is 0 mg fumarate agent. 
     
     
         91 . A method of treating multiple sclerosis in a human subject in need thereof comprising
 (a) administering a therapeutically effective amount of dimethyl fumarate to the subject; and   (b) administering a vaccine to the subject.   
     
     
         92 . The method of  claim 91 , wherein the therapeutically effective amount of dimethyl fumarate is a maintenance dose that is repeatedly administered over at least a period of time, and said step (b) of administering said vaccine is during said period of time. 
     
     
         93 . The method of  claim 91  or  92 , wherein the maintenance dose is orally administered 240 mg dimethyl fumarate twice daily. 
     
     
         94 . The method of any of  claims 91 - 93 , wherein the period of time is 1 week. 
     
     
         95 . The method of any of  claims 91 - 93 , wherein the period of time is 6 months. 
     
     
         96 . The method of any of  claims 91 - 95 , wherein the immune response to said vaccine is decreased in said subject relative to the immune response in the absence of said step (a) of administering a therapeutically effective amount of dimethyl fumarate. 
     
     
         97 . The method of any of  claims 91 - 96 , wherein the multiple sclerosis is a relapsing form of multiple sclerosis. 
     
     
         98 . The method of  claim 97 , wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.