THERAPEUTIC METHODS FOR THE TREATMENT OF DIABETES AND RELATED CONDITIONS FOR PATIENTS WITH HIGH BASELINE HbA1c

Abstract

The present invention is directed to treatments for a disease or condition, in a subject in need thereof, that provide alternatives to treatment by injection that give, relative to treatment by injection, improved treatment outcomes, 100% treatment compliance, reduced side effects, and rapid establishment and/or termination of substantial steady-state drug delivery. The method includes providing continuous delivery of a drug from an implanted osmotic delivery device, wherein substantial steady-state delivery of the drug at therapeutic concentrations is achieved within about 7 days after implantation of the osmotic delivery device in the subject and the substantial steady-state delivery of the drug from the osmotic delivery device is continuous over a period of at least about 3 months. In one embodiment, the present invention is directed to treatment of type 2 diabetes mellitus using insulinotrophic peptides. In embodiments, a subject has a baseline HbA1c % of greater than 6.5% or 10.0%.

What is claimed is: 
     
         1 . A method of treating type 2 diabetes mellitus in a subject having a baseline hemoglobin A1c (HbA1c) % of greater than 10.0% comprising providing the subject a continuous delivery of an insulinotrophic peptide from an osmotic delivery device. 
     
     
         2 . The method of  claim 1 , wherein a substantial steady-state delivery of the insulinotrophic peptide at a therapeutic concentration is achieved within a time period of about 7 days after implantation of the osmotic delivery device in the subject. 
     
     
         3 . The method of  claim 2 , wherein the time period is selected from the group consisting of about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, and about 1 day. 
     
     
         4 . The method of  claim 1 , wherein the substantial steady-state delivery of the insulinotrophic peptide from the osmotic delivery device is continuous over an administration period of at least about 1 month. 
     
     
         5 . The method of  claim 1 , wherein the substantial steady-state delivery of the insulinotrophic peptide from the osmotic delivery device is continuous over an administration period of at least about 2 months. 
     
     
         6 . The method of  claim 1 , wherein the substantial steady-state delivery of the insulinotrophic peptide from the osmotic delivery device is continuous over an administration period of at least about 3 months. 
     
     
         7 . The method of  claim 4 , wherein the substantial steady-state delivery of the insulinotrophic peptide from the osmotic delivery device is continuous over an administration period selected from the group consisting of at least about 1 month to about two years, at least about 2 months to about two years, at least about 3 months to about two years, at least about 4 months to about two years, at least about 5 months to about two years, at least about 6 months to about two years, at least about 8 months to about two years, and at least about 9 months to about two years, about 1 year, at least one year to about two years, at least about 14 months to about two years, at least about 16 months to about two years, at least 18 months to about two years, at least about 20 months to about two years, at least about 22 months to about two years, and about two years. 
     
     
         8 . The method of  claim 4 , wherein the substantial steady-state delivery of the insulinotrophic peptide from the osmotic delivery device is continuous over an administration period selected from the group consisting of at least about 1 month to about a year, at least about 2 months to about a year, about 3 months, at least about 3 months to about a year, at least about 4 months to about a year, at least about 5 months to about a year, about 6 months, at least about 6 months to about a year, at least about 8 months to about a year, about 9 months, at least about 9 months to about a year, at least about 10 months to about a year, at least about 11 month to about a year, and about a year. 
     
     
         9 . The method of  claim 4 , wherein the method produces a significant decrease in the subject's fasting plasma glucose concentration after implantation of the osmotic delivery device in the subject, relative to the subject's fasting plasma glucose concentration before implantation of the osmotic delivery device. 
     
     
         10 . The method of  claim 9 , wherein the significant decrease in the subject's fasting plasma glucose concentration is within a number of days selected from the group consisting of about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, and about 1 day. 
     
     
         11 . The method of  claim 10 , wherein the significant decrease in the subject's fasting plasma glucose concentration is achieved, relative to the subject's fasting plasma glucose concentration before implantation of the osmotic device, within about 1 day of implantation of the osmotic delivery device in the subject. 
     
     
         12 . The method of  claim 9 , wherein the significant decrease in fasting plasma glucose is maintained over the administration period. 
     
     
         13 . The method of  claim 4 , wherein the method produces a significant decrease in the subject's HbA1c % after implantation of the osmotic delivery device in the subject, relative to the subject's baseline HbA1c %. 
     
     
         14 . The method of  claim 13 , wherein the significant decrease in the subject's HbA1c % is achieved within about six weeks after implantation of the osmotic delivery device. 
     
     
         15 . The method of  claim 14 , wherein the significant decrease in the subject's HbA1c % is achieved within about five weeks after implantation of the osmotic delivery device, within about four weeks after implantation of the osmotic delivery device, within about three weeks after implantation of the osmotic delivery device, within about two weeks after implantation of the osmotic delivery device, or within about one week after implantation of the osmotic delivery device 
     
     
         16 . The method of  claim 13 , wherein the significant decrease in the subject's HbA1c % is maintained over the administration period. 
     
     
         17 . The method of  claim 1 , wherein termination of the continuous delivery of the insulinotrophic peptide produces a concentration of the insulinotrophic peptide that is substantially undetectable in a blood sample from the subject within about 6 half-lives of the insulinotrophic peptide after termination of continuous delivery, within about 5 half-lives of the insulinotrophic peptide after termination of continuous delivery, within about 4 half-lives of the insulinotrophic peptide after termination of continuous delivery, or within about 3 half-lives of the insulinotrophic peptide after termination of continuous delivery. 
     
     
         18 . The method of  claim 17 , wherein removal of the osmotic delivery device from the subject terminates continuous delivery of the insulinotrophic peptide. 
     
     
         19 . The method of  claim 17 , wherein the insulinotrophic peptide is detected by a radioimmunoassay (RIA), a chromatographic method, an electrochemiluminescent (ECL) assay, an enzyme linked immunosorbent assay (ELISA), or an immunoenzymatic sandwich assay (IEMA). 
     
     
         20 . The method of  claim 1 , wherein the osmotic delivery device comprises
 an impermeable reservoir comprising interior and exterior surfaces and first and second open ends,   a semi-permeable membrane in sealing relationship with the first open end of the reservoir,   an osmotic engine within the reservoir and adjacent the semi-permeable membrane,   a piston adjacent the osmotic engine, wherein the piston forms a movable seal with the interior surface of the reservoir, the piston divides the reservoir into a first chamber and a second chamber, the first chamber comprising the osmotic engine,   a suspension formulation, wherein the second chamber comprises the suspension formulation and the suspension formulation is flowable and comprises the insulinotrophic peptide, and   a diffusion moderator inserted in the second open end of the reservoir, the diffusion moderator adjacent the suspension formulation.   
     
     
         21 . The method of  20 , wherein the reservoir comprises titanium or a titanium alloy. 
     
     
         22 . The method of  claim 20 , wherein the suspension formulation comprises a particle formulation comprising the insulinotrophic peptide and a vehicle formulation. 
     
     
         23 . The method of  claim 22 , wherein the insulinotrophic peptide comprises an exenatide peptide, a peptide analog thereof, or a peptide derivative thereof. 
     
     
         24 . The method of  claim 23 , wherein the particle formulation comprises particles comprising the exenatide peptide, the peptide analog thereof, or the peptide derivative thereof in particles of from about 2 microns to about 50 microns in diameter. 
     
     
         25 . The method of  claim 23 , wherein the insulinotrophic peptide is the exenatide having the amino acid sequence of SEQ ID NO: 1. 
     
     
         26 . The method of  claim 1  or  25 , wherein the continuous delivery provides to the subject a mcg/day dose of an exenatide selected from the group consisting of about 10 mcg/day, about 20 mcg/day, about 30 mcg/day, about 40 mcg/day, about 50 mcg/day, about 60 mcg/day, about 70 mcg/day, or about 80 mcg/day. 
     
     
         27 . The method of  claim 26 , wherein the mcg/day dose of the exenatide is about 20 mcg/day. 
     
     
         28 . The method of  claim 26 , wherein the mcg/day dose of the exenatide is about 40 mcg/day. 
     
     
         29 . The method of  claim 26 , wherein the mcg/day dose of the exenatide is about 60 mcg/day. 
     
     
         30 . The method of  claim 1  or  25 , wherein termination of the continuous delivery results in a concentration of the exenatide that is substantially undetectable in a blood sample from the subject after termination of continuous delivery within a number of hours selected from the group consisting of about 72 hours, about 48 hours, about 24, about 12 hours, about 6 hours, and about 4 hours. 
     
     
         31 . The method of  claim 30 , wherein removal of the osmotic delivery device from the subject terminates continuous delivery of the insulinotrophic peptide. 
     
     
         32 . The method of  claim 1 , wherein the method further comprises a first continuous administration period of the insulinotrophic peptide at a first mcg/day dose that is followed by a second continuous administration period providing a dose escalation of the insulinotrophic peptide to a second mcg/day dose, wherein the second mcg/day dose is greater than the first mcg/day dose. 
     
     
         33 . The method of  claim 32 , wherein the first mcg/day dose is delivered by a first osmotic delivery device and the second mcg/day dose is delivered by a second osmotic delivery device, and delivery of the insulinotrophic peptide from at least the first or the second osmotic delivery device is continuous over the administration period of at least about 1 month. 
     
     
         34 . The method of  claim 32 , wherein the first mcg/day dose is delivered by a first osmotic delivery device and the second mcg/day dose is delivered by a second osmotic delivery device, and delivery of the insulinotrophic peptide from at least the first or the second osmotic delivery device is continuous over the administration period of at least about 2 months. 
     
     
         35 . The method of  claim 32 , wherein the first mcg/day dose is delivered by a first osmotic delivery device and the second mcg/day dose is delivered by a second osmotic delivery device, and delivery of the insulinotrophic peptide from at least the first or the second osmotic delivery device is continuous over the administration period of at least about 3 months. 
     
     
         36 . The method of  claim 32 , wherein the second mcg/day dose is at least two times greater than the first mcg/day dose. 
     
     
         37 . The method of  claim 32 , wherein the method further comprises at least one more continuous administration period providing a dose escalation of the insulinotrophic peptide to a higher mcg/day dose relative to the second mcg/day dose. 
     
     
         38 . The method of  claim 32 , wherein the method further comprises at least one more continuous administration period providing a dose at the same mcg/day dose as the second mcg/day dose. 
     
     
         39 . The method of  claim 32 , wherein the insulinotrophic peptide is an exenatide, and the first mcg/day dose followed by the second mcg/day dose for continuous delivery is selected from the group consisting of: about 10 mcg/day followed by about 20 mcg/day; about 10 mcg/day followed by about 40 mcg/day; about 10 mcg/day followed by about 60 mcg/day; about 10 mcg/day followed by about 80 mcg/day; about 20 mcg/day followed by about 40 mcg/day; about 20 mcg/day followed by about 60 mcg/day; about 20 mcg/day followed by about 80 mcg/day; about 40 mcg/day followed by about 60 mcg/day; about 40 mcg/day followed by about 80 mcg/day; and about 60 mcg/day followed by about 80 mcg/day. 
     
     
         40 . The method of  claim 39 , wherein the first mcg/day dose followed by the second mcg/day dose for continuous delivery is about 20 mcg/day followed by about 40 mcg/day. 
     
     
         41 . The method of  claim 39 , wherein the first mcg/day dose followed by the second mcg/day dose for continuous delivery is about 20 mcg/day followed by about 60 mcg/day. 
     
     
         42 . The method of  claim 1  or  20 , wherein the insulinotrophic peptide comprises GLP-1 or an incretin mimetic selected the group consisting of a GLP-1 peptide, a peptide analog of GLP-1, a peptide derivative of GLP-1, the exenatide having the amino acid sequence of SEQ ID NO: 1, native exendin-4, an exenatide peptide, a peptide analog of exenatide, and a peptide derivative of exenatide. 
     
     
         43 . The method of  claim 1  or  22 , wherein the insulinotrophic peptide is selected from the group consisting of lixisenatide, liraglutide, albiglutide, and taspoglutide. 
     
     
         44 . The method of  claim 1  or  22 , wherein the vehicle formulation comprises a solvent and a polymer. 
     
     
         45 . The method of  claim 44 , wherein the vehicle formulation has a viscosity of between about 10,000 poise and about 20,000 poise at 37° C. 
     
     
         46 . The method of  claim 44 , wherein the solvent is selected from the group consisting of benzyl benzoate, lauryl lactate, and lauryl alcohol. 
     
     
         47 . The method of  claim 44 , wherein the polymer is a polyvinylpyrrolidone. 
     
     
         48 . The method of  claim 1 , wherein the subject has a baseline HbA1c % of less than or equal to 12.0%. 
     
     
         49 . The method of  claim 1 , wherein the subject is a human. 
     
     
         50 . The method of  claim 1 , wherein the subject has not previously received a drug for treating type 2 diabetes mellitus. 
     
     
         51 . The method of  claim 1 , wherein the subject is further provided one or more other drugs for treating type 2 diabetes mellitus. 
     
     
         52 . The method of  claim 51 , wherein the one or more other drugs is insulin or an anti-diabetic drug selected from the group consisting of a DPP4 inhibitor, a SGLT2 inhibitor, metformin, a sulfonylurea, and a thiazolidinedione (TZD).