`
`(19) World Intellectual Property Organization
`International Bureau
`
`10 November 2011 (10.11.2011) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2011/138421 Al
`
`
`(51) International Patent Classification:
`A61K 31/00 (2006.01)
`A61P 3/04 (2006.01)
`AG61K 31/522 (2006.01)
`A61P 3/10 (2006.01)
`AG1K 38/00 (2006.01)
`(21) International Application Number:
`
`eqs
`.
`(22) International Filing Date:
`
`(25) Filing Language:
`
`PCT/EP201 1/057256
`
`5 May 2011 (05.05.2011)
`English
`
`English
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): KLEIN, Thomas
`[DE/DE]; Boehringer
`Ingelheim GmbH, Corporate
`Patents, Binger Str. 173, 55216 Ingelheim Am Rhein
`(DE). GREMPLER, Rolf [DE/DE]; Boehringer Ingel-
`heim GmbH, Corporate Patents, Binger Str. 173, 55216
`Ingelheim Am Rhein (DE). MARK, Michael [DE/DE];
`Boehringer Ingelheim GmbH, Corporate Patents, Binger
`Str. 173, 55216 Ingelheim Am Rhein (DE).
`
`
`
`
`
`(74) Agents: HAMMANN,et al, Heinz et al.; Boehringer In-
`gelheim GmbH, Corporate Patents, Binger Str. 173,
`55216 Ingelheim Am Rhein (DE).
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,GT,
`HN,HR, HU,ID,IL,IN,IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI
`NO, NZ, OM,PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`(26) Publication Language:
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`(30) Priority Data:
`TT, TZ, UA, UG,US, UZ, VC, VN, ZA, 2M, ZW.
`EP
`5 May 2010 (05.05.2010)
`10162036.7
`EP (84) Designated States (unless otherwise indicated, for every
`21 February 2011 (21.02.2011)
`11155154.5
`(for
`all designated States
`except US):
`kind of regional protection available): ARIPO (BW, GH,
`(71) Applicant
`BOEHRINGER INGELHEIM INTERNATIONAL
`GM, KE, LR, LS, MW, MZ, NA,SD,SL, SZ, TZ, UG,
`GMBH[DE/DE]; BingerStr. 173, 55216 Ingelheim Am
`2M, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ,
`Rhein (DE).
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW,ML, MR,NE,SN, TD, TG).
`Declarations under Rule 4.17:
`
`wo2011/138421At|IMDTIMNITINNININTTINNYAEAN (54) Title: COMBINATION THERAPY
`
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17(ii))
`Published:
`
`with international search report (Art. 21(3))
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 1
`
`(57) Abstract: The present invention relates to methods for treating and/or preventing metabolic diseases comprising the com-
`bined administration of a GLP-1 receptor agonist and a DPP-4 inhibitor.
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 1
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`
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`WO 2011/138421
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`PCT/EP2011/057256
`
`Combination therapy
`
`The present invention relates to methods for treating and/or preventing metabolic diseases,
`
`especially type 2 diabetes mellitus, obesity and/or conditions related thereto (e.g. diabetic
`
`complications) comprising the combined administration of a GLP-1 receptor agonist (e.g.
`
`exogenous GLP-1 or a GLP-1 analogue) and a certain DPP-4 inhibitor, to pharmaceutical
`
`compositions and combinations comprising such active components, and to certain
`
`therapeutic uses thereof.
`
`10
`
`Further, the present invention relates to a method for reducing and maintaining body weight
`
`and/or body fat in a patient in need thereof, such as e.g. in an overweight or obesity patient
`
`with or without diabetes (particularly type 2 diabetes patient being obese or overweight),
`
`comprising the combined (e.g. separate, simultaneous or sequential) administration of a
`
`GLP-1 receptor agonist (e.g. GLP-1 or GLP-1 analogue) and a certain DPP-4 inhibitor;
`
`15
`
`preferably said method comprising the sequential administration of a GLP-1 receptor agonist
`
`followed by a certain DPP-4 inhibitor.
`
`Furthermore, the present invention relates to a method for reducing and maintaining body
`
`weight and/or body fat in a patient in need thereof, such as e.g. in an overweightor obesity
`
`patient with or without diabetes (particularly type 2 diabetes patient being obese or
`
`20
`
`overweight), comprising i) inducing body weight loss (e.g. by administering an effective
`
`amount of a GLP-1 receptor agonist to the patient) and ii.) administering an effective amount
`
`of a certain DPP-4 inhibitor to the patient.
`
`Moreover, the present invention relates to a certain DPP-4 inhibitor for use in preventing of
`
`body weight and/or body fat gain or controlling, stabilizing or maintaining a reduced body
`
`25
`
`weight and/or body fat followed discontinuation of weight reducing treatment (such as e.g.
`
`diet, exercise and/or treatment with an anti-obesity or body weight reducing agent),
`
`particularly after discontinuation of treatment with a GLP-1 receptor agonist.
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in delaying body
`
`weight and/or body fat gain and/or maintaining reduction in body weight and/or body fat in a
`
`30
`
`subject (particularly an obesity patient with or without diabetes), particularly subsequent to
`
`cessation of or withdrawn from body weight reducing and/or fat reducing treatment.
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in a method of
`
`delaying body weight and/or body fat gain and/or maintaining body weight and/or bodyfat
`
`loss induced by treatment with a GLP-1 receptor agonist in a subject, said method
`
`35
`
`comprising cessation of GLP-1 receptor agonist treatment and transferring the subject from
`
`GLP-1 receptor agonist to DPP-4 inhibitor treatment.
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 2
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 2
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`WO 2011/138421
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`PCT/EP2011/057256
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`-2-
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`Furthermore, the present invention relates to a DPP-4 inhibitor for use in reducing,
`
`maintaining loss of or delaying increase of body weight and/or body fat in a subject actively
`
`putting on weight.
`
`Yet furthermore, the present invention relates to a DPP-4 inhibitor for use in reducing,
`
`maintaining loss of or delaying increase of body weight and/or body fat in a subject being in
`
`condition of actively putting on weight and/or increasing body weight through the deposition
`
`of fat, such as e.g. after withdrawing a weight loss treatment or under a treatment associated
`
`with weight gain (e.g. through the action of sulphonylureas, glinides, insulin and/or
`
`thiazolidinediones, the use of which is associated with weight gain).
`
`10
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in reducing intra-
`
`myocellular fat and/or hepatic fat in a patient in need thereof, such as e.g. in an overweight
`
`or obesity patient with or without diabetes (particularly type 2 diabetes patient being obese or
`
`overweight).
`
`Further, the present invention relates to a DPP-4 inhibitor for use in achieving a reduction in
`
`15
`
`the dose of GLP-1 receptor agonist medication, e.g. required for effective therapy of
`
`metabolic diseases (such as e.g. type 2 diabetes mellitus, obesity and/or conditions related
`
`thereto (e.g. diabetic complications)), e.g. in an overweight or obesity patient with or without
`
`diabetes (particularly type 2 diabetes patient being obese or overweight).
`
`Moreover, the present invention relates to a certain DPP-4 inhibitor for use in treating,
`
`20
`
`preventing or reducing the risk of skin necrosis, particularly associated with or induced by
`
`infusions or injections, e.g. of a GLP-1 receptor agonist, insulin or insulin analogue or other
`
`drugs administered subcutaneously and/or via needle or syringe, typically pierced through
`
`the skin.
`
`Further, the present invention relates to the DPP-4 inhibitors and/or GLP-1 receptor agonists,
`
`25
`
`each as defined herein, for use in the combination therapies as described herein.
`
`Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a
`
`complex pathophysiology involving the dual endocrine effects of insulin resistance and
`
`impaired insulin secretion with the consequence not meeting the required demands to
`
`30
`
`maintain plasma glucoselevels in the normal range. This leads to chronic hyperglycaemia
`
`and its associated micro- and macrovascular complications or chronic damages, such as e.g.
`
`diabetic nephropathy, retinopathy or neuropathy, or macrovascular (e.g. cardio- or cerebro-
`
`vascular) complications. The vascular disease componentplays a significant role, but is not
`
`the only factor in the spectrum of diabetes associated disorders. The high frequencyof
`
`35
`
`complications leads to a significant reduction oflife expectancy. Diabetes is currently the
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 3
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 3
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`
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`WO 2011/138421
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`most frequent cause of adult-onset loss of vision, renal failure, and amputation in the
`
`Industrialised World because of diabetes induced complications and is associated with a two
`
`to five fold increase in cardiovascular disease risk.
`
`Furthermore, diabetes (particularly type 2 diabetes) is often coexistent and interrelated with
`
`obesity and these two conditions together impose a particularly complex therapeutic
`
`challenge. Because ofthe effects of obesity on insulin resistance, weight loss and its
`
`maintainanceis an important therapeutic objective in overweight or obese individuals with
`
`prediabetes, metabolic syndrome or diabetes. Studies have been demonstrated that weight
`
`10
`
`reduction in subjects with type 2 diabetes is associated with descreased insulin resistance,
`
`improved measures of glycemia and lipemia, and reduced blood pressure. Maintainance of
`
`weight reduction over longer term is considered to improve glycemic control and prevent
`
`diabetic complications (e.g. reduction of risk for cardiovascular diseases or events). Thus,
`
`weight loss is recommendedfor all overweight or obese indivuduals who haveor areat risk
`
`15
`
`for diabetes. However, obese patients with type 2 diabetes have much greaterdifficulty
`
`losing weight and maintain the reduced weight than the general non-diabetic population.
`
`Overweight may be defined as the condition wherein the individual has a body mass index
`
`(BMI) greater than or 25 kg/m? and less than 30 kg/m?. The terms "overweight" and "pre-
`
`20
`
`obese" are used interchangeably.
`
`Obesity may be defined as the condition wherein the individual has a BMI equalto or greater
`
`than 30 kg/m?. According to a WHO definition the term obesity may be categorized as
`
`follows: class | obesity is the condition wherein the BMI is equal to or greater than 30 kg/m?
`
`25
`
`but lower than 35 kg/m?; classII obesity is the condition wherein the BMI is equal to or
`
`greater than 35 kg/m? but lower than 40 kg/m?; classIll obesity is the condition wherein the
`
`BMI is equal to or greater than 40 kg/m?. Obesity may include e.g. visceral or abdominal
`
`obesity.
`
`30
`
`Visceral obesity may be defined as the condition wherein a waist-to-hip ratio of greater than
`
`or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance
`
`and the development of pre-diabetes.
`
`Abdominal obesity may usually be defined as the condition wherein the waist circumference
`
`35
`
`is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 4
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 4
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`WO 2011/138421
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`PCT/EP2011/057256
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`-4-
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`Japaneseethnicity or Japanese patients abdominal obesity may be defined as waist
`
`circumference 2 85 cm in men and 2 90 cm in women(see e.g. investigating committee for
`
`the diagnosis of metabolic syndrome in Japan).
`
`Diabetes patients within the meaning of this invention may include patients having obesity or
`
`overweight.
`
`Obesity patients within the meaning of this invention may include, in one embodiment,
`
`patients with diabetes (particularly having type 2 diabetes).
`
`10
`
`Obesity patients within the meaning ofthis invention may include, in another embodiment,
`
`patients without diabetes (particularly without type 1 or type 2 diabetes).
`
`The treatment of type 2 diabetes typically begins with diet and exercise, followed by oral
`
`15
`
`antidiabetic monotherapy, and although conventional monotherapy mayinitially control blood
`
`glucosein some patients, it is however associated with a high secondary failure rate. The
`
`limitations of single-agent therapy for maintaining glycemic control may be overcome, atleast
`
`in somepatients, and for a limited period of time by combining multiple drugs to achieve
`
`reductions in blood glucose that cannot be sustained during long-term therapy with single
`
`20
`
`agents. Available data support the conclusion that in most patients with type 2 diabetes
`
`current monotherapywill fail and treatment with multiple drugs will be required.
`
`But, because type 2 diabetes is a progressive disease, even patients with goodinitial
`
`responses to conventional combination therapy will eventually require an increase of the
`
`dosage or further treatment with insulin because the blood glucoselevel is very difficult to
`
`25
`
`maintain stable for a long period of time. Although existing combination therapy has the
`
`potential to enhance glycemic control, it is not without limitations (especially with regard to
`
`long term efficacy). Further, traditional therapies may show an increasedrisk for side effects,
`
`such as hypoglycemia or weight gain, which may compromisetheir efficacy and
`
`acceptability.
`
`30
`
`Thus, for many patients, these existing drug therapies result in progressive deterioriation in
`
`metabolic control despite treatment and do not sufficiently control metabolic status especially
`
`over long-term and thus fail to achieve and to maintain glycemic control in advanced or late
`
`stage type 2 diabetes, including diabetes with inadequate glycemic control despite
`
`conventional oral or non-oral antidiabetic medication.
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`35
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 5
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 5
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`Therefore, although intensive treatment of hyperglycemia can reduce the incidence of
`
`chronic damages, many patients with type 2 diabetes remain inadequately treated, partly
`
`becauseoflimitations in long term efficacy, tolerability and dosing inconvenience of
`
`conventional antihyperglycemic therapies.
`
`In addition, obesity, overweight or weight gain (e.g. as side or adverse effect of some
`
`conventional antidiabetic medications) further complicates the treatment of diabetes and its
`
`micorvascular or macrovascular complications.
`
`10
`
`This high incidence of therapeutic failure is a major contributor to the high rate of long-term
`
`hyperglycemia-associated complications or chronic damages(including micro- and
`
`makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy,
`
`or cardiovascular complications) in patients with type 2 diabetes.
`
`15
`
`Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line,
`
`and/or mono- or (initial or add-on) combination therapy) include, without being restricted
`
`thereto, metformin, sulphonylureas, thiazolidinediones, glinides and a-glucosidaseinhibitors.
`
`Non-oral (typically injected) antidiabetic drugs conventionally used in therapy (such as e.g.
`
`20
`
`first- or second-line, and/or mono-or (initial or add-on) combination therapy) include, without
`
`being restricted thereto, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.
`
`However, the use of these conventional antidiabetic or antihyperglycemic agents can be
`
`associated with various adverse effects. For example, metformin can be associated with
`
`25
`
`lactic acidosis or gastrointestinal side effects; sulfonylureas, glinides and insulin or insulin
`
`analogues can be associated with hypoglycemia and weight gain; thiazolidinediones can be
`
`associated with edema, bone fracture, weight gain and heart failure/cardiac effects; and
`
`alpha-glucosidase blockers and GLP-1 or GLP-1 analogues can be associated with
`
`gastrointestinal adverse effects (e.g. dyspepsia, flatulence or diarrhea, or nausea or
`
`30
`
`vomiting) and, most seriously (but rare), pancreatitis.
`
`Therefore, it remains a needin the art to provide efficacious, safe and tolerable antidiabetic
`
`therapies, particularly for obese or overweight diabetes patients.
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 6
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 6
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`WO 2011/138421
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`Further, it remains a needin the art to provide efficacious, safe and tolerable therapies for
`
`obesity patients with or without diabetes, particularly for reducing body weight and
`
`maintaining reduced body weight as well as for preventing rebound of weight gain following
`
`cessation of weight loss treatment in such patients.
`
`Within the management of the dual epidemic of type 2 diabetes and obesity (“diabesity”), it is
`
`an objective to find therapies which are safe, tolerable and effective in the treatment or
`
`prevention of these conditions together, particularly in achieving long term weight reduction
`
`and improving glycemic control.
`
`10
`
`Further, within the therapy of type 2 diabetes, obesity or both, it is a need for treating the
`
`condition effectively, avoiding the complications inherent to the condition, and delaying
`
`disease progression.
`
`15
`
`Furthermore, it remains a needthat antidiabetic treatments not only prevent the long-term
`
`complications often found in advanced stagesof diabetes disease, but also are a therapeutic
`
`option in those diabetes patients who have developed complications, such as renal
`
`impairment.
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`20
`
`Moreover, it remains a need to provide prevention or reduction of risk for adverse effects
`
`associated with conventional antidiabetic therapies.
`
`The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26is a serine protease
`
`knownto lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins
`
`25
`
`having at their N-terminal end a prolin or alanin residue. Due to this property DPP-4 inhibitors
`
`interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are
`
`considered to be promising drugs for the treatment of diabetes mellitus.
`
`For example, DPP-4 inhibitors and their uses are disclosed in WO 2002/068420, WO
`
`30
`
`2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148,
`
`WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO
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`2006/027204, WO 2006/029769, WO2007/014886; WO 2004/050658, WO 2004/111051,
`
`WO 2005/058901, WO 2005/097798; WO 2006/068163, WO 2007/071738, WO
`
`2008/017670; WO 2007/128721, WO 2007/128724, WO 2007/128761, or WO 2009/121945.
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`35
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 7
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`Glucagon-like peptide-1 (GLP-1) is a hormon secreted from enteroendocrine L cells of the
`
`intestine in response to food. Exogenous GLP-1 administration at pharmacological doses
`
`results in effects that are beneficial for treating type 2 diabetes. However, native GLP-1 is
`
`subject to rapid enzymatic degradation. The action of GLP-1 is mediated through the GLP-1
`
`receptor (GLP-1R).
`
`In the monitoring of the treatment of diabetes mellitus the HbA1c value, the product of a non-
`
`enzymatic glycation of the haemoglobin B chain, is of exceptional importance. Asits
`
`formation depends essentially on the blood sugar level and the life time of the erythrocytes
`
`10
`
`the HbA‘1c in the sense of a "blood sugar memory"reflects the average blood sugar level of
`
`the preceding 4-12 weeks. Diabetic patients whose HbA1c level has been well controlled
`
`over a long time by moreintensive diabetes treatment (i.e. < 6.5 % of the total haemoglobin
`
`in the sample) are significantly better protected from diabetic microangiopathy. The available
`
`treatments for diabetes can give the diabetic an average improvement in their HbA1c level of
`
`15
`
`the order of 1.0 — 1.5 %. This reduction in the HbA1C level is not sufficient in all diabetics to
`
`bring them into the desired target range of < 7.0 %, preferably < 6.5 % and more preferably <
`
`6 % HbA‘c.
`
`Within the meaning ofthis invention, inadequate orinsufficient glycemic control means in
`
`20
`
`particular a condition wherein patients show HbA1c values above 6.5%, in particular above
`
`7.0%, even more preferably above 7.5%, especially above 8%. An embodiment of patients
`
`with inadequate or insufficient glycemic control include, without being limited to, patients
`
`having a HbA‘1c value from 7.5 to 10% (or, in another embodiment, from 7.5 to 11%). A
`
`special sub-embodiment of inadequately controlled patients refers to patients with poor
`
`25
`
`glycemic control including, without being limited, patients having a HbA1c value = 9%.
`
`Within glycemic control, in addition to improvementof the HbA1c level, other recommended
`
`therapeutic goals for type 2 diabetes mellitus patients are improvement of fasting plasma
`
`glucose (FPG) and of postprandial plasma glucose (PPG) levels to normal or as near normal
`
`30
`
`as possible. Recommendeddesired target ranges of preprandial (fasting) plasma glucose
`
`are 70-130 mg/dL (or 90-130 mg/dL) or <110 mg/dL, and of two-hour postprandial plasma
`
`glucose are <180 mg/dL or <140 mg/dL.
`
`In one embodiment, diabetes patients within the meaning of this invention may include
`
`35
`
`patients who have not previously been treated with an antidiabetic drug (drug-naive
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 8
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 8
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`-8-
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`patients). Thus, in an embodiment, the therapies described herein may be used in naive
`
`patients. In another embodiment, diabetes patients within the meaning ofthis invention may
`
`include patients with advancedor late stage type 2 diabetes mellitus (including patients with
`
`failure to conventional antidiabetic therapy), such as e.g. patients with inadequate glycemic
`
`control on one, two or more conventional oral and/or non-oral antidiabetic drugs as defined
`
`herein, such as e.g. patients with insufficient glycemic control despite (mono-)therapy with
`
`metformin, a thiazolidinedione (particularly pioglitazone), a sulphonylurea, a glinide, GLP-1 or
`
`GLP-1 analogue, insulin or insulin analogue, or an a-glucosidaseinhibitor, or despite dual
`
`combination therapy with metformin/sulphonylurea, metformin/thiazolidinedione (particularly
`
`10
`
`pioglitazone), metformin/insulin, pioglitazone/sulphonylurea, pioglitazone/insulin, or
`
`sulphonylurea/insulin. Thus, in an embodiment, the therapies described herein may be used
`
`in patients experienced with therapy, e.g. with conventional oral and/or non-oral antidiabetic
`
`mono- or dual or triple combination medication as mentioned herein.
`
`15
`
`A further embodiment of diabetic patients within the meaning of this invention refers to
`
`patients ineligible for metformin therapy including
`
`- patients for whom metformin therapy is contraindicated, e.g. patients having one or more
`
`contraindications against metformin therapy according to label, such as for example patients
`
`with at least one contraindication selected from:
`
`20
`
`renal disease, renal impairment or renal dysfunction (e.g., as specified by product
`
`information of locally approved metformin),
`
`dehydration,
`
`unstable or acute congestive heart failure,
`
`acute or chronic metabolic acidosis, and
`
`25
`
`hereditary galactose intolerance;
`
`and
`
`- patients who suffer from one or more intolerable side effects attributed to metformin,
`
`particularly gastrointestinal side effects associated with metformin, such as for example
`
`patients suffering from at least one gastrointestinal side effect selected from:
`
`30
`
`nausea,
`
`vomiting,
`
`diarrhoea,
`
`intestinal gas, and
`
`severe abdominal discomfort.
`
`35
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 9
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`-9-
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`A further embodiment of the diabetes patients which may be amenable to the therapies of
`
`this invention may include, without being limited, those diabetes patients for whom normal
`
`metformin therapy is not appropriate, such as e.g. those diabetes patients who need reduced
`
`dose metformin therapy due to reduced tolerability, intolerability or contraindication against
`
`metformin or due to (mildly) impaired/reduced renal function (including elderly patients, such
`
`as e.g. 2 60-65 years).
`
`A further embodiment of diabetic patients within the meaning of this invention refers to
`
`patients having renal disease, renal dysfunction, or insufficiency or impairment of renal
`
`10
`
`function (including mild, moderate and severe renal impairment), e.g. as suggested by
`
`elevated serum creatinine levels (e.g. serum creatinine levels above the upper limit of normal
`
`for their age, e.g. = 130 - 150 mol/l, or = 1.5 mg/dl (= 136 umol/l) in men and 2 1.4 mg/dl (=
`
`124 umol/l) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR)
`
`< 30 - 60 ml/min).
`
`15
`
`In this context, for more detailed example, mild renal impairment may be e.g. suggested by a
`
`creatinine clearance of 50-80 ml/min (approximately corresponding to serum creatine levels
`
`of $1.7 mg/dL in men and $1.5 mg/dL in women); moderate renal impairment maybee.g.
`
`suggested by a creatinine clearance of 30-50 ml/min (approximately corresponding to serum
`
`20
`
`creatinine levels of >1.7 to $3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women); and severe
`
`renal impairment may be e.g. suggested by a creatinine clearance of < 30 ml/min
`
`(approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5
`
`mg/dL in women). Patients with end-stage renal disease require dialysis (e.g. hemodialysis or
`
`peritoneal dialysis).
`
`25
`
`For other more detailed example, patients with renal disease, renal dysfunction or renal
`
`impairment include patients with chronic renal insufficiency or impairment, which can be
`stratified according to glomerularfiltration rate (GFR, ml/min/1.73m’)into 5 disease stages:
`
`stage 1 characterized by normal GFR 2 90plus either persistent albuminuria or known
`
`30
`
`structural or hereditary renal disease; stage 2 characterized by mild reduction of GFR (GFR
`
`60-89) describing mild renal impairment; stage 3 characterized by moderate reduction of
`
`GFR (GFR 30-59) describing moderate renal impairment; stage 4 characterized by severe
`
`reduction of GFR (GFR 15-30) describing severe renal impairment; and terminal stage 5
`
`characterized by requiring dialysis or GFR < 15 describing established kidneyfailure (end-
`
`35
`
`stage renal disease, ESRD).
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 10
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 10
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`
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`WO 2011/138421
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`PCT/EP2011/057256
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`-10-
`
`Within the scope of the present invention it has now been found that certain DPP-4 inhibitors
`
`as defined herein as well as pharmaceutical combinations, compositions or combined uses
`
`according to this invention of these DPP-4 inhibitors and GLP-1 receptor agonists (e.g.
`
`exogenous GLP-1 or GLP-1 analogues) as defined herein have unexpected and particularly
`
`advantageous properties, which make them suitable for the purposeofthis invention and/or
`
`for fulfilling one or more of above needs.
`
`The present invention thus relates to a combination comprising a certain DPP-4 inhibitor
`
`10
`
`(particularly BI 1356) and a GLP-1 receptor agonist (e.g. exogenous GLP-1 or a GLP-1
`
`analogue), each as defined herein, particularly for simultaneous, separate or sequential use
`
`in the therapies described herein.
`
`The present invention further relates to a method for treating and/or preventing metabolic
`
`15
`
`diseases, especially type 2 diabetes mellitus, obesity and/or conditions related thereto (e.g.
`
`diabetic complications) comprising the combined (e.g. simultaneous, separate or sequential)
`
`administration of an effective amount of a GLP-1 receptor agonist (e.g. exogenous GLP-1 or
`
`a GLP-1 analogue) as defined herein and of an effective amount of a DPP-4 inhibitor as
`
`defined herein to the patient (particularly human patient) in need thereof, such as e.g a
`
`20
`
`patient as described herein.
`
`The present invention further relates to at least one of the following methods:
`
`- preventing, slowing the progression of, delaying or treating a metabolic disorder or
`
`disease, such as e.g. type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose
`
`25
`
`tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial
`
`hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia,
`
`hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic
`
`inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy,
`
`nephropathy, polycystic ovarian syndrome, and/or metabolic syndrome;
`
`30
`
`-
`
`improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial
`
`plasma glucose and/or of glycosylated hemoglobin HbA‘1c;
`
`- preventing, slowing, delaying or reversing progression from pre-diabetes, impaired
`
`glucosetolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or
`
`from metabolic syndrome to type 2 diabetes mellitus;
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 11
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 11
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`
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`WO 2011/138421
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`PCT/EP2011/057256
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`-11-
`
`- preventing, reducing the risk of, slowing the progression of, delaying or treating of
`
`complications of diabetes mellitus such as micro- and macrovascular diseases, such as
`
`nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy,
`
`learning or memory impairment, neurodegenerative or cognitive disorders, cardio- or
`
`cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis,
`
`hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome,
`
`unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease,
`
`cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis, and/or stroke;
`
`-
`
`reducing body weight and/or body fat and/or liver fat and/or intra-myocellular fat or
`
`10
`
`preventing an increase in body weight and/or body fat and/or liver fat and/or intra-
`
`myocellular fat or facilitating a reduction in body weight and/or body fat and/or liver fat
`
`and/or intra-myocellular fat;
`
`- preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or
`
`the decline of the functionality of pancreatic beta cells and/or for improving and/or
`
`15
`
`restoring the functionality of pancreatic beta cells and/or stimulating and/or restoring or
`
`protecting the functionality of pancreatic insulin secretion;
`
`- preventing, slowing, delaying or treating non alcoholic fatty liver disease (NAFLD)
`
`including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis
`
`(such as e.g. preventing, slowing the progression, delaying, attenuating, treating or
`
`20
`
`reversing hepatic steatosis, (hepatic) inflammation and/or an abnormal accumulation of
`
`liver fat);
`
`- preventing, slowing the progression of, delaying or treating type 2 diabetes with failure to
`
`conventional antidiabetic mono- or combination therapy;
`
`achieving a reduction in the dose of conventional antidiabetic medication required for
`
`adequate therapeutic effect:
`
`reducing the risk for adverse effects associated with conventional antidiabetic medication;
`
`25
`
`-
`
`-
`
`and/or
`
`- maintaining and/or improving the insulin sensitivity and/or for treating or preventing
`
`hyperinsulinemia and/or insulin resistance;
`
`30
`
`in a patient in need thereof (such as e.g a patient as described herein), said method
`
`comprising combined (e.g. simultaneous, separate or sequential) administration of a DPP-
`
`4 inhibitor as defined herein and a GLP-1 receptor agonist as defined herein.
`
`In addition, the present invention relates to the combination according to this invention
`
`35
`
`comprising a DPP-4 inhibitor as defined herein and a GLP-1 receptor agonist as defined
`
`SUN EXHIBIT 1011, IPR2024-00107, PAGE 12
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`SUN EXHIBIT 1011, IPR2024-00107, PAGE 12
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`
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`WO 2011/138421
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`PCT/EP2011/057256
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`-12-
`
`herein for use in treating and/or preventing (including slowing the progession or delaying the
`
`onset) of metabolic diseases as defined herein, particularly diabetes (especially type 2
`
`diabetes and obesity, or conditions related thereto, including diabetic complications),
`
`optionally in combination with one or more other therapeutic agents as described herein.
`
`In addition, the present invention relates to the use of a combination according to this
`
`invention comprising a DPP-4 inhibitor as defined herein and a GLP-1 receptor agonist as
`
`