Current Opinion in Molecular Therapeutics 2010 12(6):790-797
`
` Thomson Reuters (Scientific) Ltd ISSN 2040-3445
`
`DRUG PROFILE
`
`Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody
`fragment for the potential treatment of type 2 diabetes
`Espen Jimenez-Solem1, Mette H Rasmussen2, Mikkel Christensen3 & Filip K Knop3*
`
`Addresses
`1University of Copenhagen, Bispebjerg Hospital, Department of Clinical Pharmacology,
`Tagensvej 20, 2200 Copenhagen, Denmark
`
`2University of Copenhagen, Bispebjerg Hospital, Department of General Practice,
`Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
`
`3University of Copenhagen, Gentofte Hospital, Department of Internal Medicine F,
`Niels Andersens Vej 65, 2900 Hellerup, Denmark
`Email: filipknop@dadlnet.dk
`
`*To whom correspondence should be addressed
`
`Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment
`of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby
`protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. In vitro and in vivo studies on T2DM models demonstrated
`glucose-dependent insulin secretion stimulation. Pharmacokinetic studies demonstrated a t1/2 in humans of up to 90 h, making
`dulaglutide an ideal candidate for once-weekly dosing. Clinical trials suggest that dulaglutide reduces plasma glucose, and has an
`insulinotropic effect increasing insulin and C-peptide levels. Two phase II clinical trials demonstrated a dose-dependent reduction in
`glycated hemoglobin (HbA1c) of up to 1.52% compared with placebo. Side effects associated with dulaglutide administration were
`mainly gastrointestinal. To date, there have been no reports on the formation of antibodies against dulaglutide, but, clearly, long-term
`data will be needed to asses this and other possible side effects. The results of several phase III clinical trials are awaited for
`clarification of the expected effects on HbA1c and body weight. If dulaglutide possesses similar efficacy to other GLP-1 analogs, the
`once-weekly treatment will most likely be welcomed by patients with T2DM.
`
`Introduction
`In 2000, an estimated 171 million people worldwide
`had diabetes (all types). This igure is expected to
`increase by 144% to 366 million by 2030, as a result of
`increasing
`longevity, obesity and sedentary
`lifestyle
`[880516]. The most common
`form of diabetes
`is
`type 2 diabetes mellitus (T2DM), which is characterized
`by two main physiological defects: β-cell dysfunction
`and insulin resistance [995537], [995560]. Additionally,
`T2DM
`is characterized by
`fasting and postprandial
`hyperglucagonemia contributing
`to
`the hyperglycemic
`state of
`the patients via glucagon-induced hepatic
`glucose production. It
`is evident
`that T2DM
`is a
`progressive disease with an almost linear decline in β-cell
`function over time [995565]. Consequently, the current
`treatment paradigm aims to counteract the progressive
`deterioration in blood glucose homeostasis.
`include
`The classical oral antidiabetic drugs (OADs)
`insulin sensitizers, such as biguanides (eg, metformin)
`and thiazolidinediones (TZDs; eg, pioglitazone), insulin
`secretagogs, such as sulfonylureas (SUs; eg, glibenclamide)
`and meglitinides (eg, repaglinide), or drugs that delay
`glucose absorption
`through gut enzyme
`inhibition,
`
`Therapeutic Dulaglutide
`
`Originator Eli Lilly
`
`Status Phase III Clinical
`
`Indication Type 2 diabetes mellitus
`
`Actions Glucagon-like peptide-1 analog, Glucose-lowering agent
`
`Technologies Antibody fragment, Biological therapeutic, Protein
`fusion, Subcutaneous formulation
`
`Synonym LY-2189265
`
`such as acarbose. These medications enable modest
`reductions of glycated hemoglobin (HbA1c), usually
`between 0.5 and 1.5%, but are not able to correct either
`the impairment or the progressive decline of β-cell function
`[995569]. Therefore, regardless of optimal treatment, the
`endogenous insulin response becomes attenuated, and,
`in later stages of disease, lost, necessitating exogenous
`insulin replacement [931356]. It is currently believed
`that treatments that preserve or improve β-cell function
`may halt or delay disease progression in T2DM, thereby
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`insulin
`for
`the need
`delaying or even preventing
`therapy [995571]. Medications that are able to address
`cardiovascular risk factors, as well as provide glycemic
`control and preserve or improve β-cell function, thereby
`possibly halting or delaying disease progression, are
`highly anticipated [995571].
`The scientiic knowledge regarding optimal HbA1c levels
`has been recently complicated by the publication of
`mega trials demonstrating limitations to the paradigm
`of an overzealous glucose lowering strategy [1048568],
`[1147074],
`[1147078]. However,
`because
`of
`the
`long-standing evidence
`for an association between
`poor glycemic control and long-term diabetes-related
`complications, the overall scientiic consensus and major
`guidelines still advocate intensiication of treatment to
`maintain a HbA1c level of < 7.0% [996028]. The majority
`of patients fail to achieve this target, as exempliied in a
`recent trial in the US, which demonstrated that more
`than half of patients with diabetes did not meet a target
`HbA1c level of < 7.0% [996031]. This may, in part,
`be a result of reluctance on the part of physicians to
`prescribe
`therapies with
`unwanted
`side
`effects;
`hypoglycemia, a common side effect of insulin and also
`frequently associated with SUs, may be of particular
`concern. Diabetes is a complex disease to manage and
`primary care physicians rate diabetes as harder to treat
`than other common diseases [996035]. Another limiting
`factor to treatment may be the patient's own acceptance
`of a prescribed regimen. Common barriers to patient
`adherence
`include concern about unwanted weight
`gain [996037],
`fear of hypoglycemia and perceived
`inconvenience
`[996040],
`[996603], which may all
`indirectly undermine glycemic control if the prescribed
`therapy is not followed.
`is
`insulin secretion
`Under physiological conditions,
`including
`the
`incretin
`controlled by several
`factors
`hormone glucagon-like peptide-1 (GLP-1). This hormone,
`secreted by endocrine cells in the intestine, stimulates
`glucose-dependent insulin secretion and accounts for a
`considerable part of the insulin response to glucose
`[827063], [996043], [1147079]. The physiological effects
`of GLP-1 are mediated by a G-protein-coupled receptor
`[996045], which is widely distributed across different
`tissues. As a result, the peripheral and central nervous
`systems, heart, stomach,
`lungs,
`intestines, pituitary,
`endothelium, kidneys and pancreas are all affected by
`GLP-1 [827063], [996047]. In addition to its incretin
`effect, GLP-1 exerts several effects
`that are also
`potentially beneicial in the treatment of T2DM. These
`include preservation of β-cell mass [439499], [475556],
`[996049], potentiation of glucose-induced suppression
`from pancreatic a-cell, a
`of glucagon
`secretion
`protective effect on the cardiovascular system [580626],
`[996071], delayed gastric emptying and an increase in
`the feeling of satiety [996074]; the latter two factors
`can contribute to a decreased energy intake.
`The early established role of GLP-1 in glucose homeostasis
`prompted research into its potential for therapeutic use
`in T2DM [874585], [875837]. It is noteworthy that in
`
`Dulaglutide Jimenez-Solem et al 791
`
`patients with T2DM, despite a frequently impaired secretion
`of GLP-1 [875837], [996163], [996169], the insulinotropic
`effect is preserved [931364]. This established GLP-1 as
`a therapeutic candidate for the treatment of T2DM, and
`subsequent trials have demonstrated that exogenous
`native GLP-1 normalizes the insulin response in individuals
`with impaired glucose tolerance [996079] and decreases
`blood glucose levels in patients with T2DM [475562],
`[760698].
`While native GLP-1 offers signiicant beneits for patients
`with T2DM, its rapid breakdown by the enzyme dipeptidyl
`peptidase 4 (DPP-4) incurs the critical disadvantage of a
`short half-life
`(1
`to 2 min)
`following
`intravenous
`administration [996173]; thus, native GLP-1 would need
`to be continually infused for effective therapy. To circumvent
`this physiological degradation, DPP-4-resistant GLP-1
`analogs have been developed. Two such compounds are
`currently on the market: exenatide, a synthetic version
`of exendin-4(1-39), which is a hormone isolated from
`the saliva of the Gila monster lizard [996232], and
`liraglutide, an acylated GLP-1 analog with 97% amino acid
`sequence homology to endogenous human GLP-1(7-37)
`[1070808]. However, many more agents are in phase II
`or III clinical development [1147081].
`The focus of this review is dulaglutide (LY-2189265), a
`novel, long-acting GLP-1 analog, being developed by
`Eli Lilly for the treatment of T2DM. Dulaglutide consists
`of a DPP-4–protected GLP-1 analog covalently linked to
`an Fc fragment of human IgG4, thereby increasing its
`duration of pharmacological activity. The irst phase III
`clinical trials of dulaglutide were initiated in early 2008
`[970293].
`
`Synthesis and SAR
`Dulaglutide comprises a DPP-4-protected GLP-1(7-37)
`analog fused to a modiied IgG4 Fc fragment [1100363].
`Initial studies using DPP-4-protected GLP-1 fused to
`IgG1 demonstrated signiicantly reduced in vitro activity
`compared with
`free DPP-4-protected GLP-1. Linker
`sequences between the C-terminus of the GLP-1 analog
`and the N-terminus of the Ig molecule were assessed
`in an attempt to
`improve activity, and IgG1 was
`replaced with a modiied IgG4 (Phe234Ala and Leu235Ala to
`reduce interaction with high-afinity Fc receptors, and
`Ser228Pro to eliminate half-antibody formation) to reduce
`the potential of complement- and/or antibody-dependent
`cell-mediated cytotoxicity. An Arg36Gly mutation
`in
`GLP-1 was introduced to de-immunize the fusion protein
`and the C-terminal lysine of the IgG4-Fc was removed.
`Dulaglutide exhibited 4-fold greater
`in vitro activity
`than the free DPP-4-protected GLP-1. The GLP-1-Fc fusion
`proteins used in these studies were expressed from
`HEK293-EBNA cells [1100363].
`
`Preclinical development
`In vitro
`Isolated rat islets were used to measure the effect
`of dulaglutide on glucose-induced
`insulin secretion
`[1100363]. At high glucose levels (16.8 mM) the insulin
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`
`secretion was enhanced 2.5- to 3-fold by the addition
`of 3 or 30 nM dulaglutide to the extracellular medium.
`No enhancement was observed at low glucose levels
`(2.8 mM). In comparison, human GLP-1 (3 nM) caused a
`4-fold increase in insulin secretion at 16.8 mM glucose.
`At 2.7 nM dulaglutide, half-maximal stimulation of
`insulin secretion was observed, and the maximal 4-fold
`stimulation was observed with 300 nM dulaglutide. The
`addition of the GLP-1 receptor antagonist exendin(9-39)
`(1 µM) to the medium reversed the effects of dulaglutide
`on insulin secretion. In islets isolated from cynomolgus
`monkeys, dulaglutide increased insulin secretion in a
`concentration-dependent manner at high concentrations
`of glucose [1100363].
`
`In vivo
`
`Dose-dependent increases in glucose-dependent insulin
`secretion were demonstrated 24 h after a single dose
`of dulaglutide (0.3, 1, 3 or 30 nmol/kg sc) in conscious
`rats receiving a graded glucose infusion. However, only
`the 3- and 30-nmol/kg doses achieved statistically
`signiicant (p < 0.05) increases in insulin secretion (up to
`4-fold) compared with vehicle [1100363].
`Insulin secretion in response to graded glucose infusion
`was evaluated 1, 5 and 7 days after a single dose of
`dulaglutide (1.7 nmol/kg sc) to cynomolgus monkeys
`[1100363]. Plasma concentrations of dulaglutide remained
`detectable
`throughout
`the 7 days.
`Insulin
`(2-fold
`versus vehicle; p < 0.0001) and C-peptide levels were
`signiicantly enhanced during the 7-day period, whereas
`glucose, GLP-1 and glucagon levels were unaffected.
`Multiple dosing of dulaglutide (1.7 nmol/kg sc, qw for
`4 weeks) before graded glucose infusion (4 days after the
`last dose) was also assessed in cynomolgus monkeys.
`Progressively
`increasing
`glucose-stimulated
`insulin
`release (2-fold versus vehicle; p < 0.0002) and C-peptide
`levels were observed following the glucose infusion.
`Triglyceride
`levels were
`reduced, but glucose and
`glucagon levels remained unaltered [1100363].
`In 5-week-old diabetic (db/db) mice treated with dulaglutide
`(10 nmol/kg sc, biw for 4 weeks), plasma glucose levels
`were consistently decreased
`throughout
`the study
`period (p < 0.001 versus vehicle); treated mice also
`exhibited a small, but signiicant, reduction in body
`mass versus vehicle (body mass = 35.5 versus 38.5 g;
`p < 0.02) [1100363].
`
`Toxicity
`At the time of publication, toxicity data were not available.
`
`Metabolism and pharmacokinetics
`The pharmacokinetic proile of single-dose dulaglutide
`(0.1 mg/kg sc) was assessed in rats and cynomolgus
`monkeys. In rats and monkeys respectively, Cmax values
`were 179.7 and 292.2 ng/ml, Tmax values were 24.0 and
`16.7 h, AUC0-∞ values were 10,537 and 15,207 ng/ml·h,
`t1/2 values were 38.2 and 51.6 h, clearance was 9.6 and
`
`7.3 ml/h/kg, and the volume of distribution was 525.0
`and 557.5 ml/kg [1100363].
`The pharmacokinetics of dulaglutide (0.1 to 12 mg sc;
`administered ≥ 3 weeks apart) were analyzed in healthy
`volunteers (n = 20). The t1/2 value of dulaglutide was
`~ 90 h and the Tmax value was between 24 and 48 h.
`When the dose was doubled, Cmax and AUC0-∞ of plasma
`dulaglutide increased by 1.84- and 1.88-fold, respectively,
`suggesting
`linear kinetics
`[1013502],
`[1087432].
`In
`patients (n = 43) with T2DM, dulaglutide (0.05 to
`8 mg sc, qw) had a t1/2 value of ~ 95 h [1087431],
`[1087438].
`
`Clinical development
`Phase I
`In a randomized, double-blind, placebo-controlled, three-
`period, crossover, single-center clinical trial, the safety,
`tolerability, pharmacokinetics and insulinotropic activity
`of escalating single doses of dulaglutide (0.1 to 12 mg sc;
`administered ≥ 3 weeks apart) were analyzed in healthy
`volunteers (n = 20). Compared with placebo, there
`was a glucose-dependent increase in insulin secretion
`after graded glucose infusion, and a suppression of
`plasma glucose after an oral glucose tolerance test at
`all doses [1013502], [1087432].
`In an open-label, parallel clinical trial, the effects of
`dulaglutide (1 or 3 mg sc, qw for 4 weeks) on gastric
`emptying were assessed in healthy volunteers (n = 30)
`using paracetamol (1 g po) pharmacokinetics as a probe.
`Both the 1- and 3-mg doses of dulaglutide caused a
`reduction in paracetamol Cmax (36 and 50%, respectively)
`and a delay in Tmax (1 and 2 h, respectively), indicating a
`delay in gastric emptying; this was only observed after
`the irst dose of dulaglutide and not at steady-state. The
`body mass of volunteers was also signiicantly decreased
`by 1.4 and 2.4 kg from baseline in the 1- and 3-mg dose
`groups, respectively [1109660].
`The effects of dulaglutide (1.5 mg sc, qw for 4 weeks) on
`gastric emptying would also be assessed by scintigraphy
`in a phase I, randomized, double-blind, placebo-controlled
`clinical trial (ClinicalTrials.gov identiier: NCT01215968).
`At the time of publication, patients (estimated n = 40)
`with T2DM were being recruited to this trial.
`
`Phase II
`
`A double-blind, placebo-controlled, parallel group, 5-week
`clinical trial assessed the effects of dulaglutide (0.05 to
`8 mg sc, qw) in patients (n = 43) with T2DM. Statistically
`signiicant decreases in HbA1c (-0.69 to -1.34%) were
`observed at all dose levels. Increases in insulin and
`C-peptide AUC values were also observed, indicating an
`insulinotropic effect. Fasting and postprandial plasma
`glucose excursions were signiicantly
`reduced with
`dulaglutide doses ≥ 1 mg. At dulaglutide doses ≥ 5 mg,
`statistically signiicant effects on gastric emptying after
`the irst dose and weight loss after the last dose were
`observed [1087431], [1087438].
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`randomized, double-blinded, placebo-
`II,
`A phase
`controlled, parallel assignment, multicenter clinical trial
`(EGO; NCT00630825) assessed the safety and eficacy of
`dulaglutide
`in patients (n = 262) with uncontrolled
`T2DM (baseline HbA1c = 8.2%) and a BMI of 33.9 kg/m2.
`Patients were randomized into three dulaglutide groups
`or a matching placebo. The dulaglutide groups were:
`0.5 mg (sc, qw) for 4 weeks titrated to 1.0 mg (sc, qw)
`for 12 weeks, 1.0 mg (sc, qw) for 16 weeks, or 1.0 mg
`(sc, qw) for 4 weeks titrated to 2.0 mg (sc, qw) for
`12 weeks [1016672], [1087434], [1087444], [1109617],
`[1122363], [1140475]. At 16 weeks, the mean reduction
`from baseline in HbA1c was -1.28, -1.29 and -1.52%
`in the 0.5/1.0-, 1.0/1.0- and 1.0/2.0-mg dose groups,
`respectively,
`compared with
`-0.27%
`for placebo
`(p < 0.001). Reductions were also observed in fasting
`plasma glucose (-2.09, -2.04 and -2.64 versus -0.49 mm;
`p < 0.001), solid mixed meal test glucose excursions
`(30.71, 32.21 and 28.24 versus 36.36 mM∙h; p < 0.001)
`and body mass (-1.58, -1.40 and -2.51 versus -0.07 kg;
`p < 0.05) [1016672], [1087444]. β-cell function was
`also signiicantly increased compared with placebo, as
`assessed by
`the homeostatic model assessment of
`β-cell function (HOMA%B: 39.20, 44.26 and 45.61 versus
`1.04%; p < 0.05) [1087444].
`In addition, the impact of Hispanic ethnicity was assessed
`[1109617], [1122363], [1140475]. At baseline, HbA1c
`levels were signiicantly greater (p = 0.006) in Hispanic
`patients (8.4%) compared with non-Hispanic Caucasian
`patients (8.1%); the decrease in HbA1c at week 16 was
`also greater in Hispanic patients (-1.5 versus -1.1%;
`p = 0.02). Furthermore, the reduction in postprandial
`glucose excursion was signiicantly greater in Hispanic
`patients (-2.8 versus -0.5 mM∙h; p = 0.003), although fasting
`plasma glucose, insulin levels and β-cell function were
`not affected by ethnicity [1109617], [1122363], [1140475].
`Further to these trials, additional phase II, randomized,
`double-blind,
`placebo-controlled, multicenter
`clinical
`trials of dulaglutide were listed in the NIH clinical trial
`registry at the time of publication. Trial NCT00791479
`assessed
`the dose-dependent effects of dulaglutide
`(0.1, 0.5, 1.0 and 1.5 mg sc, qw for up to 12 weeks)
`on glycemic control in patients (estimated n = 168)
`with T2DM;
`this
`trial had been completed. Trial
`NCT01001104 was
`assessing
`the
`dose-response
`characteristics of dulaglutide (0.25, 0.50 and 0.75 mg sc,
`qw for up to 12 weeks) on HbA1c in Japanese patients
`(estimated n = 144) with inadequately controlled T2DM
`who were taking no more than one OAD (not DPP-4
`inhibitors); patient recruitment to this trial was complete,
`although the trial was still ongoing. Data were not
`available from either trial.
`
`Phase III
`
`At the time of publication, a phase II/III, randomized,
`double-blind,
`placebo-controlled, multicenter
`clinical
`trial (NCT00734474) comparing dulaglutide (0.25, 0.5,
`0.75, 1.0, 1.5, 2.0 and 3.00 mg sc, qw) with the DPP-4
`inhibitor sitagliptin (100 mg po, qd) was ongoing in
`
`Dulaglutide Jimenez-Solem et al 793
`
`patients (estimated n = 1566) with T2DM. Treatment
`would last for 2 years and the primary outcome was
`HbA1c change from baseline to 12 months.
`Additionally, Eli Lilly has
`initiated a program of
`phase III, randomized, multicenter clinical trials known as
`AWARD. The placebo-controlled, double-blind AWARD-1
`(NCT01064687) clinical
`trial was
`recruiting patients
`(estimated n = 980) with T2DM inadequately controlled
`with metformin and pioglitazone. This
`trial would
`determine the eficacy of dulaglutide (0.75 and 1.5 mg sc, qw),
`compared with
`placebo
`or
`exenatide,
`as
`an
`add-on to baseline therapy. The open-label AWARD-2
`(NCT01075282) clinical
`trial was
`recruiting patients
`(estimated n = 837) with T2DM inadequately controlled
`with metformin and the SU agent glimepiride. The
`trial would compare
`the eficacy and safety of
`dulaglutide (0.75 and 1.5 mg sc, qw), compared with
`insulin glargine, as an add-on to baseline therapy. The
`placebo-controlled, double-blind AWARD-3 (NCT01126580)
`clinical trial was recruiting patients (estimated n = 753)
`with T2DM. The trial would compare the eficacy and
`safety of dulaglutide (0.75 and 1.5 mg/kg sc, qw) with
`metformin (1500 to 2000 mg/day po). The open-label
`AWARD-4 (NCT01191268) clinical
`trial would
`recruit
`patients (estimated n = 837) with T2DM. The trial would
`compare the eficacy and safety of dulaglutide (0.75
`and 1.5 mg/kg sc, qw) with insulin glargine, both in
`combination with insulin lispro.
`
`Side effects and contraindications
`In
`the
`trial evaluating single escalating doses of
`dulaglutide (0.1 to 12 mg sc) in healthy volunteers, the
`most frequent adverse event was dyspepsia. Statistically
`signiicant
`increases
`in supine heart rate at doses
`≥ 0.3 mg and in supine diastolic blood pressure at
`doses ≥ 1 mg compared with placebo were noted.
`Dose-dependent increases in the rates of headache,
`injection-site irritation, nausea and vomiting were also
`reported. Importantly, hypoglycemia or antibodies against
`dulaglutide were not reported [1013502], [1087432].
`In the trial evaluating the effects of dulaglutide (1 or 3 mg)
`on gastric emptying
`in healthy volunteers, safety
`and
`tolerability were also assessed. Gastrointestinal
`disturbances were the most frequent adverse events.
`Furthermore, signiicant
`increases
`from baseline
`in
`pulse rate (7.8 and 9.6 bpm at 1 and 3 mg, respectively)
`and decreases from baseline in systolic blood pressure
`(4.1 and 7.7 mmHg at 1 and 3 mg, respectively) were
`also observed [1109660].
`In the 5-week trial of dulaglutide (0.05 to 8 mg sc, qw)
`in patients with T2DM, dulaglutide was generally well
`tolerated. Nausea, vomiting, headache and diarrhea
`were the most common adverse events. At the 5-mg
`dose, a statistically signiicant increase in heart rate was
`reported. Antibodies against dulaglutide were not
`detected [1087431], [1087438].
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`In the EGO trial in patients with T2DM, dulaglutide
`(1 mg for 16 weeks, 0.5 mg for 4 weeks titrated to
`1 mg for 12 weeks, or 1 mg for 4 weeks titrated to
`2 mg for 12 weeks; all sc qw) was generally well tolerated.
`The most common adverse events were nausea (13%),
`diarrhea
`(8.8%) and abdominal distension
`(8.0%).
`The frequency of hypoglycemic episodes did not differ
`among treatment groups [1016672], [1087444].
`Because of the effects on heart rate and blood pressure
`observed
`in
`the
`initial clinical
`trials, a phase
`II,
`randomized, double-blind, placebo-controlled, multicenter
`clinical trial (NCT01149421) was initiated to assess these
`parameters. Patients (estimated n = 693) with T2DM
`treated with one or more OAD were treated with
`dulaglutide (0.75 and 1.5 mg sc, qw) for up to 26 weeks.
`Inclusion criteria included HbA1c between 7 and 9.5%,
`blood pressure > 90/60 and < 140/90 mmHg, and
`BMI ≥ 23 kg/m2.
`
`Patent summary
`The genesis of dulaglutide appears to have come from
`the GLP-1
`fusion proteins
`claimed
`in Eli Lilly's
`WO-00246227, most
`likely protecting
`forms of
`the
`company's GLP-1 analog LY-548806 and involving some
`of the same inventors as listed on the product patent
`for dulaglutide. Although WO-00246227 has generic
`claims covering the GLP-1 analog and the peptide linker
`present in dulaglutide, the IgG4 Fc component does
`not have the amino acid substitutions present in the
`dulaglutide moiety that stabilize heavy chain dimer
`formation and eliminate their natural effector function.
`The irst
`two claims of WO-2005000892 describe
`dulaglutide, including its peptide linker. WO-2005000892
`is part of the WO-2004110472 family covering a whole
`range of Fc fragment fusion proteins including one based
`on FGF-21. The granted equivalents relating speciically
`to GLP-1
`fusion proteins are EA-00008831 and
`EP-01641483 both expiring in June 2024, and US-07452966
`expiring in July 2024 after a short patent term extension.
`Further patenting by Eli Lilly has concentrated on
`providing more stable
`formulations
`for dulaglutide.
`WO-2006068910 claims a buffer solution
`for
`the
`protein, which gives greater resistance to protease, and
`WO-2009009562 claims a solution giving greater physical
`stability. Only the earlier of the two applications has had
`any granted applications, by the European and Eurasian
`authorities. There
`is also WO-2009020802 claiming
`combinations of dulaglutide or LY-548806 with FGF-21
`for the potential treatment of obesity.
`The only patenting on dulaglutide by third parties has
`been by Amylin Pharmaceuticals, Eli Lilly's partner for
`the development and
`launch of exenatide. Amylin's
`WO-2009143014 claims a cell-based assay for measuring
`the activity of multiple GLP-1 agonists,
`including
`dulaglutide and exenatide.
`
`Current opinion
`Incretin-based therapies represent an important addition
`to the conventional antidiabetic treatments by targeting
`several key metabolic defects in T2DM. Even if the
`promising effects on β-cell proliferation and preservation
`observed in preclinical studies are not replicated in the
`clinic, the GLP-1 analogs as a class still represent strong
`drug candidates. Firstly,
`they represent a versatile
`physiological approach, targeting both pancreatic a- and β-cell
`dysfunction and obesity, combined with improvements
`in glycemic indices that are comparable with traditional
`OADs. Secondly, severe
`limitations associated with
`existing therapies, including the risk of hypoglycemia
`(as observed with insulin and SUs) and unsuitability for
`patients with renal impairment (metformin) or signiicant
`cardiovascular disease
`(TZDs),
`creates opportunity
`for incretin-based therapies in an expanding diabetic
`drug market. Thirdly, there are several potential future
`indications that may prove worthwhile to pursue, such
`as management of obesity, postmyocardial
`infarction
`size reduction [996601], adjunction to insulin therapy in
`patients with type 1 diabetes mellitus [996602] and,
`depending on the eventual trophic effects on β-cells,
`pancreatic islet transplantation patients.
`the GLP-1
`Regarding
`the eficacy and safety of
`analogs, there appears to be a class effect. The main
`difference between compounds appears to rely in the
`pharmacokinetic proile. In this regard, the relatively long
`t1/2 value of dulaglutide (~ 90 h) could prove to be a
`signiicant advantage. Clinical data suggests that a more
`stable pharmacokinetic proile (ie, a longer t1/2) leads
`to higher eficacy, and lower frequencies of nausea and
`vomiting [953142]. Furthermore, the beneits to patient
`convenience and compliance are obvious.
`There are also limitations to consider. Firstly, there is a
`general problem concerning gastrointestinal side effects,
`especially nausea. Even if the nausea and vomiting
`were more infrequent with dulaglutide (because of an
`increased t1/2) compared with some other GLP-1 analogs,
`its use will still be limited to patients who are able to
`manage these side effects and, for example, use them
`as a positive reinforcement strategy for weight loss.
`Ultimately,
`it appears that ~ 5% of patients with
`T2DM do not tolerate GLP-1 analogs currently on the
`market [976021], [996244], [996601]. Secondly,
`the
`consequences of antibody formation are not yet fully
`known. Evidence
`from clinical
`trials of exenatide
`suggests some signiicance with regard to glycemic
`control especially in patients exhibiting high antibody
`titers [996596]. Dulaglutide consists of GLP-1(7-37)
`covalently linked to an Fc fragment of human IgG4,
`thereby protecting it from DPP-4 cleavage and increasing
`its duration of pharmacological activity. One concern is
`that
`treating patients with engineered bioproducts
`could lead to the formation of antibodies against foreign
`epitopes. From the published data, it is not possible to
`ignore the potential formation of antidrug antibodies,
`which could lead to decreased eficacy of dulaglutide in
`
`MPI EXHIBIT 1029 PAGE 5
`
`MPI EXHIBIT 1029 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1029-0005
`
`

`

`Dulaglutide Jimenez-Solem et al 795
`
`is the
`isotope, which
`patient subgroups. The IgG4
`carrier protein for dulaglutide, has so far been unable
`to demonstrate that it activates complement in vitro
`[1147082]. However, further evaluation and long-term
`data,
`including measurements of anti-GLP-1-Fc titers
`in humans, are required. Thirdly, it is evident from
`studies of barriers to
`insulin therapy that
`injection
`therapy remains a signiicant concern for many patients
`and diabetes care providers [996040], [996603], which
`may
`limit
`the acceptance of dulaglutide. However,
`as hypoglycemia is also a major concern, it can be
`speculated that the
`low
`frequency of hypoglycemia,
`combined with weight loss and only once weekly dosing,
`could make dulaglutide more acceptable than insulin
`
`therapy.
`
`Demonstration of comparable eficacy (not only on
`HbA1c, but also on mortality and/or hard micro
`and/or macrovascular endpoints) and,
`in particular,
`long-term safety compared with other GLP-1 analogs,
`incretin enhancers (ie, DPP-4 inhibitors) or even other
`OADs will be of crucial importance in determining the
`role of dulaglutide. The
`incretin enhancers, which
`also
`increase
`levels of GLP-1 agonism,
`lack
`the
`weight-reducing capacity (albeit weight neutral) observed
`with GLP-1 analogs, but the lower incidence of nausea
`
`and the oral route of administration clearly favors the
`use of these agents as initial therapy.
`In conclusion, the GLP-1-Fc fusion protein dulaglutide is a
`new GLP-1 analog intended for once-weekly dosing with
`longer plasma residence than the native hormone. The
`pharmacokinetic proile is the main difference between
`dulaglutide and the other GLP-1 analogs. Conirmation
`that dulaglutide and other GLP-1 analogs can alter the
`natural course of diabetes is still awaited. With the
`present knowledge,
`the use
`in clinical practice of
`GLP-1 analogs is justiied by the evidence of improved
`postprandial and throughout-the-day glycemic control,
`resulting
`in placebo-corrected
`lowering of HbA1c by
`0.5 to 1.5%. The main limitations of the clinical use of
`GLP-1 analogs are the insuficient long-term safety and
`eficacy data, subcutaneous route of administration and
`the high treatment cost compared with the classical
`therapeutic agents. Consequently, a place for GLP-1
`analogs in endocrinologists' drug armamentaria appears
`certain, but with only minor differences in potency
`between the different GLP-1 analogs, head-to-head trials
`will be needed to determine the drug of choice. Lastly,
`the potential of GLP-1 analogs to reduce cardiovascular
`disease and
`increase
`lifespan among T2DM patients
`still needs to be conirmed in long-term clinical trials.
`
`Development status
`
`Developer
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Eli Lilly
`
`Country
`
`Canada
`
`Europe
`
`India
`
`South Korea
`
`Taiwan
`
`US
`
`South America
`
`Australia
`
`South Africa
`
`Puerto Rico
`
`Japan
`
`Status
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase III
`
`Phase II
`
`Indication
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Type 2 diabetes mellitus
`
`Date
`
`28-AUG-08
`
`28-AUG-08
`
`28-AUG-08
`
`28-AUG-08
`
`28-AUG-08
`
`28-AUG-08
`
`28-AUG-08
`
`23-FEB-10
`
`18-MAY-10
`
`18-MAY-10
`
`22-OCT-09
`
`Reference
`
`942857
`
`942857
`
`942857
`
`942857
`
`942857
`
`942857
`
`942857
`
`1088280
`
`1146159
`
`1146159
`
`1088285
`
`Associated pate