CJC-1131 ConjuChem
`Nick Giannoukakis
`
`Address
`University of Pittsburgh School of Medicine
`Diabetes Institute
`3460 Fifth Avenue
`Pittsburgh
`PA 15213
`USA
`Email: ngiann1@pitt.edu
`
`Current Opinion in Investigational Drugs 2003 4(10):1245-1249
` Current Drugs ISSN 1472-4472
`
`ConjuChem is developing CJC-1131, a drug affinity complex
`conjugate of glucagon-like peptide 1 for the potential treatment
`of type 2 diabetes. In August 2003, a phase I/II trial was
`completed and a phase II trial was expected to begin in October.
`
`Introduction
`The ever-increasing incidence of diabetes means that new
`therapies and approaches are needed to treat this disorder.
`Recent interest in bioactive peptides has spawned efforts
`culminating in the discovery of a class of proteins termed
`incretins [478031]. The production and release of these
`proteins, originally identified in the gut, is stimulated by
`insulin at physiological concentrations in the presence of
`elevated blood glucose concentrations. The prototype
`incretin of pharmaceutical interest is glucagon-like peptide
`(GLP)-1, produced from the endocrine L-cells of the gut in
`response to food intake [306812], [362275]. GLP-1 functions
`as an incretin hormone promoting insulin secretion, and its
`glucoregulation activity has led to its consideration as a
`potential therapeutic agent in the treatment of type 2
`diabetes. A number of studies have confirmed its potential
`as a glucoregulator and as an appetite regulator [233337],
`[306810], [478018], [478025], [478028]. The short duration of
`action of GLP-1 in vivo (due primarily to NH2-terminal
`cleavage and inactivation by dipeptidyl peptidase (DPP)-IV)
`[233314], [505939] has, however, precluded the maintenance
`of therapeutic levels by subcutaneous dosing, prompting the
`search for analogs with longer durations of action [439496],
`[478018], [478025], [478028].
`
`Injectable GLP-1 analogs enhance glucose-dependent insulin
`synthesis and secretion in the pancreas, increase peripheral
`glucose utilization and decrease insulin resistance, lower
`postprandial glucose spikes by slowing down gastric
`emptying, decrease glucagon production and hepatic
`glucose genesis, and act as β-cell growth factors [478018],
`[478025], [478028]. GLP-1 analogs have demonstrated very
`good safety profiles with few side effects compared with
`currently prescribed antidiabetic agents. Insulin secretion is
`only stimulated in the presence of hyperglycemia; therefore,
`the drugs have the potential to induce normoglycemia
`effectively. GLP-1 analogs appear to have positive effects on
`type 2 diabetes-related hyperlipidemia and may promote
`moderate weight loss. As mentioned, the promise of GLP-1
`analogs is counterbalanced by their limited serum half-life
`(approximately 5 min), which is due to the activity of
`peptidases [478018], [478025], [478028].
`
`
`
`1245
`
`Originator ConjuChem Inc
`
`Status Phase II Clinical
`
`Indications Non-insulin dependent diabetes
`
`Actions Glucagon-like peptide 1 agonist, Hypoglycemic
`agent, Insulin metabolism modulator
`
`Synonyms DAC:GLP-1
`
`CJC-1131 is a peptidase-resistant GLP-1 analog which
`selectively and covalently binds to serum albumin using
`drug affinity complex (DAC) technology developed by
`ConjuChem. This enables a long plasma elimination half-life
`of approximately 20 days. The DAC conjugates selectively
`with albumin, yet still retains full biological activity
`[374863]. CJC-1131 is thus expected to be as potent as the
`stabilized GLP-1 analog from which it was derived, and to
`retain the pharmacokinetic (PK) profile of the DAC
`conjugate [410194].
`
`Synthesis and SAR
`In order to circumvent the rapid cleavage of GLP-1 and thus
`prolong the in vivo half-life, amino acid substitutions can be
`made that reduce the affinity of GLP-1 for DPP-IV. In the
`case of this DAC-GLP-1 affinity complex, it was also
`important that CJC-1131 bound covalently to albumin. To
`achieve these effects, GLP-1 was subjected to a single amino
`acid substitution of L-Ala8 to D-Ala8 at position 2 and a Lys37
`addition to the C-terminus with selective attachment of a [2-
`[2-[2-maleimidopropionamido]ethoxy]ethoxy]acetamide
`to
`the ε amino group of Lys37 to create CJC-1131 [498249].
`
`CJC-1131 was produced using solid-phase peptide synthesis
`utilizing 9-fluorenylmethyloxycarbonyl chemistry. It binds
`selectively and irreversibly to Cys34 of circulating serum
`albumin. Albumin is known to exhibit a longer half-life in
`vivo (approximately 19 days in humans [240408]), which is
`much longer than the half-life of short regulatory peptides,
`such as GLP-1. In rodents, CJC-1131 bound purified human
`serum albumin with an efficiency of approximately 98%.
`The CJC-1131-albumin complex bound to the human GLP-1
`receptor with nanomolar affinity and stimulated cAMP
`production in human GLP-1 receptor-transfected CHO cells
`with near identical activity to native GLP-1 [454095].
`
`Preclinical Development
`In vitro the CJC-1131-albumin conjugate bound the GLP-1
`receptor and activated cAMP formation in heterologous
`fibroblasts expressing the GLP-1 receptor. The conjugate had
`a similar potency to native GLP-1, with EC50 values of 11 to
`13 and 13 nM, respectively. The displacement of [125I]GLP-1
`by native GLP-1 and CJC-1131 was also similar over a range
`of CJC-1131 concentrations, with Ki values of 5.16 and 12
`nM, respectively [498249].
`
`rodents
`in normal
`testing
`tolerance
`Oral glucose
`demonstrated that the ability of CJC-1131 to reduce blood
`glucose to normal following a glucose challenge was nearly
`
`MPI EXHIBIT 1110 PAGE 1
`
`

`

`(1.5 to 20.5 µg/kg) was administered to seven sequential
`cohorts of healthy male and female volunteers (five to six
`individuals per cohort) and revealed an average Tmax
`ranging from 23 to 76 h; Cmax and AUC∞ values suggested
`dose
`proportionality.
`CJC-1131
`exhibited
`a
`multicompartmental PK profile and the elimination half-
`life was generally slow, with group averages ranging from
`221 to 353 h [492844].
`
`Toxicity
`The toxicity of CJC-1131 was assessed using a range of drug
`doses considerably above the expected therapeutic dosing
`range for GLP-1 analogs in vivo. To assess the acute toxicity
`of CJC-1131, CD rats were administered single doses (0.75 to
`6 mg/kg sc); the drug was generally well tolerated, with
`decreased fecal output and decreased food and water
`consumption at all doses. A sub-chronic study in which CJC-
`1131 (0.12 to 3 mg/kg sc) was administered to rats every
`other day for 14 days gave similar results of decreased fecal
`output,
`reduced
`food
`intake and
`reduced water
`consumption compared with control animals. At 3 mg/kg,
`there was also a dose-dependent decrease in body weight
`gain. There were no other effects noted and minimal
`depletion of vacuoles in the cytoplasm of treated rats was
`observed. CJC-1131 was generally well tolerated at up to 3
`mg/kg [498254].
`
`The acute toxicity of CJC-1131 was also examined in beagle
`dogs following single subcutaneous doses (2 to 8 mg/kg).
`Clinical signs included decreased fecal output at doses of ≥ 4
`mg/kg and emesis at 8 mg/kg; however, there were no
`treatment-related effects on survival, physical examination,
`blood pressure, organ weights, clinical pathology or gross
`necroscopy. Decreased food consumption in both sexes and
`decreased water consumption in male rats was attributed to
`the pharmacological action of GLP-1. A sub-chronic study of
`CJC-1131 (0.25 to 4 mg/kg), administered every other day
`for 14 days, produced a slight dose-dependent weight loss
`and transient decreases in food and water consumption
`compared with
`control
`animals. Mild
`reversible
`inflammation at the injection site in all dose groups was also
`observed. The authors concluded that CJC-1131 was
`generally well tolerated in beagle dogs up to 4 mg/kg every
`other day [454061], [498258].
`
` A
`
`in rats
` 7-day repeat dose administration study
`demonstrated that CJC-1131 (2.4 mg/kg/day) was well
`tolerated, with decreases in food and water consumption
`and a 15 to 20% weight loss observed at the end of the
`study period. No abnormalities were detected in clinical
`pathology or biochemistry studies conducted during
`single- and multiple-dose regimens in either rats or dogs
`[454061].
`
`Clinical Development
`Phase I/II
`Four phase I/II trials have been initiated, investigating single-
`and multidose subcutaneous administration, single-dose
`intravenous administration and re-challenge subcutaneous
`administration, to evaluate the immunogenicity risk of CJC-
`1131 [488830], [493231].
`
`
`
`1246 Current Opinion in Investigational Drugs 2003 Vol 4 No 10
`
`identical to the parent GLP-1 peptide. In diabetic db/db mice,
`CJC-1131 normalized blood glucose for up to 24 h after an
`oral glucose load. Basal glucose levels were also stabilized at
`physiological levels for the same time period [410194]. Acute
`administration of CJC-1131 to normal Wistar rats or CD1
`mice during intraperitoneal or oral glucose challenge
`increased circulating
`insulin and decreased glycemic
`excursion. Long-term administration of CJC-1131
`to
`C57BL/6 mice lowered fasting and postprandial blood
`glucose over a 4-week period [454256]. CJC-1131 was
`inactive in GLP-1 receptor-deficient mice, yet significantly
`reduced glycemic excursion following oral glucose tolerance
`testing in db/db mice. Basal glucose and glycemic excursion
`remained reduced 12 h following CJC-1131 administration
`[454479].
`
`The safety and efficacy of CJC-1131, native GLP-1,
`metaclopramide and CCK-8 were compared in a study of
`gastric emptying in rats. CJC-1131 and GLP-1 significantly
`inhibited gastric emptying, whereas metaclopramide
`increased gastric emptying in control experiments. Single
`and escalating CJC-1131 dose regimens (0.2 to 8.0 mg/kg)
`produced a decrease in food and water intake and a
`decrease in fecal output, particularly at the higher doses
`[454061].
`
`The efficacy of CJC-1131 to treat severe experimental
`diabetes and insulin resistance was examined in 9-week-old
`db/db mice treated with CJC-1131 (25 µg) or saline twice
`daily for 4 weeks. Following oral and intraperitoneal glucose
`challenge, CJC-1131
`significantly
`reduced glycemic
`excursion (p < 0.01 to 0.05); however, levels of glucose-
`stimulated insulin were comparable in control- and CJC-
`1131-treated groups. CJC-1131 significantly reduced food
`intake in short-term, 24-h feeding studies in non-diabetic
`wild-type and db/db mice; however, over the 4-week study
`period, body weight was not significantly lowered. Weekly
`glucose levels were significantly lower in CJC-1131-treated
`wild-type and db/db mice over the study period and
`remained significantly lower at 1 week, but not 2 weeks
`following discontinuation of CJC-1131 administration. The
`levels of pancreatic pro-insulin mRNA transcripts were
`markedly increased in db/db mice treated with CJC-1131 for 4
`weeks, but returned to control
`levels 3 weeks after
`discontinuation of therapy [454479], [498249].
`
`Metabolism and Pharmacokinetics
`Human plasma stability experiments demonstrated that
`native GLP-1 is rapidly hydrolyzed to the inactive GLP-1(9-
`36) metabolite; in contrast, no metabolites were generated
`from CJC-1131. PK studies in rodents demonstrated that
`CJC-1131 binds selectively to rat albumin in vivo. GLP-1
`radioimmunoassays indicated a terminal half-life of 15 to 20
`h (consistent with that of the DAC conjugate), volume of
`distribution at steady state (Vdss) value of 150 ml/kg and
`systemic clearance rate of between 0.1 and 0.6 ml/min/kg,
`suggesting exclusion from the liver and kidney [410194],
`[454095].
`
` A
`
` phase I study was conducted to determine the PK profile
`of CJC-1131
`following administration of a
`single
`subcutaneous dose to healthy human volunteers. CJC-1131
`
`MPI EXHIBIT 1110 PAGE 2
`
`

`

`The multidose program was divided into two parts. In the
`first part, three cohorts consisting of both healthy volunteers
`and diabetic patients received 2, 4, 8 or 12 µg/kg/day of
`CJC-1131 for 14 days, and were then followed and assessed
`on safety, PK and preliminary efficacy parameters. The
`objective of the first part of the program was to build the
`plasma concentration of CJC-1131 to an efficacious level
`with minimal unwanted side effects. The second part of the
`study was aimed at determining the dosage required to
`maintain
`the efficacy with
`longer
`intervals between
`administrations [482594]. Patients (n = 9) received CJC-1131
`at 2, then 4, then 8 µg/kg/day, each for 3 days, followed by
`12 µg/kg/day for the next 11 days (ie, 20 days in total).
`Average mean daily glucose level and fasting glucose level
`were significantly reduced. Glucose normalization or near
`normalization was achieved in all patients in the cohort
`(both for the mean daily glucose level and the fasting
`glucose level); glucose excursions were also significantly
`reduced 7 days post-treatment. An average body-weight
`reduction of 3 kg occurred [502385].
`
`In the immunogenicity trial in healthy volunteers (n = 12)
`and diabetic patients (n = 21), the former were previously
`exposed to CJC-1131 and received two re-challenge doses
`of 2 µg/kg 6 weeks apart. Patients received the drug
`subcutaneously every day for up to 20 days and were
`monitored for up to 70 days after receiving their last dose.
`There were no signs of clinical immunogenicity, specific
`IgG or IgE antibodies, lymphocyte activation, nor change
`in plasma concentration (no neutralizing antibodies)
`[502385].
`
`The single-dose intravenous trial was designed to enroll
`type 2 diabetics (n = 30) in five cohorts of six patients each
`(five patients given CJC-1131 and one given placebo); each
`cohort was to receive an ascending dose (0.5, 1, 2, 4 or 8
`µg/kg), and safety, tolerability, PKs and preliminary
`efficacy were assessed. If successful, ConjuChem plans to
`follow this trial with a multidose protocol [488830].
`
`
`
`CJC-1131 Giannoukakis 1247
`
`Side Effects and Contraindications
`To date, the compound has been well tolerated in phase I/II
`trials. Side effects are consistent with other GLP-1
`compounds and included mild nausea and vomiting. In the
`multidose studies, where only two cases of nausea were
`reported
`in
`the patient population,
`this
`symptom
`substantially decreased or was eliminated with repeat
`administration of CJC-1131. After 14 consecutive days of
`administration, there were no clinical or biological signs of
`immunogenicity or irritation at the injection site [493231],
`[502385].
`
`Current Opinion
`The use of insulinotropic drugs currently available for the
`treatment of diabetes, mainly sulfonylureas, is hampered by
`two major drawbacks, the risk of hypoglycemia and the loss
`of efficacy after several years of treatment. In conjunction
`with the inhibitory effects on gastric emptying and glucagon
`secretion, GLP-1 receptor stimulation appears to be a
`promising new treatment strategy for type 2 diabetes. The
`preclinical and clinical data on CJC-1131 demonstrate
`efficacy and safety; however, results of phase II trials will be
`pivotal in determining the ultimate outcome and utility of
`this agent. A number of other competing GLP-1 analogs are
`also currently in development and include the acylated
`albumin-bound GLP-1 analog liraglutide (Novo Nordisk
`A/S) and two exendin-4 derivatives (exenatide; Eli Lilly &
`Co/Amylin Pharmaceuticals Inc and ZP-10; Aventis SA).
`Exendin-4 is more potent at lowering glucose concentrations
`than human GLP-1 and has a longer half-life; clinical studies
`with exendin-4 derivatives have demonstrated their good
`activity and safety profile. Marketing will be a crucial
`determinant of commercial success of these agents, in
`addition to the ability to co-administer such agents with
`other glucoregulatory compounds.
`
`Commercial Opinion
`In September 2003, analysts at Dlouhy Merchant predicted
`the launch of CJC-1131 in 2008, with 2008 sales of US $19.4
`million [506488].
`
`
`Development history
`In July 2002, a phase I trial was initiated, with data expected by the end of 2002 [457323]. However, in October 2002, the
`company revealed that results would not be disclosed until the first half of 2003, as a result of the need to manufacture a
`reformulated clinical batch of the compound to complete the trial [466084]. In February 2003, ConjuChem resolved the
`formulation issues and resumed its single-dose phase I trial [479418]. In March 2003, ConjuChem initiated the multidose
`component of a phase I/II trial [482594], and in May 2003 began the final stages of the study [488830]. In August 2003, a
`phase I/II trial was completed and a phase II trial was expected to begin in October of the same year [502385].
`
`
`Developer
`ConjuChem Inc
`
`Country
`Canada
`
`Status
`Phase II
`
`Indication
`Non-insulin dependent diabetes
`
`Date
`19-MAR-03
`
`ConjuChem Inc
`
`US
`
`Phase II
`
`Non-insulin dependent diabetes
`
`27-MAY-03
`
`Literature classifications
`Chemistry
`Study Type
`Synthesis
`and SAR.
`
`Result
`A single amino acid substitution of L-Ala8 to D-Ala8 at position 2 and a Lys37 addition to the C-terminus with
`selective attachment of a [2-[2-[2-maleimidopropionamido]ethoxy]ethoxy]acetamide to the ε amino group of
`Lys37 created CJC-1131.
`
`
`Reference
`498249
`
`Reference
`482594
`
`488830
`
`
`MPI EXHIBIT 1110 PAGE 3
`
`

`

`1248 Current Opinion in Investigational Drugs 2003 Vol 4 No 10
`
`Biology
`Study Type Effect Studied
`In vitro
`Binding and activation
`of the GLP-1 receptor.
`
`Experimental Model
`Heterologous fibroblasts
`transfected with GLP-1
`receptor cDNA.
`
`In vitro
`
`Binding specificity of
`conjugate.
`
`Radioligand competition
`assay.
`
`In vivo
`
`Efficacy in reducing
`glucose levels.
`
`Diabetic db/db mice.
`
`In vivo
`
`Efficacy on gastric
`emptying and effect on
`food intake.
`
`In vivo
`
`Safety and toxicity.
`
`Metabolism
`Study Type Effect Studied
`In vivo
`Pharmacokinetics.
`
`In vivo
`
`Pharmacokinetics.
`
`Single and escalating
`CJC-1131 dose
`regimens ranging from
`0.2 to 8.0 mg/kg in
`normal rats.
`
`Normal rats and dogs
`administered CJC-1131.
`
`Model Used
`Healthy human volunteers
`administered a single
`subcutaneous dose of
`CJC-1131 (1.5 to 20.5
`mg/kg) in seven
`sequential cohorts (five to
`six individuals per cohort).
`
`Rats administered CJC-
`1131.
`
`Clinical
`Study Type
`Safety and tolerability.
`
`Efficacy.
`
`Model Used
`Phase I/II trial of single, increasing CJC-
`1131 doses to establish the minimal
`tolerated dose.
`
`A multidose trial (n = 9) in which patients
`received escalating doses of CJC-1131
`(2 to 12 µg/kg/day sc).
`
`Immunogenicity.
`
`Phase I/II trial in type 2 diabetics and
`healthy volunteers (n = 33).
`
`
`Associated patent
`
`Title Insulinotropic peptides with improved stability and longer duration of
`action and their value in the treatment of diabetes.
`
`Assignee Conjuchem Inc/Benoit L'Archeveque
`
`Publication WO-00069911 23-NOV-00
`
`Priority US-00134406 17-MAY-99
`
`Inventors Bridon DP, L' Archeveque B, Ezrin AM, Holmes DL, Leblanc A, St Pierre S.
`
`Result
`The CJC-1131 albumin conjugate bound the GLP-1
`receptor and activated cAMP formation in
`heterologous fibroblasts expressing the GLP-1
`receptor. Native GLP-1 exhibited an EC50 of 13 nM
`compared with 11 to 13 nM for CJC-1131.
`
`The displacement of [125I]GLP-1 by native GLP-1
`versus CJC-1131 was similar over a range of CJC-
`1131 concentrations (Ki = 5.16 nM for native GLP-1
`versus 12 nM for CJC-1131).
`
`CJC-1131 was effective for up to 24 h in normalizing
`blood glucose after an oral glucose load. Basal
`glucose levels were also stabilized at physiological
`levels over the same period.
`
`CJC-1131 and GLP-1 significantly inhibited gastric
`emptying, decreased food and water intake, and
`decreased fecal output, particularly at the higher
`doses.
`
`Reference
`498249
`
`498249
`
`410194
`
`454061
`
`No abnormalities were detected in clinical pathology
`or biochemistry studies conducted during single- and
`multiple-dosing regimens in either rats or dogs.
`
`
`454061
`
`Result
`Average Tmax ranged from 23 to 76 h. The
`elimination half-life was generally slow, with group
`averages ranging from 221 to 353 h. Cmax and AUC∞
`values suggested dose-proportionality.
`
`Reference
`492844
`
`GLP-1 radioimmunoassays indicated a terminal half-
`life of 15 to 20 h, Vdss value of 50 ml/kg and systemic
`clearance rate of between 0.1 and 0.6 ml/min/kg.
`
`
`454095
`
`Result
`A single subcutaneous dose had an average half-
`life of 10 to 12 days and was well tolerated.
`
`Reference
`479418
`
`Average mean daily glucose levels and fasting
`glucose levels were significantly reduced. An
`average body weight reduction of 3 kg also
`occurred.
`
`There were no signs of clinical immunogenicity,
`specific IgG or IgE antibodies, lymphocyte
`activation, nor change in plasma concentration of
`CJC-1131.
`
`
`502385
`
`502385
`
`Associated references
`
`233314 Degradation of glucose-dependent insulinotropic polypeptide
`and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl
`peptidase IV. Kieffer TJ, McIntosh CH, Pederson RA ENDOCRINOLOGY
`1995 136 8 3585-3596
`
`233337 Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric
`and pancreatic functions in man. Wettergren A, Schjoldager B, Mortensen
`PE, Myhre J, Christiansen J, Holst JJ DIG DIS SCI 1993 38 4 665-673
`
`240408 Serum albumin. Peters T Jr ADV PROTEIN CHEM 1985 37 161-245
`
`
`
`MPI EXHIBIT 1110 PAGE 4
`
`

`

`306810 A role for glucagon-like peptide-1 in the central regulation of
`feeding. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K,
`Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP et al NATURE 1996
`379 6560 69-72
`
`306812 Glucagon-like peptides. Drucker DJ DIABETES 1998 47 2 159-169
`
`intestinal hormone,
`362275 Glucagon-like peptide 1 (GLP-1): An
`signalling nutritional abundance, with an unusual therapeutic potential.
`Holst JJ TRENDS ENDOCRINOL METAB 1999 10 8 229-235
`
`374863 Product Pipeline. Conjuchem Inc COMPANY WORLD WIDE WEB
`SITE 2000 July 18
`
`its
`Inc announces preclinical progression of
`410194 ConjuChem
`DAC:GLP-1 compound for type II diabetes. ConjuChem Inc PRESS
`RELEASE 2001 May 23
`
`439496 Development of glucagon-like peptide-1-based pharmaceuticals
`as therapeutic agents for the treatment of diabetes. Drucker DJ CURR
`PHARM DESIGN 2001 7 14 1399-1412
`
`454061 CJC-1131, the novel long acting GLP-1 analogue, delays gastric
`emptying and demonstrates safety and tolerability in preclinical testing.
`Lawrence B, Wen SY, Jette L, Thibadeau K, Castaigne JP DIABETES 2002
`51 2 A340-OR
`
`454095 The long-acting GLP-1 agonist CJC-1131 exhibits high potency
`and extended pharmacokinetics in vivo. Bridon DP, Thibaudeau K,
`Archeveque BP, Pham H, Robitaille MF, Drucker DJ, Leger R, Castaigne JP
`DIABETES 2002 51 2 A378-P
`
`454256 Development and characterization of long-acting degradation
`resistant GLP-1-DAC compounds for the treatment of type 2 diabetes.
`Thibaudeau K, Smith DC, Jette L, Castaigne JP, Bridon DP, Kim JG, Baggio
`LL, Drucker DJ DIABETES 2002 51 2 A471-P
`
`454479 The GLP-1-DAC analogue CJC-1131 upregulates insulin gene
`expression and exerts a memory effect on glycemic control in db/db
`mice. Kim JG, Baggio LL, Drucker DJ DIABETES 2002 51 2 A1391-P
`
`457323 ConjuChem announces start of phase I trial for DAC:GLP-1, a
`type II diabetes drug candidate. ConjuChem Inc PRESS RELEASE 2002
`July 08
`
`466084 ConjuChem updates status of phase I trial for diabetes drug
`candidate. ConjuChem Inc PRESS RELEASE 2002 October 07
`
`478018 Novel peptides under development for the treatment of type 1
`and type 2 diabetes mellitus. Baron AD, Kim D, Weyer C CURR DRUG
`TARGETS IMMUNE ENDOCR METABOL DISORD 2002 2 63-82
`
`478025 Insulinotropic actions of exendin-4 and glucagon-like peptide-1
`in vivo and in vitro. Parkes DG, Pittner R, Jodka C, Smith P, Young A
`Metabolism 2001 50 5 583-589
`
`
`CJC-1131 Giannoukakis 1249
`
`478028 Glucagon-like peptide-1: A major regulator of pancreatic β-cell
`function. Perfetti R, Merkel P EUR J ENDOCRINOL 2000 143 6 717-725
`
`478031 The entero-insular axis in type 2 diabetes - incretins as
`therapeutic agents. Creutzfeldt W EXP CLIN ENDOCRINOL DIABETES
`2001 109 Suppl 2 S288-S303
`
`479418 ConjuChem resumes DAC:GLP-1 clinical program, provides
`updates. ConjuChem Inc PRESS RELEASE 2003 February 20
`
`482594 ConjuChem's DAC:GLP-1 clinical program advances. ConjuChem
`Inc PRESS RELEASE 2003 March 19
`
`488830 ConjuChem starts US trial for DAC(TM):GLP-1. ConjuChem Inc
`PRESS RELEASE 2003 May 08
`
`492844 CJC-1131, a long acting GLP-1 derivative, exhibits an extended
`pharmacokinetic profile in healthy human volunteers. Lawrence B,
`Dreyfus JF, Wen S, Guivarc'h PH, Drucker DJ, Castaigne J-P DIABETES
`2003 52 Suppl 6 Abs 534-P
`
`493231 ConjuChem reports positive preliminary DAC:GLP-1 results.
`ConjuChem Inc PRESS RELEASE 2003 June 11
`
`498249 Development and characterization of a glucagon-like peptide 1-
`albumin conjugate: The ability to activate the glucagon-like peptide 1
`receptor in vivo. Jung-Guk K, Baggio LL, Bridon DP, Castaigne J-P,
`Robitaille MF, Jette L, Benquet C, Drucker DJ DIABETES 2003 52 3 751-759
`
`498254 CJC-1131, a long-acting GLP-1 analogue, is well tolerated in rats
`up to 14 days. Lawrence B, Wen S, Dunn D, Iordanova V, Castaigne J
`TOXICOL SCI 2003 72 S-1 49
`
`498258 CJC-1131, a long-acting GLP-1 analogue, exhibits safety and
`tolerability in dogs. Wen S, Wilson S, Trebec D, Pham K, Castaigne J,
`Lawrence B TOXICOL SCI 2003 72 S-1 48
`
`502385 ConjuChem's strong clinical results hit primary endpoints in
`type 2 diabetes trials. ConjuChem Inc PRESS RELEASE 2003 August 21
`
`502385 ConjuChem's strong clinical results hit primary endpoints in
`type 2 diabetes trials. ConjuChem Inc PRESS RELEASE 2003 August 21
`
`inhibitory
`IV hydrolyses gastric
`505939 Dipeptidyl-peptidase
`polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine
`methionine and is responsible for their degradation in human serum.
`Mentlein R, Gallwitz B, Schmidt WE EUR J BIOCHEM 1993 214 3 829-835
`
`506488 Analyst evaluation of ConjuChem
`MERCHANT GROUP 2003 September 15 1-6
`
`
`Inc. Loe DW DLOUHY
`
`MPI EXHIBIT 1110 PAGE 5
`
`