Moving from Basic Research to NewTherapies for Endocrine Disorders87th Annual Meeting of the Endocrine Society; 4–7 June 2005; San Diego, California, USA; andAmerican Diabetes Association 65th Scientific Sessions; 10–14 June 2005;San Diego, California, USA

David WilliamsonAdis International Ltd, Auckland, New Zealand

MEETING REPORT Int J Pharm Med 2005; 19 (3): 179-1831364-9027/05/0003-0179/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

The 2005 annual meeting of the Endocrine Society (ENDO)attracted a wide range of attendees from basic research scientiststhrough to clinical practitioners. The meeting took the theme‘Pathways to Discovery and Practice’, and included in the pro-gramme were a number of theme-related symposia and eventsfocusing on the translation of advances in basic endocrine re-search into new therapies for endocrine diseases. Some meetinghighlights, particularly developments in drug therapy, are brieflyreported here.

1. Glucagon-Like Peptide-1 (GLP-1) Analogues:New Class for Type 2 Diabetes Mellitus

Glucagon-like peptide-1 (GLP-1) analogues are a new classof agents for the treatment of patients with type 2 diabetes, andexenatide is the first from this class to become available, havingrecently been approved and launched in the US. Exenatide mim-ics the actions of naturally occurring GLP-1, which is an incretinhormone secreted by intestinal cells in response to food intake. Itenhances the release of insulin, inhibits glucagon release, in-creases satiety and slows gastric emptying – effects that havebeen shown to translate into improved glycaemic control and re-duction of bodyweight.

Studies were presented at the meeting on the long-term useof subcutaneously administered exenatide in addition to oral anti-hyperglycaemic agents, as well as its use as a single agent for type2 diabetes. The long-term data were from three separate studiesin patients with type 2 diabetes who were also receivingmetformin,[1] a sulfonylurea,[2] or both,[3] and showed that pa-tients who received exenatide throughout the study had sustained

improvements in glycosylated haemoglobin and progressiveweight reduction. Patients who were randomised to placebo dur-ing the initial 30-week study and switched to exenatide treatmentat the beginning of the 52-week extension had similar reductionsin glycosylated haemoglobin to those who received exenatidethroughout the 82 weeks, with accompanying reductions in body-weight. Data supporting the efficacy of exenatide as a singleagent were also reported from two phase II studies in patientswith type 2 diabetes inadequately controlled with diet and exer-cise alone or with metformin.[4]

2. Osteoporosis: Bisphosphonates and Beyond

Oral bisphosphonates are effective agents for the treatmentof postmenopausal osteoporosis, although problems with gastro-intestinal tolerability and complicated dose administration in-structions impose limitations on their use in some patients.Bisphosphonates are sequestered in bone and, thus, exhibitsustained antiresorptive activity, lending these agents to the de-velopment of less frequently administered oral or intravenousformulations with potential advantages of minimising gastro-intestinal effects and improving adherence to therapy.

2.1 Interim Results from DIVA and MOBILE

The ongoing 2-year DIVA (Dosing IntraVenous Administra-tion) study of ibandronate is assessing two-monthly and three-monthly intravenous regimens. Both were reported to be at leastas effective as the currently established daily oral regimen basedon first-year results.[5] Efficacy was based on bone mineraldensity (BMD) and the levels of bone turnover markers. For

BMD gains at the lumbar spine, both of the intravenous regimenswere found to be superior to the daily oral regimen, and overallsafety and tolerability profiles were similar for the intravenousand daily ibandronate regimens.

Data from the 2-year MOBILE (Monthly Oral iBandronateIn LadiEs) study examining three different monthly oralibandronate regimens were also presented. Based on compari-sons of BMD and bone turnover markers, the results after 1 yearshow that monthly administration appears at least equivalent inefficacy to daily oral ibandronate.[6,7]

Another issue relating to bisphosphonate therapy is thethreshold for intervention, and the comparative efficacy ofbisphosphonates in patients with different BMD T-scores. In astudy investigating the antifracture efficacy of risedronate inpostmenopausal women, benefits were found to be independentof baseline BMD.[8] The data were derived from four phase IIIplacebo-controlled studies that included 2575 postmenopausalwomen treated with the bisphosphonate for up to 3 years.

2.2 Other Therapeutic Approaches

In a basic research/clinical interface symposium, severalpotential therapeutic approaches to osteoporosis were discussed.

The molecular actions of vitamin D and aspects of potency,efficacy and selectivity of vitamin D analogues were discussedby Dr John Pike from the University of Wisconsin-Madison, US.In particular, the new analogue 2MD has displayed a potency ofaction that is 2-3 log greater than that of vitamin D. The super-agonist-like properties of this analogue appear to be due to thefact that structurally it does not bind to vitamin D binding protein(DBP). In animal studies, 2MD has demonstrated profound ef-fects on bone formation, bone strength and BMD, and may havefuture potential as an anabolic agent for the treatment of patientswith osteoporosis.

The importance of receptor activator of nuclear factor kappaB ligand (RANKL) in the regulation of osteoclast differentiationand function was discussed by Dr Michael McClung from theProvidence Medical Center and Oregon Osteoporosis Center inPortland, US, who also reported some results from clinicalstudies with RANKL-targeted therapy. RANKL, through itsactivation of osteoclasts, plays a central role in disorders ofincreased bone resorption, and RANKL inhibition thereforepresents a potential new option for the treatment and preventionof bone loss. Data presented on AMG 162, a fully humanmonoclonal antibody that blocks the binding of RANKL to itsreceptor, shows rapid and durable reduction of bone resorption.The BMD responses observed have been typical of those seen

with bisphosphonates. AMG 162, however, appears more revers-ible in its effects than the bisphosphonates, which remain in bonefor a relatively long period of time, and may therefore have alower risk of bone turnover oversuppression.

Finally, an update of progress in the development of se-lective estrogen receptor modulators (SERMS) and selectiveandrogen receptor modulators (SARMS) was presented by DrSundeep Khosia from the Mayo Clinic College of Medicine inRochester, US. Raloxifene is currently the only SERM availablefor the treatment of osteoporosis, although several others are cur-rently undergoing phase III trials, including arzoxifene,bazedoxifene and lasofoxifene. Clinical trial data will show howthese compare with raloxifene in terms of their effects on boneas well as other tissues. Compared with the SERMS, the devel-opment of SARMs is much less advanced, with the first havingentered phase I trials. Dr Khosia noted that it is likely that initiallySERMs will be developed for use in postmenopausal women andSARMs for use in ageing men, but this may change with increas-ing understanding of the broader mechanisms of estrogens andandrogens.

3. Developments in Growth Hormone Therapy

Several interesting developments in the delivery of growthhormone therapy were covered in sessions at the conference,among them reports of insulin-like growth factor-1 (IGF-1)-based dosages of growth hormone in children, and progress withnew sustained-release and inhaled formulations.

In the clinical trials session a study was presented on theoptimisation of growth hormone therapy in children using doseadjustment according to IGF-1 levels.[9] Levels of IGF-1correlate with response to growth factor, but there are large vari-ations in individual IGF-1 responses when conventional weight-based dosages are used. This is important both in terms of gainingan adequate IGF-1 response to administered growth hormone andin avoiding excessively high levels of IGF-1. In this study inchildren with growth hormone deficiency or idiopathic short stat-ure (ISS), individualising growth hormone doses by targeting tohigher (+2SD) IGF-1 levels, rather than to mean IGF-1 levels,was found to increase growth by 45% in children with growthhormone deficiency and by 58% in children with ISS.

Efficacy and safety data were reported from a phase II studyof a new sustained-release formulation of recombinant humangrowth hormone (LB03002).[10] This study compared the sustained-release growth hormone at two different doses with daily recom-binant growth hormone in children with confirmed growthhormone deficiency. Increases in height velocity over 6 months

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were comparable between the regimens, as were increases inIGF-1 and IGF binding protein-3, and tolerability.

Pharmacokinetic and safety results were also presented foran inhaled formulation, somatropin inhalation powder (SIP).[11]

The single-dose comparison study with subcutaneous humangrowth hormone was conducted in 12 healthy adults. SIP de-livered therapeutic concentrations of growth hormone, based onpharmacokinetic profiles, and IGF-1 levels were increased by amean of 70% from baseline levels. SIP was well tolerated andthere were no significant changes in pulmonary function duringthe study.

4. Tackling Diabetes from All Angles

The American Diabetes Association’s (ADA) scientific ses-sions followed the ENDO meeting, attracting over 12 000 inter-national researchers, clinicians and other health professionals.Sessions covered all aspects of diabetes, from basic researchareas including islet cell biology and insulin mechanisms,through epidemiology and genetics, to clinical management ofdiabetes and its complications. There were many interesting pre-sentations relating to new developments in drug therapy, some ofwhich are highlighted here.

5. Targeting Cannabinoid Receptors in Obesityand Diabetes

The cannabinoid receptor antagonist rimonabant is a newagent under development for the treatment of obesity and otherrisk factors contributing to the metabolic syndrome. The RIO(Rimonabant In Obesity) phase III trial series includes a studyspecifically in obese or overweight patients with type 2 diabetes(RIO-Diabetes), the results of which were presented in the late-breaking clinical trials session.

In RIO-Diabetes, rimonabant lowered haemoglobin A1c

(HbA1c) and produced significant reductions in bodyweight,waist circumference and triglyceride levels, with a significantincrease in HDL-cholesterol. A significant reduction in theprevalence of the metabolic syndrome was also reported amongpatients who received rimonabant. It was estimated that morethan half of the observed benefits in glycaemic control and HDL-cholesterol levels were independent of weight loss. Overall, theclinical improvements were found to be consistent with thosereported to date from the other trials in the series (RIO-NorthAmerica, RIO-Europe and RIO-Lipids).

6. Dual Peroxisome Proliferator-ActivatedReceptor agonists

Several studies of muraglitazar, a dual peroxisome prolifer-ator-activated receptor (PPAR) α/γ agonist, were reported at themeeting. The rationale behind the use of dual PPAR agonists isto combine the PPARγ-mediated effects on glycaemic controland insulin sensitivity with the PPARα-mediated effects on lipidmetabolism.

Results were presented from comparative studies withmuraglitazar or the thiazolidinedione pioglitazone, as well aslong-term data from an earlier dose-ranging study of muraglitazarin patients with type 2 diabetes. In the comparative trial,muraglitazar was shown to reduce blood glucose levels moreeffectively than pioglitazone, when each was added to metformintherapy.[12] Muraglitazar produced significantly greater reduc-tions in HbA1c than pioglitazone, and more patients achieved theADA target for HbA1c. Triglyceride levels were also significantlylower in muraglitazar-treated patients. Another PPAR α/γagonist, tesaglitazar, showed similar improvements in glycaemicand lipid parameters in phase II studies presented.[13]

7. Intense Interest in Incretin-Based Therapies

Intense interest in the development of incretin-based thera-pies for the treatment of type 2 diabetes was also evident in anumber of studies presented at the ADA meeting.

7.1 GLP-1 analogues

A comparative study assessed the potential of exenatide asan alternative to insulin glargine in patients with type 2 diabetesinadequately controlled with metformin and/or sulfonylurea.[14]

In this 26-week phase III study, both exenatide and insulin glarg-ine achieved similar reductions in HbA1c and similar percentagesof patients in the two groups achieved HbA1c values below 7%.Exenatide was associated with a mean weight loss of 2.3kg in thisstudy, compared with a mean gain of 1.8kg in the insulin glarginegroup. Exenatide was also more effective in reducing postpran-dial glucose excursions and had a lower incidence of nocturnalhypoglycaemia than insulin glargine. As in other studies of ex-enatide, nausea was a common adverse event, occurring in 57%of patients.

An analysis of cardiovascular risk factors (triglycerides, totalcholesterol, HDL, LDL, apolipoprotein B, and systolic and dias-tolic blood pressure) was presented from the three long-termphase III trials of exenatide.[15] Long-term exenatide treatmentshowed sustained improvements in glycaemic parameters, pro-gressive weight reduction, and improvements in lipids and blood

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pressure. Improvements in cardiovascular risk factors were seento be largest in those patients with the greatest weight loss.

Another GLP-1 analogue CJC-1131 exhibits an extendedcirculatory half-life, through its binding to human albumin invivo. In a 12-week study in patients with type 2 diabetes inade-quately treated with metformin or sulfonylurea, the addition ofCJC-1131 significantly reduced HbA1c with no increased risk ofhypoglycaemia.[16] Nausea was again a frequent adverse eventwith an overall incidence of 25% during the first 4 weeks of thestudy, decreasing in frequency thereafter.

7.2 Dipeptidyl Peptidase IV (DPPIV) Inhibitors

Natural GLP-1 has a short circulatory half-life, due to itsproteolytic inactivation by the enzyme dipeptidyl peptidase IV(DPPIV). An alternative therapeutic approach to the develop-ment of modified GLP-1 analogues, such as exenatide andCJC-1131, is therefore the development of specific DPPIV inhib-itors. A potential advantage of DPPIV inhibitors is that they maybe administered orally.

An example of this class of agent is sitagliptin (MK0431);phase II studies were presented on the use of this agent as mono-therapy or as an adjunct to metformin in patients with type 2diabetes. In a 12-week study, sitagliptin, as a single agent, pro-duced dose-dependent decreases in fasting plasma glucose andHbA1c.[17] Similarly, sitagliptin was reported to be effective andgenerally well tolerated when added to existing metformin ther-apy in poorly controlled patients. [18] Sitagliptin caused no sig-nificant changes in bodyweight in either of these studies.

8. Inhaled Insulin: Long-Term Efficacy and Safety

A number of studies were presented on inhaled insulins. Themost advanced of the inhaled insulins in development isExubera® 1, and studies were presented on efficacy and tolerabil-ity in both type 1 and type 2 diabetes. In patients with type 1diabetes, therapy over 3 months was reported to be well toleratedand as effective as subcutaneous short-acting insulin.[19] Long-term data from a number of phase III studies in type 2 diabetespatients were presented, concluding that over a 2-year period,glycaemic control was maintained and no new safety concernsemerged.[20] The results showed that over 2 years, there were nosignificant changes in parameters of lung function. Insulin anti-body levels plateaued in patients between 6 and 12 months in thevarious studies, and the presence of antibodies was not associated

with effects on glycaemic control or with adverse events in anyof the studies.

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1 The use of trade names is for product identification purposes only and does not imply endorsement.

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© 2005 Adis Data Information BV. All rights reserved. Int J Pharm Med 2005; 19 (3)