Early Clinical Development of Pharmaceuticals for Type 2 Diabetes Mellitus: From Preclinical Models to Human Investigation

John A. Wagner

Department of Clinical Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Dr. John A. Wagner, Department of Clinical Pharmacology, Merck Research Laboratories, P.O. Box 2000, RY34-A548, 126 East Lincoln Avenue, Rahway, New Jersey 07065. E-mail: wagner{at}merck.com.

Current treatments for endocrinological diseases were largely developed without well defined molecular targets. Today’s advances in genomics promise not only a more advanced understanding of the pathogenesis of endocrinological diseases, but also a better definition of molecular targets for potential new treatments. In fact, modern genomics has created new challenges for early clinical development by increasing the number of new targets and molecules that require evaluation in Phase I and II clinical studies. The scope of this perspective is limited to developments in type 2 diabetes, an area accounting for a large number of new treatment strategies in endocrinology. This perspective will review new therapeutic approaches in type 2 diabetes nearing or in early clinical development as well as the use of biomarkers as a strategy to optimize the transition from preclinical models to human investigation. In particular, this perspective will highlight the need for the discovery and development of biomarkers capable of assessing whether new therapeutic mechanisms work in preclinical models and in humans in early Phase I or II studies.

Molecular targets in type 2 diabetes

Accelerated research and advances in genomics have resulted in great strides toward a more detailed understanding of the molecular pathophysiology of type 2 diabetes. This, in turn, has led to the identification of several corresponding molecular mechanisms on which many current therapeutic strategies are focused: 1) reducing excessive glucose production by the liver, 2) increasing glucose-stimulated insulin secretion, and 3) targeting the insulin signaling pathway. These approaches have been recently reviewed (1) and are summarized in Table 1Go.


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Table 1. Molecular targets in type 2 diabetes

 
Reducing excessive hepatic glucose production

One mechanism resulting in the development of fasting hyperglycemia in patients with type 2 diabetes is increased rates of hepatic glucose production (2). Thus, diminishing hepatic glucose production is an important target (1, 2). Several molecular mechanisms offer new avenues for diminishing excessive hepatic glucose production. Antagonists of the glucagon receptor could potentially reduce hyperglycemia by blocking gluconeogenic and glycogenolytic pathways (3). Another important molecular target is inhibition of hepatic glycogen phosphorylase, an enzyme involved in the rate-limited steps in the glycogenolytic pathway (1).

Increasing glucose-stimulated insulin secretion

A second key component of the pathophysiology of type 2 diabetes is the defect in insulin secretion from pancreatic ß-cells (4). Again, the development of fasting hyperglycemia in patients with type 2 diabetes is due in part to the failure of the ß-cell to compensate for increasing insulin resistance. In addition, defective ß-cell function is probably an early predisposing factor in the development of type 2 diabetes. Clearly, sulfonylureas and related therapeutics act through this mechanism by stimulating glucose-independent insulin secretion, but a better, more tailored approach may be to potentiate glucose-dependent insulin secretion.

Incretins, including glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), potentiate glucose-stimulated insulin secretion (5). Administration of these incretins to humans potentiates insulin secretion, whereas selective gene disruptions of either the GLP-1 or GIP receptors produces a phenotype of impaired glucose-stimulated insulin secretion (5). GLP-1 and GIP are subject to rapid amino-terminal degradation by dipeptidylpeptidase IV (DP-IV), a proline-specific serine dipeptidase. Modified GLP-1 peptide agonists that are resistant to DP-IV (such as exendin 4) have the potential to bypass this rapid degradation pathway. Incretin degradation can also be slowed by DP-IV inhibitors. Supporting the utility of this approach, DP-IV-null mice have increased circulating active GLP-1 along with enhanced insulin secretion (6). In addition, early clinical trials of DP-IV inhibitors have shown evidence for glucose-lowering efficacy in humans with type 2 diabetes (7, 8).

Targeting the insulin signaling pathway

A third factor in the pathogenesis of type 2 diabetes is insulin resistance, which can be due to multiple defects in signal transduction. The insulin receptor itself can be targeted by small molecules that can activate the insulin receptor (9) or by blocking the deactivation of the receptor. A number of specific protein tyrosine phosphatases (PTPs) are involved in deactivation of the insulin receptor (10). PTP-1B is an intracellular enzyme specifically implicated in the deactivation of insulin signaling (10). PTP-1B-null mice are healthy and have markedly enhanced sensitivity to insulin (11). In addition, treatment of insulin-resistant rats with PTP-1B antisense potentiates insulin action (12). Other putative negative regulators of insulin signaling have recently been implicated as independent drug targets, including glycogen synthase kinase-3, Src homology 2 domain-containing inositol 5-phosphatase type 2, I{kappa}B kinase, and protein kinase C-{theta} (1).

The peroxisome proliferator-activated receptors (PPARs) form a subfamily in the nuclear receptor superfamily with three isoforms: PPAR{gamma}, PPAR{alpha}, and PPAR{delta}. The insulin-sensitizing thiazolidinediones (TZDs) were originally developed on the basis of their glucose-lowering effects in preclinical models. Subsequently, TZDs were shown to increase the expression of adipocyte genes, including the adipocyte fatty acid-binding protein aP2 (13, 14), through a peroxisome proliferator response element on the aP2 gene (15). These observations led the way to establishing that TZDs were PPAR{gamma} agonists and that their in vitro PPAR{gamma} activities were related to their in vivo insulin-sensitizing actions (16, 17). Several TZDs, including troglitazone, rosiglitazone, and pioglitazone, have insulin-sensitizing and antidiabetic activities in humans with type 2 diabetes and impaired glucose tolerance (18). Farglitazar is a very potent non-TZD PPAR{gamma}-selective agonist that was recently shown to have antidiabetic as well as lipid-altering efficacy in humans (18).

PPAR{gamma} is expressed predominantly in adipose tissue, and the efficacy of PPAR{gamma} agonists is thought to result largely from direct actions on adipose cells along with secondary effects in skeletal muscle and liver. This contention is supported by the lack of glucose-lowering efficacy of rosiglitazone in a mouse model of severe insulin resistance where white adipose tissue was essentially absent (19) and the observation that in vivo treatment of insulin-resistant rats produces acute (<24 h) normalization of adipose tissue insulin action, whereas insulin-mediated glucose uptake in muscle was not improved until several days after the initiation of therapy (20). As discussed in greater detail below, 30-kDa adipocyte-related complement protein (Acrp30; or adiponectin) is a secreted adipocyte-specific protein that decreases glucose, triglycerides, and free fatty acids (21, 22). In comparison with normal human subjects, patients with type 2 diabetes have reduced plasma levels of Acrp30 (23). Treatment of diabetic mice and nondiabetic human subjects with PPAR{gamma} agonists increased plasma levels of Acrp30 (24). Induction of Acrp30 by PPAR{gamma} agonists might therefore also play a key role in the insulin-sensitizing mechanism of PPAR{gamma} agonists in diabetes (Fig. 1Go). The beneficial metabolic effects of PPAR{gamma} agonists on muscle and liver may be mediated by their ability to 1) augment insulin-mediated adipose tissue uptake and metabolism of free fatty acids (25), 2) induce the production of circulating adipose-derived factors with potential insulin-sensitizing activity (e.g. Acrp30), and/or 3) suppress the circulating levels of adipose-derived factors associated with insulin resistance, including TNF{alpha} or resistin (26).



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Figure 1. Putative roles Acrp30 may play in insulin sensitization. The expression of Acrp30 (or adiponectin) is induced in adipocytes after treatment with PPAR{gamma} agonists. Resulting increased circulating Acrp30 levels may increase insulin sensitivity by 1) induction of fatty acid oxidation in skeletal muscle and 2) augmentation of hepatic insulin action.

 
PPAR{alpha} has been shown to play a critical role in the regulation of cellular uptake, activation, and ß-oxidation of fatty acids. Activation of PPAR{alpha} induces the expression of fatty acid transport proteins and enzymes in the peroxisomal ß-oxidation pathway (27, 28, 29, 30). Thus, PPAR{alpha} is an important lipid sensor and regulator of cellular energy metabolism. Dyslipidemia in type 2 diabetes is characterized by elevated triglyceride-rich particles and low levels of high density lipoprotein cholesterol and is also associated with an increased risk of coronary artery disease (31). In patients with dyslipidemia, treatment with fibrate PPAR{alpha} agonists resulted in substantial lowering of triglyceride levels and modest high density lipoprotein-raising efficacy (32), and a recent large prospective trial showed that treatment with the PPAR{alpha} agonist gemfibrozil reduced cardiovascular events or death by 22% (32, 33). Thus, PPAR{alpha} agonists can effectively improve cardiovascular risk factors and have a net benefit to improve cardiovascular outcomes. In fact, fenofibrate was recently approved in the United States for treatment of type IIA and IIB hyperlipidemia. Mechanisms by which PPAR{alpha} activation cause decreases in triglycerides are likely to include the effects of PPAR{alpha} agonists to suppress hepatic apo-CIII gene expression while also stimulating lipoprotein lipase gene expression (34, 35). TZDs and non-TZDs have also been identified that are dual PPAR{gamma}/{alpha} agonists (18). By virtue of the additional PPAR{alpha} agonist activity, this class of compounds has potent lipid-altering efficacy in addition to antihyperglycemic activity in animal models of diabetes and lipid disorders. KRP-297 is an example of a TZD dual PPAR{gamma}/{alpha} agonist; DRF-2725 and AZ-242 are non-TZD dual PPAR{gamma}/{alpha} agonists (18).

Strategies to optimize early clinical development studies

For selected mechanisms of action, the early clinical studies of potential therapeutic agents in type 2 diabetes may be hampered by the relatively long duration of treatment required for pharmacodynamic effects. For example, fasting plasma glucose reaches a nadir after approximately 6–12 wk of treatment in previous trials of selected TZDs (36, 37). One strategy to optimize early clinical development is to discover and explore the use of biomarkers or pharmacodynamic endpoints that may have responses early in the course of treatment and/or more robust effect sizes. Ideally, these biomarkers could be evaluated in preclinical models as well. Biomarkers are measurable parameters that can be indicators of normal biological processes, disease processes, or pharmacological responses to therapeutic intervention. A pharmacodynamic endpoint specifically refers to a biomarker of a pharmacological response.

Biomarker discovery can be facilitated by many approaches, including proteomic and genomic analyses. Proteomic-based approaches include mass spectrometry-based analysis of proteins and low molecular weight molecules and two-dimensional gel electrophoresis with or without mass spectometry to identify unknown analytes. Known analytes can be measured by cytometry or immunoassays. Genomic approaches include gene expression profiling by use of microarrays or other technologies. An example of the use of gene expression profiling experiments is detailed below; this approach is especially useful for drugs such as PPAR{gamma} agonists that regulate gene expression. At present, there are no clearly defined human biomarkers that are specific for in vivo activation of PPAR{gamma} as well as useful in healthy subjects and patients with type 2 diabetes. In patients with type 2 diabetes, measures of glucose metabolism, including fasting plasma glucose, are useful biomarkers, but these measures are not specific to activation of PPAR{gamma}.

One putative specific PPAR{gamma} biomarker was highlighted by results from gene expression profiling experiments (24). The cDNA encoding the protein Acrp30 was originally identified by subtractive cloning or mRNA differential display from cultured adipocytes vs. preadipocytes (38, 39). Acrp30 is a protein of 247 amino acids with substantial homology to complement factor C1q. The protein contains both an amino-terminal collagenous domain and a C-terminal globular domain, and x-ray crystallography reveals that the globular domain is structurally similar to TNF{alpha} (40). The distribution of Acrp30 mRNA in mouse, rat, and human is confined almost exclusively to adipose tissue, and its expression is increased during differentiation of cultured preadipocytes and decreased in white adipose tissue derived from obese mice (ob/ob and db/db) or humans vs. that in lean controls (24, 38, 39). In addition, Acrp30 is a secreted protein that circulates in plasma at high concentrations (5–10 µg/ml) (38). These observations suggest that Acrp30 may be a circulating adipose-derived factor that, like leptin or resistin, could influence energy balance and/or metabolism, possibly associated with obesity.

Acrp30 may be functionally related to insulin sensitization (21, 22, 41). Acute administration of recombinant Acrp30 lowered postprandial levels of glucose, triglycerides, and free fatty acids in mice fed a high fat and sucrose diet (21). Both the full-length protein and a truncated 27-kDa version of the protein containing the globular head domain had efficacy in reducing postprandial glucose levels, and the 27-kDa protein was shown to induce fatty acid oxidation in cultured skeletal muscle cells. Kadowaki and colleagues (41) have shown that Acrp30 increased the expression of enzymes associated with fatty acid oxidation and energy dissipation in muscle. Acrp30 in combination with leptin resulted in insulin sensitization in lipoatrophic mice (41). Single injections of full-length recombinant Acrp30 produced lowering of postprandial glucose levels in both normal and ob/ob mice (22). Recombinant Acrp30 could also enhance the effect of insulin to suppress glucose output from cultured hepatocytes, suggesting that a primary effect of this protein may be to augment hepatic insulin action (22, 42).

Expression profiling experiments revealed that PPAR{gamma} agonists of multiple structural classes could strongly induce Acrp30 mRNA expression in cultured 3T3-L1 preadipocytes (24). Quantitative PCR demonstrated that in vivo treatment with rosiglitazone increased Acrp30 mRNA levels in white adipose tissue of obese, insulin-resistant, db/db mice (24). Increased Acrp30 was observed at doses of rosiglitazone that were also associated with decreases in glucose and triglycerides. Quantitative Western analysis revealed that circulating Acrp30 levels could also be increased in vivo by PPAR{gamma} agonist treatment (24). In db/db mice, rosiglitazone increased circulating Acrp30 levels, and these changes were more pronounced (4- to 6-fold) than the changes observed at the RNA level in adipose tissue (2- to 3-fold). The PPAR{gamma} agonist-associated increases in Acrp30 are specific to PPAR{gamma}, because no Acrp30 increases were observed following administration of the PPAR{alpha} agonist fenofibrate to db/db mice or following administration of the non-PPAR-associated antihyperglycemic agent metformin to high fat fed/streptozotocin-treated mice despite appropriate levels of lipid-altering and glucose-lowering efficacy (24).

Circulating Acrp30 levels were also increased in vivo by PPAR{gamma} agonist treatment in humans (24, 43). In healthy subjects, a 2-wk treatment with rosiglitazone (4 mg twice daily) produced a marked increase in Acrp30 levels in a placebo-controlled clinical study (24). Similar to observations in mice, the PPAR{alpha} agonist fenofibrate (200 mg once daily for 2 wk) did not alter circulating Acrp30 levels in humans, supporting the specificity of Acrp30 as a biomarker for PPAR{gamma} activity. Importantly, increased Acrp30 levels were also observed after a 6-month rosiglitazone treatment in patients with type 2 diabetes in a placebo-controlled clinical study (43).

The mechanism by which PPAR{gamma} agonists increase Acrp30 mRNA expression is unclear because there are no consensus peroxisome proliferator response element sites in the murine Acrp30 promoter region (44); however, potential sites for CCAAT/enhancer-binding protein-ß suggest a potential mechanism for induction of Acrp30 during adipocyte differentiation and/or as a secondary mechanism by which PPAR{gamma} might induce Acrp30 gene expression. The magnitude of the induction as well as the observation that elevated levels are sustained for the duration of the treatment suggest that a solely posttranslational mechanism is unlikely (24). The rapid induction of Acrp30 levels after initiation of PPAR{gamma} agonist treatment also suggests that an increase in the number of new adipocytes could not fully account for this phenomenon. In addition, increased adiposity generally does not lead to an increase in Acrp30 levels in serum (22, 45).

Regulation of Acrp30 message and circulating levels by PPAR{gamma} agonists in preclinical animal models, healthy human subjects, and patients with type 2 diabetes suggests a role for this protein as a novel PPAR{gamma}-specific biomarker. In addition, a mechanistic role for Acrp30 related to insulin sensitization (21, 22, 41) strengthens the validity of this approach as a PPAR{gamma} biomarker. Figure 1Go summarizes some of the putative roles Acrp30 may play in insulin sensitization, including effects on liver and muscle. The data from preclinical models and healthy human subjects suggest that increased Acrp30 is a relatively early, specific response to activation of PPAR{gamma}. A detailed time-course experiment in healthy subjects and patients with type 2 diabetes will be necessary to demonstrate that Acrp30 increases precede overt changes in glycemic control or other measures of the metabolism. Further studies will also be required to assess whether improvements in insulin sensitivity correlate with Acrp30 induction and to define a PPAR{gamma} agonist dose-response relationship. Acrp30 may prove very useful in relatively short-term clinical studies in healthy subjects or in patients with type 2 diabetes to assess whether a new potential PPAR{gamma} agonist is efficacious in humans, possibly reducing the requirement for longer early "proof of concept" clinical studies in patients with type 2 diabetes. In addition, Acrp30, if affected during short periods of treatment in patients with type 2 diabetes, could prove valuable for the determination of whether individual patients were responding to treatment with PPAR{gamma} agonists. Given that suppressed Acrp30 levels were observed in patients with dominant negative PPAR{gamma} mutations (24), it is also tempting to speculate that Acrp30 deficiency has an important role in the pathogenesis of the severe insulin resistance and type 2 diabetes that is present in these patients.

Another strategy to assess new therapeutics in Phase I and II clinical development is to optimize existing biomarkers of glucose lowering or insulin sensitization in early patient studies. One early "proof of mechanism" study of farglitazar, a non-TZD PPAR{gamma} agonist, assessed 24-h insulin and glucose profiles in a double-blind, randomized, placebo-controlled study in patients with type 2 diabetes. After only 2 wk of treatment with 7 or 21 mg farglitazar daily, decreases in the 24-h profiles of glucose and insulin were observed (46). The glucose-lowering efficacy in patients with type 2 diabetes was confirmed in a larger, randomized, double-blind, placebo-controlled Phase II study that was 12 wk in duration (47). This strategy demonstrates that a short duration proof of mechanism clinical study with intensive glucose and insulin end points may be used to rationally focus the dose range of a PPAR{gamma} agonist.

The mechanism of action of putative therapeutic agents guides early clinical development strategy. Another example of biomarker use in early clinical studies is the measurement of active GLP-1 after treatment with DP-IV inhibitors. In a single dose study, DP-IV inhibition was shown to increase postprandial circulating active GLP-1 levels (48), as expected due to slowing of incretin degradation. Single doses of DP-IV inhibitors were also shown to decrease postprandial glucose excursions (7, 48), and glucose-lowering efficacy in patients with type 2 diabetes was confirmed in a larger, double-blind, placebo-controlled Phase II study that was 4 wk in duration (8). This strategy suggests that single dose clinical studies can provide proof of mechanism for DP-IV inhibition.

Expression profiling experiments and optimizing physiological or pharmacodynamic end points may be useful in the discovery and qualification of other potential biomarkers for novel type 2 diabetes therapeutic targets. Such biomarkers may prove useful not only in early clinical development, but also in refining the understanding of the pathophysiology of type 2 diabetes and in optimizing treatment of patients with type 2 diabetes.

Acknowledgments

I thank Paul Deutsch, Keith Gottesdiener, and David Moller for productive discussions on earlier versions of this manuscript.

Footnotes

The views expressed in this article are those of the author alone and should not be interpreted to represent the views or policies of The Endocrine Society, the Journal Editorship, or the pharmaceutical company by which the author (J.A.W.) is employed.

Abbreviations: Acrp30, 30-kDa adipocyte-related complement protein; DP-IV, dipeptidylpeptidase IV; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide-1; PPAR, peroxisome proliferator-activated receptor; PTP, protein tyrosine phosphatase; TZD, thiazolidinedione.

Received June 11, 2002.

Accepted August 27, 2002.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals