Drug discovery and development
The global epidemic of diabetes, obesity and related metabolic disorders continues to progress relentlessly. The International Diabetes Federation predicts an even greater diabetes burden by 2035 (>590 million people afflicted) which will disproportionately affect developing nations. Even in wealthy developed nations, a significant proportion of patients diagnosed with diabetes does not achieve accepted glycemic control goals, and has pertaining issues in the control of blood pressure and lipids. The conjunction of the expanding epidemic, the limitations of current available drug treatments and the undeniable unmet medical needs for such chronic and slowly progressing disease, provide a strong rationale for continued emphasis on finding and developing novel therapeutic approaches with improved long-term efficacy and safety profiles. This chapter provides an overview of the Drug Discovery and Early Development process in the search for new medicines for type 2 diabetes.
Critical unmet medical needs to be addressed
The key objectives for the treatment of type 2 diabetic patients are to obtain a combination of crucial clinical end-points such as:
- Blood glucose regulation as normal as possible (with as few hypoglycaemic episodes as possible)
- Regulation of energy balance (diabetes-associated obesity)
- Reduction of plasma triglycerides, FFA and LDH/HDL ratio (diabetic dyslipidemia)
- Preservation/regeneration of functional pancreatic β-cell mass
Several pharmacotherapies, which act by increasing insulin secretion, improving insulin action, delaying breakdown and absorption of carbohydrates, and/or modulating glucose supply, are currently available to treat the metabolic abnormalities characteristic of type 2 diabetes (such as abnormalities in hepatic glucose production, insulin resistance, and a progressive decline in insulin-producing β-pancreatic islet cell function over time). Yet most existing glucose-lowering drug classes for diabetes have substantial issues with efficacy profiles falling short of achieving accepted treatment goals, even when used in combination therapy.
Drug Discovery and Development of true disease-modifying agents that would deliver longer term benefits – to prevent disease and/or disease progression – should address the critical unmet medical needs by:
- Safely achieving greater glycemic efficacy whilst preserving/improving β-cell health
- Mitigating the cardiovascular risk associated with diabetes, obesity and dyslipidemia (and
- Helping patients with, or at-risk of, diabetes to meaningful and safe weight loss
- Attenuating the progression of microvascular complications
Drug Discovery research process towards the identification of clinical drug development candidates
Most drug discovery projects for type 2 diabetes and related metabolic disorders currently focus on individual drug targets.
Drug Discovery targets are proteins that can be modulated (activated or inhibited) by small synthetic chemical molecules or biologics (e.g. monoclonal antibodies) or recombinant proteins or peptides. There are different types of drug targets such as:
- “Novel” target: Target with no known synthetic modulator and therefore a “drug tractability” (“druggability”) assessment of the target is required to evaluate the feasibility of development of such modulators.
- “Validated” target: Target with already some synthetic modulator(s) showing some solid proof-of-concept efficacy in relevant in vivo pharmacological models of type 2 diabetes.
- “Fast-Follower” target: Fully validated target with already some synthetic modulators that have shown efficacy in clinical development, but where there are opportunities of developing similar but novel modulators outside the scope of the existing patents of clinical candidate(s), and/or with improved efficacy and/or safety and/or pharmacokinetics and/or delivery profiles.
There are several steps in the drug discovery research process towards the identification of novel therapeutic agents:
1) Target Evaluation and Selection
Target preliminary proof-of-concept can include for example phenotypes detected in transgenic and knockdown mice, siRNA-mediated gene knockdown, and pharmacology in relevant animal models. It is also essential for target validation to establish links between the target and human disease as early as possible in the drug discovery process. This can include human genetic association and/or regulation of expression in the context of disease.
Computational data mining approaches to pre-existing information sources –
Figure 1: “Target” Evaluation: Some Key Decision Criteria for Drug Discovery Target Selection. (Click to enlarge) including genetic data, microarray data, proteomic data, metabolite profile (metabolonomics) data – conjoined by integrated pathway mapping, can also be of relevance.
The decision to initiate and/or develop a drug discovery project around a specific target is based on a selection of criteria, listed in Figure 1, which can then allow a Strengh-Weakness-Opportunities-Threats (SWOT) analyses of the target to assist the decision – including of course additional internal criteria specific to each Drug Discovery organisation.
2) Drug Discovery Cascade and Target Validation
It is crucial to select carefully the target before developing a full drug discovery project as there are many steps involved in order to identify a suitable and
Figure 2: Drug Discovery Process from “Target” Identification to “Target” Validation and Preclinical Drug Development Candidate. (Click to enlarge) valuable preclinical Development candidate, as illustrated in Figure 2 with an overview example of the drug discovery process to identify synthetic orally available small molecules specific to a target.
Once target modulators (e.g. synthetic small molecules) are discovered (e.g. through screening in primary assays specific to the target and leads generation), lead optimisation typically follows. In this phase of optimisation for chemical compounds, many molecules are synthetised seeking improved drug-like properties, potency, selectivity, pharmacokinetics and pharmacodynamics, toxicology, etc.
It is absolutely essential to characterise the quality of the tools used in the process, from the specificity of antibodies, for example, to the target (exogenous and endogenous) expression level in different relevant cell models in which the function of the modulators can be tested, and mechanism of action studies can be studied physiologically in endogenously expressing target cells.
It is also crucial to test the lead candidates in both acute and chronic settings in several relevant pharmacology models of metabolic disorders, including diabetes, obesity, dyslipidemia, etc.
From target identification to preclinical development candidate identification and its entering into clinical testing, the average time is 3 to 5 years.
3) Early Clinical Development and Further Target Validation
Drug candidates selected for early development undergo further toxicology tests and initial (Phase I) human trials, but clear signals of efficacy are usually not evident until the end of Phase I or Phase II, where more definitive human proof-of-concept is generally established.
Further target validation is also critical. High-quality human experiments with early efficacy signals can elucidate next steps in research. For example, both first-in class DPP4 inhibitors and GLP-1 agonists have been progressed from extensive basic research to continuously establish and characterize well the pathways involved in their actions. In metabolic disease drug development, especially when weight loss is the desired clinical effect, the poor track record in translating efficacy in animal models to meaningful clinical efficacy remains challenging. Therefore better understanding of disease pathogenesis remains essential, including tissue-gene expression profiling, development of disease cell models and tissue banks, and earlier clinical biomarkers. Also, as new anti-hyperglycemic drugs should exclude significant cardiovascular risk prior to initial approval by the drug authorities, exploring any potential cardiovascular side effect should therefore be addressed as early as possible in the process of R&D. Better translational medicine tools and molecular probes allow a more thorough and earlier clinical target assessment.
Targeting type 2 diabetes and related metabolic disorders
Figure 3: Some examples of type 2 diabetes drug discovery targets/projects (which have been or are explored). (Click to enlarge)There are several drug targets which have delivered some current therapies for type 2 diabetes and related metabolic disorders. In addition, many other targets have been explored and Figure 3 shows a non-exhaustive list of drug discovery projects on “validated” targets i.e. with at least some preclinical data. Some of these projects are currently in clinical development; some have not yet been in clinical trials; some have been dropped and/or are currently on hold.
Screening technologies and chemistry trends have driven the selection of targets towards “druggable” classes. Examples include enzymes (e.g. Glucokinase activators, cell surface receptors (e.g. Glucagon antagonism) and nuclear transcription factors (e.g. PPARα/δ). Peptides and larger circulating proteins have also been explored as targets for biomolecules e.g. peptide YY, fibroblast growth factor 21 (FGF21) and proprotein convertase subtilisin/kexin type 9 (PCSK9).
One of the most successful target classes in drug discovery is represented by modulators of G-protein-coupled receptors (GPCRs), which have also been identified as prime candidates for novel treatments for type 2 diabetes and associated disorders (such as GLP-1 analogues). Modulators of non-peptide-binding GPCRs (e.g. GPR119 agonists), are also of interest, as being more amenable to orally available small molecule pharmaceutical approaches, which could be also of value in combination therapy. Moreover, emerging multi-GPCR target approaches are showing promises such as GLP-1/Glucagon/Gastric Inhibitory Peptide (GIP) receptors tri-agonists (engineered small peptides) currently being explored as potential new clinical candidates for combinatorial hormone therapy for the treatment of type 2 diabetes associated with obesity.
Another emerging target research field is GPCR nutrient sensors. G-protein-coupled taste receptors (similar to those in the lingual system) that respond to sweet, bitter, umami, and fatty acids (Free Fatty Acid FFA receptors), are expressed in endocrine cells within the gut mucosa, and coordinate, together with other chemosensory signalling elements, the release of hormones that regulate energy and glucose homeostasis. As malfunction of these nutrient sensors in the gut may be responsible for a variety of metabolic dysfunctions associated with obesity, gut G-protein-coupled taste receptors could also provide new promising pharmacological targets.
As the prevention and management of cardiometabolic diseases requires a multifactorial approach, targeting inflammation is also being explored as a potential valuable add-on therapy, to improve insulin sensitivity and ameliorate glucose control. Several anti-inflammatory agents (e.g. cytokine IL-1β antagonists) are being clinically evaluated for their potential to protect from cardiovascular risk and to prevent or ameliorate type 2 diabetes.
Moreover, other research avenues to potential new therapeutics are also being undertaken. Epigenetic[a] Drug Discovery is an emerging research field with some strong links between epigenetic factors, changes in gene expression and diseases such as diabetes. Epigenetic modifications are highly regulated, dynamic and reversible. Many epigenetic protein families are “druggable” and therefore represent also some potential novel drug discovery targets (e.g. microRNAs, histone deacetylases).
Development of new drugs is a long process involving extensive testing for safety and efficacy, which often results in termination of numerous compounds before reaching late clinical phases and/or approval.
Efficient progression of drug discovery projects towards successful clinical read-outs is at the heart of translational medicine, and remains one of the key challenges for the development of tailored treatments for type 2 diabetes and related metabolic disorders. Future success for the discovery and development of long-term efficacious and safe drugs requires that researchers and clinicians learn from all previous experiences and continue to explore and apply new technology platforms, and innovative research and development paradigms.
For example, in drug discovery, strict adherence to the single-target approach may need to be revisited since all older and even many newer drug classes were discovered using phenotypic screening, without initial knowledge of a defined molecular target. In development, further identification of biomarkers and relevant early end-points are being evaluated. Moreover, future success requires also a more integrated approach within the R&D process.
In addition, efforts are being made in the area of novel and controlled drug delivery systems, for example for oral hypoglycemics for achieving sustained and controlled drug delivery for overcoming the limitations (such as frequent dosing, short half-life and low bioavailability) related to the conventional dosage forms of oral hypoglycemics. Medical efforts are also being made in better profiling the type 2 diabetic patients in order to develop a more personalised combinatory treatment (judiciously added or sequentially used) without overmedication.
Developing groundbreaking therapeutics focusing on the unmet medical needs of diabetic patients requires a fully coordinated commitment from clinicians and basic and applied researchers, with an understanding of the drug target profile and patient population early in the development process. Future success requires a closer relationship between applied and basic research as well as active knowledge sharing between research groups through for example consortia and also establishment of shared tools and data banks. The on-going wish for development of constructive partnerships between university-based basic disease research and industry translational science could lead to a powerful means to bridge the innovation gap, and should facilitate a critical build-up of mature cooperation of skills and capabilities essential to address the multidisciplinary requirement and many challenges of drug discovery and development.
Diabetes area participation analysis: a review of company and targets described in the 2008-2010 patent literature. Carpino PA, Goodwin B. Expert Opinion on Therapeutic Patents (2010) 20: 1627-1646
Metabolic Disease Drug Discovery – “Hitting the target” is easier said than done. Moller D. Cell Metabolism (2011) 15: 19-24
How were new medicines discovered? Swinney DC, Anthony J. Nature Review Drug Discovery (2011) 10: 507-519
Emerging combinatorial hormone therapies for the treatment of obesity and T2M. Sadry SA and Drucker DJ. Nature Reviews Endocrinology (2013) 9: 425-433
Nutrient sensing in the gut: new roads to therapeutics? Janssen S, Depoortere I. Trends in Endocrinology and Metabolism (2013) 24:92-100
Discontinued drugs in 2013: diabetic drugs. Hedrigton MS & Davis SN. Expert Opinion Investigational Drugs (2014) 23: 1703-1711
Recent advances in drug delivery systems for anti-diabetic drugs: a review. Grover M, Utreja P. Current Drug Delivery (2014) 11: 444-457
Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies. Expert Opinion Investigational Drugs (2014) 23: 1055-1066
Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Esser N, Paquot N and Scheen AJ. Expert Opinion Investigational Drugs (2014) Oct 25: 1-25 [Epub ahead of print]
Micro RNA: An Epigenetic Regulator of Type 2 Diabetes. Kadamkode V, Banerjee G.. Microrna (2014) 3: 86-97
"Duality of Interest Statement": Dr C. Reynet currently does not hold stocks in R&D Pharmaceutical companies and has no conflicting interest relevant to this review article written in December 2014.
^ Epigenetic describes changes in gene expression and cellular phenotype through mechanisms that do not involve changes in the underlying DNA sequence.