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European Pharmaceutical Contractor

Diabetes: Making Strategic Partnerships

Rickey Reinhardt of Covance evaluates the unmet medical needs of the growing epidemic, and how CRO partnerships are part of the solution

The incidence and prevalence of Type 2 diabetes mellitus has been increasing at an alarming rate globally. Moreover, most patients in the US with diabetes have metabolic syndrome – namely hyperglycaemia, hypertension, dyslipidemia and obesity – all of which greatly increase the risk for devastating micro- and macrovascular complications. Although several therapeutic options exist, achieving the recommended glycaemic target remains a challenge. Combination therapy is required in almost all patients and most of the approved therapies have undesirable side-effects, including weight gain, hypoglycaemia, various gastrointestinal issues, fluid retention, and so on. There remains an unmet medical need for more efficacious therapies with a better side effect profile. Given the current conservative regulatory environment and high costs associated with bringing a drug to market, innovative drug development will be necessary to bring forward those diabetes therapies with the best risk/benefit profile in a timely manner. Pharma will need to think outside of the box and consider other development approaches such as strategic partnering with CROs.

TYPE 2 DIABETES MELLITUS

Diabetes mellitus is characterised by high blood glucose levels and was once referred to as a condition of insulin or non-insulin dependence. However, over the years it has become apparent that there are multiple phenotypes and underlying causes as multiple types have been described, namely 1, 1a, 2, 3, and MODY. Type 2 diabetes mellitus (T2DM) appears to account for nearly 90 to 95 per cent of all cases and presumably starts with peripheral insulin resistance, predominately in muscle and fat cells, where the ability to move glucose into these cells becomes more difficult. The insulin-secreting pancreatic B-cells counter this by increasing their output of insulin in order to maintain normal blood sugar levels. After several years, there is a net loss of pancreatic B-cells and eventually the body cannot respond effectively; blood sugar begins to rise, eventually leading to a variety of complications. As the seventh leading cause of death in the US, diabetes can cause cardiovascular disease, coronary heart disease and stroke, retinopathy and blindness, kidney disease, nervous system damage, and amputations (1). As a result, diabetes is a major focus for the pharmaceutical industry.

The World Health Organization in 2009 surmised that 220 million people in the world have been diagnosed with diabetes (nearly 24 million in the US), and predicted that the number of diabetesrelated deaths will double between 2005 and 2030 (2). Approximately 3.8 million men and women worldwide were estimated to have died from diabetesrelated causes such as cardiovascular disease in 2007. This is more than six per cent of total world mortality (3).

The ultimate determining factor of diabetes is dependent on the genes of the patient. However, unhealthy lifestyle choices have certainly accelerated the incidence for T2DM as the obesity epidemic is tracking along with the diabetes epidemic. Without proper care and lifestyle changes, the rate of incidence will continue to rise, especially since 57 million people in America have prediabetes, and many of those will develop T2DM within 10 years (1). Educating individuals to implement a healthy lifestyle would be the best and most effective therapy, but until we become more successful at this approach, it will be necessary to focus on drug therapies.

TREATMENTS TODAY

Metformin has globally become the first line drug therapy of choice. Subsequent to that, several classes of drugs are viable options including sulfonylureas, glinides, thiazolidinediones, alpha glucosidase, bromocriptine, colesevelam, insulin and, more recently, the incretin-based therapies such as glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase (DPPIV- 1) inhibitors. Those likely to be approved soon include long-acting GLP-1 agonists (once a week) and sodium-glucose cotransporters (SGLT)-1 inhibitors. While there are a number of therapeutic options, most patients require multiple drugs to reach the recommended targets and many patients become intolerant to side effects of certain drugs, such as:

  • Gastrointestinal tolerability and nausea issues with metformin, GLP-1 agonists, bromocriptine, colesevelam and alpha glucosidase-I
  • Weight gain and hypoglycaemia with sulfonylureas, glinides and insulin
  • Weight gain and potential cardiovascular harm with thiazolidinediones

Given the risks and benefits of currently marketed diabetes therapies, there remains an unmet medical need and pharma has good opportunities to bring forth drugs that are more effective with improved side effect profiles. As the regulatory authorities have tightened their safety standards, it is crucial for a diabetes drug in development to not cause cardiovascular harm, have no adverse changes in blood pressure or lipids, be weight neutral or result in weight loss, and minimise hypoglycaemia. The hurdles for bringing a new diabetes drug to commercialisation demonstrate the need for improving the R&D process to bring the new diabetes therapies to the market sooner.

CROs AS A STRATEGIC PARTNER

History of CRO Evolution
Over the last three decades, CROs have evolved from a nascent industry to become strategic partners to the pharmaceutical industry. Initially used by pharmaceutical companies as spill-over capacity for tactical projects when internal resources were limited, sporadic demand for CRO services for specific projects defined the tactical outsourcing typical during the 1980s to 1990s.

By the turn of the century, the biotech industry experienced sudden, rapid growth; new companies emerged with plenty of funding and promising molecules to develop, but limited internal capacity to carry drugs through the development process. As a result, the biotech industry turned to CROs to handle drug development which reduced the need for various fixed costs. The resulting infusion of capital from more consistent demand fuelled the growth of CROs, allowing them to invest in global infrastructure, scientific expertise and technologies.

Around 2005, pharmaceutical companies began to rely more heavily on full-service CROs, motivated largely by the need for complex clinical trial support, as well as to contain rising R&D costs. Partnership models began to emerge as both pharma and biotech required strategic outsourcing solutions.

Flexible Solutions for Maximum R&D Efficiency
One key partnership model is integrated drug development; this is defined as the strategic, managed development of a molecule, or portfolio of molecules, coupling an overarching scientific and regulatory strategy with commercial and operational coordination. With respect to integrated drug development, execution can include the entire plan from discovery through commercialisation or part of the plan. This can be a particularly attractive model even to Big Pharma as the operational execution of drug development is usually much more efficient by CROs, thus saving companies time to market and the need for internal resources, resulting in money savings.

CONCLUSION

T2DM is a growing epidemic that is readily increasing the demand for effective diabetes therapies. Although recent developments in diabetes therapies have introduced novel strategies, the quantity and variety of adverse effects emphasises the need for further research and drug development. Compliance with regulatory standards and balancing consumer demands with company objectives may prove difficult.

Today pharmaceutical and biotechnology companies are beginning to partner with CROs, not only on outsourcing components of drug development but also on developing the strategy in an integrated drug development approach. Cultivating a relationship with a CRO allows expertise and resources to be shared to bring therapies to fruition. Applying this tactic to the drugs currently in development can help to bring new diabetes therapies to the market sooner and safer.

References

  1. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007, Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention
  2. WHO, Diabetes, accessed 22 July 2010 at http://www.who.int/mediacentre/factsheets/fs312/en
  3. International Diabetes Federation, Mortality, accessed 20 July 2010 at http://da3.diabetesatlas.org/index3669.html
  4. Barnett AH, New treatments in Type 2 diabetes: a focus on the incretin-based therapies, Clinical Endocrinology 70: pp343-353, 2009
  5. Chao EC and Henry RR, SGLT2 inhibition – a novel strategy for diabetes treatment, Nature Reviews Drug Discovery 9: pp551-559, 2010

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Rickey Reinhardt, MD, PhD, is VP of Clinical Integrated Drug Development, Strategic Partnering and Integrated Drug Development at Covance. He received his PhD in Pharmacology and MD from LSU Medical College. With more than 14 years of experience in drug development, Rickey held a pharmaceutical consulting role where he provided clinical development and medical affairs strategy to biotech and major pharmaceutical companies prior to Covance. Rickey also spent 11 years at Novo Nordisk where he was responsible for building and managing a clinical pharmacology and clinical research section and driving clinical development from discovery through to Phase IV in cardiometabolics, including diabetes, obesity and dyslipidemia. His experience has included clinical development, regulatory and medico-marketing strategy, preparation of clinical development and risk management plans, and hands-on experience with all aspects of the clinical trial process for clinical pharmacology, registration and medical affairs trials.
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