Type 2 Diabetes: Current Trends and Challenges in Clinical Development

Transcription

1 Type 2 Diabetes: Current Trends and Challenges in Clinical Development

2 Executive Summary Type 2 diabetes is an escalating global health problem further driven by the epidemic in obesity. Worldwide, type 2 diabetes affects 198 million people and is increasing at a rate of 3% annually. Obesity affects nearly one third of the United States population and is on the rise throughout the developed world. Therapeutic advances are emerging from new classes of anti-diabetes agents including DDP-4 inhibitors and GLP-1 analogs, third-generation therapies with potential to provide better control of blood sugar levels and reduce risk for kidney disease and retinopathy. But today s promising pipeline must be delivered in an environment of increasing regulatory requirements for cardiovascular safety. The leading cause of death among diabetics is heart disease. Prompted by growing concerns that antidiabetes drugs may increase cardiovascular risk the Food and Drug Administration s 2008 guidance requires larger and longer clinical trials. The trend is toward clinical databases of 3,000 to 5,000 roughly twice the size of previous development programs. Regulators are seeking more data on safety and durability of drug effects in populations that are more reflective of real-world treatment. To address growing challenges in study design and patient recruitment, sponsors who are developing anti-diabetes drugs will require more scientific expertise and greater operational capabilities. A case study of a Phase II DDP-4 inhibitor trial is presented to illustrate both the research challenges and the value of partnering to expand critical development resources. 2

3 Introduction The future of diabetes clinical research is being shaped by two urgent needs: to improve therapy for an escalating global epidemic and to ensure acceptable levels of safety for these interventions in a treatment landscape complicated by evolving standards of care. Today s biopharma pipeline holds hundreds of new agents with the potential to advance treatment, but rising regulatory requirements to demonstrate cardiovascular safety demand clinical trials that are dramatically larger, longer and more complex. The trend is toward clinical databases of 3,000 to 5,000 roughly twice the size of past programs. New agents will have to be evaluated in many different combinations, with insulin and other approved therapies. In addition, clinical drug evaluation will have to be more reflective of a real-world treatment experience. These increasing demands are putting intense pressure on development resources, making partnering a vital strategy for diabetes drug development. Mary Parks, PhD, director of the Food and Drug Administration (FDA) Division of Metabolic and Endocrine Drug Products for the Center for Drug Evaluation and Research (CDER), gave this assessment of what this means for anti-diabetes drug developers: We are informing companies that, given the chronic and complex nature of diabetes, they should aim for larger and longer exposures that would inform us about safety and durability of drug effects, she noted in a recent interview. It s also important for them to enroll a patient population that may be more reflective of the population the drug will be marketed towards. 1 3

4 Type 2 Diabetes: A Growing and Undertreated Epidemic Type 2 diabetes has reached pandemic levels, affecting more than 198 million people worldwide and increasing at a rate of 3% each year. 2,3 In type 2 diabetes, the body s ineffective use of insulin results in a daunting list of life-threatening co-morbidities heart attack, stroke, kidney failure, blindness, vascular damage, nerve damage and numerous tertiary diseases. The World Health Organization (WHO) calculates that nearly 3 million deaths worldwide are attributable to diabetes each year; by 2030, that figure is expected to double. 4 The rising prevalence of type 2 diabetes is driven by an alarming epidemic in obesity that affects approximately one third of the United States (U.S.) population and is on the rise throughout the developed world. 5 WHO estimates that more than 1 billion adults are overweight worldwide and at least 300 million are obese. 6 Obesity increases risk for diabetes: about 85% of type 2 diabetics are overweight; about 55% are obese. 7 The cohort of conditions common to both disorders has been dubbed diabesity. An important trend in diabetes clinical research is the epidemic in childhood obesity and the accompanying increase in childhood type 2 diabetes. Since 1980, obesity has tripled among U.S. schoolage children and adolescents. A 2010 study reports that 17% of U.S. children aged two to 19 years were at or above the 95th percentile of weight-forrecumbent-length growth charts. 8 Type 2 diabetes is difficult to diagnose in children, but the Centers for Disease Control reports that the disease now affects 151,000 U.S. children and adolescents. 9 There will be a growing need for pediatric clinical trials, which involve special considerations related to safety and recruitment. While there have been notable treatment advances, the International Diabetes Federation reports that optimal management to improve immediate and long-term quality of life is not reaching many, perhaps the majority, of patients due to the complexity of the disease, lack of proven, cost-effective resources and diverse standards in clinical practice Years of Progress in Diabetes Therapy Progress is being made in diabetes treatment by combining old and new therapies to control blood sugar levels with increasing effectiveness. Statins, Angiotensin Converting Enzymes (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) also helped to reduce risk for heart and kidney disease in diabetics. The U.S. Centers for Disease Control (CDC) reported a decline of 3.9% in the age-adjusted death rate for diabetes in Source: CDC, MMR Report

5 Treatment Landscape: Diverse Targets, Issues in Standard of Care The diverse mechanisms that underlie control of glucose levels and weight gain offer diverse targets for intervention. Advancing research has generated nine classes of anti-diabetes drugs six in the past 20 years. 11 Although a wide range of factors and pathways have been implicated, there is still no unifying explanation for pathogenesis. The resulting uncertainties impact both clinical care and drug development. The leading cause of death among diabetics is cardiovascular disease. The relationship between reduced blood sugar levels and cardiovascular disease remains unclear. There is conflicting evidence about the overall cardiovascular benefit of lowering blood glucose levels, together with growing concern about the cardiovascular risks posed by glucose-lowering drug therapies. Standards of care are evolving, and measures of effectiveness are expanding beyond the endpoints of glucose levels and body mass index to address a constellation of diabetes- and obesityrelated complications, including cardiovascular outcomes, nephropathy and retinopathy. These trends impact both clinical care and drug development. Standard of Care: HbA1c Targets There is continuing debate regarding the optimal target for glycosylated hemoglobin levels (HbA1c), the traditional biomarker for glycemic control and drug efficacy. The American Diabetes Association calls for maintenance of HbA1c levels at <7%. 12 The International Diabetes Federation and the American Association of Clinical Endocrinologists recommend a more intensive target of 6.5%. 13,14 As therapeutic advances make it possible to reduce HbA1c levels further, there are questions regarding the benefits of more aggressive therapy. Results from major studies have found benefits in reducing HbA1c levels, but effects on macrocardiovascular events remain ambiguous. The 10-year UK Prospective Diabetes Study (UKPDS) published in 1998 compared outcomes for control at 7.9% and more intensive control at 7% with either sulfonylureas or insulin. UKPDS found that more intensive control substantially reduced risk for microvascular disease but not for macrovascular disease or overall mortality. 15 The ADVANCE (Action in Diabetes and Vascular Disease) study compared outcomes for control at 7% and at 6.5% using a gliclazide in 11,140 patients. Results published in 2008 at the five-year point showed that intensive control at 6.5% reduced the combined rate of cardiovascular death, nonfatal stroke, nonfatal MI, nephropathy and retinopathy by 10%. However, there was no benefit for macrovascular events or for overall mortality. 16 5

6 Current Therapy At present, the goal of therapy is to maintain HbA1c glucose levels at a 7% or 6.5% target long term and without weight gain to protect against heart attack, stroke, kidney disease and retinopathy. A combination of drugs offering different mechanisms of action usually is required to achieve these targets. Metformin remains the first-line treatment for type 2 diabetes. This older therapy, favored because it does not promote weight gain, typically is used in combination with newer agents. These include thiazolidinediones (TZDs), DPP-4 inhibitors and GLP-1 analogs. TZDs reduce peripheral insulin resistance, primarily by their effect on adipose tissue. They have been shown to provide better maintenance of glucose levels over time, 17 and there is some evidence that TZDs may protect insulin-producing beta cells. The newest anti-diabetes agents, DPP-4 inhibitors and GLP-1 analogs, are interventions based on the hormone GLP-1 (glucagonlike peptide 1). GLP-1 plays a major role in regulating blood glucose levels by stimulating insulin secretion, suppressing glucagon levels and slowing gastric emptying. DPP-4 inhibitors act to prevent the enzyme dipeptidyl peptidase 4 from inactivating GLP-1, while GLP-1 analogues are synthetic versions of the hormone that increase GLP-1 activity. DPPIV-inhibitors include sitaglyptin (Januvia) and saxaglyptin (Onglyza), introduced in 2006 and 2009, and alogliptin, expected to reach market in These new agents reduce blood glucose levels as effectively as existing therapies but with less risk of hypoglycemia and weight gain. They are used in combination with either metformin or a TZD and can also be used as monotherapy; developers usually design trials to evaluate candidates for both uses. Mechanisms of Action in Current Therapies Key strategies of current anti-diabetes drugs include: Stimulating the pancreas to release more insulin: sulfonylureas (Diabeta, Amaryl) and meglitinides (Prandin, Starlix) Reducing insulin resistance that is, making cells more sensitive to insulins: Biguanides (first-line therapy metformin) and TZDs (Avandia, Actos) Reducing absorption of glucose and carbohydrates in the intestine: disaccha ride inhibitors (Acarbose) and glucosidase inhibitors (Precose, Glyset) Blocking the inactivation of GLP-1, which stimulates insulin secretion and regulates glucose levels: DPP-4 inhibitors (Januvia, Onglyza, alogliptin) Enhancing action of GLP-1: GLP-1 analogs (Syncria, in Phase III) 6

7 Research Landscape: Promising Pipeline, Growing Safety Issues The biopharma pipeline currently holds more than 500 anti-diabetes agents. 18 In addition to DPP-4 inhibitors and GLP-1 analogs, a new class of sodium glucose co-transporter-2 (SGLT-2) inhibitors is advancing. Other novel mechanisms in development include glucokinase activators, glucagon antagonists, and sirtuins. Among the most promising are the FGF-21 agonists, potent activators of glucose uptake on adipocytes; candidates are in various stages of development from preclinical to Phase II trials. The number of clinical diabetes trials has increased dramatically. At the same time, the development path of new diabetes drugs has become longer, more complex and increasingly expensive due to increasing requirements to demonstrate cardiovascular safety. long-term RECORD study of rosiglitazone safety also showed an increased cardiovascular risk. 20 The rosiglitazone issue raised serious questions about whether longer clinical trials should be required to evaluate cardiovascular outcomes in anti-diabetes drugs seeking market approval. In 2008, the FDA updated its guidance for diabetes drug and biologic development. The new recommendations were intended to ensure that anti-diabetes drugs do not add unacceptable risk for cardiovascular disease. Major provisions address cardiovascular endpoints in Phase II and III, study designs to support meta-analysis and requirements for postmarketing safety trials. 21 The additional requirements are having a profound impact on increases in research costs and timelines FDA Guidance on Cardiovascular Risk Evaluation Safety issues surrounding the TZD rosiglitazone (Avandia) intensified concerns about cardiovascular risks associated with anti-diabetes drugs. In 2007, a meta-analysis of 42 clinical trials, most comparing rosiglitazone to placebo, found an increased risk for myocardial ischemia. 19 In 2009, findings from the 7

8 FDA 2008 Guidance: Evaluating Cardiovascular Risk in New Antidiabetic Therapies Summary of Recommendations for Sponsors 18 Establish an independent cardiovascular end points committee to evaluate cardiovascular events, in a blinded fashion, during Phase II and III studies Ensure that Phase II and III trials are designed and conducted so that a metaanalysis can be performed to appropriately account for important study design features and patient- or study-level covariates Provide a protocol describing the statistical methods for the proposed meta-analysis. Studies will need to be longer e.g., a minimum of two years rather than the typical length of three to six months in order to obtain enough events and provide data on longer-term cardiovascular risk for chronically used therapies Perform a meta-analysis of the important cardiovascular events across Phase II and III trials; explore similarities and differences in subgroups (age, sex, race) if possible Compare the incidence of important cardiovascular events that occur with the investigational agent to the incidence of the same types of events that occur in the control group to show that the upper bound of the two-sided 95% confidence interval for the estimated risk ratio is less than 1.8. This can be accomplished using the meta-analysis, or by conducting an additional single, large safety trial, either alone or added to other trials If the premarketing application includes clinical data that show the upper bound of the two-sided 95% confidence interval for the estimated increased risk is between 1.3 and 1.8, and the overall risk-benefit analysis supports approval, a postmarketing safety trial generally will be necessary to show that the upper bound of the two-sided 95% confidence interval for the estimated risk ratio is less than 1.3. This can be accomplished by conducting a single trial or by combining the results from a premarketing safety trial with a similarly designed postmarketing safety trial If the premarketing application contains clinical data that show the upper bound of the two-sided 95% confidence interval for the estimated increased risk is less than 1.3 and the overall risk-benefit analysis supports approval, then a postmarketing cardiovascular trial generally may not be necessary 8

9 Design Challenges for Clinical Trials Sponsors face major challenges both in study design and implementation. In order to meet the increasing requirements for cardiovascular safety, sponsors must collect data for 15,000 exposures for a minimum of six months, and 400 exposures for a minimum of one year. This standard of safety requires studies of 3,000 to 5,000 patients maintained on the experimental drug for as long as three years. A comparator group of the same size must be recruited and followed as well. Sponsors must decide how much data is sufficient, given the trend toward increasing safety requirements. They may choose to meet approval requirements as quickly as possible, or they may take a more conservative approach and collect data that could address additional regulatory questions and safety issues. Comparator Drugs According to FDA s Mary Parks, the choice of comparator drug will be increasingly important. With many therapies available, companies cannot avoid the question of what it means to be better. Will new agents have to show better efficacy; better safety and efficacy; or some middle ground, given that the drug is likely to be used in combination therapy? Standards for approval do not require that a drug show that it s superior or comparable in effect to other therapies, she notes Companies (are going to be asked): what does this new drug offer to patients? There is more and more scrutiny about what a new drug has to offer beyond glycemic control. 1 Multiple Endpoints According to Richard Gregg, MD, chief scientific officer for Vitae Pharmaceuticals, the future points to increasing focus on the interrelated co-morbidities of diabetes and obesity. 22 In the past, the focus was almost exclusively on the hard end point of HbA1c. Moving forward, there will be greater emphasis on a drug s impact on the co-morbidities of hypertension, dyslipidemia and atherosclerosis. Evaluation will include measurements of changes in blood pressure and lipoproteins in addition to HbA1c. Going forward, it s going to be about the overall disease pathophysiology being able to focus on multiple end points, Gregg says. Gregg predicts that sponsors will need partners who can provide increasing expertise and capabilities. There will be growing needs to do biomarker studies in Phase I where a primary goal will be to understand drug actions at the molecular level. In Phase II, there will be increasing use of new technologies, including new imaging technologies, to establish that the drug is hitting those targets for example, that a DPP-4 agent is impacting GLP-1. 9

10 Inclusion/Exclusion Criteria Traditionally, diabetes clinical trials excluded patients with pre-existing cardiovascular disease. Now these at-risk patients are included in studies to provide more real-world evaluation of drug effects and to speed accrual of cardiovascular event observations. Sponsors must decide on the number of at-risk patients to enroll and the severity of illness acceptable for inclusion. A larger sample of patients with higher risk for cardiovascular events can speed event accrual, but it becomes more difficult to attribute an event in these patients to drug effects as opposed to pre-existing disease. Another design issue is the event window the time during which a study subject must have experienced a cardiovascular event in order to be eligible for enrollment. Timeframes range widely, from 60 days before enrollment to six months. Impact on Marketed Drugs For marketed drugs, the impact of emerging safety issues unfolds on a case-by-case basis. A major safety finding prompts reevaluation of an entire class, but not all drugs in a class will have the same safety profile. In some cases, new studies may be required for sponsors to bring their marketed drugs into compliance; in others, sponsors may already have sufficient data to address an emerging safety issue. Retrofitting Studies for Compliance For agents in Phase III trials when the 2008 guidance came into effect, developers have been required to initiate additional studies to demonstrate cardiovascular safety. For agents in earlier stages of development, sponsors had to consider ways to retrofit research programs to comply with the additional requirements. Such retrofitting is an ongoing challenge as new safety issues emerge from drug use in medical practice. Sponsors must devise ways to capture more information in the course of an ongoing study to address unexpected safety concerns. 10

11 Recruitment Challenges: Competition for Patients Sponsors are engaged in fierce competition to find, enroll and retain appropriate study subjects to conduct larger and longer trials. ClinicalTrials.gov lists more than 2,250 clinical trials for type 2 diabetes drugs in progress worldwide. 23 Despite the prevalence of type 2 diabetes, there is a scarcity of treatment-naïve patients needed for clinical trials and increasing competition for trial sites capable of enrolling large numbers of subjects. It is not unusual for type 2 diabetics who qualify for research participation to shop for studies that offer compensation, dropping out of one trial and enrolling in another. Quest for Research-naïve Patients In the major research venues of North America and Western Europe, type 2 diabetes is treated at early stages of the disease with a combination of oral anti-diabetes drugs, and in some cases with insulin as well. This makes the pool of treatment-naïve patients in developed regions very small. Treatmentnaïve patients also tend to be underserved by the health care system and to have additional problems in trial participation, such as workday availability and transportation. Treatment-experienced patients are difficult to enroll for different reasons. In developed regions, the majority of patients receive treatment that provides good control; neither patients nor physicians have incentives to change regimens to participate in a trial. Recruitment efforts are further strained by increasing requirements for evaluation in specific subpopulations based on gender, age and ethnicity. To access larger, treatment-naive patient populations, sponsors are conducting more trials in emerging nations where type 2 diabetes is prevalent and where patients are less likely to receive early and aggressive treatment. Type 2 diabetes is becoming more prevalent in the emerging nations of Asia and South America where obesity is also increasing along with improving economies. In these regions there are more incentives for patients to enter studies to access treatment that is not otherwise available. 11

12 Retaining Subjects is Crucial The increasing length of diabetes trials means that patients must participate in studies that last three years and longer. This puts additional pressure on drop-out rates. Drop-out rates as high as 67% have been reported for clinical trials that last for a year or more. 24 Compliance also becomes a bigger issue, since protocols can involve diet and exercise regimens. Sponsors are building retention plans into studies and educating sites to implement a variety of effective strategies. Nurse educators and nutritionists can increase compliance with dietary and exercise regimens; messaging services offer text, and phone reminders for dosing and visits and help address transportation needs. It will be increasingly important to identify potential drop-outs and retain them. One successful approach is to design a sub-study that enrolls patients who have withdrawn from a trial; the sub-study is modified in ways that make it easier for patients to continue. Conclusion As diabetes clinical research study size, duration and complexity increase, it is clear that the development of new diabetes therapies will be slower and far more costly. In the balance between acceptable safety and therapeutic advance, safety issues dominate the current environment. Delivery of today s rich pipeline of diabetes agents requires drug sponsors to expand their resources through partnerships that can provide greater levels of regulatory and design experience and greater access to global patient populations. 12

13 References 1. Parks, Mary. Biggest challenges sponsors face in diabetes trials. Interview in Applied Clinical Trials Online Podcasts. Accessed Feb 16, 2009 at appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article 2. WHO. Diabetes. Accessed Feb 18, 2010, at 3. McGarty, T. P. Type 2 diabetes: a controllable epidemic. The Telmarc Group, Notes No 61, March WHO Diabetes Facts & Figures. Accessed Feb 18, 2010, at 5. Cowen and Company. Sep Therapeutic Categories Outlook. 6. WHO Global Strategy on Diet, Physical Activity and Health Obesity and overweight. Accessed March 22, 2010, at 8. Ogden, C.L., Carroll, M.D., Curtin, L.R., et. al Prevalence of high body mass index in US children and adolescents, JAMA,303(3): Centers for Disease Control. Diabetes projects. Accessed April 19, 2010 at International Diabetes Federation. Global guideline for type 2 diabetes. Accessed Mar 8, 2010 at Gale E. A Collateral damage: the conundrum of drug safety. Diabetologia, 52: American Diabetes Association Standards of medical care in diabetes, Diabetes Care 27 (Suppl 1):S15-S International Diabetes Federation Clinical guidelines task force: Global guideline for type 2 diabetes. Available at cfm?unode=b7462ccb-3a4c e D74AD3 7. MMWR Morbidity Mortality Weekly Report. Prevalence of overweight and obesity among adults with diagnosed diabetes United States, and Nov 19; 53(45): American Association of Clinical Endocrinologists Medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-management, 2002 update. Endocr Pract 8(Suppl.1):

14 14. UK Prospective Diabetes Study (UKPDS) Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 352: ADVANCE Collaborative Group Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. NEJM, 358: Rendell, Marc Advances in diabetes for the millennium: drug therapy of type 2 diabetes. Medscape General Medicine v 6(3 suppl). 17. Pharmaprojects. Update May U.S. Food and Drug Administration. CDER Guidance for Industry: diabetes mellitus. Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm pdf 21. Gregg, Richard. Obesity drugs and co-morbidities. Interview in Applied Clinical Trials Online Podcasts. Accessed Feb 16, 2009 at ClinicalTrials.gov. Accessed March 8, 2010: browse?brwse=cond_cat_bc U.S. Food and Drug Administration. Safety: Avandia (rosiglitazone maleate) Tablets November Posted 11/19/2007. Available at ucm htm 23. Dal-Re, R., Luque A., et al Irritable bowel syndrome: attrition rates of patients identified at primary care centers during a 50-week period versus those identified in hospitals in a phase II clinical trial. Int J Clin Pharmcaol Res, 21 (3-4): U.S. Food and Drug Administration. Safety: Avandia (rosiglitazone): Ongoing Review of Cardiovascular Safety. Posted 02/22/2010. Available at ucm htm 14

15 Case Study Background This was a full-service, Phase II DPP-IV inhibitor trial. The original specifications for this trial included: Subjects experiencing inadequate glycemic control on current regimen of metformin and pioglitazone 300 sites across 22 countries Global enrollment target 760 subjects Enrollment period January 2007 through June 2008 Challenges PPD faced a challenging start-up timeline and regulatory delays in several countries. The start-up delays were primarily due to: 1. Delays in obtaining appropriate insurance certificates 2. Review cycle for sponsor approval of informed consents customized to meet local requirements 3. Delays in site contract and budget negotiations 4. Delays in ethics committee and ministry of health approvals due to numerous regulatory agencies requesting a protocol amendment to exclude subjects with New York Heart Association criteria Class I-IV heart failure Strategy PPD recognized the critical nature of the clinical trial application negotiation process and capitalized on existing relationships with sites by using previously negotiated language to expedite the contract negotiation process and activate sites as quickly as possible. With client collaboration and approval, the number of sites in the United States was increased to mitigate delays in regulatory approvals in the Europe/ Middle East/Africa and Asia-Pacific regions, and put the timelines back on schedule. Secondly, sites were asked to identify potential subjects ahead of initiation to ensure interested subjects were screened immediately following site activation. During the pre-study site visits, PPD leveraged our experience in this indication by selecting an appropriate mix of sites that had performed well on previous type 2 diabetes studies with less experienced sites that showed evidence of the patient population in their practice. For less experienced sites, PPD focused additional site management efforts on continual training, education and support to ensure the quality of the data was comparable with the most experienced sites. 15

16 Additionally, the PPD project team recognized the enrollment developed recruitment plans and strategies to continuously engage sites and motivate them to exceed their original enrollment commitments. These plans were customized on a country and site level to ensure all possible risks were mitigated. Site contracts were also amended to offer competitive financial reimbursement to those sites that met their targets. Results Despite the start-up challenges, PPD met the target for the first patient-in date of 30 January 2007 and reached the global enrollment goal of 760 patients two weeks ahead of schedule. 16

17 Case Study: The Role of Partnering in Successful Diabetes Research Programs The development of the DPP-4 inhibitor alogliptin offers valuable perspective on the scope and challenges of current diabetes research. It also illustrates the vital role partnering plays in the design and implementation of successful research programs. Alogliptin pre-registration studies were completed in record time using a highly efficient design that provided for simultaneous rather than sequential studies. Submitted in September 2008, the alogliptin new drug application (NDA) was in review when FDA s 2008 guidance came into effect. Alogliptin became the first diabetes agent to undertake an additional study in order to comply with the guidance-specified cardiovascular safety parameters; this bellwether trial indicates the current regulatory viewpoint. PPD, Inc. began development of alogliptin in 2004 after purchasing rights from the compound s originator, Syrxx Inc. As sole sponsor, PPD designed double blind, placebo-controlled studies to evaluate alogliptin as a monotherapy, and completed first-in-human and proof-of-concept trials. PPD had designed five Phase III studies and enlisted the study sites when Takeda Pharmaceutical Company Ltd. acquired Syrxx in Takeda and PPD then entered into a partnering agreement in which PPD would collaborate on all development work and downstream services. In addition to monotherapy, the partners developed a combination therapy using alogliptin together with Takeda s approved antidiabetes drug, pioglitazone (ACTOS). Efficient Design The five studies were conduced globally in Europe, Asia and Latin America. A total of 2,239 patients were randomized; one of the five studies required treatment-naïve patients. The trials were conducted simultaneously, with each site running as many of the five trials as possible. As a result, the partners were able to take alogliptin from lead optimization to NDA submission in a record 49 months. Our strategy meant that most diabetes patients treated at a given site would qualify for one of the studies, explained Paul Covington, former executive vice president of development, PPD, Inc. It also meant that sites were conducting few, if any, competing trials. We designed feeder studies to roll into long-term extension studies. We ve seen a dramatic increase in the number of diabetes studies and competition for patients, Covington notes. We were able to enroll some treatment-naïve patients in North America. But our most efficient sites were in Latin America (Brazil, Peru and Mexico) and in Eastern Europe (Russia, Ukraine and Romania). This kind of global reach is just essential now. 17

18 Long-term Safety Study The successful development program faced a new hurdle when FDA required that a single long-term cardiovascular safety study be completed to earn approval for the alogliptin and alogliptin/pioglitazone NDAs. Working closely with FDA, Takeda and PPD designed a safety study that will enroll 5,400 patients globally and collect data for 4.7 years. Enrollment criteria pose the greatest challenge. Patients must not only have type 2 diabetes and participate in a study lasting nearly five years; they must also have experienced acute coronary syndrome within 15 to 60 days prior to enrollment. If alogliptin succeeds in the massive safety study, the new diabetes therapy will reach patients in Pharmaceutical Product Development, Inc. All rights reserved. 18