2012 Annual Report Diabetes With the approval of  Forxiga  (dapagliflozin) in the EU and the company’s  acquisition of Amylin Pharmaceuticals, both in 2012, Bristol-Myers Squibb  solidly enhanced the breadth of our product portfolio and the possibilities for addressing unmet medical need in diabetes treatment. And by focusing on the cardiovascular co-morbidities that patients with type 2  diabetes often encounter, including obesity and hypertension, we have contin- ued to expand our efforts beyond glycemic control to cardiovascular protection.  The result: through our Diabetes Alliance with AstraZeneca, we are offering  physicians more options for making the right choices for individual patients. “What resonates best with physicians is to talk about treatment objectives,  based on the patient’s characteristics, including their behavior,” says Patrick  Loustau, senior vice president, Global Commercialization, Cardiovascular and  Metabolics. “We believe our major treatments can fit well into different types  of treatment objectives.” Chris Cann, disease area lead for Metabolics, explains: “After you’re diagnosed,  you have to control your blood sugar, adhere to a much stricter diet, and have  better treatment for hypertension and other cardiovascular conditions and risk  factors. It often becomes challenging for a patient with diabetes to manage  these multiple co-morbidities. Having a range of options gives the physician  and patient more choices at any particular time in a patient’s disease.” Forxiga  is the first in a new class of drugs called SGLT2 inhibitors. It harnesses  the kidneys to help reduce blood sugar by excreting excess sugar into the urine,  thus lowering hemoglobin A1c levels while also providing reductions in weight  and blood pressure. Discussions with the U.S. Food and Drug Administra- tion (FDA) have created a likely path forward for the company to resubmit an  updated  Forxiga  filing for consideration in the U.S. by the summer of 2013. The Amylin acquisition added  Byetta  (exenatide), a twice-daily injectable, and  its once-weekly formulation,  Bydureon  (exenatide extended-release for inject- able suspension). Both mimic the activity of a human hormone, glucagon-like  peptide (GLP-1), which stimulates insulin secretion from the pancreas, but only  when blood sugar is high. Doing so effectively regulates glucose metabolism  while better controlling the blood sugar spikes that occur right after eating, and  slows the emptying of the stomach, which can contribute to weight loss. Byetta , launched in 2005, was the first GLP-1 agonist. When  Bydureon was approved in January 2012, it became the first and only weekly type 2  diabetes medication available. We plan to enhance the ease and convenience  of  Bydureon  administration and, over time, to transform the medicine into a  once-monthly treatment.  Symlin  (pramlintide), a third therapy developed at  Amylin, is a first-in-class therapy for patients with type 1 and type 2 diabetes  whose blood sugar is not properly controlled with mealtime insulin therapy. Company researchers had to create  innovative technological solutions to  produce  Bydureon , a novel, sustained- release, once-weekly formulation of a  twice-daily injectable for type 2 diabetes. “We take the active ingredient – exena - tide – and formulate it with a polymer  into what are biodegradable micro - spheres, a unique technology where the microspheres are slowly absorbed,  providing a controlled release of the  active drug over seven days,” explains  Bob MacKay, general manager of the  facility where  Bydureon  is produced.  “The challenge was to make the micro - spheres of the appropriate size to give  you the product release profile you  wanted – and to create a polymer with  the right composition.”  Another challenge was to build the right  manufacturing plant, one that could  produce the microspheres with the  desired qualities – including ensuring  a sterile product – and in the quantities  required. Located on 44 acres in West  Chester, Ohio, north of Cincinnati, the  highly automated plant was completed  in 2009 at a cost of about $800 million.  It became operational in late 2010 and  currently has 330 full-time employees,  representing key disciplines, including  chemical and automation engineering,  microbiology and chemistry.  r 16 Bristol-Myers Squibb  A Unique Technology for  a Novel Medicine