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2014 REPORT 7 2 2 5 3 4 6 21 23 Contents Medicine Recent ...... Approvals ...... in the Pipeline Diabetes Medicines ...... Diabetes Breakthroughs Early Diabetes — ...... Adherence Improving cation/ Intensifi Treatment Clinical Inertia ...... About Diabetes in the Facts States ...... United ...... in Development Medicines Glossary ...... Drug Development/ ...... Process Approval options for patients battling diabetes patients battling diabetes options for conditions. and diabetes-related Disease for the Centers to According death (CDC), and Prevention Control sub- people with diabetes fell for rates 40 percent—between stantially—up to decrease this CDC links and 2006. 1997 medical cardiovascular improved to better management of diabe- treatment, changes. lifestyle and some healthy tes, due rates death while the Unfortunately, of new declining, the rate diabetes are to The number of rising. cases has been with diabetes has Americans diagnosed according 1980, since than tripled more can affect choices the CDC. Lifestyle to National The CDC-led this increase. that found Program Diabetes Prevention

Nearly 26 million Americans are affected affected million Americans are 26 Nearly diabetes—including 7 million people by the disease. have they unaware who are in the 10 causes of death One of the top diabetes has far-reaching States, United fami- patients and their implications for system. care lies and our health can and exercise eating While healthy and manage type 2 diabe- help prevent in helping role a key play medicines tes, the disease. the risk of treat and reduce in found was one medicine example, For percent. 31 the risk by lower to studies classes of eight new years, And in recent ap- been type have 2 diabetes medicines and Drug Administra- the Food by proved care health giving patients and tion (FDA), treat to options powerful new providers condition. and devastating this chronic date and help to build on progress To further by the challenges posed meet biopharmaceutical America’s diabetes, 180 developing are companies research type 1 and type 2 for medicines new conditions, diabetes and diabetes-related due to failure kidney such as chronic diabetes and painful . 200 active dia- are there Additionally, States, betes clinical trials in the United started not yet including 140 that have seek- just now patients or are recruiting participate to ing volunteers and another but not recruiting active, 60 that are the critical In addition to patients. new in the development trials play these role rep- they treatments, and testing of new therapeutic valuable potentially resent Biopharmaceutical Research Companies Are Companies Research Biopharmaceutical Diabetes and Treat to 180 Medicines Developing Conditions Related

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PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES BIOPHARMACEUTICALRESEARCH AMERICA’S BY PRESENTED Diabetes MEDICINES IN DEVELOPMENT MEDICINES Medicines in Development in Development Medicines Diabetes For Key Issues

weight loss and increased physical activity in people at high risk for diabetes reduced the development of MEDICINESMEDICINES IN DEVELOPMENTDEVELOPMENT FORFOR DIABETES by 58 percent in a three-year period. BIOPHARMACEUTICAL RESEARCH According to the American Diabetes Association, most Ameri- COMPANIES ARE DEVELOPING cans with diabetes have type 2, in which relative defi - ciency combines with the body failing to properly use insulin. Between 5 percent and 10 percent of Americans with diabetes 180 MEDICINES have type 1, in which the body fails to produce insulin. TO TREAT

The medicines in the pipeline today offer hope of reducing TYPE 1 & TYPE 2 DIABETES the human toll and economic costs of diabetes. Examples of some medicines now being tested include: INCLUDING – AND – • A medicine that improves glucose-dependent insulin FOR DIABETES FOR DIABETES-RELATED secretion. 128 52 CONDITIONS • A medicine designed to inhibit an linked to diabetic neuropathy. • A treatment designed to stimulate and enhance the regeneration of insulin-producing cells.

Source: PhRMA, 2014 Medicines in Development for Diabetes While diabetes remains a challenging illness, America’s biophar- maceutical research companies are continuing their efforts to develop novel and more effective therapies to treat the disease and improve the quality of life for diabetes patients. Diabetes Medicines in the Pipeline Recent Diabetes Medicine America’s biopharmaceutical research companies continue to explore many different approaches to battle diabetes and Approvals related-conditions. Some potential innovations from the 180 New medicines approved by the FDA in the last year repre- medicines in development today, include: sent exciting steps forward in efforts to better treat diabetes. Stimulating the Formation of Insulin Producing Cells— These include: A potential fi rst-in-class treatment for is • Nesina® () is a new DPP-4 inhibitor designed to designed to stimulate and enhance the regeneration of slow the inactivation of incretin hormones GLP-1 and GIP, insulin-producing cells (islets). The treatment is a human resulting in more active incretins enabling the pancreas to consisting of the bioactive part of a gene respon- secrete insulin and better managing blood glucose levels. sible for regenerating pancreatic islets. In diabetes, there are often too few insulin-producing islets to keep up with • Invokana® (canaglifl ozin) is the fi rst sodium-glucose co- the demand for insulin. transporter 2 (SGLT2) inhibitor approved for patients with type 2 diabetes. SGLT2 inhibitors work in conjunction with Next-Generation Oral Treatment—A medicine in develop- the kidneys and the natural urination process to remove ment for the treatment of type 2 diabetes is part of the excess blood glucose from the body. DPP-4 inhibitor class, but chemically distinct from other approved medicines in this class. DPP-4 inhibitors work by • Duetact® (/) combines two previ- stimulating the production of insulin and producing less glu- ously approved type 2 diabetes medicines with comple- cose. In clinical trials, the medicine was able to inhibit more mentary actions in a single tablet. One medicine targets than 80 percent of its target enzyme for seven days, making while the other increases the amount of it potentially a once-weekly treatment versus daily. insulin produced by the pancreas. Once-Weekly Treatment—A medicine in development is in • Farxiga ™ (dapaglifl ozin) is a new SGLT2 inhibitor approved the same class of drugs as some other approved medicines to improve glycemic control in adults with type 2 diabetes. for type 2 diabetes, but with a longer therapeutic life that

2 Medicines in Development Diabetes 2014 Key Issues

MILLIONSMILLIONS OFOF AMERICANSAMERICANS AFFECTEDAFFECTED BY DIABETES TREATREATMENT ISIS IMPORTIMPORTANT TOTO CONTROLCONTROL DIABETEDIABETES

7 MILLION EACH DAY MORE THAN 26 MILLION 19 MILLION 7 MILLION 5,000 AMERICANS are are AMERICANS AMERICAN ADULTS are affected by DIAGNOSED UNDIAGNOSED are DIABETES UNDIAGNOSED are diagnosed with DIABETES 16 MILLION 3 MILLION are are DIAGNOSED TREATED but NOT TREATED 19 MILLION 79 MILLION AMERICANS AMERICAN ADULTS 8 MILLION have been have 8 MILLION have not successfully controlled DIABETES diagnosed with controlled DIABETES WITH TREATMENT DIABETES WITH TREATMENT

DIABETES AFFECTS NEARLY 8 MILLION 18 MILLION have have ABOUT ONE-QUARTER CONTROLLED UNCONTROLLED 26 MILLION DIABETES DIABETES AMERICANS } ARE UNAWARE THEY HAVE THE DISEASE Source: Centers for Disease Control and Prevention (CDC) Source: Centers for Disease Control and Prevention (CDC), National Health and Nutrition Examination Survey (NHANES)

may make it suitable for once-weekly dosing. The medicine is —a chronic progressive kidney disease that is the leading a human -like peptide (GLP-1) analogue that lowers cause of end-stage renal disease (ESRD) or . blood glucose and reduces body weight. From 1990 to 2006, ESRD due to increased 2.5 times. The medicine has demonstrated the Facilitating Glucose Regulation—A potential medicine in potential to protect kidney function and slow disease pro- development for type 2 diabetes is a gut sensory modulator gression when added to existing therapy. (GSM) delivered directly to the stomach where it intensifi es the body’s natural food-driven signals that facilitate glucose regulation. The medicine, a delayed-release formulation of Early Diabetes Breakthroughs (a medicine used to treat diabetes alone or in com- bination with other medicines), targets the lower gut to avoid Basic research is important to fi nding new treatments and systemic absorption in the bloodstream, making it potentially possibly a cure for diabetes. Recent research discoveries offer useful to diabetes patients with renal impairment who are hope that they can one day lead to new effective treatments. unable to use metformin due to the risk of building metfor- Some of the new discoveries include: min up in the blood (lactic acidosis). • Researchers at the Harvard Stem Cell Institute discovered a Painful Nerve Damage—Nerve damage is a common symp- hormone that can stimulate production of insulin-secreting tom of diabetes. About half of all people with diabetes have pancreatic beta cells up to 30 times the normal rate in mice. some form of nerve damage, or neuropathy, according to the These new cells only produce insulin when the body needs American Diabetes Association. Over time, blood glucose it, potentially leading to a natural regulation of insulin. can injure the walls of tiny blood vessels that nourish nerves • Scientists at London’s Imperial College have manipulated causing pain, especially in the legs. One medicine in develop- a patient’s own stem cells into insulin-secreting cells. ment is designed to improve the symptoms of diabetic neu- Further research aims to inject patients with 100 percent ropathy by inhibiting the activity of an enzyme that causes of insulin-producing cells that would release insulin for up the accumulation of intracellular sorbitol (a sugar alcohol) to one year. Other scientists at the Walter and Eliza Hall that causes diabetic neuropathy. Institute of Medical Research in Australia have isolated Diabetic Kidney Disease—A potential fi rst-in-class medicine stem cells from the pancreas and turned them into insulin- is in development for the treatment of diabetic nephropathy producing cells for the treatment of type 1 diabetes.

Medicines in Development Diabetes 2014 3 Key Issues

• A type 1 diabetes vaccine created by researchers at Stanford University shuts down certain segments of the DIABETESDIABETES COSTSCOSTS SOCIETSOCIETY human immune system. Most vaccines aim to boost the immune system to fi ght a virus, but the Stanford vaccine turns off portions of the immune system that are mal- TOTAL COST FOR DIABETES functioning. Type 1 diabetes is an autoimmune disease $245 BILLION IN THE UNITED STATES where the pancreas produces too little or no insulin. • Researchers at the University of Tokyo have identifi ed a $69 BILLION molecule that functions similarly to the hormone adipo- INDIRECT MEDICAL COSTS 41% nectin, which is secreted by fat cells and helps to regu- INCREASE late glucose and insulin effectiveness. But the hormone $176 BILLION IN 5 YEARS was destroyed by the digestive system when taken orally. DIRECT MEDICAL COSTS The new molecule can be taken orally and was found to be effective when studied in mice.

• Doctors at Boston Children’s Hospital have isolated a pathway in animals that triggers T cells to attack the pan- creas. With more research, the newly discovered pathway could lead to better treatments or even a cure for type 1 MEDICAL EXPENDITURES ARE 2.3 TIMES HIGHER IN PEOPLE WITH DIABETES diabetes. Source: American Diabetes Association

Diabetes Medications—Improving DIABETESDIABETES COMPLICATIONSCOMPLICATIONS ARE COSTLCOSTLY Adherence

IN THE UNITED STATES, DIABETES IS THE LEADING CAUSE OF Improved adherence to diabetes medications can lead to bet- kidney failure, non-traumatic lower limb , and new cases of blindness ter health outcomes and reduced costs. According to recent among adults. The rate of is 10 times higher in people with diabetes. research, diabetes patients who do not consistently take YEARLY $87,000 IN CONTRAST, their medicines as prescribed are 2.5 times more likely to be hospitalized than those who follow their prescribed treatment A single year of A YEAR OF MEDICINES AND SUPPLIES regimens more than 80 percent of the time. In addition, a hemodialysis for that can help a patient avoid those outcomes kidney failure patients typically averages recent study in Health Affairs projected that improved adher- ence to diabetes medications could avert more than 1 million NEARLY $40,000 emergency room visits and close to 620,000 hospitalizations The average cost annually, for a total potential savings of $8.3 billion annually. of amputation $4,110 surgery There are several recent studies showing the cost effectiveness of treating diabetes with . Some of those include:

AVERAGE $10,000 • Medicare Part A and B costs associated with poor The average cost of a hospital stay medication adherence are estimated to be up to $840 per month for benefi ciaries with diabetes. The most Source: American Diabetes Association, U.S. Renal Data System, Amputee Coalition, Agency for Healthcare Research and Quality expensive benefi ciaries were episodic medication users including discontinuers, delayed initiators, and individuals with long gaps in use, according to a study published in Health Affairs.

• Insurance plans that perform low on adherence metrics could save $2.1 billion annually for diabetes patients by improving the adherence of their enrollees to even a moderate level. In fact, adherence at a high level could save $19.3 billion, according to a new study.

4 Medicines in Development Diabetes 2014 Key Issues

ADHERENCEADHERENCE ISIS KEY TOTO IMPROVEDIMPROVED HEALTH ADHERENCEADHERENCE CREACREATESTES SASAVINGSVINGS

DIABETES PATIENTS who DID NOT consistently take medications are IMPROVED ADHERENCE TO DIABETES MEDICATIONS 2.5 TIMES MORE LIKELY COULD RESULT IN: TO BE HOSPITALIZED than those who followed their prescribed + = treatment regimens 1,082,000 618,000 $8.3 BILLION fewer fewer in potential emergency hospitalizations annual room visits annually savings

Source: Diabetes Care Source: Health Affairs

Treatment Intensifi cation and Clinical Inertia in Diabetes Care DIABETES AND MINORITIES IN THE UNITED STATES Diabetes is a complex, chronic illness that requires consistent medical care and treatment to help control blood sugar levels Racial and ethnic minority populations in the and prevent acute or long-term complications of the disease, United States are disproportionately affected by such as kidney failure and amputations. diabetes. According to the U.S. Department of Health and Human Services Offi ce of Minority Despite the availability of effective treatments and clinical Health, as compared to non-Hispanic whites: guidelines, many individuals with diabetes do not achieve optimal blood glucose levels. One reason is that patients may • African-American adults are twice as likely to not receive appropriate and timely changes to or intensifi ca- be diagnosed with diabetes. tion of their medication regimen. Multiple studies have found • Hispanic adults are 1.7 times more likely to that there are signifi cant delays in treatment intensifi cation in have diabetes. people with type 2 diabetes despite poor glycemic control. • American Indians and Alaska Natives are twice There are several factors that may contribute to optimal as likely to be diagnosed with the disease. glycemic control and infl uence treatment success. However, understanding appropriate intensifi cation of diabetes treat- • Native Hawaiians and Pacifi c Islanders are ment is critical in achieving clinical goals and value to our three times more likely to be diagnosed with overall healthcare system. diabetes. According to the CDC, of people diagnosed with diabetes, 7.1 percent are non-Hispanic whites, while 8.4 percent are Asian Americans, 12.6 percent are African Americans, 11.3 percent are Hispanic Americans, and 16.1 percent are American Indians/Alaska Natives.

Medicines in Development Diabetes 2014 5 Facts

Facts About Diabetes in the United States

Prevalence1 • Nearly 26 million Americans—8.3 percent of the population DIABETES —are affected by diabetes; including 7 million who are unaware they have the disease. INNOVATION AND ADHERENCE • One in 10 adults has diabetes now. If current trends IMPROVES CARE AND REDUCES COSTS continue, as many as one in three will be facing the disease by 2050 due to an aging population more likely to develop type 2 diabetes, increases in minority groups at high risk for the disease, and longer lifespans among diabetes patients. • Of the nearly 25.6 million adults with diabetes, 13 million are men and 12.6 million are women. • In 2010, 10.9 million people aged 65 years and older had diabetes. • About 215,000 people under the age of 20 had diabetes in 2010. • In 2010, 1.9 million patients were newly diagnosed with Diabetes-Related Conditions diabetes. • Diabetes is the leading cause of kidney failure, non-trau- • As many as 79 million people may have prediabetes. matic lower limb amputations, and new cases of blindness among adults.1 2 Types of Diabetes • The rate of amputation is 10 times higher in people with • Type 1 diabetes accounts for 5 percent of all diagnosed diabetes than those without the disease.2 cases of diabetes. This type of diabetes is usually diag- 3 nosed in children and young adults. Economic Impact • Type 2 diabetes accounts for 95 percent of all diagnosed • In 2012, the cost of diagnosed diabetes in the United cases of diabetes in adults. States was $245 billion—$176 billion for direct medi- cal costs (hospital and emergency care, offi ce visits and • Between 2 percent to 10 percent of pregnant women medications) and $69 billion in reduced productivity. That will develop during pregnancy. represents an increase of 41 percent since 2007. And, women who have had gestational diabetes have a 35 percent to 60 percent chance of developing type • Average medical expenditures among people with diabetes diabetes within the next 20 years. are 2.3 times higher than among those without diabetes. • A signifi cant portion of the U.S. health care dollar goes to Mortality treating people with diabetes. More than $1 in $10 is spent • Diabetes is the seventh leading cause of death in the directly on diabetes and associated complications, and $1 in United States.1 $5 is spent on caring for people with diabetes. • In 2011, 73,282 Americans died as a result of diabetes.1 Sources: • Death rates for heart disease and stroke are as many as 1. National Diabetes Fact Sheet, 2011, U.S. Centers for four times higher among people with diabetes compared Disease Control and Prevention (CDC), www.cdc.gov to those without the disease.3 2. Diabetes Report Card 2012, CDC, www.cdc.gov 3. Economic Costs of Diabetes in the U.S. in 2012, American Diabetes Association (ADA), www.diabetes.org

6 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase*

Afrezza® MannKind type 1 diabetes, type 2 diabetes application submitted insulin inhalation Valencia, CA www.mannkindcorp.com

GlaxoSmithKline type 2 diabetes application submitted (GLP-1 agonist) Research Triangle Park, NC www.gsk.com

alpha-1 antitrypsin (AAT) Omni Bio Pharmaceutical type 1 diabetes Phase I/II (serine proteinase inhibitor) Greenwood Village, CO www.omnibiopharma.com

AMG 876 Amgen type 2 diabetes Phase I (fusion protein) Thousand Oaks, CA www.amgen.com

analog insulin-PH20 Halozyme Therapeutics type 1 diabetes , type 2 diabetes Phase II San Diego, CA www.halozyme.com

ARI-2243 Arisaph Pharmaceuticals type 2 diabetes Phase I (DPP-4 inhibitor) Boston, MA www.arisaph.com

BI-187004 CL Boehringer Ingelheim Pharmaceuticals type 2 diabetes Phase I Ridge eld, CT www.boehringer-ingleheim.com

BIOD-123 Biodel type 1 diabetes Phase II (RHI-based ultra-rapid-acting Danbury, CT www.biodel.com insulin)

BIOD-531 Biodel type 2 diabetes Phase I (RHI-based concentrated Danbury, CT www.biodel.com ultra-rapid-acting insulin)

Bydureon® AstraZeneca type 2 diabetes Phase III weekly suspension Wilmington, DE www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

Bydureon® Dual Chamber Pen AstraZeneca type 2 diabetes application submitted exenatide extended release Wilmington, DE www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

*For more information about a specifi c medicine or company in the report, please use the website provided.

Medicines in Development Diabetes 2014 7 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

Byetta® Bristol-Myers Squibb type 2 diabetes Phase III exenatide Princeton, NJ (adolescents) www.bms.com Eli Lilly www.lilly.com Indianapolis, IN

canagli ozin/metformin Janssen Research & Development type 2 diabetes Phase III extended-release  xed-dose Raritan, NJ www.janssenrnd.com combination

canagli ozin/metformin Janssen Research & Development type 2 diabetes application submitted immediate-release  xed-dose Raritan, NJ www.janssenrnd.com combination

CJC-1134-PC ConjuChem type 2 diabetes Phase II (GLP-1 stimulant) Los Angeles, CA www.conjuchem.com

dapagli ozin/metformin AstraZeneca type 2 diabetes application submitted  xed-dose combination Wilmington, DE www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

dapagli ozin/saxagliptin AstraZeneca diabetes Phase III  xed-dose combination Wilmington, DE www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

diabetes biologic Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

diabetes biologic Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

diabetes NCE Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

diabetes NCE Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

diabetes NCE Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

diabetes NCE Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

DS-1150b Daiichi Sankyo type 2 diabetes Phase I completed (GLUT4 stimulant) Parsippany, NJ www.daiichisankyo.com

DS-7309 Daiichi Sankyo type 2 diabetes Phase I (glucokinase activator) Parsippany, NJ www.daiichisankyo.com

8 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

DS-8500 Daiichi Sankyo diabetes Phase I (GPR119 agonist) Parsippany, NJ www.daiichisankyo.com

Eli Lilly type 2 diabetes application submitted (GLP-1 agonist) Indianapolis, IN www.lilly.com

DV-0100 DiaVacs type 1 diabetes Phase II (dendritic cell vaccine) Edgewater, NJ www.diavacs.us.com ORPHAN DRUG

EGT 0001442 Theracos type 2 diabetes Phase II (SGLT2 inhibitor) Marlborough, MA www.theracos.com

empagli ozin Boehringer Ingelheim Pharmaceuticals type 2 diabetes application submitted (SGLT2 inhibitor) Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

empagli ozin/ Boehringer Ingelheim Pharmaceuticals type 2 diabetes Phase III  xed-dose combination Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

empagli ozin/metformin Boehringer Ingelheim Pharmaceuticals type 2 diabetes Phase I  xed-dose combination Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

ertugli ozin Merck type 2 diabetes Phase III (SGLT2 inhibitor) Whitehouse Station, NJ www.merck.com P zer www.pfizer.com New York, NY

Farxiga™ AstraZeneca type 2 diabetes Phase I dapagli ozin Wilmington, DE (adolescents and children) www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

gevokizumab XOMA type 1 diabetes Phase II (XOMA 052) Berkeley, CA www.xoma.com

glucagon-R antagonist Eli Lilly type 2 diabetes Phase II (LY2409021) Indianapolis, IN www.lilly.com

GSK1070806 GlaxoSmithKline type 2 diabetes Phase II (IL-18 mAb) Research Triangle Park, NC www.gsk.com

Medicines in Development Diabetes 2014 9 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

GSK1614235/GSK2330672 GlaxoSmithKline type 2 diabetes Phase I (SGLT1 inhibitor/iBAT inhibitor) Research Triangle Park, NC www.gsk.com

GSK 2330672 GlaxoSmithKline type 2 diabetes Phase II (iBAT inhibitor) Research Triangle Park, NC www.gsk.com

HE3286 Harbor Biosciences type 2 diabetes Phase II San Diego, CA www.harbortx.com

HIP-2B CureDm type 1 diabetes, type 2 diabetes Phase I (human pro-islet peptide) Wilmington, DE www.curedm.com

HM11260C Hanmi Pharmaceutical type 2 diabetes Phase II (exenatide long-acting) Seoul, South Korea www.hanmipharm.com

HM12460A Hanmi Pharmaceutical type 1 diabetes, type 2 diabetes Phase I (long-acting insulin) Seoul, South Korea www.hanmipharm.com

IDegLira Novo Nordisk type 2 diabetes Phase III / Plainsboro, NJ www.novonordisk.com (NN9068)

faster-acting Novo Nordisk type 1 diabetes, type 2 diabetes Phase III (NN1218) Plainsboro, NJ www.novonordisk.com

insulin B-chain vaccine Orban Biotech type 1 diabetes Phase I completed Brookline, MA www.orbanbiotech.com

insulin biosimilar Harvest Moon Pharmaceuticals diabetes Phase III Falls Church, VA www.harvestmoonpharma.com

insulin biosimilar Sano US diabetes Phase I Bridgewater, NJ www.sanofi.com

biosimilar Harvest Moon Pharmaceuticals diabetes in clinical trials Falls Church, VA www.harvestmoonpharma.com

insulin glargine biosimilar Wockhardt type 1 diabetes Phase I completed Mumbai, India www.wockhardt.com

insulin inhalation Dance Biopharm type 1 diabetes Phase I/II (Dance-01) San Francisco, CA www.dancebiopharm.com

Eli Lilly type 1 diabetes, type 2 diabetes in clinical trials (LY275585) Indianapolis, IN www.lilly.com

insulin peglispro Eli Lilly type 1 diabetes, type 2 diabetes Phase III (LY2605541) Indianapolis, IN www.lilly.com

10 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

ISIS-GCCRRx Isis Pharmaceuticals type 2 diabetes Phase II (antisense oligonucleotide) Carlsbad, CA www.isispharm.com

ISIS-GCGRRx Isis Pharmaceuticals type 2 diabetes Phase II (antisense oligonucleotide) Carlsbad, CA www.isispharm.com

ISIS-PTP1BRx Isis Pharmaceuticals type 2 diabetes Phase II (antisense oligonucleotide) Carlsbad, CA www.isispharm.com

ITCA 650 Intarcia Therapeutics type 2 diabetes Phase III (exenatide subcutaneous implant) Boston, MA www.intarcia.com

Janumet® Merck type 2 diabetes Phase III /metformin Whitehouse Station, NJ (adolescents and children) www.merck.com

Janumet® XR Merck type 2 diabetes Phase III sitagliptin/metformin Whitehouse Station, NJ (adolescents and children) www.merck.com extended release

JTT-851 Akros Pharma type 2 diabetes Phase II (G protein-coupled receptor 40 Princeton, NJ www.akrospharma.com agonist)

KD026 Kadmon Pharmaceuticals type 2 diabetes Phase II (MTP inhibitor) New York, NY www.kadmon.com

Kombiglyze™ XR AstraZeneca type 2 diabetes Phase I /metformin Wilmington, DE (adolescents and children) www.astrazeneca.com extended release Bristol-Myers Squibb www.bms.com Princeton, NJ

LAI287 Novo Nordisk type 1 diabetes, type 2 diabetes Phase I (NN1436) Plainsboro, NJ www.novonordisk.com

LEZ763 Novartis Pharmaceuticals type 2 diabetes Phase II completed East Hanover, NJ www.novartis.com

LGD-6972 Ligand Pharmaceuticals type 2 diabetes Phase I ( antagonist) La Jolla, CA www.ligand.com

LIK066 Novartis Pharmaceuticals type 2 diabetes Phase II (SGLT 1/2 inhibitor) East Hanover, NJ www.novartis.com

linagliptin/pioglitazone Boehringer Ingelheim Pharmaceuticals type 2 diabetes Phase III completed  xed-dose combination Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

Medicines in Development Diabetes 2014 11 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

LixiLan Sano US type 2 diabetes Phase II /insulin glargine Bridgewater, NJ www.sanofi.com  xed-ratio

luseogli ozin Taisho Pharmaceutical type 2 diabetes Phase I (TS-071) Tokyo, Japan www.taisho.co.jp

LX4211 Lexicon Pharmaceuticals type 1 diabetes, type 2 diabetes Phase II (SGLT1/SGLT2 inhibitor) The Woodlands, TX www.lexgen.com

Lyxumia® Sano US type 2 diabetes Phase III lixisenatide Bridgewater, NJ www.sanofi.com

MABp1 Xbiotech type 2 diabetes Phase II completed (T2-18C3) Austin, TX www.xbiotech.com

MBX 2982 CymaBay Therapeutics type 2 diabetes Phase II Hayward, CA www.cymabay.com

mesenchymal precursor cells Mesoblast type 2 diabetes Phase I/II (MPC) Melbourne, Australia www.mesoblast.com

AstraZeneca diabetes and application submitted ( analogue) Wilmington, DE (Fast Track) www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

MK-8521 Merck type 2 diabetes Phase I Whitehouse Station, NJ www.merck.com

MK-8655 Merck type 2 diabetes Phase I Whitehouse Station, NJ www.merck.com

MSDC-0602 Metabolic Solutions Development type 2 diabetes Phase II (mTOT modulator) Kalamazoo, MI www.msdrx.com

Nesina® Takeda Pharmaceuticals type 2 diabetes Phase I alogliptin Deer eld, IL (adolescents and children) www.takeda.com

new insulin glargine biosimilar Boehringer Ingelheim Pharmaceuticals type 1 diabetes, type 2 diabetes application submitted (LY2963016) Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

NewMet™ Elcelyx Therapeutics type 2 diabetes Phase II metformin delayed release San Diego, CA www.elcelyx.com

12 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

NGM 282 NGM Biopharmaceuticals type 2 diabetes Phase II South San Francisco, CA www.ngmbio.com

NM504 MicroBiome Therapeutics metformin-intolerant type 2 diabetes Phase 0 (microbiome modulator) Broom eld, CO www.mbiome.com ------prediabetes Phase 0 www.mbiome.com

NN1953 Novo Nordisk type 1 diabetes, type 2 diabetes Phase I (oral insulin) Plainsboro, NJ www.novonordisk.com

NN1954 Novo Nordisk type 1 diabetes, type 2 diabetes Phase I (oral insulin) Plainsboro, NJ www.novonordisk.com

NN1956 Novo Nordisk type 1 diabetes, type 2 diabetes Phase I (long-acting basal insulin Plainsboro, NJ www.novonordisk.com analogue)

NN9924 Novo Nordisk type 2 diabetes Phase II Plainsboro, NJ www.novonordisk.com

NN9926 Novo Nordisk type 2 diabetes Phase I Plainsboro, NJ www.novonordisk.com

NN9927 Novo Nordisk type 2 diabetes Phase I Plainsboro, NJ www.novonordisk.com

NN9928 Novo Nordisk type 2 diabetes Phase I Plainsboro, NJ www.novonordisk.com

Merck type 2 diabetes Phase III (DPP-4 inhibitor) Whitehouse Station, NJ www.merck.com

Onglyza® AstraZeneca type 2 diabetes Phase III saxagliptin Wilmington, DE (adolescents and children) www.astrazeneca.com Bristol-Myers Squibb www.bms.com Princeton, NJ

Oral-Lyn® Generex Biotechnology type 1 diabetes Phase III oral insulin Toronto, Canada www.generex.com

ORMD 0801 Oramed type 2 diabetes Phase II (oral insulin capsule) Jerusalem, Israel www.oramed.com

Merck type 2 diabetes Phase I completed Whitehouse Station, NJ www.merck.com

Medicines in Development Diabetes 2014 13 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

oxyntomodulin peptide Eli Lilly diabetes Phase I Indianapolis, IN www.lilly.com

P7435 Piramal Enterprises diabetes Phase I Mumbai, India www.piramal.com

P11187 Piramal Enterprises type 2 diabetes Phase I Mumbai, India www.piramal.com

PAZ320 Boston Therapeutics type 2 diabetes Phase II Manchester, NH www.bostonti.com

PB1023 PhaseBio Pharmaceuticals type 2 diabetes Phase II (weekly GLP-1R agonist) Malvern, PA www.phasebio.com

PE0139 PhaseBio Pharmaceuticals type 2 diabetes Phase I (basal native insulin) Malvern, PA www.phasebio.com

PEG-FGF21 Ambrx type 2 diabetes Phase I (pegylated- broblast growth San Diego, CA www.ambrx.com factor-21) Bristol-Myers Squibb www.bms.com Princeton, NJ

Peptide p277 Andromeda Biotech type 1 diabetes Phase III ORPHAN DRUG Yavne, Israel www.andromedabio.com

PF-04937319 P zer type 2 diabetes Phase II (partial glucokinase activator) New York, NY www.pfizer.com

PF-05175157 P zer type 2 diabetes Phase I New York, NY www.pfizer.com

PF-05231023 P zer type 2 diabetes Phase I New York, NY www.pfizer.com

PF-06291874 P zer type 2 diabetes Phase I New York, NY www.pfizer.com

PF-06342674 P zer type 1 diabetes Phase I New York, NY www.pfizer.com

ranolazine extended-release Gilead Sciences type 2 diabetes Phase III Foster City, CA www.gilead.com

14 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

RG7697 Roche type 2 diabetes Phase I (dual agonist [GLP and GIP] Nutley, NJ www.roche.com peptide analogue)

RM 493 Rhythm Pharmaceuticals diabetes Phase II (MC4R peptide therapeutic) Boston, MA www.rhythmtx.com

Ryzodeq® Novo Nordisk type 1 diabetes, type 2 diabetes application submitted insulin degludec/insulin aspart Plainsboro, NJ www.novonordisk.com

S-707106 Shionogi type 2 diabetes Phase II (insulin sensitizer) Osaka, Japan www.shionogi.co.jp

Novo Nordisk type 2 diabetes Phase III (NN9535) Plainsboro, NJ www.novonordisk.com

Mitsubishi Tanabe Pharma America type 2 diabetes Phase I (DPP-4 inhibitor) Jersey City, NJ www.mt-pharma-america.com

teplizumab Macrogenics type 1 diabetes Phase III (anti-CD3 mAb) Rockville, MD www.macrogenics.com ORPHAN DRUG

TOL-3021 Tolerion type 1 diabetes Phase II (antigen-speci c Portola Valley, CA www.tolerioninc.com immunotherapeutic vaccine)

Takeda Pharmaceuticals type 2 diabetes Phase II (DPP-4 inhibitor) Deer eld, IL www.takeda.com

Tresiba® Novo Nordisk type 1 diabetes, type 2 diabetes application submitted insulin degludec Plainsboro, NJ www.novonordisk.com ------type 1 diabetes (adolescents) Phase III completed www.novonordisk.com

TTP054 TransTech Pharma type 2 diabetes Phase II (GLP-1 receptor agonist) High Point, NC www.ttpharma.com

TTP399 TransTech Pharma type 2 diabetes Phase I/II (glucokinase inhibitor) High Point, NC www.ttpharma.com

TTP814 TransTech Pharma type 2 diabetes Phase I/II (PTP-1B inhibitor) High Point, NC www.ttpharma.com

U300 Sano US type 1 diabetes, type 2 diabetes Phase III Bridgewater, NJ www.sanofi.com

Medicines in Development Diabetes 2014 15 Medicines in Development for Diabetes

Diabetes, Type 1 Diabetes and Type 2 Diabetes

Product Name Sponsor Indication Development Phase

U-Strip™ Transdermal Specialties type 1 diabetes, type 2 diabetes Phase I insulin transdermal ultrasonic Norwalk, CT www.transdermalspecialties.com patch

Victoza® Novo Nordisk type 1 diabetes Phase III liraglutide Plainsboro, NJ www.novonordisk.com

VRS-859 Diartis Pharmaceuticals type 2 diabetes Phase I (exenatide-XTEN) Redwood City, CA www.diartispharma.com

ZP2929 Zealand Pharma type 2 diabetes Phase I (glucagon and GLP-1 receptor Copenhagen, Denmark www.zealandpharma.com agonists) Diabetes-Related Conditions

Product Name Sponsor Indication Development Phase

AKB-9778 Aerpio Therapeutics diabetic macular edema Phase II (Tie-2 activator) Cincinnati, OH www.aerpio.com

ALG-1001 Allegro Ophthalmics diabetic macular edema Phase I/II (oligopeptide therapy) San Juan Capistrano, CA www.allegroeye.com

AppliGel-G Royer Biomedical ulcers Phase I/II gentamicin topical Frederick, MD www.royerbiomedical.com

ARA 290 Araim Pharmaceuticals diabetic neuropathy Phase I/II Yorktown, NY www.araim.org

AS-3201 Eisai diabetic neuropathy Phase II/III (ranirestat) Woodcli Lake, NJ www.eisai.com

AbbVie diabetic nephropathy Phase III North Chicago, IL (adjunctive therapy) www.abbvie.com

AVP-923 Avanir Pharmaceuticals diabetic neuropathy Phase III (dextromethorphan/quinidine Aliso Viejo, CA www.avanir.com  xed-dose combination)

AZD1722/RDX5791 Ardelyx management of uid retention in Phase II (NHE3 inhibitor) Fremont, CA patients with chronic kidney disease www.ardelyx.com AstraZeneca and type 2 diabetes www.astrazeneca.com Wilmington, DE

16 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes-Related Conditions

Product Name Sponsor Indication Development Phase

AZD5213 AstraZeneca diabetic neuropathy Phase II (histamine-3 receptor Wilmington, DE www.astrazeneca.com antagonist)

baricitinib Eli Lilly diabetic nephropathy Phase II (JAK1/JAK2 inhibitor) Indianapolis, IN www.lilly.com Incyte www.incyte.com Wilmington, DE

BMS-813160 Bristol-Myers Squibb diabetic nephropathy Phase II (CCR2/CCR5 chemokine receptor Princeton, NJ www.bms.com antagonist)

GlaxoSmithKline diabetic gastroparesis Phase II (GSK962040) Research Triangle Park, NC www.gsk.com

CBX129801 Cebix diabetic neuropathy Phase II (long-acting C-peptide) San Diego, CA (Fast Track) www.cebix.com

CCX 140 ChemoCentryx diabetic nephropathy Phase II (CCR2 ) Mountain View, CA www.chemocentryx.com

Cogenzia™ Innocoll diabetic foot ulcers Phase III gentamicin implant County Westmeath, Ireland www.innocollinc.com

CTP-499 Concert Pharmaceuticals diabetic nephropathy Phase II (PDE inhibitor) Lexington, MA (adjunctive therapy) www.concertpharma.com

CureXcell™ Macrocure diabetic foot ulcers Phase III leukocyte cell therapy Petach Tikva, Israel (adjunctive therapy) www.macrocure.com

darapladib GlaxoSmithKline diabetic macular edema Phase II (Lp-PLA2 inhibitor) Research Triangle Park, NC www.gsk.com

dexamethasone palmitate Santen diabetic macular edema Phase I/II (intravetrious) Emeryville, CA www.santeninc.com

d-methadone Relmada Therapeutics diabetic neuropathy Phase I/II New York, NY www.relmada.com

DSC127 Derma Sciences diabetic foot ulcers Phase III (angiotensin receptor agonist) Princeton, NJ www.dermasciences.com

EVK-001 Evoke Pharma diabetic gastroparesis Phase II ( intranasal) Solana Beach, CA www.evokepharma.com

Medicines in Development Diabetes 2014 17 Medicines in Development for Diabetes

Diabetes-Related Conditions

Product Name Sponsor Indication Development Phase

Eylea® Bayer HealthCare Pharmaceuticals diabetic macular edema application submitted a ibercept Whippany, NJ www.bayerpharma.com Regeneron Pharmaceuticals www.regeneron.com Tarrytown, NY

 nerenone Bayer HealthCare Pharmaceuticals diabetic nephropathy Phase II Whippany, NJ www.bayerpharma.com

GKT137831 Genkyotex Innovation diabetic nephropathy Phase II Geneva, Switzerland www.genkyotex.com

GSK1278863 GlaxoSmithKline diabetic foot ulcers Phase I (prolyl hydroxylase inhibitor) Research Triangle Park, NC www.gsk.com

HO/03/03 HealOr diabetic foot ulcers Phase II/III (protein kinase C-modulating Ness Ziona, Israel www.healor.com inhibitors and stimulant)

H.P. Acthar® Gel Questcor Pharmaceuticals diabetic nephropathy Phase II repository corticotropin injection Anaheim Hills, CA www.questcor.com

iCO-007 iCo Therapeutics diabetic macular edema Phase II (antisense oligonucleotide) Vancouver, Canada www.icotherapeutics.com

Iluvien® Alimera Sciences diabetic macular edema application submitted uocinolone acetonide Alpharetta, GA (Fast Track) www.alimerasciences.com micro-insert intravitreous implant

Lucentis® Genentech diabetic macular edema Phase I ranibizumab South San Francisco, CA www.gene.com (sustained delivery implant)

nepafenac Alcon Laboratories Phase III Fort Worth, TX www.alcon.com

Nexagon® CoDa Therapeutics diabetic foot ulcers Phase II antisense oligonucleotide San Diego, CA www.codatherapeutics.com

NP-1998 Acorda Therapeutics diabetic neuropathy Phase II Ardsley, NY www.acorda.com

OC-10X OcuCure Therapeutics diabetic retinopathy Phase I Roanoke, VA www.ocucure.com

Optina™ Ampio Pharmaceuticals diabetic macular edema Phase II danazol low-dose Greenwood Village, CA www.ampiopharma.com

18 Medicines in Development Diabetes 2014 Medicines in Development for Diabetes

Diabetes-Related Conditions

Product Name Sponsor Indication Development Phase

Ozurdex® Allergan diabetic macular edema application submitted dexamethasone ophthalmic Irvine, CA www.allergan.com (intravitreous)

PDA002 Celgene diabetic foot ulcers Phase I (human placental-derived stem Summit, NJ www.celgene.com cell therapy)

pexiganan Dipexium Pharmaceuticals diabetic foot ulcers Phase III White Plains, NY www.dipexiumpharmaceuticals.com

PF-655 (RTP801i14) Quark Pharmaceuticals diabetic macular edema Phase II Fremont, CA www.quarkpharma.com

PF-00489791 P zer diabetic nephropathy Phase II New York, NY www.pfizer.com

PF-04634817 P zer diabetic nephropathy Phase II (CCR2/5 antagonist) New York, NY www.pfizer.com

pyridoxamine NephroGenex diabetic nephropathy Phase II Research Triangle Park, NC (Fast Track) www.nephrogenex.com

RGN-259 eye drops RegeneRx Biopharmaceuticals diabetic retinopathy Phase II completed ( beta-4) Rockville, MD www.regenerx.com

RM-131 Rhythm Pharmaceuticals diabetic gastroparesis Phase II (ghrelin peptide agonist) Boston, MA www.rhythmtx.com

SKL-NP SK biopharmaceuticals diabetic neuropathy Phase II Fair Lawn, NJ www.skbp.com

sodium nitrite oral TheraVasc diabetic Phase II Cleveland, OH www.theravasc.com

TGF-α/epiregulin mAb Eli Lilly diabetic nephropathy Phase I (LY3016859) Indianapolis, IN www.lilly.com

TGF-ß mAb Eli Lilly diabetic nephropathy Phase II (LY2382770) Indianapolis, IN www.lilly.com

topical clonidine gel BioDelivery Sciences International diabetic neuropathy Phase II Raleigh, NC (Fast Track) www.bdsi.com

Medicines in Development Diabetes 2014 19 Medicines in Development for Diabetes

Diabetes-Related Conditions

Product Name Sponsor Indication Development Phase

Tradjenta® Boehringer Ingelheim Pharmaceuticals diabetic nephropathy Phase III linagliptin Ridge eld, CT www.boehringer-ingelheim.com Eli Lilly www.lilly.com Indianapolis, IN

VM202 ViroMed diabetic neuropathy Phase II (modi ed hepatocyte growth Seoul, South Korea www.viromed.co.kr factor gene therapy) VM BioPharma Atlanta, GA

The content of this report has been obtained through public, government and industry sources, and the Adis “R&D Insight” database based on the latest information. Report current as of February 3, 2014. The medicines in this report include medicines being developed by U.S.-based companies conducting trials in the United States and abroad, PhRMA-member companies conducting trials in the United States and abroad, and foreign companies conducting clinical trials in the United States. The information in this report may not be comprehensive. For more specifi c information about a particular product, contact the individual company directly or go to www.clinicaltrials.gov. The entire series of Medicines in Development is available on PhRMA’s website. A publication of PhRMA’s Communications & Public Affairs Department (202) 835-3460 www.phrma.org | www.innovation.org | www.pparx.org Provided as a public service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2014 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

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20 Medicines in Development Diabetes 2014 Glossary

application submitted—An application to the vessel walls, and blocks the fl ow small intestine and is absorbed, blood for marketing has been submitted by of blood. Macroangiopathy may cause glucose levels rise. If food stays too long the company to the U.S. Food and Drug other complications, such as ischemic in the stomach, it can cause problems Administration (FDA). heart disease, stroke, and peripheral like bacterial overgrowth because the vascular disease, which contribute to the food has fermented. Also, the food can diabetes—A chronic disease in which diabetic foot ulcers and the risk of am- harden into solid masses, called bezoars, the body does not produce or properly putation. In , the walls that may cause nausea, vomiting, and use insulin, a hormone that is needed of the smaller blood vessels become so obstruction in the stomach. Bezoars can to convert sugar, starches and other thick and weak that they bleed, leak pro- be dangerous if they block the passage food into energy needed for daily life. tein, and slow the fl ow of blood through of food into the small intestine. Symptoms may include excessive thirst, the body. The decrease of blood fl ow —Kidney disease hunger, urination and weight loss. The through clot formation impairs the fl ow diabetic nephropathy or damage that can occur in people with cause of diabetes continues to be a of oxygen to cells and biological tissues diabetes. The kidneys have many tiny mystery, although both genetics and (called ischemia) and leads to cellular blood vessels that fi lter waste from the environmental factors such as obesity death (necrosis and , which in blood. High blood sugar from diabetes and lack of exercise appear to play roles. turn may require amputation). Thus, tis- can destroy those blood vessels. Over Type 1 diabetes, the more severe form, sues which are very sensitive to oxygen time, the kidney isn’t able to do its job as results from the body’s failure to pro- levels, such as the retina, develop mi- well and may stop working completely, duce insulin, which “unlocks” the cells of croangiopathy and may cause blindness which is called kidney failure. Out of 100 the body, allowing glucose to enter and (so-called proliferative diabetic retinopa- people with diabetes, as many as 40 fuel them. It is estimated that 5 percent thy). Damage to nerve cells may cause will develop kidney damage. Currently, to 10 percent of Americans who are , and to kidney diabetic nephropathy is the leading cause diagnosed with diabetes have type 1, cells, diabetic nephropathy. which requires insulin treatment. Type 2 of chronic kidney disease in the United diabetes results from insulin resistance diabetic gastroparesis—A disorder af- States and other Western societies. It is (a condition in which the body fails to fecting people with both type 1 and type also one of the most signifi cant long- properly use insulin), combined with 2 diabetes in which the stomach takes term complications in terms of morbidity relative insulin defi ciency. Most Ameri- too long to empty its contents (delayed and mortality for individual patients with cans who are diagnosed with diabetes gastric emptying). The vagus nerve con- diabetes, which is responsible for up to have type 2, which in most cases can trols the movement of food through the 40 percent of all end-stage renal disease be controlled if treated properly by a digestive tract. If the vagus nerve is dam- (ESRD) cases in the United States. combination of dietary measures, weight aged or stops working, the muscles of —Nerve damage in loss, and oral medication. the stomach and intestines do not work diabetic neuropathy the arms, hands, legs, and feet caused normally, and the movement of food is by diabetes. The condition develops diabetic angiopathy—Similar to most slowed or stopped. Just as with other slowly and worsens over time. Depend- complications brought about by diabe- types of neuropathy (nerve damage), ing on the types of nerves involved, one tes, diabetic angiopathy is primarily due diabetes can damage the vagus nerve if or more signs and symptoms may be to or the high levels of blood glucose levels remain high over a present in diabetic peripheral neuropathy. blood sugar known as glucose. Angiopa- long period of time. High blood glucose Sensory neuropathy results in numbness thy can occur in any part of the body causes chemical changes in nerves and or tingling in the feet or pain or discom- where the effect of high glucose levels damages the blood vessels that carry fort in the feet or legs, including prickly, result in the build-up of plaque in the oxygen and nutrients to the nerves. sharp pain or burning feet. Motor neu- inner walls of the vessels. There are two Gastroparesis can make diabetes worse ropathy involves muscle weakness and types of the disease—macroangiopathy by making it more diffi cult to manage loss of muscle tone in the feet and lower or microangiopathy. In macroangiopathy, blood glucose. When food that has been legs, loss of balance, or changes in foot atherosclerosis and a resultant blood clot delayed in the stomach fi nally enters the forms on the large blood vessels, sticks shape that can lead to areas of increased

Medicines in Development Diabetes 2014 21 Glossary

pressure. Autonomic neuropathy results diabetic ulcers—The most common macular edema—A condition in which in dry feet and cracked skin. The loss of foot injuries leading to lower extremity fl uid can leak into the center of the sensation and other problems associated amputation. The vast majority of diabetic macula, the part of the eye where sharp, with nerve damage make a patient prone foot complications resulting in amputa- straight-ahead vision occurs. The fl uid to developing skin ulcers (open sores) tion begin with the formation of skin makes the macula swell, thus blurring that can become infected and may not ulcers. The three main causes of diabetic vision. It can occur at any stage of heal. This serious complication of diabe- foot ulcers are: neuropathy, poor blood diabetic retinopathy, although it is more tes can lead to the loss of a foot, a leg, supply, and infection. Up to 15 percent likely to occur as the disease progresses. or even a life. of diabetics are likely to develop a foot About half of the people with prolif- ulcer at some stage in their lives. Early erative retinopathy also have macular diabetic retinopathy—The most com- detection and appropriate treatment of edema. mon diabetic eye disease and a leading those ulcers may prevent up to 85 per- —A group of cause of blindness in American adults. cent of amputations. The risk of lower metabolic syndrome metabolic risk factors that raise the It is caused by changes in the blood extremity amputation is 15 to 46 times risk of type 2 diabetes in one person, vessels of the retina, the light sensitive higher in diabetics than in people who including: abdominal obesity (excessive tissue at the back of the eye that is nec- do not have the disease. essary for good vision. In some people fat tissue in and around the abdomen); with diabetic retinopathy, blood ves- Fast Track—A process designed to atherogenic dyslipidemia (blood fat sels may swell and leak fl uid. In others, facilitate the development and expedite disorders—high triglycerides, low HDL abnormal new blood vessels grow on the the review of drugs to treat serious cholesterol, and high surface of the retina. Over time, diabetic diseases and fi ll an unmet medical need. —New chemical entity. retinopathy, which usually affects both The status is assigned by the U.S. Food NCE eyes, can worsen and cause vision loss. and Drug Administration. The purpose Orphan Drug—A drug to treat a dis- The condition has four stages: 1) mild is to get important new drugs to the ease that has a patient population of nonproliferative retinopathy, the earli- patient earlier. Fast Track addresses a 200,000 or less in the United States, or est stage during which microaneurysms broad range of serious diseases. Gener- a disease that has a patient population occur in the retina’s tiny blood vessels; ally, determining factors include whether of more than 200,000 and a develop- 2) moderate nonproliferative retinopathy, the drug will have an impact on such ment cost that will not be recovered during which some blood vessels that factors as survival, day-to-day function- from sales in the United States. nourish the retina are blocked; 3) severe ing, or the likelihood that the disease, if nonproliferative retinopathy, when many left untreated, will progress from a less Phase 0—First-in-human trials conduct- more blood vessels are blocked and severe condition to a more serious one. ed in accordance with FDA’s 2006 guid- deprive several areas of the retina with Filling an unmet medical need is defi ned ance on exploratory Investigational New their blood supply; and 4) proliferative as providing a therapy where none ex- Drug (IND) studies designed to speed up retinopathy, the advanced stage when ists, or providing a therapy which may be development of promising drugs by es- signals sent by the retina for nourish- potentially superior to existing therapy. tablishing very early whether the tested ment trigger the growth of new blood Once a drug receives Fast Track designa- compound behaves in human subjects as vessels, which grow along the retina and tion, early and frequent communication was anticipated from preclinical studies. the surface of the clear, vitreous gel that between the FDA and a drug company is Phase I—Researchers test the drug in a fi lls the inside of the eye. If those thin, encouraged throughout the entire drug small group of people, usually between fragile blood vessels leak blood, severe development and review process. The 20 and 80 healthy adult volunteers, to vision loss and even blindness can result. frequency of communication assures that evaluate its initial safety and tolerability Up to 45 percent of Americans diag- questions and issues are resolved quickly, profi le, determine a safe dosage range, nosed with diabetes have some stage of often leading to earlier drug approval and identify potential side effects. diabetic retinopathy. and access by patients.

22 Medicines in Development Diabetes 2014 Glossary

Phase II—The drug is given to volun- involving between 1,000 and 3,000 Prediabetes—A condition characterized teer patients, usually between 100 and patients (but sometimes many more by higher than normal blood glucose 300, to see if it is effective, identify an thousands), to generate statistically levels but not yet high enough to be optimal dose, and to further evaluate its signifi cant evidence to confi rm its safety diagnosed as diabetes. Prediabetes puts short-term safety. and effectiveness. They are the longest people at a higher risk for develop- studies, and usually take place in multiple ing type 2 diabetes and cardiovascular Phase III—The drug is given to a larger, sites around the world. disease. more diverse patient population, often

Medicines in Development Diabetes 2014 23 The Drug Discovery, Development and Approval Process

Developing a new medicine takes an average of 10-15 years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved. Drug Discovery and Development: A LONG, RISKY ROAD

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG Y

5,000–10,000 250 5 VEILLANCE ONE FDA-

VER COMPOUNDS APPROVED O DRUG

PHASE PHASE PHASE ARKETING SUR 1 2 3 -M ST NUMBER OF VOLUNTEERS PRE-DISC 20–80 100–300 1,000–3,000 A SUBMITTED 0.5–2 IND SUBMITTE D 3–6 YEARS6–7 YEARS ND

YEARS PHASE 4: PO The Drug Development and Approval Process The U.S. system of new drug approvals is in people. The IND shows results of previous ate statistically signifi cant evidence to confi rm perhaps the most rigorous in the world. experiments; how, where and by whom the new its safety and effectiveness. They are the lon- studies will be conducted; the chemical structure gest studies, and usually take place in multiple It takes 10-15 years, on average, for an experi- of the compound; how it is thought to work in sites around the world. mental drug to travel from lab to U.S. patients, the body; any toxic effects found in the animal according to the Tufts Center for the Study of New Drug Application (NDA)/Biologic License studies; and how the compound is manufac- Drug Development. Only fi ve in 5,000 com- Application (BLA). Following the completion tured. All clinical trials must be reviewed and ap- pounds that enter preclinical testing make it to of all three phases of clinical trials, a company proved by the Institutional Review Board (IRB) human testing. And only one of those fi ve is analyzes all of the data and fi les an NDA or BLA where the trials will be conducted. Progress approved for sale. with FDA if the data successfully demonstrate reports on clinical trials must be submitted at both safety and effectiveness. The applications On average, it costs a company $1.2 billion, least annually to FDA and the IRB. contain all of the scientifi c information that the including the cost of failures, to get one new Clinical Trials, Phase I—Researchers test the company has gathered. Applications typically medicine from the laboratory to U.S. patients, drug in a small group of people, usually between run 100,000 pages or more. according to a recent study by the Tufts Center 20 and 80 healthy adult volunteers, to evaluate for the Study of Drug Development. Approval. Once FDA approves an NDA or BLA, its initial safety and tolerability profi le, deter- the new medicine becomes available for physi- Once a new compound has been identifi ed in mine a safe dosage range, and identify potential cians to prescribe. A company must continue the laboratory, medicines are usually developed side effects. to submit periodic reports to FDA, including as follows: Clinical Trials, Phase II—The drug is given any cases of adverse reactions and appropriate Preclinical Testing. A pharmaceutical company to volunteer patients, usually between 100 and quality-control records. For some medicines, conducts laboratory and animal studies to show 300, to see if it is effective, identify an optimal FDA requires additional trials (Phase IV) to biological activity of the compound against the dose, and to further evaluate its short-term evaluate long-term effects. targeted disease, and the compound is evalu- safety. Discovering and developing safe and effective ated for safety. Clinical Trials, Phase III—The drug is given to a new medicines is a long, diffi cult, and expensive Investigational New Drug Application (IND). larger, more diverse patient population, often process. PhRMA member companies invested an After completing preclinical testing, a com- involving between 1,000 and 3,000 patients estimated $48.5 billion in research and develop- pany fi les an IND with the U.S. Food and Drug (but sometime many more thousands), to gener- ment in 2012. Administration (FDA) to begin to test the drug