Shire is a rapidly growing, global specialty biopharmaceutical company aiming “to enable people with life-altering conditions to lead better lives.” While based in the U.K. and the U.S., it also directly markets its products in over 50 countries including Canada, Ireland, France, Germany, Belgium, Italy and Spain, and it has operations and/or offices in 29 countries including Australia, Argentina, Mexico, Japan, Russia and Thailand. Shire’s stated goal is to have half of its sales originate from beyond the U.S. and European markets by 2015.

Shire Human Genetic Therapies (HGT) are enzyme replacement therapies targeting rare, inherited conditions including Fabry disease, Hunter syndrome, Gaucher disease, hereditary angioedema and metachromatic leukodystrophy. The Specialty Pharmaceuticals division focuses on patients with attention deficit/hyperactivity disorder (ADHD), ulcerative colitis and end-stage renal disease.

Except for HGT, most of Shire’s products have emerged from a strategic acquisition, partnership or merger, which have facilitated new drug development while enlarging marketed portfolios. Shire’s corporate brand is “BRAVE,” reflecting the attitude of patients fighting life-threatening conditions and the company’s stance in taking appropriate risks by using new strategies for drug development.

In Gastrointestinal, Shire has two drugs in phase III and three in phase II. The Neurology pipeline includes two drugs in phase III, one in phase II and two in phase I/II. There is one Cardiovascular drug in phase III and one Musculoskeletal drug in phase II. Shire’s Gastrointestinal arena includes Lialda, a sustained release formulation of the anti-inflammatory drug mesalamine, a locally acting 5-aminosalicylic acid now in phase III trials for diverticulitis. The 1.2g, once-daily, delayed-release tablet is currently indicated to induce remission in patients with active, mild-to-moderate ulcerative colitis and to maintain remission in ulcerative colitis.

Resolor, in phase III development for treatment of chronic constipation in men, contains prucalopride succinate, a selective, high-affinity, 5-HT4 receptor serotonin agonist. In the U.K., 1mg tablets of Resolor are available for treatment of constipation in terminally ill patients, as well as fecal impaction and chronic constipation refractoryto treatment with laxatives. In a phase III trial, compared with placebo Resolor was more effective in increasing the number of spontaneous bowel movements, completeness of evacuation and quality of life, and in reducing perceived disease severity and the need for straining.

Another selective 5-HT4 receptor agonist is SPD 557 (M0003), in phase II testing for Gastroesophageal Reflux Disease (GERD) refractory to treatment with proton pump inhibitors (PPIs). In late 2010, an exploratory phase II program began to assess the effect of SPD 557 on reflux episodes in patients taking PPIs.

Phase II testing is also planned for SPD 556 (M0002), a selective Vasopressin V2 receptor antagonist intended to treat ascites, and for SPD 535, a novel molecule with platelet-lowering ability but without phosphodiesterase type III inhibition. SPD 535 is intended to prevent thrombotic complications associated with arteriovenous grafts in hemodialysis patients, and proof-of-principle data from phase I clinical trials have been positive. Further phase II proof-of-concept clinical trials of SPD 535 are also planned to evaluate potential alternative indications.

In Neurology, the leading candidate is Vyvanse (lisdexamfetamine dimesylate), in phase III trials for ADHD and major depressive disorder, and in phase II testing for negative symptoms and cognitive impairment in schizophrenia, excessive daytime sleepiness and binge eating disorder. This long-acting, once-daily prodrug of dextroamphetamine is being developed in partnership with Shionogi. Vyvanse should be used as part of a therapeutic regimen that may include counseling or other treatment. Its safety and tolerability profiles resemble those seen with other CNS stimulants, and because of its potential for abuse and/or dependence, Vyvanse is a federally controlled substance.

Intuniv (guanfacine), a selective alpha-2Aadrenoceptor agonist psychomodulator, was also developed in partnership with Shionogi for monotherapy and as adjunctive therapy to stimulant medications in treatment of ADHD. In February 2011, the FDA approved Intuniv extended-release tablets for once-daily use as adjunctive treatment to stimulants for children and adolescents six to 17 with ADHD. Because it is not a CNS stimulant, it has low potential for dependence or abuse and it is not a controlled substance.

HGT 2310 (Elaprase; idursulfase) is an enzyme replacement therapy, administered intrathecally (into the cerebrospinal fluid) to treat patients with CNS symptoms due to Hunter syndrome. Also known as mucopolysaccharidosis Type II, Hunter syndrome is a lysosomal storage disease caused by deficient or absent iduronate-2-sulfatase. The FDA has granted orphan designation to HGT 2310, and a phase I/II clinical trial began in early 2010.

Another intrathecally administered enzyme replacement therapy is HGT 1410, in phase I/II testing for Sanfilippo A syndrome (mucopolysaccharidosis IIIA). This agent has also received orphan drug designation in the U.S. and Europe, and a phase I/II clinical trial began in August 2010.

Shire’s HGT products also include HGT 4510 (ACE-031), in phase II development in the Musculoskeletal field for Duchenne Muscular Dystrophy (DMD). This fusion protein is designed to increase muscle mass and inhibit negative muscle regulators. In 2010, Shire acquired HGT 4510 and other members of the ActRIIB class of molecules being developed by Acceleron through an exclusive license in markets outside of North America. U.S. and European regulators have granted HGT 4510 orphan status.

In the Cardiovascular arena, Shire’s pipeline includes Xagrid, a quinazoline phosphodiesterase inhibitor intended for treatment of essential thrombocythemia. Phase III safety and efficacy trials are enrolling adults with essential thrombocythemia intolerant of or refractory to cytoreductive therapy, as reflected in failure of platelet counts to decline to an acceptable level.

In Shire’s 20 years in existence, it has made great strides in ADHD and HGT, largely targeting rare genetic diseases with enzyme replacement therapies. Strategic partnerships and agreements have enhanced Shire’s pipeline in additional areas, and future developments are eagerly anticipated.

UCB is a global biopharmaceutical company headquartered in Brussels, Belgium, marketing products in more than 40 countries. Revenue in 2010 was $4.3 billion, and the company has more than 8,500 employees and strategic partnerships with key pharmaceutical companies. Its international research and development organization includes UCB New Medicines and UCB Global Projects and Development.

UCB’s mission statement is “to help people suffering from severe central nervous system or immunological disorders lead normal, everyday lives… to offer them innovative new medicines and groundbreaking solutions that go beyond the drug [and]… to enabling cutting-edge scientific research that is driven by the patients' needs."

Its research strategy is to combine its expertise in designing large, biologically active antibody-based molecules with expertise in developing small, chemically-derived molecules. Its currently marketed products and those in the pipeline target severe diseases of the central nervous system, immune system and musculoskeletal system.

The Neurology pipeline has two drugs in phase III and one each in phase II and phase I; Immunology has two drugs in phase III and one in phase I; Rheumatology has two in phase II; and there is one phase II candidate in the Musculoskeletal arena.

In Neurology, Vimpat (lacosamide) is in phase III trials as monotherapy for epilepsy and in phase II testing for primary generalized tonic-clonic seizures in the pediatric population. Its mechanism of action is to enhance slow inactivation of sodium channels and to interact with collapsin-response mediator protein-2 (CRMP-2), which is relevant to neuroplasticity. Vimpat tablets and injection are Schedule V controlled substances, first marketed in the U.S. in May 2009 as an add-on treatment for partial-onset seizures in persons at least 17 years old.

Brivaracetam, in phase III trials for epilepsy, is chemically related to the antiepileptic drug levetiracetam (Keppra). However, binding affinity for the synaptic vesicle protein 2A of brivaracetam is tenfold greater than that of levetiracetam. Another mechanism of action of brivaracetam is inhibition of sodium channels.

For refactory epilepsy, UCB0942 is a pre-and-post synaptic inhibitor in phase I testing. In Immunology, UCB is collaborating with Immunomedics on phase III development of epratuzumab for systemic lupus erythematosus (SLE). This humanized monoclonal antibody targets the CD22 receptor and modulates activity of B-cell lymphocytes, which produce auto-antibodies, thereby causing inflammation and tissue damage.

The EMBLEM study is a phase IIb trial that assessed the efficacy and safety of various intravenous doses (200mg to 3600mg) and regimens of epratuzumab as adjunctive therapy to immunosuppressants in patients with SLE. At 12 weeks, all epratuzumab doses were superior to placebo on a validated measure of SLE disease activity, and patients receiving epratuzumab at a cumulative dose of 2400mg had meaningful and statistically significant reductions in disease activity.

Also in the Immunology pipeline for SLE is CDP7657, a monovalent Fab’ PEG anti-human CD40L antibody now in a phase I clinical study. CD40L plays an important role in modulating T-cell dependent activation of B cells and other antigen-presenting cells. A randomized, double-blind, placebocontrolled, single-dose, dose-escalating study is now underway to assess the safety, tolerability, pharmacokinetics and immunogenicity of CDP7657 in healthy volunteers and in patients with SLE.

In Rheumatology, Cimzia (certolizumab pegol), a humanized, pegylated inhibitor of tumor necrosis factor alpha, is in phase III trials for psoriatic arthritis and ankylosing spondylitis, and in phase II testing for juvenile rheumatoid arthritis. Cimzia is FDA-approved for reducing signs and symptoms of and maintenance therapy of Crohn’s disease.

In two Japanese studies (J-RAPID and HIKARI), patients with rheumatoid arthritis refractory to methotrexate had a rapid and sustained response with Cimzia compared to placebo. This response occurred as early as the first week of treatment and was sustained to 24 weeks. Benefits of Cimzia included significant inhibition of structural joint damage progression and significant improvements in physical function. In the HIKARI study, these benefits occurred in patients receiving Cimzia monotherapy and in those who also received disease modifying antirheumatic drugs other than methotrexate.

Also for rheumatoid arthritis is olokizumab, a monoclonal antibody targeting interleukin-6. A phase II, dose-finding study is underway to compare the efficacy and safety of olokizumab given subcutaneously for 12 weeks with those of placebo. This randomized, double-blind trial will enroll Asian participants with active rheumatoid arthritis refractory to treatment with TNF inhibitors.

In the Musculoskeletal field, UCB is collaborating with Amgen on phase II development of CDP7851, a humanized monoclonal antibody against sclerostin, a protein secreted by bone cells to inhibit bone formation. This antibody is designed to promote fracture healing in patients with post-menopausal osteoporosis. In a phase II international study comparing CDP7851 to placebo in postmenopausal women with low bone mineral density (BMD), those receiving this antibody had significant increases in lumbar spine BMD at 12 months. These increases were comparable to those seen with teriparatide and alendronate, drugs currently used to improve BMD.

UCB has innovatively combined its expertise in development of monoclonal antibodies with its technological advances in designing small chemicals. Both strategies should prove useful against severe diseases in the therapeutic fields of neurology, rheumatology, and immunology.

Eli Lilly has a long history of pharmaceutical innovation beginning in 1876, and it is now the tenth largest pharmaceutical company worldwide. Its global presence features products marketed in 125 countries, clinical research performed in more than 50 countries, manufacturing plants in 13 countries and R&D facilities in eight countries.

Lilly’s R&D focus is “generating potential biotech solutions alongside more traditional chemistry-based work in order to deliver innovative treatments to patients for a wide range of diseases, including cancer, diabetes, osteoporosis, rheumatoid arthritis and Alzheimer’s disease.” The company is also pursuing tailored therapies, or personalized, patient-specific medicines designed to improve outcomes for individual patients.

In addition to the numerous medicines already approved and widely marketed, Lilly’s current pipeline contains an unprecedented number of potential drugs. Products, in a wide range of therapeutic fields, include those in Oncology (three in phase III and 10 in phase II), Endocrinology (two in phase III and four in phase II), Neurology (two in phase III and two in phase II), Rheumatology (one in phase III and two in phase II), Musculoskeletal (two in phase II), Psychology/Psychiatry (one in phase III), Cardiovascular (one in phase II) and Urology (one in phase II). The pipeline also contains 29 drugs in phase I development, three undergoing regulatory review and seven being studied to treat a different disease or in a different formulation.

In Oncology, LY317615 (enzastaurin), an inhibitor of the protein kinase Cß and AKT pathways, is in phase III development for treatment of large B-cell lymphoma. Two other phase III Oncology agents, both monoclonal antibodies obtained by Lilly’s acquisition of ImClone, are LY3009806 (ramucirumab) and LY3012211 (necitumumab).

In partnership with Bristol-Myers Squibb, Lilly is developing necitumumab, an endothelial growth factor receptor (EGFR) antagonist intended for lung cancer. Ramucirumab inhibits new blood vessel growth to the tumor by binding to the extracellular domain of vascular EGFR-2 (VEGFR-2), and it is being studied as monotherapy and adjunctive therapy in multiple cancers, including metastatic breast, colorectal and gastric cancers.

A similar VEGFR monoclonal antibody is LY3012212 (formerly ImClone IMC-18F1), directed against VEGFR-1 and blocking the binding of VEGF-A, VEGF-B and placental growth factor (PlGF). This drug is currently in phase II trials for colorectal, bladder and metastatic breast cancers, as well as a variety of other cancers.

Also obtained by the ImClone acquisition is LY3012217 (cixutumumab), a fully human IgG1 monoclonal antibody targeting the human insulin-like growth factor-1 receptor (IGF-1R) and inhibiting the binding of IGF-1 and IGF-2 ligands to the IGF-1R. It is currently in phase II testing in pancreatic cancer, liver cancer and non-small cell lung cancer (NSCLC). By selectively binding to membrane-bound IGF-1R, cixutumumab prevents binding of the natural ligand IGF-1 and the subsequent activation of the PI3K/AKT signaling pathway. As the PI3K/AKT survival pathway is down-regulated, this may reduce proliferation and trigger apoptosis, or programmed cell death, of cancer cells.

Lilly’s acquisition of ImClone also gave it monoclonal antibody, LY3012207 (IMC-3G3), now in phase II testing for multiple cancers including ovarian cancer, gastrointestinal stromal tumor and glioblastoma. This monoclonal antibody targets the platelet-derived growth factor receptor alpha (PDGFRa).

Another phase II Oncology candidate for multiple cancers is LY573636 (tasisulam), which affects the cell cycle, resulting in apoptosis. In a phase II trial of tasisulam sodium as second-line therapy for patients with unresectable or metastatic melanoma, intravenous administration on Day 1 of 21-day cycles had anticancer activity and tolerable toxicity. For liver, brain and pancreatic cancer, LY2157299 is a kinase inhibitor, now in phase II trials, designed to selectively inhibit transforming growth factor-ß signaling.

Other biomolecules of potential importance in various cancers, and the drugs targeting them, include the cell cycle regulator checkpoint kinase 1 (LY2603618), Survivin ASO (LY2181308), mitotic kinesin Eg5 (LY2523355; litronesib), eIF-4E ASO (LY2275796) and glycogen synthase kinase-3ß (LY2090314). Lilly is in phase II testing of all these drugs for various cancers.

Endocrinology drugs in phase III trials for type II diabetes are empagliflozin (BI10773), a sodium glucose co-transporter-2 (SGLT-2) inhibitor being developed in partnership with Boehringer Ingelheim, and dulaglutide (LY2189265), a long-acting glucagon-like peptide-1 (GLP-1) analog Fc being studied as a once-weekly treatment. In a phase II, double-blind, international trial, once-daily empagliflozin added to metformin significantly reduced HbA1c over 12 weeks in type 2 diabetics inadequately controlled with metformin. Covalent linkage of the GLP-1 portion of dulaglutide to an Fc fragment of human antibody immunoglobulin G subclass 4 (IgG4) prevents it from being inactivated by dipeptidyl peptidase 4. Clinical trials of dulaglutide have shown reduction in plasma glucose and an insulinotropic effect with increases in insulin and C-peptide levels, as well as a dose-dependent reduction in glycated hemoglobin (HbA1c) of up to 1.52% compared with placebo.

Endocrinology candidates in phase II include LY2382770, a transforming Growth Factor-s monoclonal antibody for diabetic nephropathy; and LY2523199, an inhibitor of 11s-hydroxysteroid dehydrogenase type 1, for type 2 diabetes. Also for the treatment of type 2 diabetes is LY2409021, a glucagon receptor antagonist. In partnership with Boehringer Ingelheim, Lilly is developing LY2605541, a novel basal insulin for the treatment of type 1 and 2 diabetes.

In Neurology, LY2062430 (solanezumab) is a monoclonal antibody that binds to the mid-domain of soluble amyloid (Ab) proteins. It is currently in phase III trials for its potential to slow the progression of Alzheimer’s disease.s

LY2140023 monohydrate (pomaglumetad methionil, formerly known as mGlu2/3 prodrug) is in phase III trials as monotherapy for the treatment of schizophrenia. This agonist of the metabotropic glutamate 2/3 receptors is also in phase II trials as an add-on therapy for schizophrenia.

Also in phase III testing is LY2216684 (edivoxetine, formerly known as NERI), a norepinephrine reuptake inhibitor intended as an add-on therapy for major depressive disorder. It is also in phase II trials as monotherapy for attention deficit hyperactivity disorder.

The Rheumatology pipeline includes two phase II agents, the anti-IL-17 monoclonal antibody LY2439821 being tested for psoriasis, and the JAK1/JAK2 Inhibitor LY3009104 for rheumatoid arthritis. In phase III trials, LY2127399 is an IgG4 anti-BAFF monoclonal antibody being tested for rheumatoid arthritis, lupus and multiple myeloma. A phase II trial in patients with rheumatoid arthritis showed LY2127399 was well tolerated and effective.

In the Musculoskeletal arena, LY2541546 (otelixizumab) is a sclerostin monoclonal antibody in phase II development. An ongoing, randomized, dose-response study is comparing the effects of LY2541546 with placebo on bone mineral density in postmenopausal women. Also in phase II testing is LY2828360, a cannabinoid receptor-2 agonist addressing the pain of osteoarthritis.

The Cardiovascular pipeline has one phase II candidate, LY2484595 (evacetrapib), a potent and selective inhibitor of cholesteryl ester transfer protein intended to reduce cardiovascular events. The mechanism of action of this novel benzazepine compound is to increase beneficial high-density lipoprotein cholesterol without inducing aldosterone or increasing blood pressure.

Lilly’s phase II Urology candidate is LY900010, a combination of a selective androgen receptor modulator (SARM) and tadalafil for treatment of erectile dysfunction. The mechanism of action is inhibition of the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5.

The longstanding success of Lilly in pharmaceutical development can be attributed in part to its global efforts addressing a range of chronic diseases, its strategic partnerships and its innovative use of biotechnology, chemical synthesis and modification and tailored therapies.