Inflammation and Other Diseases

The broad applicability of our antisense technology allows us to create promising drugs in a variety of disease areas. We have successfully developed novel drugs and licensed them to highly focused satellite companies that have the specific expertise and resources to continue developing these drugs. Together with our partners we continue to advance drugs in clinical development that are outside of our core therapeutic areas. For instance, our partner, Excaliard, presented data from three Phase 2 studies demonstrating that EXC 001 reduced scarring in patients.

• Vitravene^® (CMV Retinitis)
• Alicaforsen (Ulcerative Colitis, Pouchitis)
• ATL1102 (Multiple Sclerosis)
• EXC 001 (Local Fibrosis)
• iCo-007 (Diabetic Macular Edema, Diabetic Retinopathy)
• Plazomicin (Severe Bacterial Infection)
• XEN701 (Anemia of Inflammation)

Vitravene^®

Vitravene, approved by the FDA in 1998, is an antisense drug that we discovered and developed, to treat cytomegalovirus, or CMV, retinitis in AIDS patients. Novartis Ophthalmics AG, our worldwide distribution partner for this drug, launched Vitravene in November 1998. New anti-HIV drugs, particularly protease inhibitors and combination treatment regimens, have prolonged survival in HIV-infected individuals. This has resulted in a decline in mortality from AIDS, accompanied by a decline in the incidence of many opportunistic infections, including CMV retinitis. As a result, Novartis no longer markets Vitravene. Vitravene demonstrates that we can meet FDA and European regulatory requirements for safety and efficacy, and for the commercial manufacture of antisense drugs.

Alicaforsen

Alicaforsen, now under license to Atlantic Pharmaceuticals Limited, is an antisense drug that targets intercellular adhesion molecule 1, or ICAM-1. ICAM-1 is over-expressed in a wide variety of inflammatory disorders, including ulcerative colitis and pouchitis. Ulcerative colitis, or UC, is an inflammatory bowel disease, or IBD, of the colon, a part of the large intestine, and pouchitis is an inflammation of the surgically constructed internal pouch created in UC patients who have had their diseased colons removed.

In 2007, we licensed alicaforsen to Atlantic Pharmaceuticals for pouchitis, UC and other inflammatory diseases. The FDA and European Medicines Agency, or EMA, have since granted alicaforsen Orphan Drug Designation for the treatment of pouchitis in the United States and Europe, respectively. Atlantic Pharmaceuticals currently supplies alicaforsen in response to physicians' requests under international Named Patient Supply regulations for patients with IBD. Atlantic Pharmaceuticals is currently pursuing opportunities to fund further development of alicaforsen.

ATL1102

ATL1102 is an antisense drug that ATL is developing for the treatment of multiple sclerosis, or MS. ATL1102 inhibits CD49d, a subunit of Very Late Antigen-4, or VLA-4. Studies in animal models have demonstrated that inhibiting VLA-4 positively affects a number of inflammatory diseases, including MS. We licensed ATL1102 to ATL in December 2001 and in February 2008, ATL licensed ATL1102 to Teva. In 2008, ATL and Teva reported Phase 2a results of ATL1102 showing significantly reduced disease activity in patients with relapsing remitting MS. In 2010, Teva terminated its agreement with ATL and returned ATL1102 back to ATL. ATL is seeking a partner to continue developing ATL1102 in patients with MS.

EXC 001

EXC 001 is an antisense drug that targets connective tissue growth factor, or CTGF, a growth factor that is over-expressed in damaged skin or tissue following a traumatic event. We co-discovered EXC 001 and licensed it to Excaliard for the local treatment of fibrotic diseases, including scarring. In November 2011, Pfizer Inc. acquired Excaliard and plans to continue to develop EXC 001. Fibrosis represents a significant and expanding area of unmet medical need where antisense drugs could offer a unique advantage as anti-fibrotic agents.

Excaliard reported the successful completion of three Phase 2 studies of EXC 001. In one Phase 2 study, treatment with EXC 001 produced a significant improvement in the appearance of scarring in patients who had revision surgery for excessive scarring. In another Phase 2 study, treatment with EXC 001 also reduced the severity of fine line scars and accelerated resolution of scarring compared to placebo. In a third Phase 2 study, treatment with EXC 001 produced a dose-dependent reduction in CTGF and inhibition of CTGF-induced collagen and other pro-fibrotic genes. In all three studies, Excaliard reported that treatment with EXC 001 produced statistically significant reductions in scar severity compared to placebo and patients tolerated EXC 001 well with no important drug related adverse effects observed. Pfizer Inc. plans to continue developing EXC 001 to address unmet medical needs in patient groups who suffer from excessive skin scarring.

iCo-007

iCo-007 is an antisense drug that targets c-Raf kinase. In preclinical studies, clinicians associated antisense inhibition of c-Raf kinase with a reduction in the formation and leakage of new blood vessels in the eye, suggesting inhibiting c-Raf kinase can help patients with diabetic macular edema and diabetic retinopathy. Diabetic retinopathy is one of the leading causes of blindness in people in the United States, and a high percentage of type 1 diabetics have evidence of retinopathy by age 20. Additionally up to 21 percent of people with type 2 diabetes have retinopathy at the time of the first diagnosis of diabetes, and most will eventually develop some degree of retinopathy over time. We discovered iCo-007 and licensed it to iCo Therapeutics Inc., or iCo, for the treatment of various eye diseases that occur as complications of diabetes.

In May 2010, investigators evaluating iCo-007 in patients with diffuse diabetic macular edema presented positive results from the Phase 1 study showing that subjects tolerated iCo-007 well. In this study, a number of individuals exhibited a decrease of central macular edema compared to baseline using an analytical method called optical coherence tomography. In August 2011, iCo initiated a Phase 2 study on iCo-007 in patients with diabetic macular edema.

Plazomicin

Plazomicin, formerly ACHN-490, is a next-generation aminoglycoside drug that Achaogen, Inc. is developing for the treatment of multi-drug resistant gram-negative bacterial infections. Aminoglycosides are a group of antibiotics that inhibit bacterial protein synthesis and that clinicians use to treat serious bacterial infections. Achaogen discovered plazomicin based on technology licensed from us.

Plazomicin has displayed broad-spectrum activity in animals against multi-drug resistant gram-negative bacteria that cause systemic infections, including E. coli, and against methicillin-resistant staphylococcus aureus, or MRSA. In preclinical studies, plazomicin demonstrated an acceptable safety profile and the potential for once-daily dosing. Achaogen has completed a Phase 1 study of plazomicin in healthy volunteers and is evaluating plazomicin in a Phase 2 study in patients with complicated urinary tract infections or acute kidney infections. Achaogen plans to complete this Phase 2 study in 2012.

XEN701

XEN701 is an antisense drug designed to treat anemia of inflammation, or AI. Anemia is a condition in which the body has a lower than normal number of red blood cells. AI is a type of anemia that commonly occurs with chronic, or long-term illnesses, including cancer and inflammatory disorders. Patients with AI cannot use iron properly, which results in a reduction of red blood cell production. XEN701 targets a hormone secreted by the liver in response to inflammatory mediators that inhibits intestinal iron uptake and release of stored iron.

XEN701is the first drug to enter development in our collaboration with Xenon Pharmaceuticals to develop antisense drugs that target the hepcidin-hemojuvelin pathway to treat AI. Antisense drugs targeting hemojuvelin and hepcidin should provide therapeutic benefit to patients with AI by reversing iron disturbances and facilitating red blood cell production.