Severe and Rare

We are pursuing the discovery and development of antisense drugs for severe and rare diseases in which there is a need for new treatment options. According to the NIH there are approximately 5,000 to 8,000 rare diseases, many life-threatening or fatal. Unfortunately there are few effective therapeutics available to treat many of these severe and rare diseases. Since most severe and rare diseases are genetic or have a genetic component, parents often pass the disease to their children, creating a legacy of the disease and resulting in profound effects on the family. In some cases, disease onset is characterized by the presence of a protein that, through a genetic defect, cannot function properly in the cell.

We are focused on developing antisense drugs to treat severe and rare diseases. Due to the severe nature of these diseases and the lack of available treatments, there is an opportunity for more flexible development paths to the market. This means that, in many cases, the studies necessary for us to demonstrate proof-of-concept with a particular drug may also be the studies that complete our marketing registration package. This allows us a relatively rapid path to market with potential new treatments for devastating and often fatal diseases.

• ATL1103 (Acromegaly, Diabetic Retinopathy)
• ISIS-SMN_Rx (Spinal Muscular Atrophy)
• ISIS-TTR_Rx (TTR Amyloidosis)
• ISIS-AAT_Rx (AATD-Associated Liver Disease)

ATL1103

ATL1103 is an antisense drug that targets the growth hormone receptor, or GHr, a receptor that, when inhibited, reduces the level of circulating insulin-like growth factor-1, or IGF-1, produced in the liver. IGF-1 is a hormone that contributes to various diseases, including acromegaly, an abnormal growth disorder of organs, face, hands and feet, as well as diabetic retinopathy, a common disease of the eye and a leading cause of blindness, diabetic nephropathy of the kidney and certain forms of cancer. In preclinical studies, ATL1103 demonstrated significant reductions in IGF-1 levels in the blood and inhibition of neovascularization, or new blood vessels, in the eye in a mouse retinopathy model.

Antisense Therapeutics Limited, or ATL, is developing ATL1103. ATL has completed a Phase 1 study in healthy volunteers demonstrating that ATL1103 was safe and well tolerated and plans to evaluate ATL1103 in a Phase 2 study in patients with acromegaly in 2012.

ISIS-SMN_Rx

ISIS-SMN_Rx is an antisense drug we designed to treat spinal muscular atrophy, or SMA, a severe motor-neuron disease that is the leading genetic cause of infant mortality. SMA affects approximately 30,000 to 35,000 patients in the United States, Europe and Japan. One in 50 people, approximately six million people in the United States, are carriers of the SMA gene. Carriers experience no symptoms and do not develop the disease. When both parents are carriers, however, there is a one in four chance that their child will have SMA.

SMA is caused by a loss of, or defect in, the survival motor neuron 1, or SMN1, gene leading to a decrease in the protein, survival motor neuron, or SMN. SMN is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular growth and function. The severity of SMA correlates with the amount of SMN protein. Infants with Type I SMA, the most severe life-threatening form, produce very little SMN protein and have a shortened life expectancy. Children with Type II and Type III SMA have greater amounts of SMN protein and have less severe, but still life-altering, forms of SMA.

We designed ISIS-SMN_Rx to potentially treat all types of childhood SMA by altering the splicing of a closely related gene, SMN2, that leads to the increased production of fully functional SMN protein. The FDA granted Orphan Drug Designation with Fast Track Status to ISIS-SMN_Rx for the treatment of patients with SMA. In December 2011, we initiated the first Phase 1 clinical study evaluating ISIS-SMN_Rx in children with SMA. The Phase 1 study of ISIS-SMN_Rx is a single-dose, dose-escalation study we designed to assess the safety, tolerability and pharmacokinetic profile of the drug in children with SMA between the ages of two and 14 who are medically stable. In this study, the study physicians will administer ISIS-SMN_Rx intrathecally as a single injection directly into the spinal fluid. We plan to complete this study in 2012.

In January 2012, we and Biogen Idec entered into a preferred partner alliance that provides Biogen Idec an option to develop and commercialize ISIS-SMN_Rx . Under the agreement, we received an upfront fee and are responsible for developing ISIS-SMNRx. Biogen Idec has the option to license ISIS-SMN_Rx upon completion of the earlier of the first successful Phase 2/3 study, or the completion of two Phase 2/3 studies. We will receive milestone payments from Biogen Idec as ISIS-SMN_Rx advances through development. We acknowledge support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, and Families of Spinal Muscular Atrophy. We have licensed intellectual property from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.

More information on SMA can be found at:
SMA Foundation: www.smafoundation.org
Families of SMA: www.curesma.org

More information on Isis' SMN and splicing:
SMN Splicing Factsheet.pdf

ISIS-TTR_Rx

ISIS-TTR_Rx is an antisense drug we designed to treat transthyretin amyloidosis, or TTR amyloidosis, a severe and rare genetic disease in which the patient inherits a mutant gene that produces a misfolded form of TTR, which progressively accumulates in tissues. In patients with TTR amyloidosis, both the mutant and normal forms of TTR can build up as fibrils in tissues, including heart, peripheral nerves, and the gastrointestinal tract. The presence of TTR fibrils interferes with the normal functions of these tissues, and as the TTR protein fibrils enlarge more tissue damage occurs and the disease worsens.

There are two common types of TTR amyloidosis, familial amyloid cardiomyopathy, or FAC, which affects more than 40,000 patients worldwide, and familial amyloid polyneuropathy, or FAP, which affects more than 10,000 patients worldwide. Patients with FAC have TTR build up in the heart muscle and succumb to heart failure approximately five to six years after symptom onset. Patients with FAP have TTR build up in peripheral nerve tissue leading to the loss of nerve function and wasting.

We designed ISIS-TTR_Rx to inhibit the production of all forms of TTR, and to offer an alternative approach to treat all types of TTR-related amyloidosis. ISIS-TTR_Rx is the first drug to enter development under our preferred partner alliance with GSK. Because we did not disclose the target of ISIS-TTR_Rx at the time we selected the drug as a development candidate, we previously referred to ISIS-TTRRx as ISIS-GSK1_Rx. We are responsible for developing the drug through Phase 2 proof-of-concept, at which time GSK has the option to license ISIS-TTR_Rx from us. We will continue to receive milestone payments from GSK as ISIS-TTR_Rx advances through development.

We completed a Phase 1 study evaluating the safety and activity of ISIS-TTR_Rx in healthy volunteers. In this study, ISIS-TTR_Rx produced rapid, dose-dependent reductions of up to 80 percent in plasma TTR protein. Subjects treated with ISIS-TTR_Rx generally tolerated the drug well. We plan to initiate a clinical study evaluating the efficacy of ISIS-TTR_Rx in patients with FAP in 2012.

ISIS-AAT_Rx

ISIS-AAT_Rx is an antisense drug that reduces production of alpha-1 antitrypsin, or AAT, for the treatment of liver disease in patients with alpha-1 antitrypsin deficiency, or AATD. AATD is a genetic disease in which the patient does not produce normal AAT, a protein primarily produced in the liver that protects lung tissue from damage. AATD affects 1 out of every 2,500 people in the United States and can lead to severe liver disease, including liver scarring, cirrhosis and liver cancer.

Patients with AATD inherit a mutant gene from one or both parents. Physicians characterize patients who inherit a mutant gene from both parents as having severe AATD. Approximately 10 percent of infants and 15 percent of adults with severe AATD experience liver damage due to progressive accumulation of misfolded AAT protein in the liver. There are currently no available therapies for patients with AATD-associated liver disease, and liver transplantation is the only available option for patients who develop severe liver dysfunction due to accumulation of mutant AAT protein. Symptoms of AATD-associated liver disease can manifest as early as infancy, and AATD is the most common genetic disease requiring pediatric liver transplantation. The Alpha-1 Association estimates that approximately 10 to 15 percent of all liver transplant candidates have AATD.

ISIS-AATRx is the second drug to enter development under our preferred partner alliance with GSK. We are responsible for developing ISIS-AAT_Rx through Phase 2 proof-of-concept, at which time GSK has the option to license ISIS-AAT_Rx from us. We will continue to receive milestone payments from GSK as ISIS-AAT_Rx advances through development. We believe that ISIS-AAT_Rx offers a unique approach to treat AATD-associated liver disease. We plan to initiate a Phase 1 study in 2012.