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 National Institutes of Health, or 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. Many of these diseases are genetic or have a genetic component. In some cases, the onset of disease is characterized by the presence of a protein that, through a genetic defect, does not function properly in the cell and often causes toxicity. In order to treat these diseases, we can discover and develop antisense drugs that selectively inhibit the production of only the disease-causing protein. In other cases, alternative splicing can result in the omission of proteins that are critical for normal cellular function. Using antisense technology, we can direct alternate splicing to potentially correct for a genetic defect. For example, our drug, ISIS-SMN_Rx, increases the production of a protein that is necessary for normal motor neuron function but that is absent in disease.

Many neurodegenerative diseases are also severe and rare diseases. Our most advanced neurodegenerative drug is ISIS-SOD1_Rx, an antisense drug to treat amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease.

• ISIS-SOD1_Rx (Amyotrophic Lateral Sclerosis)
• ISIS-TTR_Rx (TTR Amyloidosis)
• ISIS-SMN_Rx (Spinal Muscular Atrophy)
• ATL1103 (Acromegaly, Diabetic Retinopathy)
• ISIS-AAT_Rx (AATD-Associated Liver Disease)

ISIS-SOD1_Rx

ISIS-SOD1_Rx is an antisense drug that targets superoxide dismutase, or SOD1, a protein associated with an inherited, aggressive form of ALS. The FDA granted ISIS-SOD1_Rx Orphan Drug designation for the treatment of ALS. Because antisense drugs do not cross the blood-brain barrier, we administer the drug directly into the cerebral spinal fluid. Clinicians call this type of administration intrathecal injection. This route of administration is commonly used for a variety of drugs.

Researchers reported in the Journal of Clinical Investigation that treatment with ISIS-SOD1_Rx prolonged life in rats that showed many symptoms of ALS. By delivering our drug directly to the fluid that circulates within the CNS, we and our collaborators lowered production of the mutant protein in neurons and surrounding cells.

The ALS Association and the Muscular Dystrophy Association are providing funding for ISIS-SOD1_Rx. Additionally, as part of our alliance with Genzyme, Genzyme has a right of first negotiation to license ISIS-SOD1_Rx from us. We are evaluating ISIS-SOD1_Rx in a Phase 1 study in patients with the familial form of ALS.

Click here to access an informational discussion about ALS clinical trials and ISIS-SOD1_Rx

ISIS-TTR_Rx

ISIS-TTR_Rx is an antisense drug we designed to treat transthyretin amyloidosis, or TTR amyloidosis, a severe and rare disease in which the patient inherits a bad gene that produces a mutant form of transthyretin, or TTR. TTR is a carrier protein that transports a thyroid hormone and retinol in the blood. In patients with TTR amyloidosis, both the mutant and normal forms of TTR can build up as fibrils in tissue. ISIS-TTR_Rx inhibits the production of all forms of TTR, offering a unique approach to treating TTR amyloidosis. There are two types of TTR amyloidosis, familial amyloid cardiomyopathy, or FAC, and familial amyloid polyneuropathy, or FAP. Patients with FAC have TTR build up in the heart muscle leading to heart failure, and patients with FAP have TTR build up in peripheral nerve tissue leading to the loss of nerve function and wasting. We plan to initially develop ISIS-TTR_Rx for patients with FAP.

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-TTR_Rx 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 receive milestone payments from GSK as ISIS-TTR_Rx advances through development.

We have completed a Phase 1 study evaluating the safety and activity of ISIS-TTR_Rx in healthy volunteers. In this study, ISIS-TTR_Rx produced significant reductions of greater than 80 percent in TTR protein. In this study, ISIS-TTR_Rx was generally well tolerated with no significant adverse events. We and GSK are planning a clinical program studying ISIS-TTR_Rx designed to achieve rapid registration.

ISIS-SMN_Rx

ISIS-SMN_Rx is an antisense drug designed to treat 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 6 million people in the United States, are carriers of the SMA gene. Carriers experience no symptoms and do not develop the disease, however, when both parents are carriers, 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 (SMN1) gene leading to a decrease in the protein, survival motor neuron (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 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.

ISIS-SMN_Rx is designed to 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 United States Food and Drug Administration 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 designed to assess the safety, tolerability and pharmacokinetic profile of the drug in children with SMA between the ages of 2-14 who are medically stable. In this study, ISIS-SMN_Rx will be administered intrathecally as a single injection directly into the spinal fluid.

ISIS-SMN_Rx is the first drug to enter development under our preferred partner alliance with Biogen Idec. We are responsible for developing ISIS-SMN_Rx prior to licensing. Biogen Idec has the option to license ISIS-SMN_Rx until completion of the first successful Phase 2/3 study. We will receive milestone payments from Biogen Idec as ISIS-SMNR_Rx advances through development. We are currently evaluating ISIS-SMN_Rx in a Phase 1 study in children with SMA.

We acknowledge support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, Families of SMA and intellectual property licensed 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

ATL1103

ATL1103 is an antisense drug that targets 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 and diabetic retinopathy. Diabetic retinopathy is a common disease of the eye and a leading cause of blindness. Abnormal growth of organs, face, hands and feet characterizes acromegaly. In preclinical studies, ATL1103 demonstrated significant reductions in IGF-1 levels in the blood. ATL is evaluating ATL1103 in a Phase 1 study in healthy volunteers.

ISIS-AAT_Rx

ISIS-AAT_Rx is an antisense drug designed to inhibit the 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 to produce misfolded AAT protein, which can progressively accumulate in the liver and cause liver disease. Patients who inherit a mutant gene from both parents are characterized as severe AATD. Approximately 10 percent of infants and 15 percent of adults with severe AATD experience liver damage. 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. Symptoms of AATD-associated liver disease can manifest as early as infancy, and it is the most common genetic disease for which pediatric liver transplantation is performed. It is estimated that 10-15 percent of all liver transplant candidates have AATD.

ISIS-AAT_Rx 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.