Severe and Rare

Our severe and rare disease franchise is the largest franchise in our pipeline. We believe that our antisense technology could offer effective therapies for patients with severe and rare diseases that are life-threatening or fatal and for which there are limited 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, patients with many of these severe and rare diseases have few effective therapies available. 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.

We are discovering and developing antisense drugs to treat severe and rare diseases for which there is a need for new treatment options. Our partners, Biogen Idec, Roche and GSK, allow us to expand our drug discovery and development efforts beyond what we would choose to do internally. Due to the severe nature of these diseases and the lack of available treatments, there is an opportunity for more flexible and efficient development paths to the market. This means that, in some 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, thereby providing us with a relatively rapid path to market for potential new treatments for devastating and often fatal diseases.

KYNAMRO® (mipomersen sodium)



KYNAMRO® (mipomersen sodium) is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

KYNAMRO is approved for use in patients with HoFH in the United States, Mexico, Argentina and South Korea.

U.S. Product Web Site

U.S. Prescribing Information (PDF)


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 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 pouchitis and other indications. We are eligible to receive royalties on product sales, including product sales under the Named Patient Supply from Atlantic Pharmaceuticals. Atlantic Pharmaceuticals is currently pursuing opportunities to fund further development of alicaforsen.


ISIS-TTRRx is an antisense drug we designed to treat 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, such as the 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-TTRRx to inhibit the production of all forms of TTR, and to offer an alternative approach to treat all types of TTR-related amyloidosis. ISIS-TTRRx is the first drug to enter development under our preferred partner alliance with GSK. We have earned $24 million from GSK as ISIS-TTRRx has advanced in development and are eligible to earn an additional $46 million in pre-licensing milestone payments to support the Phase 3 study of ISIS-TTRRx. In addition, we are eligible to earn regulatory and sales milestone payments from GSK should ISIS-TTRRx achieve registration and meet certain sales thresholds. We are also eligible to receive double-digit royalties on sales of ISIS-TTRRx.

We completed a Phase 1 study evaluating the safety and activity of ISIS-TTRRx in healthy volunteers. In this study, ISIS-TTRRx produced rapid, dose-dependent reductions in plasma TTR protein with an average of 75 percent reduction in TTR protein, with some subjects achieving approximately 90 percent reduction. In addition, there were several subjects that reached TTR protein levels that were below the limit of assay detection. Subjects treated with ISIS-TTRRx generally tolerated the drug well. In February 2013, we initiated a Phase 3 study to evaluate the efficacy of ISIS-TTRRx in patients with FAP. In this study, we plan to enroll approximately 200 patients and evaluate the efficacy of ISIS-TTRRx by measuring neurological dysfunction and quality of life in patients with FAP.

Visit our TTR Study website »


ISIS-SMNRx is an antisense drug we discovered in collaboration with Dr. Adrian R. Krainer at Cold Spring Harbor Laboratory. ISIS-SMNRx is 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 six million people in the United States, carry the gene mutation that causes SMA. 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 significantly 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. The FDA granted Orphan Drug Designation with Fast Track Status to ISIS-SMNRx for the treatment of patients with SMA.

In January 2012, we and Biogen Idec entered into a preferred partner alliance that provides Biogen Idec an option to develop and commercialize ISIS-SMNRx. Under the agreement, we received an upfront fee and are responsible for developing ISIS-SMNRx. Biogen Idec has the option to license ISIS-SMNRx until completion of the first successful Phase 2/3 study or the completion of two Phase 2/3 studies. We are eligible to receive milestone payments from Biogen Idec as ISIS-SMNRx advances through development.

We designed ISIS-SMNRx to potentially treat all types of childhood SMA by altering the splicing of a closely related gene, SMN2, which leads to the increased production of fully functional SMN protein. We developed a biomarker assay to measure levels of SMN protein in the cerebral spinal fluid of children and infants with SMA. In February 2014, we reported the first set of data using this biomarker assay. Using this assay, we observed dose-dependent increases in SMN protein levels in children with SMA treated with ISIS-SMNRx from both the single- and multiple-dose studies. In the single-dose study, SMN protein levels more than doubled in the two highest dose cohorts, 6 and 9 mg, with average increases of approximately 120 percent and 160 percent compared to baseline, respectively, approximately nine to 14 months after dosing. Similarly, in the multiple-dose study, we observed substantial increases in SMN protein levels in the 9 mg cohort of 115 percent compared to baseline approximately three months, or day 86, after the first dose.

In March 2013, we reported encouraging data from a single-dose, open-label Phase 1 clinical study evaluating ISIS-SMNRx in children with SMA. In this study, we reported that ISIS-SMNRx was well tolerated when administered intrathecally as a single dose directly into the spinal fluid. In addition, the children tolerated the intrathecal injection procedure well. We also showed that concentrations of ISIS-SMN Rx measured in cerebral spinal fluid were consistent with levels predicted from preclinical studies, indicating that the drug half-life in nervous system tissues is very long and that dosing once every six to nine months is feasible. Although the study was not designed to provide evidence of functional activity, we observed increases in the Hammersmith Functional Motor Scale-Expanded, or HFMSE, a measure of muscle function, in a number of these children. The mean increase in the HFMSE scores observed in the highest dose cohort (9 mg) at 3 months was 3.1 points or a 17.6% increase from baseline, with six of ten patients experiencing an increase of greater than four points. Observed increases in HFMSE scores equal to or greater than a 4 point compared to baseline were distributed by age with half in children under the age of five and half in children five and older.

In September 2013, we reported a follow-up analysis of the single-dose, open-label Phase 1 study of ISIS-SMNRx in children with SMA. In this study, we observed that most children with SMA who received a single dose of one of the two highest doses of ISIS-SMNRx, 6 mg or 9 mg, continued to show increases in muscle function scores up to 14 months after a single injection of the drug.

We are evaluating ISIS-SMNRx in a Phase 2 open-label, multiple-dose, dose-escalation study in children with SMA. In this study, we are evaluating four dose levels, 3, 6, 9, and 12 mg in children with SMA ages two to 15. We reported interim results from the 3, 6 and 9 mg cohorts from this study in February 2014 showing that treatment with ISIS-SMNRx was well tolerated. In addition, we observed dose- and time-dependent increases in HFMSE scores in children treated with multiple doses of ISIS-SMNRx. Children in the 3 mg, 6 mg, and 9 mg cohorts achieved mean increases in HFMSE scores of 1.5, 2.3 and 3.7 points, respectively, nine months following the first dose of ISIS-SMNRx. Children in the 9 mg cohort achieved mean increases in HFMSE scores of 2.7 and 3.7 points three and nine months after the first dose of ISIS-SMNRx, respectively.

We are also evaluating ISIS-SMNRx in a Phase 2 open-label, multiple-dose, dose-escalation pilot study in infants who have been diagnosed with SMA. In this study, we are evaluating two dose levels, 6 and 12 mg in infants with SMA. We reported interim results from this study in February 2014 showing that all four infants in the 6 mg cohort had been on study for over six months and are now approximately nine and a half to 16 months in age with an average age of approximately 12 and a half month. We reported that all four infants were alive and none had required permanent respiratory assistance. In addition, all four infants had tolerated intrathecal administration of ISIS-SMNRx well.

We acknowledge support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, and Cure SMA. 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:
Cure SMA:


ISIS-APOCIIIRx is an antisense drug we designed to reduce apoC-III protein production and lower triglycerides. ApoC-III regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. This approach is validated by the fact that people who have certain mutations in the gene for apoC-III that result in lower levels of apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. Also, people with elevated levels of apoC-III have increased dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, people with elevated triglycerides are at increased risk for type 2 diabetes, and people with severely elevated triglycerides are at high risk for acute pancreatitis and other serious conditions.

We are developing ISIS-APOCIIIRx for patients with FCS and patients with severely high triglycerides. FCS is a rare orphan disease that affects an estimated 3,000 to 5,000 people worldwide. FCS patients often have triglyceride levels higher than 2,000 mg/dL and experience a number of health problems such as recurrent acute pancreatitis that often requires hospitalization, abdominal pain, and enlargement of the liver and spleen. We believe that the significant unmet medical need for an effective triglyceride-lowering drug for patients with FCS and the robust, consistent effects we observed with ISIS-APOCIIIRx should enable us to rapidly move this program forward toward the market.

We are also developing ISIS-APOCIIIRx for the treatment of patients with severely high triglycerides. These are patients with triglyceride levels greater than 880 mg/dL who are also at a higher risk of pancreatitis and other serious conditions. For all patients who cannot reduce their triglycerides to acceptable levels, the primary therapy is diet, which requires strict adherence and is often unsuccessful.

In preclinical studies, ISIS-APOCIIIRx diminished signs of metabolic syndrome and reduced atherosclerosis in mice. In a Phase 1 study in healthy volunteers, ISIS-APOCIIIRx produced rapid, dose-dependent median reductions in blood of up to 78 percent in apoC-III protein levels and up to 44 percent in triglyceride levels.

We completed a broad Phase 2 program evaluating ISIS-APOCIIIRx in patients with high, very high, and severely high triglycerides, in patients with type 2 diabetes and in patients with FCS. We also evaluated ISIS-APOCIIIRx both as a single agent and in combination with fibrates. Patients in our Phase 2 program entered with baseline triglyceride levels ranging from moderately high to severely high. In all patient groups studied, irrespective of their incoming triglyceride levels, treatment with ISIS-APOCIIIRx consistently reduced apoC-III, triglycerides and apoC-III-associated VLDL complexes, and increased HDL, with a positive effect on non-HDL. Data from the 300 mg/week dose from each of these studies are summarized in the table below.

Table 1: Comparison of the effects on key lipids for patients treated with 300 mg/week of ISIS-APOCIIIRx

  Single Agent in Diabetics with High TG Single Agent in Very High TG In Addition to Fibrates in Very High TG Single Agent in FCS
Baseline Mean mg/dL (range)
ApoC-III 14 (9-20) 23 (14-33) 18 (12-30) 25 (19-35)
Triglycerides 259 (187-356) 559 (291-952) 394 (224-932) 1844 (1406-2083)
HDL-C 43 (35-55) 34 (22-52) 34 (14-53) 13 (8-16)
Non-HDL-C 178 (128-300) 175 (76-312) 185 (118-243) 262 (214-327)
Mean % Change from Baseline (Standard Deviation)
ApoC-III -88% (6.0) -80% (9.3) -70% (12.5) -81% (9.8)
Triglycerides -72% (8.3) -71% (14.1) -64% (8.9) -69% (15.6)
HDL-C +40% (19.8) +46% (24.0) +52% (23.7) +78% (74.6)
Non-HDL-C -28% (16.4) -11% (38.3) -19% (28.8) -58% (14.3)

Consistent across the Phase 2 program, ISIS-APOCIIIRx demonstrated a good safety profile and was well tolerated. The most common adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no treatment-related elevations in liver enzymes greater than three times the upper limit of normal, no abnormalities in renal function and no clinically meaningful changes in other laboratory values.


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. IGF-1 also contributes to 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 and has completed a Phase 1 study in healthy volunteers demonstrating that ATL1103 was safe and well tolerated. ATL is evaluating ATL1103 in a Phase 2 study in patients with acromegaly. ATL reported interim results from this study showing that patients treated with the highest dose, 200 mg twice weekly for 3 months, experienced an average of 30 percent reduction in serum insulin-like growth factor-I, or sIGF-I, the primary activity endpoint for the study.


ISIS-DMPK-2.5Rx is an antisense drug we designed to correct the underlying genetic defect that causes Myotonic Dystrophy Type 1, or DM1. DM1 is the most common form of muscular dystrophy in adults. It is caused by a genetic defect in the dystrophia myotonica-protein kinase, or DMPK, gene in which a sequence of three nucleotides, CTG, repeats extensively. This DNA expansion produces an abnormally large toxic RNA that accumulates in cells, including muscle cells, and prevents production of proteins essential for normal cellular function. In addition to disabling muscle spasms and progressive muscle wasting and weakness, DM1 also affects many other organs within the body. Patients with DM1 can experience insulin insensitivity, cataracts and infertility. DM1 is estimated to affect approximately 150,000 patients in the United States, Europe and Japan. The severity and age of onset of DM1 correlates with the number of times the three nucleotides repeat, which increases from one generation to the next. Currently, there are no disease-modifying therapies for patients with DM1 and treatments are intended only to manage symptoms.

In 2012, we and Biogen Idec entered into an alliance that provides Biogen Idec an option to develop and commercialize ISIS-DMPK-2.5Rx. Under the agreement, we received an upfront fee and are responsible for developing ISIS-DMPK-2.5Rx. Biogen Idec has the option to license ISIS-DMPK-2.5Rx up through completion of the Phase 2 study. We will receive milestone payments from Biogen Idec as ISIS-DMPK-2.5Rx advances through development.

ISIS-DMPK-2.5Rx targets DMPK to reduce the toxic RNA in the cells. In preclinical studies, we showed that an antisense compound targeting the DMPK messenger RNA, or mRNA, entered muscle cells and significantly reduced the toxic RNA. Effective reduction of toxic RNA led to a reversal of the disease symptoms that was sustained for up to one year after treatment in a mouse model of DM1. By removing toxic RNA, ISIS-DMPK-2.5Rx could be an effective approach to treating patients with DM1.


ISIS-GCCRRx is an antisense drug that targets the glucocorticoid receptor, or GCCR. Glucocorticoid hormones affect a variety of processes throughout the body, and excessive levels of glucocorticoid hormones can have a detrimental effect on many of the tissues and organs in the body. Cushing’s Syndrome is an orphan disease caused by prolonged exposure to high levels of glucocorticoids. If untreated, patients with Cushing’s Syndrome can develop hypertension, diabetes and impaired immune functions and have an increased risk of early death. Although there are approved treatments for Cushing’s Syndrome, current medicines are associated with significant side effects, such as hypertension and diabetes, and there remains a high unmet medical need for new therapies for these patients. We have already demonstrated that subjects tolerated ISIS-GCCRRx well in a Phase 1 study in healthy volunteers, and we observed reductions of GCCR specifically in the liver and fat tissues, consistent with our preclinical observations.

We are currently evaluating ISIS-GCCRRx in a Phase 2 study in patients with type 2 diabetes.


ISIS-PKKRx is an antisense drug we designed to prevent hereditary angioedema, or HAE, attacks. ISIS-PKKRx inhibits the production of prekallikren, or PKK, a protein produced in the liver that plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. HAE is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea. HAE affects approximately 20,000 patients in the United States and Europe and can be fatal if swelling occurs in the larynx. In patients with frequent or severe attacks, doctors may use prophylactic treatment approaches to prevent and reduce the severity of HAE attacks. However, current prophylactic treatment approaches are very limited and have major tolerability issues due to challenging administration requirements leaving patients with few therapeutic options. By inhibiting the production of PKK, ISIS-PKKRx could be an effective prophylactic approach to preventing HAE attacks.


ISIS-HTTRx is an antisense drug we designed to correct the underlying genetic defect that causes Huntington’s disease (HD). HD is an inherited genetic brain disorder that results in the progressive loss of both mental faculties and physical control. It is caused by the expansion of the CAG trinucleotide sequence in the huntingtin (HTT) gene. The resulting mutant HTT protein is toxic and gradually damages neurons. Symptoms usually appear between the ages of 30 and 50, and worsen over a 10 to 25 year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective treatment or cure for the disease, and current available medicines only mask the patient’s symptoms but do not slow down the underlying loss of neurons.

In April 2013,we and Roche entered into an alliance to develop treatments for HD based on our antisense technology and utilizing Roche’s scientific expertise in developing neurodegenerative therapeutics. Under the agreement, we are responsible for all research and development through the first Phase 1 study. Roche has the option to license the program through the completion of the first Phase 1 study and thereafter assume worldwide development, regulatory and commercial responsibilities. We will receive milestone payments from Roche as ISIS-HTTRx advances through development.

ISIS-HTTRx is designed to block production of all forms of HTT protein. As such, ISIS-HTTRx has the potential to treat all HD patients. In preclinical studies, we demonstrated an antisense compound targeting HTT mRNA produced a significant reduction in HTT mRNA and protein, delayed disease progression and prolonged the survival in a mouse model of HD. By reducing the expression of HTT protein, ISIS-HTTRx represents effective potentially comprehensive approach to treating patients with HD.


ISIS-BIIB3Rx is an antisense drug to an undisclosed target designed to treat a neurodegenerative disease. ISIS-BIIB3Rx is the third clinical program from our partnership with Biogen Idec. We are eligible to receive milestone payments from Biogen Idec as ISIS-BIIB3Rx advances in development. Biogen Idec has the option to license ISIS-BIIB3Rx from us for a license fee. We are also eligible to receive double-digit royalties from sales of ISIS-BIIB3Rx.


RG-012 is a preclinical drug candidate Regulus is developing, which is an anti-miR that targets microRNA-21, or miR-21. Regulus reports that subcutaneous administration of RG-012 significantly decreased the rate of renal fibrosis and increased the lifespan of mice treated with RG-012 up to 50 percent in a mouse model of Alport Syndrome. Alport Syndrome is a life-threatening disease in which patients experience progressive loss of kidney function.

Regulus currently plans to develop RG-012 to proof-of-concept. At that stage of development, Regulus’ partner Sanofi has an exclusive option to license. We are eligible to receive a portion of all milestone payments and royalties Regulus receives from Sanofi if Sanofi chooses to exercise its option to license RG-012 from Regulus and RG-012 advances in development.

About Isis

We know that sick people depend on us, and we have the technology to change the way diseases are treated.

Learn More

Mission & Values

Our mission is to provide antisense drugs to patients with significant unmet medical needs.

Learn More

TTR Study

Isis Pharmaceuticals is currently enrolling a Phase 3 study that is designed to evaluate the safety and efficacy of ISIS-TTRRx in patients with Familial Amyloid Polyneuropathy (FAP), the form of TTR amyloidosis that causes nerve damage.

Learn More About the Study