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 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) 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).
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. 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-SMNRx 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.
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. We will 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, that leads to the increased production of fully functional SMN protein. The FDA granted Orphan Drug Designation with Fast Track Status to ISIS-SMNRx for the treatment of patients with SMA.
In March 2013, we reported positive 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 and that no safety concerns related to the drug were identified. In addition, the children tolerated the intrathecal injection procedure well. We also showed that concentrations of ISIS-SMNRx 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 improvements in the Hammersmith Functional Motor Scale-Expanded (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 4 to 7 points. Observed improvements in HFMSE scores equal to or greater than a 4 point increase were distributed by age with half (3) in children under the age of five and half in children five and older.
We are evaluating ISIS-SMNRx in a Phase 1b/2a multiple-dose, dose-escalation study in children with SMA. In this study, children will either receive two or three doses of ISIS-SMNRx over the course of the study. We are also evaluating ISIS-SMNRx in a Phase 2 open-label, multiple-dose, dose-escalation pilot study in eight infants who have been diagnosed with SMA. To meet enrollment criteria for the Phase 2 infant study, infants must be between the ages of three weeks and seven months, live in close proximity to a study site and pass screening evaluations conducted at study sites. For more information on both of these studies, please visit www.clinicaltrials.gov and search for ISIS-SMNRx.
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.
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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. ATL 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.
ISIS-TTRRx 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-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. In October 2012, we amended our agreement with GSK to reflect an accelerated development plan for ISIS-TTRRx. Under the terms of the original collaboration agreement with GSK, which includes six programs, we are eligible to receive on average up to $20 million in milestone payments per program before Phase 2 proof-of-concept plus a licensing fee, additional post-licensing milestone payments and double digit royalties on sales from each product. Under the amended terms of the agreement, we received a $2.5 million upfront payment in December 2012, and received a $7.5 million milestone payment in February 2013 upon initiation of the ISIS-TTRRx Phase 2/3 study. We have already received $17.5 million in milestone payments from GSK related to the development of ISIS-TTRRx, including the $7.5 million milestone payment we received in February 2013. We are also eligible to earn an additional $50 million in pre-licensing milestone payments to support the ISIS-TTRRx Phase 2/3 study. In addition, GSK has increased the regulatory and sales milestones payable to us should the product 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 many subjects achieving greater than 80 percent reduction in TTR protein and several subjects reaching TTR protein levels that were below the limit of assay detection at the highest doses. Subjects treated with ISIS-TTRRx generally tolerated the drug well. In February 2013, we initiated a Phase 2/3 study to evaluate the efficacy of ISIS-TTRRx in patients with FAP. In this study, we will enroll approximately 200 patients and evaluate the efficacy of ISIS-TTRRx by measuring neurological dysfunction and quality of life in patients with FAP.
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.
ISIS-PKKRx is an antisense drug designed to prevent hereditary angioedema, or HAE, attacks. ISIS-PKKRRx 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-DMPKRx is an antisense drug we designed to correct the underlying genetic defect that causes Myotonic Dystrophy Type 1 (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 (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 effect approximately 150,000 patients in the US, Europe and Japan. The severity and age of onset of DM1 correlates with the number of triplet repeats, 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-DMPKRx. Under the agreement, we received an upfront fee and are responsible for developing ISIS-DMPKRx. Biogen Idec has the option to license ISIS-DMPKRx up through completion of the Phase 2 study. We will receive milestone payments from Biogen Idec as ISIS-DMPKRx advances through development.
ISIS-DMPKRx targets DMPK to reduce the toxic RNA in the cells. In preclinical studies, we showed that an antisense compound targeting the DMPK mRNA entered muscle cells and significantly reduced the toxic RNA. Effective reduction of toxic RNA led to a reversal of the disease symptoms that were sustained for up to one year after treatment in a mouse model of DM1. By removing toxic RNA, ISIS-DMPKRx could be an effective approach to treating patients with DM1.