Cardiovascular Disease

Cardiovascular disease is the leading cause of death in the United States. Its underlying cause is atherosclerosis, or hardening of the arteries, that occurs when cholesterol and inflammatory cells accumulate in blood vessels. Researchers have shown a strong correlation between high cholesterol levels and subsequent cardiovascular diseases. Lowering cholesterol is a key component in the prevention and management of cardiovascular disease. Another independent risk factor for cardiovascular disease is high levels of C-reactive protein, or CRP, which are associated with significantly worse outcomes in patients with cardiovascular disease. (return to top)

Mipomersen (ISIS 301012) — Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol.

On January 7, 2008, Isis announced the licensing of mipomersen to Genzyme as the preferred partner to continue development, commercialize and market the drug. Mipomersen is currently in phase 3 development for patients with homozygous familial hypercholesterolemia, a disease which creates a greatly increased risk of premature cardiovascular disease (CVD) and CVD-related death. In phase 2 studies, mipomersen, a weekly injectable therapeutic, was observed to reduce cholesterol and other atherogenic lipids beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets.

The initial indication sought for mipomersen will be for patients with homozygous FH, and a phase 3 trial in this patient population is ongoing. A U.S. filing for this indication is expected during the second half of 2010. The companies also plan to study mipomersen's use in other very high risk patient groups, including apheresis-eligible patients. Data from a trial in apheresis-eligible patients is expected before the filing for the initial homozygous FH indication.

LDL apheresis is a blood-filtering procedure that targets "bad" cholesterol, and is indicated for individuals for whom diet and maximum drug therapy has either been ineffective or not tolerated. Specific LDL levels defining apheresis eligibility vary by country. Many patients who are eligible, however, choose not to undergo apheresis due to its negative impact on quality of life. The procedure is painful and inconvenient, requiring patients to go to apheresis centers for treatment once every one to two weeks. Apheresis can cost $75,000 to $150,000 per year.

The trial in apheresis-eligible patients is an important addition to the mipomersen development program. Like homozygous FH patients, apheresis-eligible patients are characterized by extremely high LDL levels and are not able to be managed by existing therapies. There are an estimated 10,000 – 15,000 apheresis-eligible patients in the United States and Europe.

Genzyme and Isis expect to begin three additional trials of mipomersen in high risk patients during the second half of this year. These trials will include: one for heterozygous FH patients, and two for high-risk, high cholesterol patients. These trials will continue to build the body of clinical evidence around mipomersen's value in managing very high risk patients.

Data from these five trials will also inform the design of the morbidity and mortality outcome study for potential expansion of mipomersen's label to include a larger group of at-risk, high cholesterol patients. In addition to the ongoing discussions with the FDA, plans are underway to engage in discussions with regulatory authorities in Europe, where the development path for mipomersen may differ from that in the U.S. (return to top)

ISIS 353512—ISIS 353512 is a generation 2.2 antisense inhibitor that targets C-reactive protein, or CRP. Excessive amounts of CRP have been linked to coronary artery disease and a growing body of evidence from clinical trials implicates CRP in cardiovascular disease progression. These results suggest that it may be therapeutically beneficial to significantly decrease CRP levels in patients who are at risk for coronary events.

In preclinical studies, ISIS 353512 produced dramatic suppression of liver and serum CRP levels in monkeys. In additional animal studies, ISIS 353512 dramatically reduced human CRP levels in transgenic mice. We have an agreement with the Korea Institute of Technology which will conduct toxicology and other IND-enabling studies to support clinical development of ISIS 353512. This partnership enables us to advance the drug’s development and reduce preclinical costs substantially in exchange for a nominal royalty. (return to top)

ISIS 113715—ISIS 113715 is our second-generation antisense inhibitor of protein tyrosine phosphatase 1b, or PTP‑1b, for the treatment of type 2 diabetes. PTP‑1b is responsible for turning off the activated insulin receptor, so by reducing levels of PTP‑1b, ISIS 113715 enhances the activity of insulin. Because ISIS 113715 is an insulin sensitizer that acts by increasing the activity of the insulin receptor in response to insulin, the most logical place for this drug in the diabetes treatment regimen is as an adjunct to insulin therapy, and that’s how we initially plan to develop this drug for registration. ISIS 113715 presents us with a unique opportunity of being first in class with a novel mechanism of action, as an insulin signal enhancer with anti-obesity and lipid lowering potential.

PTP‑1b has long been recognized as an attractive target for treatment of diabetes, but due to structural similarities among closely related proteins, it has been difficult to identify small molecule drugs with sufficient specificity to be safe. Antisense technology allows us to design very specific drugs that inhibit PTP‑1b and that do not inhibit other family members, making it possible to reduce PTP‑1b activity without having other effects on closely related proteins that would likely lead to unwanted side effects.

In June 2006, we announced positive Phase 2 results in patients with type 2 diabetes treated with ISIS 113715 as a single agent. The study was conducted in newly diagnosed type 2 diabetic patients with moderate diabetes and divided into two parts, a six week safety portion with ascending doses, and a three month portion at a weekly ISIS 113715 dose of 200 mg/week designed to determine the effects of treatment with ISIS 113715 on several measures of blood glucose control. We analyzed the activity of ISIS 113715 in the three month 200 mg/week portion, and showed statistically significant improvements in multiple measures of glucose control along with statistically significant reductions in LDL-cholesterol. In this study we did not see a statistically significant improvement in glycosylated hemoglobin, or HbA1c, a measure of long-term glucose control. We believe this reflects the combined factors of small size, short duration and high placebo response rate in the trial, since these were newly-diagnosed diabetics being counseled on diet and exercise modifications for the first time. In the study, ISIS 113715 was well tolerated and did not cause low blood sugar, called hypoglycemia, or weight gain.

We are currently conducting a combination study of ISIS 113715 in patients with type 2 diabetes. Because our initial registration plan for ISIS 113715 is as an adjunct to insulin therapy, we are evaluating it in combination with sulfonylureas. Sulfonylureas, which are commonly prescribed oral antidiabetic drugs, increase insulin secretion in the body and therefore they offer the best approximation of a combination with insulin therapy in the milder disease setting appropriate for this first combination experience with ISIS 113715.

In addition, we are conducting a Phase 2 study of ISIS 113715 in patients with type 2 diabetes to further assess the effects of ISIS 113715 on insulin sensitivity, fasting and post meal time glucose control and lipid metabolism. (return to top)

ISIS 325568—We have licensed ISIS 325568 to Ortho-McNeil, Inc., a Johnson & Johnson company, as part of the Companies’ antisense drug discovery and development collaboration in metabolic diseases.  ISIS 325568 is a generation 2.2 antisense drug that targets the glucagon receptor (GCGR). Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose. In type 2 diabetes, unopposed action of glucagon can lead to increased blood glucose levels. Reducing the expression of GCGR using antisense inhibitors, and thereby reducing excessive liver glucose production, should lower blood glucose and help control type 2 diabetes.

In preclinical studies, ISIS 325568 produced excellent glucose control and reduced levels of blood triglycerides without producing hypoglycemia. While this is justification enough to pursue GCGR as a therapeutic target, the additional activity of ISIS 325568 in increasing circulating glucagon-like peptide, or GLP-1, makes it an even more attractive drug for development. GLP-1 is a hormone that helps to preserve pancreatic function, enhancing insulin secretion.

ISIS 325568 is currently being evaluated in a Phase 1 study designed to assess its activity, including its effect on liver glucose production, as well as safety and pharmacokinetic profiles, providing the opportunity to demonstrate proof-of-concept in this first human trial.(return to top)

ISIS 377131—We have licensed ISIS 377131 to Ortho-McNeil, Inc., a Johnson & Johnson company, as part of the Companies’ antisense drug discovery and development collaboration.  ISIS 377131 is a generation 2.2 antisense drug that targets the glucocorticoid receptor (GCCR). Excessive glucocorticoid action causes a spectrum of clinical features, including obesity, insulin resistance and glucose intolerance. Glucocorticoids promote breakdown of protein and fat from storage and ultimately result in increased liver glucose production. Because of the tissue distribution properties of antisense drugs, with ISIS 377131 we expect to inhibit glucocorticoid signaling selectively in liver and fat tissue, and not in the central nervous system or adrenal glands. We anticipate that ISIS 377131 will improve blood glucose levels and also have lipid-lowering effects. Therefore, this drug may prove to have an attractive profile in treating diabetic dislipidemia and even obesity which often goes hand-in-hand with type 2 diabetes.

In preclinical studies, ISIS 377131 produced pronounced glucose lowering effects, and a robust lowering of blood cholesterol and triglycerides. Furthermore, we also observed a reduction in body fat and reduction of fat build up in the liver. Fatty liver is observed in over 40% of the diabetic population and is believed to contribute to defective insulin action in these patients. We saw no effects of ISIS 377131 on glucocorticoid activity in the brain or other tissues such as the adrenal glands and lymphocytes.

ISIS 377131 is currently in IND-enabling preclinical studies. (return to top)

ISIS 388626—ISIS 388626 is a generation 2.2 antisense inhibitor of sodium dependent glucose transporter type 2, or SGLT2, for the treatment of type 2 diabetes. SGLT2 is the primary transporter responsible for glucose reabsorption in the kidney. Decreasing SGLT2 function promotes glucose excretion and thereby reduces blood sugar levels. Therefore, SGLT2 is an attractive target for the treatment of type 2 diabetes. ISIS 388626 is our first drug targeted to the kidney, which along with the liver, fat cells, bone marrow and spleen, is a tissue to which antisense drugs naturally distribute.

In preclinical studies, our antisense inhibitors of SGLT2 effectively reduced target mRNA levels, increased urinary glucose excretion and consequently lowered blood glucose levels and HbA1c without causing dangerously low levels of blood sugar. Furthermore, ISIS 388626 is among the most potent drugs we have ever tested in preclinical models. We attribute this, in part, to the shorter oligonucleotide composition of the drug that results in increased RNaseH activity, as well as increased distribution to specific areas in the kidney.

We recently added ISIS 388626 to our pipeline as a development candidate. (return to top)

Cancer

OGX‑011—OGX‑011 is a second-generation antisense inhibitor of clusterin, which we are co-developing and commercializing with OncoGenex. We and OncoGenex designed OGX‑011 to inhibit the secreted protein clusterin, which acts as a cell-survival protein and is over-expressed in response to anti-cancer agents, like chemotherapy, hormone ablation and radiation therapy. Based on analysis of human tumor tissue, clusterin is over-expressed in several cancers, including prostate, breast, renal, bladder, non-small cell lung and ovarian. Increased clusterin production is linked to faster rates of cancer progression, treatment resistance and shorter survival duration. OncoGenex has published results of its Phase 1 study evaluating OGX‑011 in combination with hormone ablation therapy in patients with high-risk prostate cancer. The study showed that once weekly intravenous administration of OGX‑011 was well tolerated, achieved excellent drug concentration in target tissue, and produced a 91% dose-dependent reduction of its target, clusterin, in prostate cancer. OGX‑011 is being evaluated in Phase 2 clinical trials in combination with chemotherapy in patients with prostate, breast and non-small cell lung cancer (NSCLC). Preliminary data presented in June of 2007 offer encouraging results in both prostate and NSCLC. In the prostate cancer study, hormone refractory advanced prostate cancer patients were randomized to receive 640 mg/week of OGX-011 with docetaxel and predisone or docetaxel and predisone alone. Both arms met the primary endpoint of PSA responses, and there were clinically meaningful benefits seen in OGX-011 arm including prolonged durations of progression-free survival and increased disease stabilization (fewer patients’ disease progressed). In the ongoing single-arm NSCLC study in which OGX-011 was added to gemcitabine plus cisplatin or carboplatin in first-line therapy for advanced NSCLC, the estimated median overall survival was 14 months compared with historical expectations for gemcitabine plus cisplatin or carboplatin in the range of 8 – 11 months. In addition, the percent of patients surviving at one year (54%) was higher than historically reported for the chemotherapy regimen (33%-43%). Earlier in 2007, OncoGenex reported preliminary results of the Phase 2 breast cancer study. In the study, clinical activity was seen for the combination of OGX-011 and docetaxel in patients with metastatic disease, but the results did not meet the pre-determined criteria of six or more patients achieving tumor size reductions exceeding 30 percent required to expand the trial into a second stage of accrual. OncoGenex expects to announce results of the remaining Phase 2 trials in 2007. It plans to evaluate the results of the Phase 2 studies to determine which cancer indications and which treatment combinations demonstrate promise and will design Phase 3 clinical trials accordingly. (return to top)

OGX‑427—OGX‑427, the second anti-cancer drug in our collaboration with OncoGenex, is a second-generation antisense inhibitor targeting heat shock protein 27, or Hsp27. Hsp27 is a cell survival protein that is over-produced in response to many cancer treatments, including hormone ablation therapy, chemotherapy and radiation therapy. Increased Hsp27 production is observed in many human cancers, including prostate, non-small cell lung, breast, ovarian, bladder, renal, pancreatic, multiple myeloma and liver cancers. Increased Hsp27 production is linked to faster rates of cancer progression, treatment resistance and shorter survival duration. In single agent preclinical studies, OGX‑427 demonstrated significant anti-tumor activity at low concentrations. In addition, when combined with chemotherapy, in preclinical prostate cancer studies, OGX‑427 was able to significantly enhance the anti-tumor activity of the widely used chemotherapy drug, paclitaxel. OncoGenex is currently conducting a Phase 1 clinical study of OGX‑427 in patients with breast, ovarian, bladder, prostate or lung cancer. (return to top)

AIR645 (ISIS 369645)—We have licensed AIR645 to newly formed Altair Therapeutics, a venture capital funded biotechnology that has been created to focus on the discovery, development and commercialization of Isis’ antisense drugs to treat respiratory conditions.  AIR645 is a second-generation inhaled antisense drug for the treatment of asthma and related respiratory conditions.  AIR645 is an inhibitor of the alpha subunit of the interleukin 4 receptor, IL-4R-alpha. Inhibiting the production of IL-4R-alpha inhibits the activity of two important cytokines in asthma, IL-4 and IL-13, which regulate inflammation, mucus overproduction and airway hyper-responsiveness.

In preclinical studies, antisense inhibitors of IL-4R-alpha potently reduced target mRNA and protein levels, and had pharmacologic activity in mouse models of asthma that included reducing lung cytokine production, inflammation, and airway hyper-responsiveness. In addition, these studies showed that, when delivered by inhalation, AIR645 rapidly distributed to the airways and achieved therapeutic drug concentrations in multiple cell types with little systemic exposure.

AIR645 is currently in IND-enabling studies. (return to top)