Navigate the Isis Pharma ISIS Research Pages
- Introduction (valuation, financials, outlook, company catalysts)
- Antisense background (science, technology, intellectual property, manufacturing)
- KYNAMRO - mipomersen (lead program in regulatory review for familial hypercholesterolemia)
- Mipomersen Liver Safety (special feature pages with extensive notes on long-term safety and efficacy of the drug)
- Cardiovascuar Disease pipeline (addtional CV drugs besides mipomersen)
- Metabolic Disease pipeline (several drugs for type II diabetes, as well as obesity)
- Cancer pipeline (including partnered with Eli Lilly $LLY and OncoGenex $OGXI)
- Severe, Rare, and Neurodegenerative Disease pipeline (incude GSK collaboration)
- Licensing deals and Satellite/spin-off companies (key business development activities)
- Discontinued Programs (not everything works out when you have a large and broad biotech portfolio)
Cardiovascular Disease Franchise
- "Cardiovascular disease is the leading cause of death in the United States. A common cause of cardiovascular disease 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 preventing and managing cardiovascular disease. Another independent risk factor for cardiovascular disease is high levels of C-reactive protein, or CRP, which clinicians associate with significantly worse outcomes in patients with cardiovascular disease." (2010 10k)
- "These are patients who are on a regimen of cardiovascular disease therapies and who are still at high risk for a cardiac event or death. The liver is an ideal target organ for cardiovascular disease therapies, and antisense drugs in particular, because there are many liver-produced targets that affect the production of cholesterol particles, clotting factors and other factors that contribute to the inflammatory components of cardiovascular disease. Our antisense drugs distribute to the liver and inhibit the production of many targets associated with cardiovascular risk, creating an opportunity for us to develop many complementary and effective antisense drugs for cardiovascular disease." (2010 10k)
- 4/2010 CC: Expect all ISIS CV drugs to be used by patients w/ significant CV risk and in addition to other treatments; expect staged development for most
- uniquely able to show POC in p1/2 trials
- focus on targets in liver now, acutal plaques next (6/2011 Annual Meeting described "novel target to affect cells at vascular plaque sites").
- Plan to add Lp(a) and Factor VII candidate to pipeline in 2011. Only Lp(a) is mentioned in 2010 10k.
C-reactive Protein (CRP) inhibitor
- Antisense against CRP, which is produced in the liver. Elevated CRP is associated with numerous inflammatory diseases (including Crohn's and rheumatoid arthritis), coronary artery disease, CV disease progression, end-stage renal disease, and multiple myeloma.
- Previously known as ISIS-353512. But 8/2011 RA phase 2 trial listing refers to ISIS-329993.
- Isis drug will be the first to answer the question of whether lowering CRP will benefit patients in these diseases
- CRP is a complex glycoprotein - very hard to develop small molecule inhibitors
- Detailed info on the CRP program featured on this poster from 6/2011 Annual Meeting.
- Preclinical: reduced liver and serum levels of CRP
- Conducted blinded, randomized, double-blind, placebo controlled phase 1 trial. Achieved stat-sig reductions in CRP in healthy subjects with elevated CRP
- Phase 2 plan- evaluate in diseases with elevated CRP that will provide rapid clinical proof of concept. Multiple myeloma and RA are the first indications planned.
- Phase 2 trial in Rheumatoid Arthritis (NCT01414101). Initiated 8/2011. Randomized, double-blind, placebo-controlled trial of 48 patients. Primary endpoint is safety at 99 days, secondary endpoint is serum CRP levels at 57 days: note there are no RA efficacy endpoints.
- 4/2010: p1 data early fall 2010 (delayed b/c not many healthy indivs w/ elevated CRP but now just moving fwd anyway)
- Phase 1 data: saw >70% decrease in CRP levels on average vs baseline, well tolerated up to 600 mg/week
- 9/2010: broad p2 pgm in late 2010 would be in multiple myeloma, rheumatoid arthritis, late stage renal disease, organ transplants or atrial fibrillation.
- CRP is assoc w/ poor outcome in numerous diseases.
- Some indications would have simple p3 plans, others (CV) would need outcome studies.
- Majority of CRP made in liver, but can get drug into bone marrow for MM.
- 11/2010: p1 dosing complete; p2 start 4q10 first in MM, RA w/ elevated CRP, and autologous BM transplant, then renal, all to prep for CV indications
- Mid-2011 expect to initiate phase 2 trials in multiple myeloma (give before and after autologous stem cell transplant, acute CRP elevated) and rheumatoid arthritis (stable, chronic CRP elevation)
- Later phase 2 indications: end-stage renal disease, atrial fibrilation, secondary prevention of heart attacks
Factor XI (FXI) Inhibitor
- Antisense targeting Factor XI for clotting disorders. FXI is produced in the liver and plays a role in the coagulation cascade. Reducing FXI may help prevent blood clots with low risk of bleeding. Humans deficient for FXI have a lower incidence of thromboembolic events. Plan staged development for various thromboses (market opportunities in both arterial and venous thromboses).
- Convenient, no more than once weekly dosing. Clotting factors have potential efficacy in other diseases (inflammation, cancer) as well
- FXI is first candidate selected in thrombosis program
- The FXI program was featured on this poster at the 6/2011 Annual Meeting.
- 2/2011: initiated p1 trial.
- Phase 2 study populations will include Venous Thromboembolism (VTE; common but preventable) and Antrial Fibrillation/Stroke
APOC-III Inhibitor
- Antisense targeting apolipoprotein C-III (apoC-III), a glycoprotein which is produced mainly in the liver and inhibits clearance of triglycerides from serum. Reduction in apoC-III leads to decreased triglycerides. High triglycerides are an independent CV risk factor, a risk factor for stroke, and a hallmark of metabolic syndrome (common in type 2 diabetes).
- Genetic validation: "Humans with genetic loss of apoC-III have low triglyceride levels & low cardiovascular risk"
- Difficult to specifically target via traditional drug discovery
- The ApoC-III program was featured on this poster at the 6/2011 Annual Meeting.
- Preclinical: successfully improved metabolic syndrome and reduced plaques
- 9/2010: after p1 plan to move rapidly into p2 w/ pts w/ elevated APOCIII and triglycerides for efficacy.
- Possible initial indication for pancreatitis caused by high triglycerides (>500)...then elevated, then diabetes [staged devel like mipo].
- 12/2010: initiated p1 in hypertriglyeridemia "Blinded, randomized, placebo-controlled, dose-escalation study in healthy volunteers...Designed to assess safety & pharmacokinetic profile; exploratory evaluation of effects on apoC-III & triglycerides