QUOTE AND NEWS
New York Times  4 hrs ago  Comment 
Gen. Martin E. Dempsey, the chairman of the Joint Chiefs of Staff, told Congress he would recommend deploying limited Special Operations forces if airstrikes were not successful.
Motley Fool  6 hrs ago  Comment 
Will ISIS push on to Saudi Arabia to obtain its oil wells? And why did Budweiser switch to natural gas vehicles?
New York Times  6 hrs ago  Comment 
A neighborhood in the tourist district of the capital, Ankara, has become a hub for wooing new members of the Islamic State, even as the group holds Turkish hostages.
Forbes  9 hrs ago  Comment 
The US has succeeded in efforts to build an international coalition to battle Islamic State militants in Iraq and Syria. During a crisis meeting in Paris, 24 countries pledged to join the US in defeating the "global threat" posed by the militants....
New York Times  9 hrs ago  Comment 
Republicans will insist on a careful accounting of how the plan fits into a larger strategy to defeat the militant group.
Canada.com  Sep 16  Comment 
The campaign has involved the use of Arab military bases, but the entry of Arab warplanes, especially if contributed by Persian Gulf nations, would be significant
New York Times  Sep 16  Comment 
The offensive is the first expansion of the United States’ campaign against the Islamist militant group that President Obama outlined last week in a speech to the nation.
New York Times  Sep 16  Comment 
After Mr. Foley was kidnapped by ISIS, the government offered sympathy but little active support, his family said, leaving them overwhelmed and unsure of what to do.
New York Times  Sep 16  Comment 
Counterterrorism officials said they are far more concerned that a militant will enter the country in a quite typical way: legally, on a commercial airline flight.
New York Times  Sep 16  Comment 
Secretary of State John Kerry spoke at a Paris conference on the Iraqi security crisis, as Iran’s supreme leader said the American plan for bombing ISIS was absurd.




 
TOP CONTRIBUTORS

Isis Pharmaceuticals, Inc. is a drug discovery and development company focused on the therapeutic target RNA and developing products from RNA-based technologies, such as antisense. Antisense drugs are the first class of drugs targeted to control expression of genes through interactions with RNA. Beyond antisense, Isis scientists have created another technology that exploits their knowledge of RNA. Ibis Biosciences, Inc., a wholly owned subsidiary of Isis, has developed and is commercializing the Ibis T5000 Biosensor System for rapid identification and characterization of organisms. The Ibis T5000 is capable of identifying virtually all bacteria, viruses and fungi, and can provide information about drug resistance, virulence and strain type of these pathogens. Commercial applications for the Ibis T5000 Biosensor System include epidemiologic surveillance, monitoring of pandemic diseases, identification of emerging or previously unknown pathogens, forensic characterization of human samples, identification of sources of hospital-associated infections, and, in the future, human infectious disease diagnostics. The company has over 1,500 issued patents worldwide and controls one of the largest antisense and RNA patent estates in the pharmaceutical industry. As of December 31, 2006, Isis has recognized over $77 million from licensing its intellectual property. The company was founded in 1989 and employs roughly 275 people.

Antisense Technology

Proteins are fundamental components of all living cells and include many types of molecules necessary for carrying out the body's functions, such as enzymes, hormones and antibodies. The overproduction or abnormal production of proteins is implicated or associated with many diseases. Genes contain the information necessary to produce proteins. A gene is made up of bases (Adenine, Thymine, Cytosine and Guanine commonly referred to as A, T, C and G), which are linked together to form a two-stranded structure that resembles a twisted ladder, known as DNA (deoxyribonucleic acid). The nucleotides on one side of the ladder interact with complementary nucleotides on the other side of the ladder according to specific rules (A pairs with T, C pairs with G), creating the ladder's rungs. The sequence or order of these nucleotides establishes the cell's recipe for making proteins. One of the DNA strands is called the sense strand and the other is called the antisense strand. Protein production occurs in two phases called transcription and translation. In the transcription phase, the DNA strand is used as a template for manufacturing a RNA molecule. The RNA strand of nucleotides is complementary to the DNA sense strand with one exception: Uracil (U), instead of Thymine, is the base complementary to A. Messenger RNA (mRNA) is responsible for communicating the genetic message found in DNA to other areas of the cell so that protein production can take place. Unlike DNA, mRNA is single-stranded and able to leave the nucleus of the cell. In the translation phase, the mRNA travels to the ribosome, which is the cell's machinery that assembles proteins based on the instructions it carries. Antisense technology has the potential to interrupt this translation phase of the protein production process by preventing the mRNA instructions from reaching the ribosome.

Antisense drugs are short, chemically-modified complementary nucleotide chains that bind to a specific complementary area of mRNA thereby inhibiting translation (protein production) enacted by the ribosome complex. By inhibiting the production of proteins involved in disease, antisense drugs can create therapeutic benefits for patients. There are several types of antisense drugs that can be developed. In fact, Isis scientists know of at least 12 different mechanisms that can be exploited once an antisense drug binds to its target RNA. The differences stem from the enzymes that cleave the RNA complex. Two important mechanisms that have received significant investor attention are small interference RNA (siRNA) and RNA interference (RNAi). Isis is collaborating with partners such as Alnylam Pharmaceuticals and Eli Lilly to explore the potential of both siRNA and RNAi therapeutics.

Antisense drugs have several specific advantages over traditional protein or small-molecule derived therapeutics. Firstly, antisense drugs are highly specific and bind to only the complimentary mRNA strain that codes for the specific protein being targeted. This has the potential to greatly reduce unwanted side-effects that occur through secondary mechanisms of action. Secondly, since all proteins are coded by mRNA, antisense drugs have the potential to work on a broad number of diseases including cardiovascular, metabolic, inflammatory, ocular, viral, neurodegenerative disease, and cancer. Finally, because all antisense drugs start with the basic hybridization of mRNA targets, development timelines are shortened and response is often predictable in the early-stage of development. Sciences need only choose a specific protein to target and then create a small antisense molecule to bind to the transcribed mRNA. This creates efficiency in drug discovery and time to market.

IBIS Biosciences

The Ibis division of Isis Pharmaceuticals was founded to take advantage of Isis' expertise in RNA and utilize that knowledge and innovation to create a fundamentally different approach to the identification of infectious microorganisms. The Ibis T5000 is a Biosensor System that has the potential to dramatically improve the identification of infectious diseases. The wide range of applications of the Ibis T5000 Biosensor System have the potential to enhance and improve national security, healthcare infection management, forensics and ultimately, infectious disease diagnosis. Along with its government and non-government partners the Ibis team is developing a number of applications to accomplish this objective. Ibis has partnered with several organizations to leverage the potential power of the T5000 system. These partners include, among others, the Department of Defense, the Federal Bureau of Investigation, the Centers for Disease Control and Prevention, The National Institutes of Health, and the Department of Homeland Security. These partners are also all potential major customers of the T5000, as well as private organizations in the agricultural industry, or hospitals and major medical centers around the globe. In the third quarter 2007 Ibis achieved commercial revenues of $4.64 million and a loss from operations of $1.25 million. Isis management believes that Ibis is on schedule to deliver a total of eight T5000 units for the full year 2007.

Regulus Therapeutics

Regulus Therapeutics is a biopharmaceutical company created to discover, develop and commercialize microRNA (miRNA) therapeutics. The company was formed through a joint venture between Isis a pioneer in oligonucleotide drug technologies and a leader in the field of antisense therapeutics, and Alnylam a leader in the field of RNAi therapeutics, in September 2007. Regulus intends to address therapeutic opportunities that arise from abnormal expression or mutations in miRNA. Since miRNAs regulate the expression of broad networks of genes and biological pathways, miRNA therapeutics define a new strategy to target multiple points on disease pathways. Regulus has assembled world-class scientists and the foremost authorities in the field of miRNA research to lead this new venture. In addition, Regulus has been formed combining the leading capabilities and intellectual property estates of its two parent companies. Thus, in Regulus, its founders have created the leading microRNA therapeutics company, a company that will translate one of the most important new frontiers in modern biology into an entirely new approach for innovative medicines by targeting the pathways of human disease with microRNA therapeutics.


Vitravene

Vitravene (fomivirsen) was the first antisense drug developed by Isis to achieve marketing clearance in August 1998. The product was also approved in Europe in 1999. Vitravene was used to treat a condition called cytomegalovirus (CMV) retinitis mostly commonly found in patients with AIDS. The FDA relegated Vitravene to use in patients that are no longer responding to other therapies and given new breakthroughs in anti-CMV medications, the product is no longer viable. Isis licensed Vitravene to Novartis AG and previously received royalties, licensing fees, and reimbursement for manufacturing on the product. Yet, despite the fact that Vitravene is no longer being promoted, the approval was an enormous step forward for Isis because it validates antisense technology and clears the way for approval of additional products in the coming years.

Mipomersen (ISIS-301012)

Isis Pharmaceuticals leading pipeline candidate is mipomersen (formerly ISIS-301012), a second generation compound that recently began phase III trials for familial hypercholesterolemia (high cholesterol). Mipomersen is an antisense drug that targets the protein apoB-100. ApoB-100 is a protein that is critical to the synthesis and transport of LDL "bad" cholesterol. By potentially knocking out the apoB-100 protein via antisense technology, Isis scientists believe they can effectively lower the cholesterol of patients and reduce the risk of serious cardiovascular disease. Preclinical data on mipomersen shows that inhibition of apoB-100 causes changes fat metabolism that reduced liver fat. This mechanism has potential in reducing LDL, VLDL, triglycerides and lipoprotein(a) (Lp(a), an independent cardiovascular risk factor). Given the novel mechanism and the focus on FH, the FDA granted mipomersen orphan drug status in June 2006.

Given the antisense mechanism, mipomersen may offer a significant advantage in familial hypercholesterolemia (FH), a genetic disorder that causes extremely high cholesterol levels and has been associated with early onset heart disease. Management has completed phase II dose-escalation trial in patients with FH that are not currently achieving their goal on traditional lipid-lowering medications such as statins. Isis presented encouraging data recently at the Drug Affecting Lipid Metabolism (DALM) meeting in October 2007. The data shows that 300mg/week of mipomersen reduced LDL by 36%, ApoB by 33%, total cholesterol by 22%, and Lp(a) by 25%. Isis has also studies mipomersen in-combination with statins. Patients who received 300 mg/week of mipomersen in this study achieved a 51% reduction in LDL-cholesterol (LDL), a 42% reduction in total cholesterol (TC), and a 41% reduction in triglycerides (TG) beyond the levels achieved with statins alone. We present some of the data below from the 300mg/week cohort vs. placebo. The data represents the percent change from baseline at the primary endpoint of 5 weeks of treatment.


Placebo

(n=11)

300mg/week

(n=8)

p-value


ApoB

-1%

-52%

p<0.0001


LDL-Cholesterol

-4%

-51%

p<0.0001


VLDL-Cholesterol

7%

-63%

p=0.08


Non-HDL-Cholesterol

-1%

-51%

p<0.0001


HDL-Cholesterol

9%

5%

p=0.41


ApoA-1

0%

2%

p=0.67


Total Cholesterol

2%

-42%

p<0.0001


Total Triglycerides

0%

-41%

p=0.04


Isis also tested 30mg, 100mg, 200mg, and 400mg per week. We think the 300mg/week looked the best from a TC and TG standpoint. This is highly encouraging data both from a mono- and combination therapy. No significant safety concerns were seen in the trial and tolerability was high. Importantly, treatment with mipomersen did not result in evidence of liver toxicity or instances of transaminase (ALT) elevations. The benefit on dosing with mipomersen is that long half-life of roughly 30 days. Management is testing once weekly doses of the drug, but the potential exists that to have bi-weekly doses in the future. This would be a big convenience over once daily statins.

Isis recently held an "end of phase II meeting" with the U.S. FDA. On the third quarter conference call management noted that they are waiting to hear back on several questions from the meeting. Mainly, what is necessary in terms of a phase III program for mipomersen. At this point we are unsure of the patient population for the phase III program. Is it a general population of familial hypercholesterolemia, or will the FDA require separate studies in heterozygous and homozygous populations? Also, what enrollment size is necessary? We are estimating somewhere around 1,500 patients. Isis will need to conduct two phase III trials for approval. Management has begun dosing in the first trial but has yet to divulge the details of the trial.

The trial only just initiated so the parameters and are still flexible and dependent on some of the answers from the FDA. Management expects to update the Street shortly on the finalized program. What we do know is that Isis is testing 300mg/wk mipomersen in FH, and will probably look to initiate another trial in 2008. Management is currently seeking a development partner mipomersen. We applaud management for initiating the phase III trial, but it unlikely the company will progress much further without a partner.

Our model currently assumes that this trial can be completed and a New Drug Application (NDA) can be filed by Isis' partner in late 2009. Based on the novel mechanism, the impressive phase II results, and the ability to co-administer with mega-blockbuster statin drugs, we believe that mipomersen has billion-dollar plus potential. Our financial model assumes a launch in early 2010 with $250 million in worldwide sales. We model a 25% royalty payment from Isis' partner on worldwide sales.


ISIS-113715

Another important proprietary candidate under phase II development at Isis is ISIS-113715, a second generation compound for type-II diabetes. ISIS-113715 is an antisense compound that targets the protein PTP-1B. PTP-1B is an enzyme that has been show to play a key role in reducing the ability of insulin to regulate blood sugar levels by inactivating the insulin receptor. By knocking out PTP-1B the body's insulin receptors may stay active longer and thus allow for more glucose uptake. Similar to ISIS-301012 in hyperlipidemia, this is a completely new mechanism of action for type-II diabetes and allows for the combination of therapy with currently approval medications such as metformin, glitazones, and sulfonylurea.

In June 2006, Isis reported positive phase II results in patients with type-II diabetes treated with ISIS-113715 as a single-agent. An intent-to-treat analysis of all patients enrolled in the trial treated with 200 mg/wk for three months showed statistically significant improvement in multiple measures of glucose control such as lowering HbA1C levels and fasting glucose levels. Additionally, important safety data was observed in the trial. ISIS-113715 did not cause hypoglycemia (low blood sugar), did not cause weight gain and was well tolerated throughout.

Isis recently initiated a combination study of ISIS-113715 in patients with type-II diabetes. The phase II dose-escalation study will evaluate the safety and activity of ISIS-113715 in combination with oral antidiabetic drugs. ISIS-113715 will be administered in patients with type-II diabetes being treated with sulfonylurea or with sulfonylurea and metformin over a 13 week treatment period. In addition, Isis is conducting a phase II study of ISIS-113715 in patients with type-II diabetes at Yale University to further assess the effects of ISIS-113715 on insulin sensitivity, fasting and postprandial glucose control and lipid metabolism.

Preclinical

Rounding out Isis' proprietary preclinical program, the company is working on ISIS-353512, a next-generation antisense compound that targets C-reactive protein (CRP) for the treatment of cardiovascular disease and inflammation. Isis has developed and optimized these next generation antisense compounds to be potentially as much as 10x more potent than second generation molecules. This increased potency and specificity may allow for less frequent dosing. Preclinical testing with ISIS-353512 has demonstrated dramatic blocking of CRP production. CRP is a special type of protein produced by the liver that is only present during episodes of acute inflammation. Excessive amounts of CRP have recently been linked to coronary artery disease. A growing body of evidence from recent clinical trials implicates CRP in cardiovascular disease progression, thus targeting and blocking CRP may lead to an enormous potential in addressing cardiovascular disease.

Isis was active earlier in the year at the American Diabetes Association (ADA) meeting presenting data on four new targets for diabetes. The targets, SGLT2 and PKC-delta for diabetes and JNK1 and mDIC, may also have important roles in obesity. Management is particularly interested in SGLT2, or sodium dependent glucose transporter type 2. The target is expressed in the kidney and contributes to glucose reuptakes back into the bloodstream following filtration by the kidney. So inhibiting SGLT2 function promotes glucose excretion into urine and that is expected to help reduce blood sugar level. The action is highly complementary to the other mechanisms to treat diabetes and offers management an opportunity to explore further. At the ADA meeting, data from several animal species demonstrated that antisense inhibitors of SGLT2 effectively reduced target messenger RNA levels, increased glucose excretion into urine and consequently lowered blood glucose level without causing hypoglycemia or dangerously low blood sugar. The reported data included studies conducted in dogs and rats with different treatment periods ranging from 6 to 20 weeks. In genetically diabetic rats weekly treatment with a low dose of the antisense drug to inhibit SGLT produced a sustained and significant 40% decrease in plasma glucose levels and a decrease in HBA1C of greater than 4 percentage points compared to untreated or control treated groups.

One additional preclinical candidate to mention is ISIS-333611. The candidate is a second-generation antisense drug in development for the treatment of amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig's disease. The drug works through the inhibition of Cu/Zn superoxide dismutase (SOD1), a molecule that is associated with an inherited, aggressive form of ALS. In preclinical rodent studies, inhibition of SOD1 extended survival of rats that show many features of ALS. The ALS Association and the Muscular Dystrophy Association are providing funding for IND-enabling studies of ISIS 333611. In December 2007 the U.S. FDA granted ISIS-333611 orphan drug status for the treatment of ALS. This allows for economic incentives and entitles Isis to seven years of U.S. market exclusivity.

Partnered Programs

Isis' proprietary development pipeline focuses on cardiovascular, metabolic, and inflammatory disease. However, in areas including ocular, viral, neurodegenerative disease, and oncology, Isis has out-licensed technology and partnered its pipeline for development.

Alicaforsen (ISIS-2302) is a first generation enema formulation that has completed phase II trials in patients with ulcerative colitis. Alicaforsen is an antisense inhibitor of ICAM-1, a molecule that plays a key role in a wide range of inflammatory and autoimmune conditions such as Crohn's disease (CD) and ulcerative colitis (UC). It is involved in the recruitment and activation of immune cells associated with the inflammatory response in these diseases. ICAM-1 is part of a molecular family (known as Cellular Adhesion Molecules, or CAMs) that can be found on the surface of virtually every cell in the body, including cells that line the inflamed gastrointestinal (GI) tract. In phase II trials alicaforsen enema produced significant and long-lasting disease improvement, as measured by changes in Disease Activity Index (DAI) scores and other indicators of disease. In particular, a substantial number of patients treated with alicaforsen enema experienced mucosal healing, as well as decreases in rectal bleeding and in stool frequency manifestations of the disease that cause considerable discomfort, inconvenience and pain to patients. Isis partnered the drug with Atlantic Healthcare in March 2007 for an upfront payment of $2 million and future development milestones and royalties. We believe that Atlantic can move toward a pivotal trial in 2008.

ATL1102 is a second-generation antisense inhibitor of VLA-4 in development for multiple sclerosis (MS). Inhibition of VLA-4 has been shown to have positive effects in multiple animal models of inflammatory diseases, including MS.

Isis licensed ATL1102 to Australian-based Antisense Therapeutics Limited (ATL) in 2001. Isis completed preclinical studies, and ATL is responsible for future clinical development, manufacturing and commercialization. In June 2006, ATL reported that dosing has commenced in phase IIa clinical trial of ATL1102 in 80 patients with relapsing remitting MS. Patients will receive ATL1102 or placebo over 8 weeks. ATL1102 will be delivered by subcutaneous injection of 400mg twice-a-week dosing. The goal of the phase IIa trial is to obtain preliminary evidence of the drug's effectiveness which will be evaluated using MRI (magnetic resonance imaging) indices. MRIs will be conducted at monthly intervals over the 8 weeks dosing period and during the 8 week period following completion of dosing.

Isis has several oncology targets under development as well. OGX-011 is a second-generation antisense inhibitor of clusterin, which Isis is co-developing with OncoGenex Technologies Inc. OGX-011 is currently in phase II clinical trials for patients with various types of cancer including, prostate cancer, non-small cell lung cancer, and breast cancer. All phase II programs are being tested in combination with chemotherapy. OncoGenex and Isis reported data in early June 2007 at the American Society of Clinical Oncology (ASCO) demonstrating encouraging improvements in progression free survival (PFS) for patients with hormone refractory prostate cancer when OGX-011 was added to standard chemotherapy docetaxel (7.3 months vs. 5.9 months). Also at ASCO in June 2007 was encouraging preliminary median survival data in non-small cell lung cancer. Patients taking OGX-011 plus standard chemotherapy had a median survival of approximately 14 months as well as improvements in partial response and disease stabilization over the control of chemotherapy alone. Isis and OncoGenex are also working on a preclinical candidate, OGX-427, that is a second generation antisense agent targeting the heat shock protein 27 (Hsp27). OGX-427 has potential in multiple tumor types including prostate, breast, and ovarian cancers. OGX-427 recently began phase I trials in the third quarter 2007.

Isis has partnered two cancer compounds with Eli Lilly. LY2181308 is a second generation antisense agent that targets survivin a protein that allows the survival of cells that would normally undergo programmed apoptosis. Knocking out survivin may inhibit cancer cell growth and reproduction. LY2181308 is currently in phase II trials at Lilly being tested on various types of cancer including liver, prostate, ovarian, non-small cell lung, and leukemia. LY2275796 is a second-generation antisense drug targeting eukaryotic initiation factor-4E (eIF-4E), a protein involved in the translation of key growth and survival factors that drive tumor progression, angiogenesis and metastases. LY2275796 is also in several phase II trials at Lilly specifically looking at breast, head and neck, prostate, lung, bladder, colon, and thyroid cancers.

In 2004, Isis licensed to Alnylam the use of certain patent estates for development of double-stranded siRNA drugs in return for an portion of the up front fees Alnylam receives for deals involving sublicensing these patents, as well as milestones and royalties on Alnylam's and its partners' products enabled by Isis technology. The value of this deal was recently seen when Alnylam formed an alliance with Roche totaling $1B in potential milestone. As a result of the Alnylam Roche deal, Isis received a portion of the upfront cash totaling $26.5 million.

In May 2007, Isis entered into a collaboration with Bristol-Myers Squibb (BMS) to develop and commercialize novel antisense drugs targeting proprotein convertase subtilisin kexin 9 (PCSK9) for the prevention and treatment of cardiovascular disease. PCSK9 is a protein that helps regulate the amount of cholesterol in the bloodstream. As part of the collaboration, Isis licensed to BMS exclusive access to its PCSK9 research program. BMS will fund all activities under the collaboration, and companies will be responsible for preclinical development. BMS will be responsible for clinical development, regulatory, and commercialization activities. In addition, BMS will work with Isis to leverage Isis' extensive oligonucleotide medicinal chemistry expertise for identification of follow-on PCSK9 antisense drugs with advanced antisense chemistries that may offer even greater potency and oral bioavailability. BMS paid Isis a $15 million upfront licensing fee, and will provide Isis with at least $9 million in research funding over a period of three years. Isis may also receive up to $168 million for the achievement of pre-specified development and regulatory milestones for the first drug in the collaboration, as well as additional milestones associated with development of follow-on compounds. BMS will also pay Isis royalties on sales of products resulting from the collaboration.

In August 2007, Isis entered into a strategic alliance with Archemix to discover Aptamer therapeutic candidates for various diseases. Aptamers are synthetically-derived oligonucleotides that may have a broad range therapeutic use. Isis licensed certain intellectual property to Archemix and may receive developmental milestones upon advancement of clinical candidates in the future.

In September 2007, Isis entered into another massive collaboration with Ortho-McNeil, Inc., a division of Johnson & Johnson. The collaboration aims to discover, develop and commercialize antisense drugs to treat metabolic diseases, including Type 2 diabetes. As part of the collaboration, Isis will grant to Ortho-McNeil worldwide development and commercialization rights to two of its diabetes development candidates, ISIS-325568 and ISIS-377131, which selectively inhibit the production of glucagon receptor (GCGR) and glucocorticoid receptor (GCCR), respectively. Additionally, Ortho-McNeil will provide funding to Isis to support the joint discovery of novel drugs to treat metabolic diseases, including diabetes and obesity. Ortho-McNeil paid Isis a $45 million upfront licensing fee, and will provide Isis with research and development funding of $15 million over the period of the collaboration. So far in the fourth quarter 2007 Isis earned a $5 million milesone on the initation of phase I "proof-of-concept" trial for ISIS-325568, as well as $2 million in research funding. In addition to the licensing fee, Isis could receive over $230 million in milestone payments upon successful development and regulatory approvals of ISIS-325568 and ISIS-377131, as well as royalties on sales. ISIS-377131 is in IND-enabling studies.


In October 2007 Isis entered into a licensing agreement with Altair Therapeutics, a privately held venture capital funded biotechnology company focused solely on the development and commercialization of antisense drugs for the treatment of asthma and other respiratory conditions. Isis licensed ISIS-369645, a second generation candidate that targets the alpha protein component of the interleukin 4 receptor (IL4-alpha), to Altair in return for an 18% ownership (in the form of preferred stock) in Altair. Isis has demonstrated that inhibiting the production of IL4R-alpha inhibits the activity of two important cytokines in asthma, IL4 and IL13, that regulate inflammation, mucus overproduction and airway hyper-responsiveness. If successful, Altair will pay development milestones and royalties on sales to Isis.

In 2005, iCo Therapeutics, licensed iCo-007, a second-generation antisense drug that inhibits the production of c-Raf kinase, an enzyme associated with the formation of new and often abnormal or fragile blood vessels in the eye. Blood vessel breakage and leakage can contribute to vision loss, and iCo-007 is expected to decrease swelling in the retina and related visual impairment by decreasing the signaling of various growth factors such as VEGF that signal through the c-Raf kinase / MAP kinase pathway. In October 2007, iCo Therapeutics paid a $1.25 million milestone to Isis based on the initiation of a phase I trial for iCo-007. The candidate has potential in the treatment of various eye diseases, including diabetic macular edema.

In October 2007, Isis announced that CHDI, a non-profit foundation pursuing treatments for Huntington's Disease (HD), will provide up to $9.9 million in funding to Isis for the discovery and development of an antisense drug for the treatment of HD. HD is a fatal neurodegenerative disease. CHDI's funding builds upon an earlier successful collaboration between Isis and CHDI, in which CHDI provided Isis with funding for studies that demonstrated the feasibility of using antisense drugs to treat HD. CHDI will provide Isis with up to $9.9 million in funding over three years to identify and conduct IND-enabling studies on an antisense drug targeting the huntingtin gene. Mutations in the huntingtin gene are responsible for the production of the abnormal proteins, which ultimately leads to onset and progression of the neurodegenerative disease.

Finally, in November 2007, Isis and Excaliard Pharmaceuticals announced a new collaboration to discover and develop antisense drugs for the local treatment of fibrotic diseases, including scarring. Isis has granted Excaliard an exclusive worldwide license for the development and commercialization of certain antisense drugs. Excaliard made an upfront payment to Isis in the form of equity and paid Isis $1 million cash for the licensing of a particular gene target. In addition, Isis is eligible to receive development milestones and royalties on antisense drugs developed by Excaliard.

KEY THERAPEUTIC AREAS

Cholesterol / Cardiovascular Disease

According to the American Heart Association, nearly 100 million American adults have total blood cholesterol values of 200 mg/dL and higher, and of these about a third have levels of "high risk" levels above 240. Low-density lipoprotein, or LDL, known as the "bad" cholesterol, can clog arteries, increasing the risk of heart attack and stroke. According to the World Health Organization (WHO), heart disease and stroke kill 17 million people a year, which is almost one-third of all deaths globally. By 2020, the WHO projects that heart disease and stroke will become the leading cause of both death and disability worldwide, with the number of fatalities projected to increase to over 20 million a year and by 2030 to over 24 million a year. Familial hypercholesterolemia (FH) is a dominantly inherited genetic condition that results in markedly elevated LDL (low-density lipoprotein) cholesterol levels beginning at birth, and resulting in heart attacks at an early age. Affected people have consistently high levels of low-density lipoprotein, which leads to premature atherosclerosis of the coronary arteries. Treatment for FH is inadequate, and the most severely affected patient may undergo an expensive and time consuming procedure called apheresis, a process similar to kidney dialysis to remove the "bad" cholesterol from the blood. Homozygous FH is rare, affecting about 1 in 1 million people, but heterozygous FH is much more common with a prevalence of approximately 1 in every 500 people.

Type-II Diabetes

Type-II diabetes is the most common form of diabetes. In type-II diabetes, either the body does not produce enough insulin or the cells do not respond to insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems: cells may be starved for energy or over time, high blood glucose levels may affect the eyes, kidneys, nerves or heart. According to the American Diabetes Association, diabetes affects over 20 million people and type-II diabetes constitutes about 90% of those cases.

Asthma

According to the American Lung Association, approximately 20 million Americans suffer from asthma. Asthma and the condition accounted for an estimated 12.8 million lost school days in children and 24.5 million lost work days in adults. Asthma ranks within the top ten prevalent conditions causing limitation of activity and costs the U.S. over $16 billion in health care costs annually.




References

Kidney Infection Signs

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