Pipeline

Clinical | Preclinical

Therapeutic Area

Phase

Severe & 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 and neurological disorders 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. IONIS-SMNRx, the most advanced neurological drug in our pipeline, is now in two Phase 3 studies for the treatment of infants and children with SMA.

We are discovering and developing antisense drugs to treat severe and rare and neurological diseases for which there is a need for new treatment options. We have established strategic alliances in drug development areas that are high risk or in which our partners have significant expertise and resources to allow us to expand our drug discovery and development efforts beyond what we would choose to do internally. For example, our strategic partnerships with Biogen Idec and Roche have supported advancing five drugs for the treatment of neuromuscular or neurological diseases in our pipeline.

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.

Drug
Target
Partner
Indication
P1
P2
P3
C

KYNAMRO®

ApoB-100

Kastle

Homozygous FH

Generation 2.0 antisense drug

Indication:

Homozygous Familial Hypercholesterolemia (HoFH)

Description/Summary:

KYNAMRO(R) (mipomersen sodium) injection 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, total cholesterol, and non-high density lipoprotein-cholesterol in patients with HoFH. KYNAMRO(R) is approved for use in patients with HoFH in the United States and certain other countries.

Click here to download full Prescribing Information and Medication Guide.

Current Status

KYNAMRO is approved for use in patients with HoFH in the United States and certain other countries.

Clinical Data

In August 2015, we reported that the FOCUS FH study met its primary efficacy endpoint, a statistically significant reduction in LDL-cholesterol after 60 weeks of treatment of once weekly injections of 200 mg of KYNAMRO compared to placebo. LDL-cholesterol reduction was similar to that observed in previous Phase 3 studies. In addition, based on the data available for review, the safety profile of KYNAMRO observed in the FOCUS FH trial was similar to the safety profile reported in previous Phase 3 studies.

About Homozygous Familial Hypercholesterolemia

HoFH is a rare genetic disease characterized by extreme cholesterol levels. People with HoFH have inherited mutations that limit the body's ability to clear cholesterol. HoFH is extremely rare: it is believed to occur in only one out of every one million persons. Today, it is estimated that HoFH affects about 6,000 people globally. HoFH may be diagnosed by clinical or genetic parameters, and may be considered in cases of unusually high LDL-C, such as greater than 500 mg/dL without treatment, or 300 mg/dL after taking cholesterol-lowering medication. Because HoFH is genetic, it is important that all family members of people with HoFH know their cholesterol levels, regardless of their age.

Selected Publications

  1. Raal, F.J. et al. (2010) Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 375, 998-1006.
  2. Santos, R.D. et al. (2014) Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension (2015) Eur Heart J. 36, 566-575.
  3. Stein, E.A. et al. (2012) Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 126, 2283-2292
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Alicaforsen

ICAM-1

Atlantic

Pouchitis

Antisense drug

Indication*:

Pouchitis

Description/Summary:

Alicaforsen is an antisense drug we designed to reduce the production of intercellular adhesion molecule 1, or ICAM-1. Ulcerative colitis, or UC, is an inflammatory bowel disease 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. Atlantic Pharmaceuticals is developing alicaforsen for the treatment of UC and currently supplies alicaforsen in response to physicians' requests under international Named Patient Supply regulations for patients with inflammatory bowel disease.

Selected Publications

  1. Barish, C.F. (2005) Alicaforsen therapy in inflammatory bowel disease. Expert Opin Biol Ther. 5, 1387-1391.
  2. Miner, P. et al. (2004) An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Aliment Pharmacol Ther. 19, 281-286.
  3. Philpott, J.R. & Miner, P.B. Jr. (2008) Antisense inhibition of ICAM-1 expression as therapy provides insight into basic inflammatory pathways through early experiences in IBD. Expert Opin Biol Ther. 8, 1627-1632.
  4. van Deventer, S.J. et al. (2006) A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther. 23, 1415-1425.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described Back to top
 
 
 
 

IONIS-TTRRx

TTR

GSK

Familial Amyloid Polyneuropathy

Generation 2+ antisense drug

Indication*:

Familial Amyloid Polyneuropathy

Description/Summary

IONIS-TTRRx is an antisense drug designed to reduce the production of transthyretin, or TTR, to treat all forms of TTR amyloidosis, a severe, rare and fatal disease. In patients with TTR amyloidosis both the mutant and wild type (wt) TTR build up as fibrils in tissues, such as the peripheral nerves, heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. 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, resulting in poor quality of life and eventually death.

We are developing IONIS-TTRRx as one drug and product presentation, in one broad development plan for the treatment of patients with all forms of TTR amyloidosis. IONIS-TTRRx is being administered as one injection, once a week for all TTR amyloidosis patients.

The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to IONIS-TTRRx for the treatment of patients with FAP. The European regulatory agency has granted Orphan Drug Designation to IONIS-TTRRx for the treatment of patients with TTR amyloidosis.

Clinical Data

In November 2015, we reported positive data from an ongoing open-label extension (OLE) study of IONIS-TTRRx in patients with familial amyloid polyneuropathy (FAP). FAP patients completing the ongoing Phase 3 study are eligible to enroll in this OLE study in which all patients receive IONIS-TTRRx. An analysis conducted on the first group of patients to reach three months of treatment in the OLE study showed a reduction in TTR protein levels up to 92 percent with a mean maximum (nadir) reduction of 76 percent compared to patients' baseline TTR levels at entry into the Phase 3 study.

For more information on the interim results of this study, please see our press release here.

In November 2015, we reported preliminary data from an ongoing Phase 2 study that showed evidence of cardiac disease stabilization in patients with TTR amyloid cardiomyopathy treated with IONIS-TTRRx for 12 months. The Phase 2, open label, investigator initiated study was conducted in patients with familial amyloid cardiomyopathy (FAC) and wild-type TTR amyloidosis (wt-TTR amyloidosis) with baseline intraventricular septum (IVS) thickness >= 1.3cm (mean =2.03). The first three patients treated with IONIS-TTRRx had a mean decrease of 1.9 percent in left ventricular (LV) mass from baseline as measured by MRI at 12 months. Based on a natural history study conducted by the same investigator in patients with the same baseline demographics, we would have expected to see a mean increase in LV mass of about 14 percent as measured by MRI.

For more information on the results of this study, please see our press release here.

Current Status

In February 2013, we initiated a Phase 3 study, NEURO-TTR, to evaluate the efficacy of IONIS-TTRRx in patients with FAP. The Phase 3 study of IONIS-TTRRx is a randomized, double-blinded, placebo-controlled, international study designed to support an application for marketing approval of IONIS-TTRRx in patients with FAP. The fifteen month study is a randomized 2:1 to receive 300 mg/week of IONIS-TTRRx or placebo and will measure the effects of IONIS-TTRRx on neurological dysfunction and on quality-of-life. We have completed target enrollment for NEURO-TTR and plan to report data from this study in 2017.

For more information about the clinical study, click here to go to clinicaltrials.gov, or click here to go to the TTR study website.

An open-label extension study, or OLE, was initiated for FAP patients who have completed treatment in the Phase 3 study to allow continuing access to drug treatment. Patients are now receiving IONIS-TTRRx in the OLE study. Our partner, GSK, plans to initiate a Phase 3 outcome study, CARDIO-TTR, in all forms of TTR amyloid cardiomyopathy, including both FAC and wt-TTR amyloidosis, in the first half of 2016. GSK is also planning to initiate a small Phase 3 study in Japan in patients with FAP in 2016 to support regulatory filings in Asia.

About TTR Amyloidosis

TTR amyloidosis is a severe, progressive and fatal disease with multiple overlapping clinical manifestations. There are three forms of TTR amyloidosis, FAP, FAC and wt-TTR amyloidosis, and all are caused by the inappropriate formation and aggregation of TTR amyloid deposits in various tissues and organs, including peripheral nerves, heart, intestinal tract, eyes, kidneys, central nervous system, thyroid and bone marrow. The progressive accumulation of TTR amyloid deposits in these tissues and organs leads to organ failure and eventually death. Although TTR amyloidosis is fatal, therapeutic options for the treatment of patients with TTR amyloidosis are very limited and there are currently no disease-modifying drugs available.

FAP is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with FAP experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromise their function and eventually leading to death within five to fifteen years of disease onset. There are an estimated 10,000 FAP patients worldwide.

TTR-related cardiomyopathy is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death within 3 to 5 years from disease onset. TTR-related cardiomyopathy includes both the genetic form of the disease, FAC, and the wild-type form of the disease, wt-TTR amyloidosis. There are an estimated 40,000 FAC patients worldwide. Patients with FAC begin to experience symptom onset between 50 and 60 years of age, whereas patients with wt-TTR amyloidosis usually begin to experience symptom onset ten or more years later, generally over 70 years of age. There are an estimated 200,000 wt-TTR amyloidosis patients worldwide.

Often patients with the polyneuropathy form of TTR amyloidosis will also have TTR build up in the heart and also experience cardiomyopathy symptoms. Similarly, patients with the cardiomyopathy form of TTR amyloidosis may often have TTR build up in their peripheral nerves and can experience nerve damage and progressive difficulty with motor functions.

Partner

In March 2010, we and GSK entered into a preferred partner alliance that provides GSK an option to develop and commercialize IONIS-TTRRx. We are responsible for completing the Phase 3 trials we are currently conducting. If GSK exercises its option, it will pay us a license fee and will assume all other global development, regulatory and commercialization responsibilities. We received an upfront payment from GSK when we initiated the broad strategic collaboration, and milestone payments related to IONIS-TTRRx. We are eligible to receive additional milestone payments as the program progresses and a license fee if GSK exercises its option to license IONIS-TTRRx. We are also eligible to receive royalties from GSK.

Select Publications

  1. Ackermann, E.J. et al. (2012) Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 19, 43-44.
  2. Benson, M.D. et al. (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve. 33, 609-618.
  3. Benson, M.D. et al. (2011) Rate of Progression of Transthyretin Amyloidosis. Am J Cardiol.108, 285-289.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 
 
 

Nusinersen

SMN2

Biogen

Infants with Spinal Muscular Atrophy

Generation 2+ antisense drug

Indication*:

Infants with Spinal Muscular Atrophy

Description/Summary

Nusinersen is an antisense drug we discovered in collaboration with Dr. Adrian R. Krainer at Cold Spring Harbor Laboratory. We designed nusinersen to treat patients with spinal muscular atrophy, or SMA. SMA is a severe motor-neuron disease that is the leading genetic cause of infant mortality. SMA occurs from a deletion or mutation of a gene responsible for producing a protein critical for normal cellular function. Nusinersen is designed to increase the production of this protein by modulating the splicing of a closely related gene, thereby compensating for the underlying genetic defect.

The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.

Clinical Data

In August 2016, we announced that nusinersen met the primary endpoint for the pre-specified interim analysis of the ENDEAR clinical study in patients with infantile-onset SMA. Infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment. Nusinersen demonstrated an acceptable safety profile in the trial. Based on these results, Biogen plans to file marketing applications for nusinersen globally in the coming months. Biogen has exercised its option to develop and commercialize nusinersen globally and paid Ionis a $75 million license fee.

Based on the results of the pre-specified interim analysis, the ENDEAR study will be stopped and participants will be able to transition into the SHINE open-label study in which all patients receive nusinersen. Data from the other endpoints of ENDEAR will be analyzed when the full data set is available. Results will be presented at future medical congresses. Additionally, participants enrolled in the sham-controlled arm of EMBRACE, a Phase 2 study which also included infantile-onset patients, will have the opportunity to receive nusinersen.

The other studies in the nusinersen program, including CHERISH (later-onset consistent with Type 2) and NURTURE (pre-symptomatic infants), will continue as planned in order to collect the data to demonstrate the safety and efficacy of nusinersen in these populations.

Biogen is working to open a global expanded access program (EAP) for eligible patients with infantile-onset SMA (consistent with Type 1) in the coming months. The EAP will initially be opened at existing nusinersen clinical trial sites in countries where EAPs are permitted according to local laws and regulations, can be operationalized, and where there is a path that can support long-term availability of nusinersen. Once the EAP is operational and required local approvals are in place, individual participating sites may start enrollment after they have transitioned ENDEAR study participants to the open-label extension study.

For more information on the results of this study, please see our press release here.

At the American Academy of Neurology meeting in April 2016, we provided an update from the ongoing Phase 2 open-label study of nusinersen in infants with SMA. The analysis, based on a January 2016 data cut, showed continued increases in mean event-free survival and muscle function scores. Infants in the study also demonstrated achievement of new development motor milestones, including motor milestones that infants with Type 1 SMA would not normally be expected to achieve, such as sitting, standing and walking. All infants continuing in the study were older than two years of age, with some infants older than three years of age. The safety and tolerability profile of nusinersen to date continued to support further development.

For more information on the results of this study, please see our press release here.

In June 2015, we provided an update on children with SMA who have completed the open-label, Phase 2 multiple-dose study of nusinersen and are continuing to receive treatment in an open-label extension (OLE) study. Consistent with earlier observations, increases in muscle function scores and additional motor function tests, including the Hammersmith Functional Motor Scale-Expanded, the six minute walk test for ambulatory patients and the upper limb module test for non-ambulatory patients, were observed in children treated with nusinersen. The safety and tolerability profile of nusinersen to date supports continued development.

For more information on the results of this study, please see our press release here.

Current Status

Together with Biogen, we are developing nusinersen to treat infants and children with SMA. We are evaluating nusinersen in a broad Phase 3 program. In August 2016, we reported that nusinersen met its primary endpoint for the pre-specified interim analysis of the ENDEAR clinical study in infants with SMA. The Phase 3 ENDEAR study is a randomized, double-blind, sham-procedure controlled, thirteen-month study in 122 infants diagnosed with SMA evaluating the efficacy and safety of a 12 mg dose of nusinersen. As a result of the positive interim analysis, both the ENDEAR study and EMBRACE study, a Phase 2, double-blind study evaluating the safety of nusinersen, will close and the sham-controlled study arms will end. All participants in ENDEAR and EMBRACE may elect to receive treatment by enrolling in an open-label extension study. Based on these positive interim results, we and Biogen plan to file marketing applications for nusinersen in the US and the EU in the coming months.

Biogen is working to open an expanded access program in the fall of 2016 to make nusinersen available for eligible patients with infantile-onset SMA who are not eligible for or currently participating in the nusinersen clinical trial program.

For more information about the ENDEAR clinical study, click here to go to clinicaltrials.gov, or click here to go to the SMA study website.

In November 2014, we initiated a Phase 3 study, CHERISH, in children with SMA. CHERISH, a Phase 3 study of nusinersen, is a randomized, double-blind, sham-procedure controlled, fifteen-month study in 126 children who are non-ambulatory with SMA between the ages of 2-12. The study will evaluate the efficacy and safety of a 12 mg dose of nusinersen with a primary endpoint of a change in the Hammersmith Functional Motor Scale-Expanded, a validated method to measure changes in muscle function in patients with SMA. Additional efficacy endpoints are also included in the study. We have completed target enrollment for CHERISH and plan to report data from this study in 2017.

For more information about the CHERISH clinical study, click here to go to clinicaltrials.gov, or click here to go to the SMA study website.

About Spinal Muscular Atrophy

SMA is 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 SMN protein. 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.

Partner

In January 2012, Ionis and Biogen entered into a preferred partner alliance that provides Biogen an option to develop and commercialize nusinersen. Ionis has received an upfront fee and numerous milestone payments from Biogen as nusinersen has advanced in development.

In August 2016, Biogen exercised its exclusive option to license nusinersen and paid Ionis a $75 million fee. Biogen is now responsible for all nusinersen development, regulatory and commercialization activities and costs. Ionis will complete the Phase 3 studies and work with Biogen on regulatory filings. The two companies will also work together to transition the clinical programs that Ionis is conducting to Biogen. Ionis is eligible to receive tiered royalties on any potential sales of nusineren up to a percentage in the mid-teens, in addition to up to $150 million in milestone payments based on regulatory approvals.

Ionis acknowledges 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.

Select Publications

  1. Finkel, R.S. et al. (2014) Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 83, 810-817.
  2. Hua, Y. et al. (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634-1644.
  3. Hua, Y. et al. (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 478, 123-126.
  4. Passini, M.A. et al. (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 3, 72ra18.
  5. Rudnik-Schoneborn, S. et al. (2009) Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling. Clin Genet. 76, 168-178.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 
 

Nusinersen

SMN2

Biogen

Children with Spinal Muscular Atrophy

Generation 2+ antisense drug

Indication*:

Children with Spinal Muscular Atrophy

Description/Summary

Nusinersen is an antisense drug we discovered in collaboration with Dr. Adrian R. Krainer at Cold Spring Harbor Laboratory. We designed nusinersen to treat patients with spinal muscular atrophy, or SMA. SMA is a severe motor-neuron disease that is the leading genetic cause of infant mortality. SMA occurs from a deletion or mutation of a gene responsible for producing a protein critical for normal cellular function. Nusinersen is designed to increase the production of this protein by modulating the splicing of a closely related gene, thereby compensating for the underlying genetic defect.

The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.

Clinical Data

In August 2016, we announced that nusinersen met the primary endpoint for the pre-specified interim analysis of the ENDEAR clinical study in patients with infantile-onset SMA. Infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment. Nusinersen demonstrated an acceptable safety profile in the trial. Based on these results, Biogen plans to file marketing applications for nusinersen globally in the coming months. Biogen has exercised its option to develop and commercialize nusinersen globally and paid Ionis a $75 million license fee.

Based on the results of the pre-specified interim analysis, the ENDEAR study will be stopped and participants will be able to transition into the SHINE open-label study in which all patients receive nusinersen. Data from the other endpoints of ENDEAR will be analyzed when the full data set is available. Results will be presented at future medical congresses. Additionally, participants enrolled in the sham-controlled arm of EMBRACE, a Phase 2 study which also included infantile-onset patients, will have the opportunity to receive nusinersen.

The other studies in the nusinersen program, including CHERISH (later-onset consistent with Type 2) and NURTURE (pre-symptomatic infants), will continue as planned in order to collect the data to demonstrate the safety and efficacy of nusinersen in these populations.

Biogen is working to open a global expanded access program (EAP) for eligible patients with infantile-onset SMA (consistent with Type 1) in the coming months. The EAP will initially be opened at existing nusinersen clinical trial sites in countries where EAPs are permitted according to local laws and regulations, can be operationalized, and where there is a path that can support long-term availability of nusinersen. Once the EAP is operational and required local approvals are in place, individual participating sites may start enrollment after they have transitioned ENDEAR study participants to the open-label extension study.

For more information on the results of this study, please see our press release here.

At the American Academy of Neurology meeting in April 2016, we provided an update from the ongoing Phase 2 open-label study of nusinersen in infants with SMA. The analysis, based on a January 2016 data cut, showed continued increases in mean event-free survival and muscle function scores. Infants in the study also demonstrated achievement of new development motor milestones, including motor milestones that infants with Type 1 SMA would not normally be expected to achieve, such as sitting, standing and walking. All infants continuing in the study were older than two years of age, with some infants older than three years of age. The safety and tolerability profile of nusinersen to date continued to support further development.

For more information on the results of this study, please see our press release here.

In June 2015, we provided an update on children with SMA who have completed the open-label, Phase 2 multiple-dose study of nusinersen and are continuing to receive treatment in an open-label extension (OLE) study. Consistent with earlier observations, increases in muscle function scores and additional motor function tests, including the Hammersmith Functional Motor Scale-Expanded, the six minute walk test for ambulatory patients and the upper limb module test for non-ambulatory patients, were observed in children treated with nusinersen. The safety and tolerability profile of nusinersen to date supports continued development.

For more information on the results of this study, please see our press release here.

Current Status

Together with Biogen, we are developing nusinersen to treat infants and children with SMA. We are evaluating nusinersen in a broad Phase 3 program. In August 2016, we reported that nusinersen met its primary endpoint for the pre-specified interim analysis of the ENDEAR clinical study in infants with SMA. The Phase 3 ENDEAR study is a randomized, double-blind, sham-procedure controlled, thirteen-month study in 122 infants diagnosed with SMA evaluating the efficacy and safety of a 12 mg dose of nusinersen. As a result of the positive interim analysis, both the ENDEAR study and EMBRACE study, a Phase 2, double-blind study evaluating the safety of nusinersen, will close and the sham-controlled study arms will end. All participants in ENDEAR and EMBRACE may elect to receive treatment by enrolling in an open-label extension study. Based on these positive interim results, we and Biogen plan to file marketing applications for nusinersen in the US and the EU in the coming months.

Biogen is working to open an expanded access program in the fall of 2016 to make nusinersen available for eligible patients with infantile-onset SMA who are not eligible for or currently participating in the nusinersen clinical trial program.

For more information about the ENDEAR clinical study, click here to go to clinicaltrials.gov, or click here to go to the SMA study website.

In November 2014, we initiated a Phase 3 study, CHERISH, in children with SMA. CHERISH, a Phase 3 study of nusinersen, is a randomized, double-blind, sham-procedure controlled, fifteen-month study in 126 children who are non-ambulatory with SMA between the ages of 2-12. The study will evaluate the efficacy and safety of a 12 mg dose of nusinersen with a primary endpoint of a change in the Hammersmith Functional Motor Scale-Expanded, a validated method to measure changes in muscle function in patients with SMA. Additional efficacy endpoints are also included in the study. We have completed target enrollment for CHERISH and plan to report data from this study in 2017.

For more information about the CHERISH clinical study, click here to go to clinicaltrials.gov, or click here to go to the SMA study website.

About Spinal Muscular Atrophy

SMA is 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 SMN protein. 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.

Partner

In January 2012, Ionis and Biogen entered into a preferred partner alliance that provides Biogen an option to develop and commercialize nusinersen. Ionis has received an upfront fee and numerous milestone payments from Biogen as nusinersen has advanced in development.

In August 2016, Biogen exercised its exclusive option to license nusinersen and paid Ionis a $75 million fee. Biogen is now responsible for all nusinersen development, regulatory and commercialization activities and costs. Ionis will complete the Phase 3 studies and work with Biogen on regulatory filings. The two companies will also work together to transition the clinical programs that Ionis is conducting to Biogen. Ionis is eligible to receive tiered royalties on any potential sales of nusineren up to a percentage in the mid-teens, in addition to up to $150 million in milestone payments based on regulatory approvals.

Ionis acknowledges 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.

Select Publications

  1. Finkel, R.S. et al. (2014) Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 83, 810-817.
  2. Hua, Y. et al. (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634-1644.
  3. Hua, Y. et al. (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 478, 123-126.
  4. Passini, M.A. et al. (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 3, 72ra18.
  5. Rudnik-Schoneborn, S. et al. (2009) Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling. Clin Genet. 76, 168-178.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 
 
 

Volanesorsen

ApoCIII

Ionis/Akcea

Familial Chylomicronemia Syndrome

Generation 2+ antisense drug

Indication*:

Familial Chylomicronemia Syndrome (FCS)

Description/Summary

Volanesorsen is an antisense drug designed to reduce apoC-III protein production and to lower triglycerides to treat patients with dyslipidemia. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. Humans who do not produce apoC-III or have mutations that result in decreased apoC-III levels have lower levels of triglycerides and a lower incidence of cardiovascular disease. In contrast, people with elevated triglycerides are at increased risk for cardiovascular disease and for type 2 diabetes, and people with severely elevated triglycerides are at high risk for acute pancreatitis and other serious conditions.

The US and European regulatory agencies have granted Orphan Drug Designation to volanesorsen for the treatment of patients with FCS.

Clinical Data

We completed a broad Phase 2 program evaluating volanesorsen in patients with high, very high, and severely high triglycerides, in patients with high triglycerides and type 2 diabetes and in patients with FCS. We also evaluated volanesorsen both as a single agent and in combination with fibrates. In our Phase 2 program, in all patient groups studied, irrespective of their incoming triglyceride levels, we observed reductions in apoC-III, triglycerides and apoC-III-associated VLDL complexes, and an increase in HDL-C, with a positive effect on non-HDL in patients treated with volanesorsen . In addition, we observed in volanesorsen-treated patients with type 2 diabetes significant improvements in glucose control with trends toward enhanced insulin sensitivity. The safety and tolerability profile of volanesorsen across the four Phase 2 studies supports continued development.

For more information on the results of the study in patients with very high to severely high triglycerides, please see our press release here.

For more information on the results of the study in patients with high triglycerides taking fibrates, please see our press release here.

For more information on the results of the study in patients with high triglycerides and type 2 diabetes, please see our press release here.

For more information on the results of the study in patients with FCS, please see our press release here.

Current Status

Akcea Therapeutics, our wholly owned subsidiary, is responsible for developing and commercializing volanesorsen. Volanesorsen is in development to treat patients with familial chylomicronemia syndrome, or FCS, and patients with familial partial lipodystrophy, or FPL. In August 2014, we initiated a Phase 3 study, APPROACH, evaluating volanesorsen in patients with FCS. The Phase 3 study, APPROACH, is a randomized, double-blind, placebo-controlled, 12 month study in approximately 50 patients diagnosed with FCS who have triglyceride levels greater than or equal to 750 mg/dL. The study will evaluate the efficacy and safety of a 300 mg once weekly dose of volanesorsen . The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing. We have completed target enrollment for APPROACH and plan to report data in 2017.

For more Information about APPROACH, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

In November 2015, we initiated a Phase 3 study, BROADEN, evaluating volanesorsen in patients with FPL.The Phase 3 study, BROADEN, is a randomized, double-blind, placebo-controlled 12 month study in patients diagnosed with FPL. The study will evaluate the efficacy and safety of a 300 mg once weekly dose of volanesorsen. The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing.

For more Information about BROADEN, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

About Familial Chylomicronemia Syndrome

FCS is an rare orphan disease that is often associated with triglyceride levels higher than 2,000 mg/dL. FCS is estimated to affect 3,000 to 5,000 patients worldwide. Because of their extremely high triglyceride levels, FCS patients are at significant risk of many serious health conditions, including frequent episodes of pancreatitis, which can require hospitalization and can be life-threatening. Current treatment options do not reduce triglyceride levels enough to reduce the risk of serious illness in patients with FCS.

Partner

Volanesorsen is a part of our lipid franchise. Akcea Therapeutics, our wholly owned subsidiary, is responsible for developing and commercializing volanesorsen.

Select Publications

  1. Austin, M.A., Hokanson, J.E. & Edwards, K.L. (1998) Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 81, 7B-12B.
  2. Gaudet, D. et al. (2014) Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med. 371, 2200-2206.
  3. Graham, M.J. et al. (2013) Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 112, 1479-1490.
  4. Jorgensen, A.B, Frikke-Schmidt, R., Nordesgaard, B.G. and Tybjaerg-Hansen, A. (2014) Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 371, 32-41.
  5. Kathiresan et al. (2014) Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. N Engl J Med. 371, 22-31.
  6. Scherer, J., Singh, V.P., Pitchumoni, C.S. & Yadav, D. (2014) Issues in hypertriglyceridemic pancreatitis: an update. J. Clin Gastroenterol. 48, 195-203.
  7. Zheng, C. (2014) Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr Opin lipidol. 25, 35-39.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 
 
 

Volanesorsen

ApoCIII

Ionis/Akcea

Familial Partial Lipodystrophy

Generation 2+ antisense drug

Indication*:

Familial Partial Lipodystrophy (FPL)

Description/Summary

Volanesorsen is an antisense drug designed to reduce apoC-III protein production and to lower triglycerides to treat patients with dyslipidemia. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. Humans who do not produce apoC-III or have mutations that result in decreased apoC-III levels have lower levels of triglycerides and a lower incidence of cardiovascular disease. In contrast, people with elevated triglycerides are at increased risk for cardiovascular disease and for type 2 diabetes, and people with severely elevated triglycerides are at high risk for acute pancreatitis and other serious conditions.

The US and European regulatory agencies have granted Orphan Drug Designation to volanesorsen for the treatment of patients with FCS.

Clinical Data

We completed a broad Phase 2 program evaluating volanesorsen in patients with high, very high, and severely high triglycerides, in patients with high triglycerides and type 2 diabetes and in patients with FCS. We also evaluated volanesorsen both as a single agent and in combination with fibrates. In our Phase 2 program, in all patient groups studied, irrespective of their incoming triglyceride levels, we observed reductions in apoC-III, triglycerides and apoC-III-associated VLDL complexes, and an increase in HDL-C, with a positive effect on non-HDL in patients treated with volanesorsen . In addition, we observed in volanesorsen-treated patients with type 2 diabetes significant improvements in glucose control with trends toward enhanced insulin sensitivity. The safety and tolerability profile of volanesorsen across the four Phase 2 studies supports continued development.

For more information on the results of the study in patients with very high to severely high triglycerides, please see our press release here.

For more information on the results of the study in patients with high triglycerides taking fibrates, please see our press release here.

For more information on the results of the study in patients with high triglycerides and type 2 diabetes, please see our press release here.

For more information on the results of the study in patients with FCS, please see our press release here.

Current Status

Akcea Therapeutics, our wholly owned subsidiary, is responsible for developing and commercializing volanesorsen. Volanesorsen is in development to treat patients with familial chylomicronemia syndrome, or FCS, and patients with familial partial lipodystrophy, or FPL. In August 2014, we initiated a Phase 3 study, APPROACH, evaluating volanesorsen in patients with FCS. The Phase 3 study, APPROACH, is a randomized, double-blind, placebo-controlled, 12 month study in approximately 50 patients diagnosed with FCS who have triglyceride levels greater than or equal to 750 mg/dL. The study will evaluate the efficacy and safety of a 300 mg once weekly dose of volanesorsen . The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing. We have completed target enrollment for APPROACH and plan to report data in 2017.

For more Information about APPROACH, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

In November 2015, we initiated a Phase 3 study, BROADEN, evaluating volanesorsen in patients with FPL.The Phase 3 study, BROADEN, is a randomized, double-blind, placebo-controlled 12 month study in patients diagnosed with FPL. The study will evaluate the efficacy and safety of a 300 mg once weekly dose of volanesorsen. The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing.

For more Information about BROADEN, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

About Familial Partial Lipodystrophy

FPL is a rare orphan disease that is estimated to affect 3,000 to 5,000 patients worldwide. Patients with FPL have diabetes and other metabolic abnormalities, including elevated triglycerides, which increases their risk of pancreatitis. We believe that the robust triglyceride reduction and the improvements in glucose control we observed in our Phase 2 program support our evaluation of volanesorsen in this patient population.

Partner

Volanesorsen is a part of our lipid franchise. Akcea Therapeutics, our wholly owned subsidiary, is responsible for development and commercialization of volanesorsen.

Selected Publications

  1. Austin, M.A., Hokanson, J.E. & Edwards, K.L. (1998) Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 81, 7B-12B.
  2. Gaudet, D. et al. (2014) Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med. 371, 2200-2206.
  3. Graham, M.J. et al. (2013) Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 112, 1479-1490.
  4. Jorgensen, A.B, Frikke-Schmidt, R., Nordesgaard, B.G. and Tybjaerg-Hansen, A. (2014) Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 371, 32-41.
  5. Kathiresan et al. (2014) Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. N Engl J Med. 371, 22-31.
  6. Scherer, J., Singh, V.P., Pitchumoni, C.S. & Yadav, D. (2014) Issues in hypertriglyceridemic pancreatitis: an update. J. Clin Gastroenterol. 48, 195-203.
  7. Zheng, C. (2014) Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr Opin lipidol. 25, 35-39.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 
 

IONIS-DMPK-2.5Rx

DMPK

Biogen

Myotonic Dystrophy Type 1

Generation 2.5 antisense drug

Indication*:

Myotonic Dystrophy Type 1

Description/Summary:

IONIS-DMPK-2.5Rx is an antisense drug designed to reduce the toxic dystrophia myotonica-protein kinase, or DMPK, RNA to treat patients with Myotonic Dystrophy Type 1 (DM1). DM1 is a genetic neuromuscular disease caused by a defect in the DMPK gene which causes the accumulation of toxic DMPK RNA. It is characterized by progressive muscle atrophy, weakness and disabling muscle spasms. There are currently no disease-modifying therapies that address DM1.

We received FDA Orphan Drug Designation for IONIS-DMPK-2.5Rx for the treatment of patients with DM1.

Clinical Data

We are evaluating IONIS-DMPK-2.5Rx in a Phase 1/2 clinical study in patients with DM1 and plan to report data from this study 2H 2016.

Current Status

Together with Biogen, we are evaluating IONIS-DMPK-2.5Rx to treat patients with DM1. We are evaluating IONIS-DMPK-2.5Rx in a randomized, placebo-controlled, dose-escalation Phase 1/2 clinical study in approximately 36 adult patients with DM1 and plan to report data from this study 2H 2016.

For more information about the clinical study, click here to go to clinicaltrials.gov.

About Myotonic Dystrophy Type 1

Myotonic Dystrophy is the most common form of muscular dystrophy in adults. DM1 is caused by a genetic defect in the 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. 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. 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. Currently, there are no disease-modifying therapies for patients with DM1 and treatments are intended only to manage symptoms.

Partner

In June 2012, we and Biogen entered into a preferred partner alliance that provides Biogen an option to develop and commercialize IONIS-DMPK-2.5Rx. We are responsible for global development of the drug through the completion of the first Phase 2 clinical trial. Biogen has the option to license the drug through the completion of the first Phase 2 trial. If Biogen exercises its option, it will assume all other global development, regulatory and commercialization responsibilities. We have received an upfront fee and milestone payments from Biogen as IONIS-DMPK-2.5Rx has advanced in development. We are eligible to receive additional milestone payments as the program progresses and a license fee if Biogen exercises its option to license IONIS-DMPK-2.5Rx. We are also eligible to receive royalties from Biogen.

Selected Publications

  1. Gao, A. and Cooper, T.A. (2013) Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy. Hum Gene Ther. 24, 499-507.
  2. Wheeler, T.M. et al. (2012) Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 488, 111-115.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 

IONIS-HTTRx

HTT

Roche

Huntington's Disease

Generation 2+ antisense drug

Indication*:

Huntington's Disease

Description/Summary

IONIS-HTTRx is an antisense drug designed to reduce the production of the huntingtin (HTT) protein, which is the genetic cause of Huntington's disease (HD). HD is caused by expansion of the CAG trinucleotide sequence in the HTT gene, which produces a toxic protein that progressively destroys neurons in the brain. As a result, HD patients experience progressive loss of mental faculties and physical control as their disease progresses.

The European Medicines Agency has granted orphan drug designation to IONIS-HTTRx for the treatment of patients with HD.

Clinical Data

We are evaluating IONIS-HTTRx in a Phase 1/2a clinical study in patients with HD.

Current Status

We are collaborating with Roche to develop IONIS-HTTRx to treat patients with HD. We initiated a Phase 1/2a clinical study in patients with HD in July 2015. The Phase 1/2a study is a randomized, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of IONIS-HTTRx in patients with early stage HD.

For more information about the clinical study, please see our press release here.

About Huntington's Disease

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 HTT gene. The resulting mutant HTT protein is toxic and gradually destroys 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.

Partner

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, Roche has the option to license IONIS-HTTRx from us through the completion of the Phase 1/2a study. Prior to option exercise, we are responsible for the discovery and development of IONIS-HTTRx. If Roche exercises its option, it will assume responsibility for global development, regulatory and commercialization activities for the drug. We will receive milestone payments from Roche as IONIS-HTTRx progresses in development, as well as royalties on sales of IONIS-HTTRx if it is commercialized.

Select Publications

  1. Kordasiewicz, H.B. et al. (2012) Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron. 74, 1031-1044.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

ATL1103

GHr

ATL

Acromegaly

Generation 2.0 antisense drug

Indication*:

Acromegaly

Description/Summary:

ATL1103 is an antisense drug we designed to reduce the production of the growth hormone receptor, or GHr, to treat patients with acromegaly. Acromegaly is a serious chronic life threatening disease triggered by excess secretion of GHr by benign pituitary tumors. In 2001, we licensed ATL1103 to Antisense Therapeutics Limited, or ATL. In May 2015, ATL entered into an exclusive license agreement that provides Strongbridge Biopharma with development and commercialization rights to ATL1103 for endocrinology applications outside Australia and New Zealand.

Selected Publications

  1. Tachas, G. et al. (2006) A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice. J Endocrinol. 189, 147-154.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 

IONIS-SOD1Rx

SOD1

Biogen

Amyotrophic Lateral Sclerosis

Generation 2+ antisense drug

Indication*:

Amyotrophic Lateral Sclerosis

Description/Summary

IONIS-SOD1Rx is an antisense drug designed to reduce the production of superoxide dismutase 1 (SOD1), which is the best understood genetic cause of familial amyotrophic lateral sclerosis (ALS). ALS is a rare, fatal neurodegenerative disorder. Patients with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. A mutation in the SOD-1 gene results in an inherited form of ALS, referred to as SOD1-ALS. There is substantial evidence that mutations in the SOD1 gene are responsible for a toxic gain of function that can lead to rapid progressive loss of motor neurons in patients with SOD1-ALS. As a result, patients with SOD1-ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Clinical Data

Biogen is evaluating IONIS-SOD1Rx in a Phase 1/2a clinical study in patients with ALS, primarily including patients with SOD1-ALS.

Current Status

We are collaborating with Biogen to develop IONIS-SOD1Rx to treat patients with SOD1-ALS. We initiated a Phase 1/2a clinical study evaluating IONIS-SOD1Rx in patients with ALS, including patients with SOD1-ALS, in December 2015. The Phase 1/2a study is a randomized, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending doses of IONIS-SOD1Rx in patients with all forms of ALS and multiple ascending doses of IONIS-SOD1Rx in patients with SOD1-ALS.

For more information about the clinical study, click here to go to clinicaltrials.gov.

About Amyotrophic Lateral Sclerosis

ALS is a rare, fatal neurodegenerative disorder. Patients with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. There is substantial evidence that mutations in the SOD1 gene are responsible for a toxic gain of function that can lead to progressive loss of motor neurons in patients with SOD1-ALS. As a result, patients with SOD1-ALS experience muscle weakness, loss of movement, difficulty in breathing and swallowing and eventually succumb to their disease. SOD1-ALS is the second most common familial form of ALS, accounting for up to 20 percent of familial ALS. Familial ALS represents approximately 10 percent of all cases of ALS. Currently, treatment options for patients with ALS are extremely limited with no drugs that significantly slow disease progression.

Partner

In September 2013, Ionis and Biogen entered into a broad, strategic collaboration to leverage antisense technology to advance the treatment of neurological diseases, including IONIS-SOD1Rx. The collaboration combines Biogen's expertise in neurology with Ionis' leadership in antisense technology to develop novel therapies to treat neurological disorders. Biogen and Ionis work closely together to select and validate neurological disease targets and conduct drug discovery activities with the goal of identifying clinical development candidates. Ionis is primarily responsible for drug discovery and early development of antisense therapies. Biogen will be responsible for later stage development and commercialization of all drugs arising from the collaboration. Current development-stage programs include antisense drugs to treat patients with spinal muscular atrophy (SMA), nusinersen; myotonic dystrophy type 1 (DM1), IONIS-DMPK-2.5Rx; amyotrophic lateral sclerosis (ALS), IONIS-SOD1Rx, and an undisclosed neurodegenerative disease, IONIS-BIIB4Rx. In addition to these four drugs, Ionis and Biogen have numerous opportunities to evaluate additional targets for the development of drugs to treat neurological disorders.

Select Publications

  1. Miller, T.M. et al. (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12(5):435-42.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-PKKRx

PKK

-

Hereditary Angioedema

Generation 2+ antisense drug

Indication*:

Hereditary Angioedema

Description/Summary:

IONIS-PKKRx is an antisense drug designed to reduce the production of prekallikrein, or PKK, to treat patients with hereditary angioedema, or HAE. PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. HAE is a rare genetic disease characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea. HAE 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.

Clinical Data

We completed a Phase 1 study evaluating IONIS-PKKRx in healthy volunteers. In this study, subjects treated with IONIS-PKKRx achieved dose-dependent reductions of up to 95 percent in PKK. The safety and tolerability profile of IONIS-PKKRx supports continued development.

For more information on the results of this Phase 1 study, please see our press release here.

Current Status

We are developing IONIS-PKKRx as a prophylactic treatment for patients with HAE. We have completed a Phase 1 study evaluating IONIS-PKKRx in healthy volunteers. The Phase 1 study was a randomized, double-blind, placebo-controlled, dose-escalation study in healthy volunteers that evaluated multiple doses of IONIS-PKKRx.

About Hereditary Angioedema

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.

Selected Publications

  1. Bhattacharjee, G. et al. (2013) Inhibition of vascular permeability by antisense-mediated inhibition of plasma kallikrein and coagulation factor 12. Nucleic Acid Ther. 23, 175-187..
  2. Revenko, A.S. et al. (2011) Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 118, 5302-5311.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 

RG-012

miR-21

Regulus

Alport Syndrome

Anti-miR oligonucleotide

Indication*:

Alport Syndrome

Description/Summary:

RG-012 is an anti-miR, or an antisense oligonucleotide inhibitor of microRNA, targeting microRNA-21, or miR-21, to treat patients with Alport syndrome. Alport syndrome is a life-threatening genetic kidney disease with no approved therapy. While there is little known information on the progression of this disease, scientists believe that miR-21 plays a critical role because they have observed increased miR-21 levels in animal models of Alport syndrome and in patients with chronic kidney disease. Regulus is developing RG-012 in a strategic alliance with Genzyme, a Sanofi company, to treat Alport syndrome. In June 2015, Regulus initiated a randomized, double-blind, placebo-controlled, single ascending dose Phase 1 study in healthy volunteers to evaluate the safety, tolerability and pharmacokinetics of RG-012.

Selected Publications

  1. Gomez, I.G. et al. (2005) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J. Clin. Invest. Epub 2014 Nov 21.
  2. Kruegel, J., Rubel, D. and Gross, O. (2004) Alport syndrome--insights from basic and clinical research. Nat. Rev. Nephrol. 9, 170-178.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
Cardiovascular

Cardiovascular disease is the leading cause of death in the United States. A common cause of cardiovascular disease is atherosclerosis, or premature plaque buildup, which occurs when cholesterol and inflammatory cells accumulate in blood vessels. Researchers have shown a strong correlation between high cholesterol levels and subsequent cardiovascular diseases. As such, lowering cholesterol is a key component in preventing and managing cardiovascular disease.

Cardiovascular disease is an area of focus for us. We have created a cardiovascular disease franchise comprised of drugs that target all the key components of cardiovascular disease, including various atherogenic lipids, inflammation and thrombosis, an aberrant blood clot formation responsible for most heart attacks and strokes. We have designed the majority of the drugs in our cardiovascular franchise to target cardiovascular risk factors. These drugs make up our lipid franchise and include IONIS-APO(a)Rx and IONIS-ANGPTL3Rx. Recent additions to our lipid franchise are our drugs that lower Lp(a) and angiopoietin-like 3 protein, or ANGPTL3. Lp(a) is another independent risk factor for cardiovascular disease. ANGPTL3 is a genetically validated target shown to play a significant role in regulating lipid levels. Humans who do not produce a functional ANGPTL3 protein due to a genetic mutation have extremely low levels of cholesterol, LDL-C, and very low levels of triglycerides and HDL-cholesterol. Currently available lipid-lowering therapies do not significantly lower apoC-III, triglycerides, Lp(a), or ANGPTL3. We believe that reducing levels of apoC-III, Lp(a) and ANGPTL3 could provide a complimentary approach to lipid-lowering therapies, including KYNAMRO(R). We are also developing follow-on LICA antisense drugs for the three drugs in our lipid franchise.

In order to maximize the value of our lipid franchise, while also maintaining control over the development and commercialization of these assets, we have created a wholly owned subsidiary, Akcea Therapeutics. Akcea is focused on the development and commercialization of our lipid franchise drugs and their follow on compounds.

In addition to our lipid franchise drugs, we have a promising anticoagulant agent, IONIS-FXIRx, in development in our cardiovascular disease franchise. We recently reported Phase 2 data on IONIS-FXIRx showing that IONIS-FXIRx-treated patients experienced a seven-fold lower incidence of venous thromboembolism and numerically fewer bleeding events compared to patients treated with enoxaparin, a commonly used anticoagulant. These data demonstrate that for the first time, an anticoagulant, IONIS-FXIRx, can prevent clotting without increasing bleeding, two biological events that were previously inseparable. Our latest drug to enter the franchise, IONIS-AGT-LRx, offers a novel approach to treating patients with high blood pressure.

Drug
Target
Partner
Indication
P1
P2
P3
C

IONIS-FXIRx
(BAY 2306001)

Factor XI

Bayer

Clotting Disorders

Generation 2+ antisense drug

Indication*:

Antithrombosis

Description/Summary:

IONIS-FXIRx is an antisense drug designed to reduce the production of Factor XI. Factor XI is a clotting factor produced in the liver that is an important component of the coagulation pathway. High levels of Factor XI increase the risk of thrombosis, which is the formation of a blood clot inside blood vessels. Thrombosis can cause heart attacks and strokes. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased bleeding, which can be fatal. Given the mechanism of Factor XI inhibition, we believe that our drug has the potential, if data warrant, to be used broadly as an anti-thrombotic in many different therapeutic settings for which additional safe and well tolerated anti-thrombotic drugs are needed.

Clinical Data

In December 2014, we presented positive data from a Phase 2 comparator-controlled study evaluating the incidence of venous thrombolic events (VTE) in patients undergoing total knee replacement surgery, or total knee arthroplasty (TKA). In this study, patients treated with 300 mg/week of IONIS-FXIRx experienced a seven-fold (p<0.0001) lower incidence of VTEs compared to patients treated with enoxaparin, a commonly used anti-coagulant. In addition, IONIS-FXIRx-treated patients experienced numerically fewer bleeding events compared to patients treated with enoxaparin. The safety and tolerability profile of IONIS-FXIRx supports continued development.

For more information on the results of this study, please see our press release here.

Current Status

In October 2015, we initiated a Phase 2 study to evaluate the efficacy of IONIS-FXIRx in patients with end-stage renal disease, or ESRD, on hemodialysis. The Phase 2 study is intended to further characterize the profile of IONIS-FXIRx and will provide essential data for Bayer's future clinical development program for IONIS-FXIRx. The Phase 2 study is a randomized, double-blind, placebo controlled study in which IONIS-FXIRx will be administered to approximately 50 patients with ESRD on hemodialysis. The study that will evaluate the safety, pharmacokinetic and pharmacodynamic effects of weekly dosing of 200mg or 300mg IONIS-FXIRx for up to 12 weeks.

For more Information about the clinical study, click here to go to clinicaltrials.gov.

About Thrombotic Disorder

Thrombosis is the aberrant formation of blood clots inside blood vessels. Blood clots can obstruct blood flow to prevent sufficient oxygen flow to tissues and organs. In addition, clot fragments can break off from the blood clot and travel downstream to occlude other parts of the circulation. Thrombosis is responsible for many heart attacks and strokes and is the leading cause of morbidity and mortality worldwide.

Current antithrombotic treatments include anticoagulants such as warfarin, oral Factor Xa and thrombin inhibitors. Although these drugs are effective at lowering the risk of thrombosis, by targeting factors required for normal coagulation, these drugs place patients at significant risk of serious bleeding.

Factor XI is a clotting factor produced in the liver that is an important component in the intrinsic pathway of the coagulation process. Factor XI's role in blood coagulation is in clot stabilization and expansion and not in clot initiation. People with high levels of Factor XI have increased risk of thrombosis while those with deficient Factor XI have a lower incidence of thromboembolic events and minimal risk of bleeding.

Partner

In May 2015, we entered into an exclusive license agreement with Bayer HealthCare (Bayer) to develop and commercialize IONIS-FXIRx for the prevention of thrombosis. Under the terms of the agreement, we are eligible to receive up to $155 million in near-term payments, including an immediate $100 million up-front payment and a $55 million payment upon advancement of the program following a Phase 2 study in patients with compromised kidney function. We are also eligible to receive milestone payments as the drug advances toward the market. In addition, we are eligible to receive tiered royalties in the low to high twenty percent range on gross margins of IONIS-FXIRx.

Selected Publications

  1. B?ller, H.R. et al. (2014) Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. N Engl J Med. Epub ahead of print.
  2. Crosby, J.R. et al. (2013) Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol. 33, 1670-1678.
  3. L?wenberg, E.C., Meijers, J.C., Monia, B.P. & Levi, M. (2010) Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost.8, 2349-2357.
  4. Younis, H.S. et al. (2012) Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood. 119, 2401-2408.
  5. Zhang, H. et al. (2010) Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood. 116, 4684-4692.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-APO(a)-LRx

Apo(a)

Ionis/Akcea

Very High Lp(a)

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

High Lp(a)

Description/Summary:

IONIS-APO(a)-LRx is a LICA-conjugated antisense drug designed to reduce apolipoprotein(a) in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). Lp(a) is an independent risk factor for cardiovascular disease. High levels of Lp(a) is associated with an increased risk of atherosclerosis, coronary heart disease, heart attack and stroke. Lp(a) levels are genetically determined, with the maximum level reached at an early age and remaining constant throughout the life of the individual. Diet and lifestyle changes have little impact on Lp(a) levels and current therapies do not adequately reduce Lp(a) to acceptable levels in patients with elevated Lp(a). As a general guideline for ideal Lp(a) levels, the European Atherosclerosis Society recommends that Lp(a) be less than or equal to 50 mg/dL. Even patients who can control their LDL-C remain at high-risk of cardiovascular events if they have high levels of Lp(a). There is a significant need for a highly specific drug that can lower Lp(a).

Clinical Data

In November 2015, we reported results from a Phase 1/2a study evaluating IONIS-APO(a)-LRx in subjects with high Lp(a). Treatment with IONIS-APO(a)-LRx resulted in dose-dependent, durable reductions in Lp(a) with single and multiple ascending doses. In this study, subjects treated with multiple doses of IONIS-APO(a)-LRx achieved up to 99 percent reduction in Lp(a), with a mean reduction of 92 percent in Lp(a). IONIS-APO(a)-LRx was equally effective regardless of starting Lp(a) levels. The safety and tolerability profile of IONIS-APO(a)-LRx supports rapid development in high unmet need patient populations.

In November 2015, we also reported positive results on IONIS-APO(a)Rx, our non-LICA Lp(a)-lowering drug, from a Phase 2 study in patients with high (50-175 mg/dL) and very high (>175 mg/dL) Lp(a) levels. In this study, subjects treated with IONIS-APO(a)Rx achieved up to 94 percent in Lp(a), with a mean reduction of 71 percent in Lp(a).

For more information on the results of this Phase 1/2a and Phase 2 study, please see our press release here.

Development Plan

Akcea Therapeutics, our wholly owned subsidiary, is responsible for the development and commercialization of IONIS-APO(a)-LRx. IONIS-APO(a)-LRx is in development to treat patients with high Lp(a) levels. Because Lp(a) levels are genetically determined, diet and lifestyle changes have little impact on Lp(a) levels and current therapies do not adequately reduce Lp(a) to acceptable levels in patients with elevated Lp(a). Ionis and Akcea have the first and only clinical program to selectively and robustly reduce Lp(a) in patients by inhibiting apo(a). Together, we plan to develop IONIS-APO(a)-LRx with a robust program that addresses near, mid and long-term commercial opportunities by focusing initially on patients who have the greatest need and, in the long-term, on patients with more generalized Lp(a)-driven cardiovascular risk.

Current Status

We completed a Phase 1/2a study for IONIS-APO(a)-LRx in subjects with high Lp(a). In 2016, we plan to evaluate IONIS-APO(a)-LRx in Phase 2b studies in patients with cardiovascular disease, including patients with recurrent cardiovascular events with very high Lp(a) and patients with calcific aortic valve stenosis with high Lp(a).

Study Description

The Phase 1/2a study is a randomized, placebo-controlled, dose-escalation study in subjects with high Lp(a). This study is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of IONIS-APO(a)-LRx. The study also assesses levels of plasma Lp(a) after administration of IONIS-APO(a)-LRx.

About Lp(a)

Lp(a) is a lipoprotein particle that is assembled in the liver that consists of an LDL-C-like particle and apolipoprotein(a). Patients with elevated levels of Lp(a) have an increased risk of cardiovascular disease and there is evidence that elevated Lp(a) levels may contribute directly to heart attacks. Lp(a) levels in blood can vary greatly between individuals due primarily to genetic variations between individuals. Because elevated Lp(a) is a genetically determined condition that is not responsive to lifestyle changes, patients are unable to adequately control their Lp(a) levels through improved diet or increased physical activity. Moreover, current therapies are not able to adequately reduce elevated levels of Lp(a) to recommended levels in patients who have high Lp(a) levels. Although Lp(a) can be measured by a routine lipid blood panel, the lack of drugs to effectively lower Lp(a) has made treating patients with Lp(a)-driven cardiovascular disease difficult.

Partner

IONIS-APO(a)-LRx is part of our lipid franchise and, as such, Akcea Therapeutics, our wholly owned subsidiary, is responsible for development and commercialization of IONIS-APO(a)-LRx.

Selected Publications

  1. Merki, E. et al. (2011) Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol. 57, 1611-1621.
  2. Nordestgaard, B.G. et al. (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 31, 2844-2853.
  3. Tsimikas, S. & Hall, J.L. (2012) Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease. J Am Coll Cardiol. 63, 716-721.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 

IONIS-ANGPTL3-LRx

ANGPTL3

Ionis/Akcea

Mixed Dyslipidemias

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

Mixed Dyslipidemias

Description/Summary:

IONIS-ANGPTL3-LRx is a ligand conjugated antisense (LICA) drug designed to reduce angiopoietin-like 3 protein, or ANGPTL3, an independent risk factor for cardiovascular disease. ANGPTL3 is a glycoprotein principally expressed in the liver and regulates lipid, glucose and energy metabolism. Humans with elevated levels of ANGPTL3 have mixed dyslipidemia that is associated with an increased risk of premature heart attacks, increased arterial wall thickness as well as multiple metabolic abnormalities, such as insulin resistance. In contrast, humans with lower levels of ANGPTL3 have lower LDL-C and triglyceride levels, which are both risk factors associated with cardiovascular disease.

Clinical Data

In March 2015, we reported results from a Phase 1 study evaluating IONIS-ANGPTL3Rx, our non-LICA ANGPTL3-lowering drug, in healthy volunteers. In this study, subjects treated with IONIS-ANGPTL3Rx achieved dose-dependent, statistically significant reductions in ANGPTL3, triglycerides and total cholesterol. The clinical activity, safety and tolerability profile of IONIS-ANGPTL3Rx supports the mechanism of action of reducing ANGPTL3 with an antisense drug and informed our decision to move forward with the LICA drug for all potential therapeutic indications.

For more information on the results of this Phase 1 study, please see our press release here.

Development Plan

Akcea Therapeutics, our wholly-owned subsidiary, is responsible for developing and commercializing IONIS-ANGPTL3-LRx. IONIS-ANGPTL3-LRx incorporates our LICA technology, which enhances its therapeutic profile and potential to address multiple dyslipidemias from rare lipid disorders to broader cardiometabolic disease, including mixed dyslipidemia, multiple lipodystrophies and fatty liver diseases.

Current Status

In December 2015, we initiated a Phase 1/2 study evaluating IONIS-ANGPTL3-LRx in healthy volunteers with elevated triglycerides and subjects with familial hypercholesterolemia.

Study Description

The Phase 1/2 study of IONIS-ANGPTL3-LRx is a randomized, placebo-controlled, dose-escalation study in healthy volunteers with elevated triglycerides and subjects with familial hypercholesterolemia. This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single or multiple doses of IONIS-ANGPTL3-LRx. Plasma lipoprotein profile and plasma ANGPTL3 levels will also be evaluated.

About ANGPTL3 and Mixed Dyslipidemias

Mixed dyslipidemia is defined as elevations in LDL cholesterol and triglyceride levels, which is often accompanied by low levels of HDL. A growing body of clinical data demonstrates an association between the elevation of cholesterol and triglycerides in apolipoprotein B-containing particles such as VLDL, VLDL remnants, and LDL with increased cardiovascular risk. Further, the increasing obesity rates throughout the world have fueled the development of metabolic syndrome, a disorder characterized by dyslipidemia, loss in insulin sensitivity and increased hepatosteatosis.

Genome-wide association studies have confirmed the association between mutations in ANGPTL3 with improvements in lipid levels. Patients with dyslipidemia often have multiple cardiovascular and metabolic risk factors that remain challenging to treat. Despite existing therapies, there remains an unmet need for a therapy that could significantly decrease multiple cardiovascular risk factors, such as LDL-C and triglycerides. Our preclinical data suggests that reducing ANGPTL3 could improve lipid parameters, including LDL-cholesterol, triglycerides, and total cholesterol, as well as metabolic parameters, such as insulin sensitivity.

Patients with fatty liver disorders, including non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), may benefit from reduced ANGPTL3 levels. Fatty liver disease is a growing problem globally due to increasing metabolic disease. Patients with NASH and NAFLD often have associated dyslipidemia. As a result, most NASH patients die from cardiovascular disease. Reducing ANGPTL3 has the potential to improve both cardiovascular risk and liver fat in these patients.

Partner

IONIS-ANGPTL3-LRx is part of our lipid franchise and, as such, Akcea Therapeutics, our wholly owned subsidiary, is responsible for development and commercialization of IONIS-ANGPTL3-LRx.

Selected Publications

  1. Fujimoto, K., Koishi, R. Shimizugawa, T. & Ando, Y. (2006) Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity. Exp Anim. 55, 27-34.
  2. Mattijssen, F. & Kersten, S. (2012) Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 1821, 782-789.
  3. Minicocci, I. et al. (2012) Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. J Clin Endocrinol Metab. 97, 1266-1275.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 
Cancer

We are discovering and developing antisense drugs to treat cancers both internally and through our partnerships with AstraZeneca and OncoGenex Technologies Inc. Cancer is an area of significant unmet medical need and an area in which our antisense technology provides us with unique advantages in discovering new drugs. Cancer is an extremely complex disease that involves a large number of targets. With our technology we can evaluate a very broad and diverse range of targets and identify their involvement in different types of cancers. Using the information we gain early in research on each of these targets, we can quickly identify promising targets for an anti-cancer drug. We select anti-cancer targets that provide a multi-faceted approach to treating cancer.

Our cancer pipeline consists of anti-cancer antisense drugs that act upon biological targets associated with cancer progression and/or treatment resistance. In 2012, we formed an anti-cancer alliance with AstraZeneca that expands our anti-cancer efforts and supports an aggressive and broad clinical development plan for IONIS-STAT3-2.5Rx and IONIS-AR-2.5Rx. AstraZeneca brings significant experience that enables the identification of novel genetic and epigenetic targets for cancer. Combining AstraZeneca\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\'s expertise with our drug discovery technology, we plan to expand our cancer franchise with a number of promising new anti-cancer targets.

We believe the favorable tolerability and early evidence of clinical benefit of the anti-cancer drugs in our pipeline demonstrate how uniquely suited our technology is to create novel cancer therapeutics. In addition, we believe our generation 2.5 chemistry enhances the potency and effectiveness of our antisense drugs, and extends the applicability of our technology to cancers that are difficult to treat. For instance, data from a Phase 1/2 clinical study of IONIS-STAT3-2.5Rx showed evidence of antitumor activity in patients with cancer, including advanced/metastatic hepatocellular carcinoma.

Drug
Target
Partner
Indication
P1
P2
P3
C

Custirsen
(OGX-011)

clusterin

OncoGenex

Prostate / Lung Cancer

Generation 2.0 antisense drug

Indication*:

Cancer

Description/Summary:

Custirsen is an antisense drug we designed to improve survival in patients with advanced cancer. We and OncoGenex jointly discovered and conducted the initial development of custirsen. In July 2008, we and OncoGenex amended the co-development agreement pursuant to which OncoGenex became solely responsible for the costs, development and commercialization of custirsen as an adjunct therapy to enhance the effectiveness of chemotherapy. OncoGenex is evaluating custirsen in two Phase 3 studies, AFFINITY and ENSPIRIT. The AFFINITY study is evaluating custirsen in combination with cabazitaxel/prednisone as a second-line chemotherapy in men with CRPC. The ENSPIRIT study is evaluating custirsen as a second-line treatment in patients with NSCLC.

The FDA granted Fast Track Designation for custirsen for the treatment of patients with metastatic prostate cancer in combination with docetaxel.

Selected Publications

  1. July, L.V. et al. (2004) Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 3, 223-232.
  2. Koltai, T. (2014) Clusterin: a key player in cancer chemoresistance and its inhibition. Onco Targets Ther. 7, 447-456.
  3. Sowery, R.D. et al. (2008) Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 102, 389-397.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 
 

Apatorsen
(OGX-427)

Hsp27

OncoGenex

Cancer

Generation 2.0 antisense drug

Indication*:

Cancer

Description/Summary

Apatorsen is an antisense drug we designed to reduce the production of heat shock protein 27, or Hsp27, to treat patients with cancer. In January 2005, we entered into an agreement with OncoGenex to develop apatorsen. Under the terms of the agreement, OncoGenex is responsible for all development costs and activities. OncoGenex and collaborators are evaluating apatorsen in multiple Phase 2 studies in patients with cancer.

Select Publications

  1. Baylot, V. et al. (2011) OGX-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer. Cell Death Dis. 2, e221.
  2. Lamoureux, F. et al. (2014) Suppression of heat shock protein 27 using OGX-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer. Eur Urol. 66, 145-155.
  3. Matsui, Y. et al. (2009) Intravesical combination treatment with antisense oligonucleotides targeting heat shock protein-27 and HTI-286 as a novel strategy for high-grade bladder cancer. Mol Cancer Ther. 8, 2402-2411.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-AR-2.5Rx
(AZD5312)

AR

-

Prostate Cancer

Generation 2.5 antisense drug

Indication*:

Cancer

Description/Summary

IONIS-AR-2.5Rx, also referred to as AZD5312, is an antisense drug designed to reduce the production of all known forms of androgen receptor, or AR, including variants of the AR gene, to treat patients with prostate cancer. Prostate cancer growth, proliferation and progression are all androgen-dependent, and AR function is involved in disease progression at all stages of prostate cancer. For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens.

Clinical Data

In January 2016, we announced that results from the Phase 1/2 study with IONIS-AR-2.5Rx in heavily pretreated, late-stage prostate cancer patients demonstrated encouraging data, including several durable reductions in PSA levels. The drug also exhibited a good safety and tolerability profile supportive of continued development. Data from this study will be presented later in the year.

Current Status

AstraZeneca completed an open-label, dose-escalation, Phase 1/2 clinical study of IONIS-AR-2.5Rx in patients with advanced tumors for which the androgen receptor pathway is potentially a contributing factor. We plan to continue developing IONIS-AR-2.5Rx, independent of AstraZeneca.

About Prostate Cancer

Prostate cancer is the second leading cause of cancer deaths in American men, with approximately 30,000 deaths each year in the United States. For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens. Although androgen deprivation therapy approaches are initially effective in delaying disease progression in patients with metastatic prostate cancer, over time the course of the disease will progress in many of these patients. Resistance to current therapies is frequent and can occur through a variety of mechanisms including the activation of AR signaling in tumor cells through the amplification, overexpression and mutation of the AR gene.

Select Publications

  1. Augello, M.A. et al. (2014) AR function in promoting metastatic prostate cancer. Cancer Metastasis Rev. 33, 399-411.
  2. Feraldeschi, R. et al. (2014) Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. Epub ahead of print.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-STAT3-2.5Rx
(AZD9150)

STAT3

AstraZeneca

Cancer

Generation 2.5 antisense drug

Indication*:

Cancer

Description/Summary

IONIS-STAT3-2.5Rx, also referred to as AZD9150, is an antisense drug designed to reduce the production of signal transducer and activator of transcription 3, or STAT3, for the treatment of patients with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma. Overactivity in STAT3 is believed to prevent cell death and promote tumor cell growth.

Clinical Data

In November 2014, at the European Cancer Symposium, AstraZeneca presented results from a Phase 1/2 study of IONIS-STAT3-2.5Rx in patients with advanced metastatic hepatocellular carcinoma, or HCC, a type of liver cancer. Results from this study showed that treatment with IONIS-STAT3-2.5Rx provided evidence of antitumor activity in patients with HCC. In this late-stage population, several patients experienced stable disease and one patient experienced a durable, partial response while on IONIS-STAT3-2.5Rx treatment.

For more information on the results of this Phase 1/2 study for IONIS-STAT3-2.5Rx, please see our press release here.

Current Status

We and AstraZeneca have evaluated IONIS-STAT3-2.5Rx in patients with advanced metastatic hepatocellular carcinoma and advanced lymphoma. AstraZeneca is evaluating IONIS-STAT3-2.5Rx in combination with MEDI4736, AstraZeneca's investigational anti-PD-L1 drug, in patients with head and neck cancer. AstraZeneca also plans to start an additional clinical study evaluating IONIS-STAT3-2.5Rx in combination with MEDI4736 in patients with diffuse large B cell lymphoma.

About STAT3 and Cancer

STAT3, or signal transducer and activator of transcription 3, is an important mediator of signaling in the JAK2/STAT3 pathway. Mutations in STAT3 and other regulatory genes could result in constitutively active STAT3. Numerous studies have demonstrated constitutive STAT3 activation promotes tumor cell growth and survival. Indeed, activated STAT3 are present in a wide variety of human tumors, including hematological malignancies (leukemia, lymphomas, and multiple myeloma) as well as diverse solid tumors (head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancer).

Partner

In 2012, we licensed IONIS-STAT3-2.5Rx to AstraZeneca for the treatment of cancer. We are conducting a clinical study evaluating IONIS-STAT3-2.5Rx in patients with advanced lymphomas, including patients with diffuse large b-cell lymphoma. We are responsible for completing our clinical study in patients with advanced lymphomas and AstraZeneca is responsible for all other global development, regulatory and commercialization activities for IONIS-STAT3-2.5Rx. We received an upfront payment from AstraZeneca when we initiated the broad strategic collaboration, and a milestone payment related to the ongoing IONIS-STAT3-2.5Rx study. We are eligible to receive additional milestone payments and royalties from AstraZeneca.

Select Publications

  1. Burel, S.A. et al. (2013) Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther. 23, 213-227.
  2. Siveen, K.S. et al. (2014) Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845, 136-154.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 
Other

The broad applicability of our antisense technology allows us to create promising drugs and we have successfully developed novel drugs designed to treat many different diseases. In therapeutic areas that are outside of our core areas of development, we have licensed our drugs to highly focused satellite companies that have the specific expertise and resources to continue developing the drugs. Together with our partners we continue to advance drugs in clinical development that are outside of our core therapeutic areas, such as the ocular and antiviral drugs we and GSK are developing under our preferred partner collaboration.

Drug
Target
Partner
Indication
P1
P2
P3
C

Plazomicin

Aminoglycoside

Achaogen

Severe Bacterial Infection

Aminoglycoside

Indication*:

Multi-drug resistant infection due to carbapenem-resistant Enterobacteriaceae (CRE)

Description/Summary:

Plazomicin is an aminoglycoside drug that Achaogen, Inc. is developing for the treatment of multi-drug resistant gram-negative bacterial infections. Aminoglycosides are a group of antibiotics that inhibit bacterial protein synthesis that physicians can use to treat serious bacterial infections. In 2006, we licensed our proprietary aminoglycoside program to Achaogen. Achaogen discovered plazomicin based on technology licensed from us. Achaogen is currently evaluating plazomicin in a Phase 3 study in patients with serious multi-drug resistant infection due to carbapenem-resistant Enterobacteriaceae, or CRE. In September 2014, Achaogen initiated a Phase 3 study, CARE, to evaluate the efficacy of plazomicin in patients with infections caused by CRE. Achaogen announced that it has a special protocol assessment, or SPA, with the FDA for this Phase 3 study. Achaogen plans to initiate a second Phase 3 study of plazomicin for the treatment of patients with complicated urinary tract infections.

Selected Publications

  1. Armstrong, E.S. & Miller, G.H. (2010) Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr Opin Microbiol. 13, 565-573.
  2. Galani, I. et al. (2012) Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J Chemother. 24, 191-194.
  3. Walkty, A. et al. (2014) In vitro activity of plazomicin against 5,015 gram-negative and gram-positive clinical isolates obtained from patients in canadian hospitals as part of the CANWARD study, 2011-2012. Antimicrob Agents Chemother. 58, 2554-2563.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 
 

ATL1102

VLA-4

ATL

Multiple Sclerosis

Generation 2.0 antisense drug

Indication*:

Multiple Sclerosis

Description/Summary:

ATL1102 is an antisense drug we designed to reduce the production of CD49d, a subunit of Very Late Antigen-4, or VLA-4, for the treatment of patients with multiple sclerosis, or MS. Results from preclinical studies demonstrate that inhibition of VLA-4 could positively affect a number of inflammatory diseases, including MS. In 2001, we licensed ATL1102 to ATL. ATL is currently undertaking a chronic toxicology study in primates to support a potential Phase 2b trial of ATL1102 in patients with MS.

Selected Publications

  1. Limmroth, V. et al. (2014) CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology. Epub ahead of print.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 

RG-101

miR-122

Regulus

Hepatitis C Virus Infection

Anti-miR oligonucleotide

Indication*:

Hepatitis C

Description/Summary:

RG-101 is an anti-miR targeting microRNA-122, or miR-122, to treat patients with hepatitis C virus, or HCV. RG-101 is wholly owned by Regulus, but Regulus has entered into a clinical trial collaboration with GSK. Regulus is evaluating RG-101 as part of an HCV combination regimen with GSK's investigational HCV compound. Regulus completed a Phase 1/2 study in patients with HCV and is evaluating RG-101 in a Phase 2 study in combination with direct acting antivirals in patients with HCV. Regulus is also evaluating RG-101 in a Phase 1 study in patients with severe renal insufficiency or end-stage renal disease.

Selected Publications

  1. Dubin, P.H. et al. (2014) Micro-RNA-122 levels in acute liver failure and chronic hepatitis C. J. Med Virol. 86, 1507-1514.
  2. Jackson, A. & Linsley, P.S. (2010)The therapeutic potential of microRNA modulation. Discov Med. 9, 311-318.
  3. Jopling, C.L. et al. (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 309, 1577-1581.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications describedBack to top
 
 

IONIS-GSK4-LRx

Undisclosed

GSK

Ocular Disease

Generation 2+ LICA antisense drug

Indication*:

Ocular disease

Description/Summary

IONIS-GSK4-LRx is a Generation 2+ LICA antisense drug designed to treat an undisclosed ocular disease. IONIS-GSK4-LRx is the second LICA antisense drug to enter the clinic.

Current Status

In September 2015, we initiated a Phase 1 study of IONIS-GSK4-LRx in healthy volunteers.

Partner

In March 2010, we and GSK entered into a preferred partner alliance that provides GSK an option to develop and commercialize IONIS-GSK4-LRx. We are responsible for development of this program up to Phase 2 proof-of-concept, at which time GSK has the exclusive option to license the drug. We are also eligible to receive double-digit royalties on sales of IONIS-GSK4-LRx.

* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.
 

IONIS-HBVRx

HBV

GSK

Hepatitis B Virus Infection

Generation 2+ antisense drug

Indication*:

Hepatitis B virus infection

Description/Summary

IONIS-HBVRx is an antisense drug designed to reduce the production of viral proteins associated with hepatitis B virus (HBV) infection and replication, including hepatitis B surface antigen, which is present in both acute and chronic infections and is associated with a poor prognosis in patients with chronic HBV infection. HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions. Chronic HBV infection is one of the most common persistent viral infections in the world.

Current Status

We have completed a Phase 1 study of IONIS-HBVRx in healthy volunteers. The Phase 1 study of IONIS-HBVRx was a randomized, placebo-controlled, dose-escalation study in approximately 30 healthy volunteers. This study was designed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of IONIS-HBVRx. We plan to initiate a Phase 2 study in HBV patients in 2015.

About Hepatitis B virus infection

Hepatitis B virus infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world. Currently available therapies, although effective in reducing circulating HBV in the blood, do not efficiently inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer

Partner

In March 2010, we and GSK entered into a preferred partner alliance that provides GSK an option to develop and commercialize IONIS-HBVRx. We are responsible for development of this program up to Phase 2 proof-of-concept at which time GSK has the exclusive option to license the drug. If GSK exercises its option, it will pay us a license fee and will assume all further global development, regulatory and commercialization responsibilities. We received an upfront payment from GSK when we initiated the broad strategic collaboration, and milestone payments related to IONIS-HBVRx. We are eligible to receive additional milestone payments as the program progresses and a license fee if GSK exercises its option to license IONIS-HBVRx. We are also eligible to receive royalties from GSK.

Select Publications

  1. Grimm, D., Thimme, R. & Blum, H.E. (2011) HBV life cycle and novel drug targets. Hepatol Int. 5, 644-653.
  2. Youssef, S.S. et al. (2014) In vitro inhibition of hepatitis C virus by antisense oligonucleotides in PBMC compared to hepatoma cells. Biomed Res Int.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 

IONIS-HBV-LRx

HBV

GSK

Hepatitis B Virus Infection

Generation 2+ LICA antisense drug

Indication*:

Hepatitis B Infection

Description/Summary

IONIS-HBV-LRx, previously referred to as IONIS-GSK6-LRx, is a LIgand Conjugated Antisense (LICA) drug designed to reduce the production of viral proteins associated with hepatitis B virus (HBV) infection and replication, including hepatitis B surface antigen, which is present in both acute and chronic infections and is associated with a poor prognosis in patients with chronic HBV infection. IONIS-HBV-LRx is the first anti-infective drug in development that incorporates our LICA technology, which is designed to increase drug potency by enhancing drug delivery to target tissue.

Current Status

In January 2016, we initiated a Phase 1 study evaluating IONIS-HBV-LRx in healthy volunteers. The Phase 1 study of IONIS-HBV-LRx is a randomized, placebo-controlled, dose-escalation study in healthy volunteers. This study is designed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of IONIS-HBV-LRx.

We have previously completed a Phase 1 study of IONIS-HBVRx, our non-LICA HBV drug, in healthy volunteers and plan to begin a Phase 2 study on this drug in patients with HBV infection in 2016.

About Hepatitis B Virus Infection

Hepatitis B virus infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world. Currently available therapies, although effective in reducing circulating HBV in the blood, do not efficiently inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.

Partner

In June 2014, Ionis and GSK added development of IONIS-HBV-LRx to the preferred partner alliance established in March 2010. GSK has the option to license IONIS-HBV-LRx and is responsible for all development activities associated with IONIS-HBV-LRx.

Select Publications

  1. Grimm, D., Thimme, R. & Blum, H.E. (2011) HBV life cycle and novel drug targets. Hepatol Int. 5, 644-653.
  2. Youssef, S.S. et al. (2014) In vitro inhibition of hepatitis C virus by antisense oligonucleotides in PBMC compared to hepatoma cells. Biomed Res Int.
*Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
Metabolic

Metabolic disorders are chronic diseases that affect millions of people. There is still a significant need for new therapies for these patients. According to the Centers for Disease Control and Prevention, diabetes affects more than 29 million people in the United States, or nine percent of the population, with type 2 diabetes constituting 90 to 95 percent of those cases.

Metabolic disease is a very large area of medical need and is another area in which we focus our drug discovery and development efforts. Our approach is to develop antisense drugs that doctors can add to existing therapies to treat diabetes. One hurdle for traditional drug development is that most traditional drugs cannot selectively target a disease-causing protein without also affecting closely related proteins, which often results in unwanted side effects. We design our antisense drugs to target the gene responsible for producing the disease-causing protein while avoiding unwanted effects on closely related proteins, thereby reducing the risk of side effects.

We have reported positive Phase 2 data from IONIS-GCGRRx and IONIS-PTP1BRx, the most advanced drugs in our metabolic franchise. These two drugs and our third drug, IONIS-GCCRRx, are designed to act upon targets in the liver or fat tissue through a distinct mechanism to improve insulin sensitivity, reduce glucose production, or affect other metabolic aspects of this complex disease.

Drug
Target
Partner
Indication
P1
P2
P3
C

IONIS-GCGRRx

GCGR

-

Diabetes

Generation 2+ antisense drug

Indication*:

Type 2 Diabetes

Description/Summary:

IONIS-GCGRRx is an antisense drug designed to reduce the production of glucagon receptors, or GCGR, to treat patients with type 2 diabetes. GCGR is a receptor for the hormone glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action can lead to significant increase in blood glucose level. In addition, reducing GCGR produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and enhances insulin secretion.

Clinical Data

In May 2014, we reported data from a Phase 2 study evaluating IONIS-GCGRRx in patients with type 2 diabetes who are poorly controlled on stable metformin therapy at the American Diabetes Association Scientific Sessions. In this study, patients treated with IONIS-GCGRRx achieved significant reductions in measures of glucose control after only 13 weeks of treatment. In addition, IONIS-GCGRRx-treated patients experienced increased plasma GLP-1 levels. The safety and tolerability profile of IONIS-GCGRRx in the Phase 2 study supports continued development.

For more information on the results of this study, please see our press release here.

Current Status

We completed a Phase 2 study of IONIS-GCGRRx in patients with type 2 diabetes who are poorly controlled on stable metformin therapy. We have initiated a second Phase 2 study to identify the optimal dose and schedule to achieve glucose control with manageable glucagon receptor-related liver enzyme elevations. This study is a double blind, randomized, placebo-controlled, phase 2 study to identify the optimal dose and schedule to achieve glucose control with manageable glucagon receptor-related liver enzyme elevations with IONIS-GCGRRx administered once weekly for 26 weeks in patients with type 2 diabetes being treated with metformin.

About Type 2 Diabetes

Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated in type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more common type, the body does not make or use insulin well and therefore, blood glucose levels are not regulated properly.

Diabetes is an epidemic that continues to grow at an alarming rate. According to the latest Center for Disease Control statistics released, there are currently 29 million people in the U.S. that have diabetes, with type 2 diabetes constituting 90 to 95 percent of those cases. Moreover, an additional 86 million American adults, or one out of every three adults, are prediabetic. It is estimated that 15 to 30 percent of prediabetic people will develop full-fledged metabolic disorder within five years.

Selected Publications

  1. Liang, Y. et al. (2004) Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes. 53, 410-417.
  2. van Dongen, M.G. et al. (2014) First proof of pharmacology in humans of a novel glucagon receptor antisense drug. J Clin Pharmacol. Epub ahead of print.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-GCCRRx

GCCR

-

Diabetes

Generation 2+ antisense drug

Indication*:

Type 2 Diabetes

Description/Summary:

IONIS-GCCRRx is an antisense drug designed to reduce the production of glucocorticoid receptor, or GCCR, to treat patients with type 2 diabetes. Glucocorticoid hormones affect a variety of processes throughout the body, including the production of liver glucose and fat storage. Excessive GCCR activity in the liver and fat is associated with obesity, insulin resistance and glucose intolerance.

Clinical Data

We completed a Phase 2 study of IONIS-GCCRRx in patients with type 2 diabetes. This study was designed to provide additional safety information, as well as evaluate short-term measures of glucose control and insulin sensitivity. In this study, the drug was safe and well tolerated. Improvements in certain measures of glucose control and insulin sensitivity were observed in patients treated with IONIS-GCCRRx; however, significant reduction in fructosamine, the study's primary endpoint, was not observed. We are evaluating alternatives for further development of IONIS-GCCRRx in patients with type 2 diabetes.

Current Status

We completed a Phase 2 study of IONIS-GCCRRx in patients with type 2 diabetes.

About Type 2 Diabetes

Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated in type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more common type, the body does not make or use insulin well and therefore, blood glucose levels are not regulated properly.

Diabetes is an epidemic that continues to grow at an alarming rate. According to the latest Center for Disease Control statistics released, there are currently 29 million people in the U.S. that have diabetes, with type 2 diabetes constituting 90 to 95 percent of those cases. Moreover, an additional 86 million American adults, or one out of every three adults, are prediabetic. It is estimated that 15 to 30 percent of prediabetic people will develop full-fledged metabolic disorder within five years.

Inhibiting GCCR has long been recognized as an attractive strategy for improving glycemic and lipid control in patients with type 2 diabetes. However, the side effects associated with systemic GCCR inhibition have challenged traditional drug developers. Targeted reduction of GCCR in the liver and fat tissues with antisense drugs is an attractive therapeutic approach because it can lower glucose and lipids without causing potential side effects associated with systemic GCCR inhibition.

Selected Publications

  1. Liang, Y. et al. (2005) Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. Metabolism. 54, 848-855.
  2. Rose, A.J. & Herzig, S. (2013) Metabolic control through glucocorticoid hormones: an update. Mol Cell Endocrinol. 380, 65-78.
  3. Watts, L.M. et al. (2005) Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. Diabetes. 54, 1846-1853.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-PTP1BRx

PTP-1B

-

Diabetes

Generation 2+ antisense drug

Indication*:

Type 2 Diabetes

Description/Summary:

IONIS-PTP1BRx is an antisense drug designed to reduce the production of protein tyrosine phosphatase-1B, or PTP-1B, to treat patients with type 2 diabetes. PTP-1B is a phosphatase that negatively regulates insulin receptor signaling and is responsible for turning off the activated insulin receptor. Reducing PTP-1B enhances insulin activity. Scientists have long recognized PTP-1B as an attractive target to treat diabetes, but due to structural similarities among closely related proteins, pharmaceutical companies have had difficulty identifying small molecule drugs with sufficient specificity to be safe. We designed IONIS-PTP1BRx to increase the body's sensitivity to the natural hormone, insulin, resulting in better glucose control for patients with type 2 diabetes. Because of its unique mechanism, IONIS-PTP1BRx may help treat patients with type 2 diabetes without causing weight gain or hypoglycemia, also known as low blood sugar. The reductions in LDL-C produced by inhibiting PTP-1B could also provide an added benefit to patients.

Clinical Data

We reported top-line data from a Phase 2 study of IONIS-PTP1BRx in patients with type 2 diabetes with or without sulfonylurea therapy. In this study, patients treated with IONIS-PTP1BRx achieved statistically significant reductions in body weight and HbA1c at 36 weeks. The safety and tolerability profile of IONIS-PTP1BRx in this Phase 1 study supports continued development.

For more information on the results of this study, please see our press release here.

Current Status

We have completed a Phase 2 study of IONIS-PTP1BRx in patients with type 2 diabetes.

About Type 2 Diabetes

Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated in type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more common type, the body does not make or use insulin well and therefore, blood glucose levels are not regulated properly.

Diabetes is an epidemic that continues to grow at an alarming rate. According to the latest Center for Disease Control statistics released, there are currently 29 million people in the U.S. that have diabetes, with type 2 diabetes constituting 90 to 95 percent of those cases. Moreover, an additional 86 million American adults, or one out of every three adults, are prediabetic. It is estimated that 15 to 30 percent of prediabetic people will develop full-fledged metabolic disorder within five years.

Scientists have long recognized PTP-1B as an attractive target for the treatment of diabetes. However, efforts to develop drugs that target PTP-1B have been challenging due to the structural similarities among closely related protein phosphatases. Targeted reduction of PTP-1B with antisense drug represents an ideal therapeutic approach because an antisense drug is designed to specifically reduce the PTP-1B mRNA, without affecting mRNAs of other protein phosphatases. This approach eliminates the off-target side effects observed with traditional small-molecule drugs.

Selected Publications

  1. Panzhinskiy, E., Ren, J. & Nair, S. (2013) Pharmacological inhibition of protein tyrosine phosphatase 1B: a promising strategy for the treatment of obesity and type 2 diabetes mellitus. Curr Med Chem. 20, 2609-2625.
  2. Zinker, B.A. et al. (2002) PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA. 99, 11357-11362.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-FGFR4Rx

FGFR4

-

Obesity

Generation 2+ antisense drug

Indication*:

Obesity

Description/Summary

IONIS-FGFR4Rx is an antisense drug designed to reduce the production of fibroblast growth factor receptor 4, or FGFR4, to treat obese patients. FGFR4 is expressed in the liver and fat tissues, and plays an important role in the regulation of fat burning and body weight. Reduction in FGFR4 decreases the body's ability to store fat while simultaneously increasing fat burning and energy expenditure. IONIS-FGFR4Rx is the first drug in our metabolic franchise to treat obesity and utilizes technology we in-licensed from Verva Pharmaceuticals Ltd.

Clinical Data

We have completed a Phase 1 study in healthy volunteers. The safety profile we observed in this study support further development of the program. In 2015, we initiated a Phase 2 clinical study of IONIS-FGFR4Rx in obese patients (body mass index between 30 and 40 kg/m2).

Current Status

We completed a Phase 1 study of IONIS-FGFR4Rx in healthy volunteers. We initiated a Phase 2 study of IONIS-FGFR4Rx in obese patients in July 2015. The Phase 2 study of IONIS-FGFR4Rx will evaluate multiple doses of IONIS-FGFR4Rx in obese patients. The primary endpoints of the study are changes in energy expenditures from baseline after 13 weeks of dosing. Energy expenditures are assessed by measuring resting metabolic rate, resting metabolic rate adjusted for changes in body composition, and resting fat oxidation. This study is a double blind, placebo-controlled 13-week study.

For more information about the clinical study, click here to go to clinicaltrials.gov.

About Obesity

Obesity has reached global epidemic proportions in both adults and children. According to the World Health Organization, in 2014, there were more 600 million adults over the age of 18 who were obese and 42 million children under the age of five who were overweight or obese in 2013. Obesity is a major risk factor for a number of chronic diseases, including type 2 diabetes, dyslipidemia, hypertension and cardiovascular diseases. Despite the growing epidemic, there are very few weight loss drugs that have been approved to treat patients with obesity. Although many anti-obesity drugs have entered development, most of them have not been approved due to their adverse effects in the CNS and/or heart. There is an unmet medical need for drugs that can cause weight loss by acting on peripheral tissues without causing cardiac or CNS related side effects.

Select Publications

  1. Yu, X.X. et al. (2013) Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. PLoS One. 8.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 

IONIS-DGAT2Rx

DGAT2

-

NASH

Generation 2+ antisense drug

Indication*:

NASH (Nonalcoholic Steatohepatitis)

Description/Summary:

IONIS-DGAT2Rx is a Generation 2+ antisense drug designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, to treat patients with NASH, or nonalcoholic steatohepatitis. NASH is a common liver disease characterized by excessive triglycerides in the liver with concurrent inflammation and cellular damage. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis, lowered blood lipid levels and reversed diet-induced insulin resistance in animal models of obesity and fatty liver disease. [3,5]

NASH is sometimes considered a "silent" liver disease because people with early-stage NASH feel well, even though they are starting to accumulate fat in their livers, and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.

Current Status

In September 2015, we initiated a Phase 1 study of IONIS-DGAT2Rx in healthy overweight volunteers (body mass index between 29 and 38 kg/m2). The Phase 1 study of IONIS-DGAT2Rx is a randomized, placebo-controlled, dose-escalation study in healthy overweight volunteers. NASH is most commonly found in persons who are overweight or obese. Our study in overweight subjects is designed to give us valuable insights on the effects of IONIS-DGAT2Rx in a patient population who are closely matched to patients with NASH. This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single or multiple doses of IONIS-DGAT2Rx. Plasma lipoprotein profile and insulin resistance will also be evaluated.

About NASH

NASH is a liver disease characterized by the presence of excessive liver fat (steatosis) that is accompanied by inflammation and cellular damage. NASH is considered a "silent" liver disease because in the early stages of the disease, patients generally feel well and are unaware they have the disease. However, as NASH progresses, scarring, or fibrosis, begins to accumulate in the liver. Ultimately, cirrhosis of the liver develops and the liver can no longer function normally. About 20 percent of NASH patients are reported to develop cirrhosis, and 30 to 40 percent of patients with NASH cirrhosis experience liver-related death. [4] Currently, liver transplantation is the only treatment for advanced cirrhosis and liver failure. Because of the high prevalence of NASH, it has recently become the third most common indication for liver transplantation in the US. [2] The exact cause of NASH is not well understood but the development of fatty liver diseases has been linked to obesity. As the number of people with obesity continues to rise globally, a parallel increase in the incidence of NASH has also been observed. Currently, it is estimated that 2 to 3 percent of the general population have NASH. [1] However, with the growing obesity epidemic, it is likely that the number of patients with NASH will also continue to rise.

Select Publications

  1. Bellentani S, Scaglioni F, Marino M, Bedogni G. (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 28,155-161.
  2. Byrne, C.D. and Targher, G. (2015) NAFLD: a multisystem disease. J Hepatol. 621, S47-64.
  3. Choi, C.S. et al. (2007) Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 282, 22678-22688.
  4. Takahashi, Y. et al. (2015) Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 21, 3777-3785.
  5. Yu, X.X. et al. (2005) Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 42, 362-371.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 

RG-125

miR-103/107

Regulus

NASH in Patients with Type 2 Diabetes/Pre-Diabetes