Pipeline

Clinical | SatCo | Preclinical

Therapeutic Area

Phase

Neurological
We are a leader in the discovery and development of antisense drugs to treat people with both rare and common neurological diseases. According to the World Health Organization, up to 1 billion people worldwide are affected by neurological disorders. In addition, the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, reports that a third of the approximately 7,000 known rare diseases are neurological disorders or thought to include a neurological component.

We have a robust pipeline of neurological disease drugs we are developing under established collaborations with Biogen and Roche. For example, SPINRAZA, which is marketed globally by Biogen and is now the standard of care for the treatment of people with spinal muscular atrophy (SMA), came from our broad strategic collaboration with Biogen. We are partnered with Roche to develop IONIS-HTTRx (RG6042) for the treatment of people with Huntington’s Disease. We also continue to build and advance our own neurological disease pipeline in parallel.

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SPINRAZA® (nusinersen)

SMN2

Biogen

Spinal Muscular Atrophy

Generation 2+ antisense drug

Indication*:

Spinal Muscular Atrophy

Description/Summary

SPINRAZA is a Generation 2+ antisense drug approved in global markets for the treatment of spinal muscular atrophy (SMA). SMA is a disease caused by mutations in the chromosome 5q that lead to SMN protein deficiency. Due to a loss of, or defect in the SMN1 gene, people with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons. SPINRAZA is designed to selectively bind to and alter the splicing of a single RNA from the SMN2 gene, a gene that is nearly identical to SMN1, in order to increase production of full-length SMN protein.

SPINRAZA is administered via intrathecal injection, which delivers therapies directly to the cerebrospinal fluid (CSF) around the spinal cord, where motor neurons degenerate in patients with SMA due to insufficient levels of SMN protein.

The most common adverse reactions reported for SPINRAZA were upper respiratory infection, lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients. Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

Current Status

SPINRAZA is the first and only approved medicine for the treatment of SMA and is currently approved in the U.S., EU, Brazil, Japan, Switzerland, Canada, and Australia. Biogen has submitted regulatory filings in additional countries and plans to initiate additional filings in other countries.

In December 2016, the U.S. Food and Drug Administration (FDA) approved SPINRAZA under Priority Review for the treatment of SMA in pediatric and adult patients. In June 2017, the European Commission (EC) granted marketing authorization for SPINRAZA for the treatment of 5q SMA, the most common form of the disease, representing approximately 95% of all SMA cases.

Biogen licensed the global rights to develop, manufacture and commercialize SPINRAZA from Ionis Pharmaceuticals in August 2016 and is now responsible for all development, regulatory and commercialization activities and costs for SPINRAZA.

For more information on the FDA and EC approvals of SPINRAZA, please see our press releases here and here.

For more information about SPINRAZA and U.S. prescribing information, visit www.SPINRAZA.com.

For SPINRAZA prescribing information in the EU, please visit http://www.ema.europa.eu/ema/.

Clinical Data

The safety and efficacy of SPINRAZA has been evaluated from multiple clinical studies in more than 270 patients, including two Phase 3 studies: ENDEAR, a randomized controlled study evaluating SPINRAZA in patients with infantile-onset SMA, and CHERISH, a randomized controlled study evaluating SPINRAZA in patients with later-onset SMA; as well as open-label studies in pre-symptomatic and symptomatic patients with, or likely to develop, Types 1, 2 and 3 SMA.

Both the ENDEAR and CHERISH studies demonstrated clinically meaningful efficacy and a favorable benefit-risk profile of SPINRAZA. In the ENDEAR end of study analysis, a statistically significant greater percentage of children with infant-onset SMA achieved improvement in motor milestones compared to untreated patients, with some infants in the SPINRAZA group achieving full head control, the ability to roll, sitting, and standing. Additionally, infants treated with SPINRAZA demonstrated a statistically significant improvement in event-free survival compared to untreated patients. For more details see our press release here. In the CHERISH pre-specified interim analysis, there was a statistically significant and clinically meaningful improvement in motor function in children with later-onset SMA treated with SPINRAZA compared to untreated children. The end of study data were consistent with the interim analysis and presented at the American Academy of Neurology annual meeting in Boston, Mass., April 2017. For more details see our press release here.

About Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is characterized by loss of motor neurons in the spinal cord and lower brain stem, resulting in severe and progressive muscular atrophy and weakness. Ultimately, individuals with the most severe type of SMA can become paralyzed and have difficulty performing the basic functions of life, like breathing and swallowing.

Due to a loss of, or defect in the SMN1 gene, people with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons. The severity of SMA correlates with the amount of SMN protein. People with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and do not achieve the ability to sit without support or live beyond two years without respiratory support. People with Type 2 and Type 3 produce greater amounts of SMN protein and have less severe, but still life-altering forms of SMA.

SPINRAZA is the first and only approved treatment for SMA.

To support awareness and education in SMA, Biogen has launched Together in SMA in the United States. Together in SMA is a program created to provide informational materials and resources to the SMA community. Learn more at www.TogetherinSMA.com.

Partner

In August 2016, Biogen exercised its option to worldwide rights to SPINRAZA and is responsible for future development, manufacturing, and commercialization.

Ionis earned a $60 million milestone payment from Biogen for the U.S. approval, a $50 million milestone payment for the EU approval, and a $40 million milestone payment for approval of pricing in Japan. As of September 2017, Ionis has earned more than $470 million from Biogen related to SPINRAZA. Ionis is eligible to receive tiered royalties on global sales of SPINRAZA.

Biogen and Ionis Pharmaceuticals acknowledge support from the following organizations for SPINRAZA: Cure SMA, Muscular Dystrophy Association, SMA Foundation, the SMA Trust, and for intellectual property licensed 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.
  6. Chiriboga, C.A. et al. (2016) Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology. 86, 890-897.
  7. Finkel, R.S. et al. (2016) Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 388, 3017-3026.
  8. * Safety and efficacy have not been evaluated by any regulatory authorities for the indications described Back to top
 
 
 
 
 

IONIS-HTTRx (RG6042)

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
 
 

IONIS-SOD1Rx (BIIB067)

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 15 to 20 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), SPINRAZA; 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-MAPTRx (BIIB080)

TAU

Biogen

Alzheimer's Disease

Generation 2+ antisense drug

Indication*:

Alzheimer's Disease

Description/Summary

IONIS-MAPTRx is an antisense oligonucleotide (ASO) drug designed to selectively reduce production of the tau protein in the brain. Microtubule-associated protein tau (MAPT) or tau, is thought to be a contributor or cause of certain neurodegenerative diseases, known as tauopathies, that are characterized by the deposition of abnormal tau protein in neurons and glia in the brain. These disorders include Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), and some forms of frontotemporal dementia (FTD).

Current Status

IONIS-MAPTRx is being evaluated in a Phase 1/2a, randomized, placebo-controlled, dose-escalation study to evaluate the safety and activity of once-monthly intrathecal injections in patients with mild AD.

For more information on the Phase 1/2a study of IONIS-MAPTRx, please see our press release here.

About Alzheimer's Disease (AD)

It is estimated that in the U.S., 10% of people age 65 and older is living with dementia. Alzheimer's disease (AD) is the most common form of dementia, accounting for an estimated 70% of cases. AD is a neurodegenerative disorder characterized by cognitive decline and behavioral disturbances that eventually result in a person's inability to perform daily activities. AD relentlessly progresses to death over 5-20 years. Unlike amyloid deposits that appear diffusely throughout the brain for up to 20 years before the onset of AD, tau deposits are temporally and spatially closely-related to where brain atrophy occurs and cognitive deficits originate.

Partner

Ionis is developing IONIS-MAPTRx under a broad strategic collaboration with Biogen. Ionis also developed and licensed SPINRAZA to Biogen under this collaboration. SPINRAZA is approved in global markets for the treatment of patients with spinal muscular atrophy (SMA). In addition, Ionis and Biogen are developing IONIS-SOD1Rx for amyotrophic lateral sclerosis (ALS), and IONIS-BIIB5Rx IONIS-BIIB6Rx and IONIS-BIIB7Rx to treat undisclosed neurodegenerative diseases. Ionis and Biogen also have over two dozen programs in preclinical development and in discovery.

Select Publications

  1. DeVos, S.L. et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Trans. Med. 9, 374.
  2. DeVos, S.L. et al. (2013) Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33:12887.
  3. * Safety and efficacy have not been evaluated by any regulatory authorities for the indications described Back to top
 
 

IONIS-MAPTRx (BIIB080)

TAU

Biogen

Frontotemporal Dementia

Generation 2+ antisense drug

Indication*:

Frontotemporal dementia (FTD)

Description/Summary

IONIS-MAPTRx is an antisense oligonucleotide (ASO) drug designed to selectively reduce production of the tau protein in the brain. Microtubule-associated protein tau (MAPT) or tau, is thought to be a contributor or cause of certain neurodegenerative diseases, known as tauopathies, that are characterized by the deposition of abnormal tau protein in neurons and glia in the brain. These disorders include Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), and some forms of frontotemporal dementia (FTD).

Current Status

IONIS-MAPTRx is being evaluated in a Phase 1/2a, randomized, placebo-controlled, dose-escalation study to evaluate the safety and activity of once-monthly intrathecal injections in patients with mild AD.

For more information on the Phase 1/2a study of IONIS-MAPTRx, please see our press release here.

Frontotemporal Dementia

Frontotemporal dementia (FTD) is a rare form of dementia resulting from neuronal damage in parts of the brain called the frontal and temporal lobes. As neurons die in these regions, these lobes atrophy. FTD typically occurs between the ages of 45 and 64 years old, with patients surviving approximately 9 years from diagnosis. In the early stages of the disease, patients experience substantial personality and social behavior changes, including apathy, loss of empathy, emotional bluntness, impulsiveness, poor judgment, communication impairment, among others. Death is typically the result of disease progression leading to pneumonia, failure to thrive, or cardiopulmonary failure.

Partner

Ionis is developing IONIS-MAPTRx under a broad strategic collaboration with Biogen. Ionis also developed and licensed SPINRAZA to Biogen under this collaboration. SPINRAZA is approved in global markets for the treatment of patients with spinal muscular atrophy (SMA). In addition, Ionis and Biogen are developing IONIS-SOD1Rx for amyotrophic lateral sclerosis (ALS), and IONIS-BIIB5Rx IONIS-BIIB6Rx and IONIS-BIIB7Rx to treat undisclosed neurodegenerative diseases. Ionis and Biogen also have over two dozen programs in preclinical development and in discovery.

Select Publications

  1. DeVos, S.L. et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Trans. Med. 9, 374.
  2. DeVos, S.L. et al. (2013) Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33:12887.
  3. * Safety and efficacy have not been evaluated by any regulatory authorities for the indications described Back to top
 
 

IONIS-C9Rx (BIIB078)

C9orf72

Biogen

Amyotrophic Lateral Sclerosis

Generation 2+ antisense drug

Indication*:

Amyotrophic Lateral Sclerosis

Description/Summary

IONIS-C9Rx, also referred to as BIIB078, is a Generation 2+ antisense drug designed to reduce the production of the mutated chromosome 9 open reading frame 72 (C9ORF72) gene. A mutation in the C9ORF72 gene results in an inherited form of amyotrophic lateral sclerosis (ALS), referred to as C9ORF72-ALS, the leading known genetic cause of ALS worldwide. There is substantial evidence that this mutation is responsible for a toxic gain of function repeat expansion that can lead to rapid progressive loss of motor neurons in people with C9ORF72-ALS. C9ORF72-ALS is a fatal disease characterized by muscle weakness, loss of movement, difficulty in breathing and swallowing. IONIS-C9Rx represents a novel approach to targeting ALS, for which there is no cure.

Current Status

We are collaborating with Biogen to develop IONIS-C9Rx to treat patients with C9ORF72-ALS. In August 2018, we initiated a Phase 1/2 clinical study evaluating IONIS-C9Rx in patients with C9ORF72-ALS. The current study is a randomized, quadruple-blind, placebo-controlled designed to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of IONIS-C9Rx administered intrathecally to adults with C9ORF72-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 characterized by loss and dysfunction of neurons in motor pathways with a prevalence of approximately five cases per 100,000 persons in the U.S.1 People with ALS suffer progressive degeneration of the motor neurons, which results in a declining quality of life and ultimately death. A mutation in the C9ORF72 gene results in an inherited form of ALS, referred to as C9ORF72-ALS. Familial ALS represents approximately 15 to 20 percent of all cases of ALS and C9ORF72-related ALS accounts for up to 34 percent of all familial cases.2,3 It is currently the leading known genetic cause of ALS worldwide. People with C9ORF72-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.

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-C9Rx. The collaboration combines Biogen's expertise in neurology with Ionis' leadership in antisense technology to develop novel therapies to treat neurological diseases. 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 programs include antisense drugs to treat patients with spinal muscular atrophy (SMA), SPINRAZA; amyotrophic lateral sclerosis (ALS), IONIS-SOD1Rx and IONIS-C9Rx; and Alzheimer’s disease, IONIS-MAPTRx. In addition to these four drugs, Ionis and Biogen have several drugs in preclinical studies for undisclosed neurological diseases and numerous opportunities to evaluate additional targets for the development of drugs to treat other neurological disorders.

Select Publications

  1. Mehta, P. et al. (2018) "Prevalence of Amyotrophic Lateral Sclerosis — United States, 2014." MMWR Morb Mortal Wkly Rep 67, 216–218.
  2. McCampbell et al. "Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models." The Journal of Clinical Investigations, Advanced Online Publication, July 16, 2018.
  3. Van Blitterswijk, M., DeJesus-Hernandez, M., & Rademakers, R. (2012). How do C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding repeat expansion disorders? Current Opinion in Neurology, 25(6), 689–700.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 
 
Severe & Rare

Our severe and rare disease franchise is the largest franchise in our pipeline. According to the National Institutes of Health, there are approximately 7,000 rare diseases, many life-threatening or fatal. Two drugs we have developed to address rare diseases are TEGSEDI for the treatment of people with hereditary ATTR amyloidosis (hATTR) amyloidosis and WAYLIVRA for the treatment of people with familial chylomicronemia syndrome (FCS). Our commercial affiliate, Akcea Therapeutics, is responsible for commercializing both TEGSEDI and WAYLIVRA.

Drug
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Partner
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TEGSEDITM (inotersen)

TTR

Akcea

hATTR

Generation 2+ antisense drug

Indication*:

TTR Amyloidosis (ATTR)

Description/Summary

TEGSEDITM (inotersen) is an antisense drug designed to reduce the production of transthyretin, or TTR protein, to treat TTR amyloidosis (ATTR), a systemic, progressive and fatal disease. In patients with ATTR, both the mutant and wild type (wt) TTR protein builds 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. As the TTR protein fibrils enlarge, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.

TEGSEDI was approved in October 2018 by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. TEGSEDI also received marketing authorization in the European Union and Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR in July and October 2018, respectively.

Clinical Data

In November 2017, Ionis presented new data from the Phase 3 NEURO-TTR study of inotersen in patients with polyneuropathy due to hereditary TTR amyloidosis (hATTR) at the first annual European ATTR Amyloidosis meeting for patients and doctors. Results from the study demonstrated benefit compared to placebo across both primary endpoints of the study: the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and the modified Neuropathy Impairment Score +7 (mNIS+7) at both eight and 15 months of treatment. In addition, consistent and significant benefit was observed in both the Norfolk-QoL-DN and mNIS+7, independent of disease stage, types of mutation, previous treatment with TTR protein stabilizers or presence of cardiomyopathy at the beginning of the study. Inotersen-treated patients benefited significantly in the quality of life primary endpoint with 50% of patients experiencing improved scores compared to baseline and a mean difference in magnitude of 11.68 points, compared to placebo-treated patients, at 15 months of treatment (mean change from baseline of 0.99 vs. 12.67, p<0.001). In addition, clinically meaningful benefit compared to placebo was observed in the SF-36 physical component score, a measure of general health quality of life. Inotersen-treated patients also benefited significantly in the co-primary endpoint of disease control, mNIS+7, with 47% of patients experiencing improved or stable scores compared to baseline and a mean difference in magnitude of 19.73 -points, compared to placebo-treated patients, at 15 months of treatment, (p < 0.001).

Two key safety issues were identified during the study: thrombocytopenia and safety signals related to renal function. Enhanced monitoring was implemented during the study to support early detection and management of these issues. Serious platelet and renal events were infrequent and easily managed with routine monitoring, which has proven effective since implementation. Other serious adverse events were observed in 24.1% of inotersen-treated patients and 21.7% of placebo-treated patients. No cumulative toxicities have been identified with long-term exposure.

Adverse events occurring in >=10% of patients and twice as frequently in inotersen-treated patients compared with placebo-treated patients, included thrombocytopenia/platelet count decreases, nausea, pyrexia, chills, vomiting, and anemia. Injection site reactions accounted for less than 1% of all injections and were mild or moderate in severity. There were no discontinuations due to injection site reactions. The overall mortality rate in the NEURO-TTR study was 2.9% and was lower than overall mortality rates reported in other studies in hATTR patients. There were a total of five deaths in the study, five (4.7%) in the inotersen arm and zero in the placebo arm. Four deaths in the inotersen arm were associated with disease progression and considered unrelated to treatment. As previously reported, there was one fatal intracranial hemorrhage in conjunction with serious thrombocytopenia. No serious thrombocytopenia was observed following implementation of more frequent monitoring.

For more information on the results of the Phase 3 NEURO-TTR study, please see the press release here.

In July 2016, Ionis reported positive data from an ongoing Phase 2 open-label, investigator-initiated study in patients with cardiomyopathy due to ATTR, and from the ongoing open-label extension (OLE) study of inotersen in patients with polyneuropathy due to hATTR who completed the Phase 3 NEURO-TTR study. The Phase 2 study being conducted by Dr. Benson of Indiana University in patients with hATTR with cardiomyopathy and wild-type TTR amyloidosis (ATTRwt) with baseline intraventricular septum (IVS) thickness >=1.3cm showed evidence of cardiac disease stabilization in patients with TTR amyloid cardiomyopathy treated with inotersen for 12 months. The first eight patients treated with inotersen had a mean decrease of 4 percent in left ventricular mass from baseline as measured by MRI at 12 months. This compares favorably to Dr. Benson's published natural history study in similar patients with an IVS >=1.3cm at study entry who had a mean increase of 14 percent in left ventricular mass as measured by MRI at 12 months. Improvements in multiple additional endpoints, including imaging, functional and biomarker endpoints also support disease stabilization.

An analysis conducted on patients with 12 different mutations who reached up to 12 months of treatment in the NEURO-TTR OLE study showed approximately equal reduction of both wild-type and mutant TTR levels as measured by liquid chromatography-mass spectrometry (LC-MS). Ionis also reported positive data from an analysis conducted in June 2016 on the subset of patients who have reached three months or more of treatment in the OLE study (n=74).

For more information on the results of these studies, please see the press release here.

Current Status

TEGSEDI is now approved in U.S. for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. TEGSEDI is also approved in the European Union and Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR.

In August 2018, PTC Therapeutics, Inc. in-licensed regional rights from Ionis’ affiliate, Akcea, to commercialize TEGSEDI in Latin America.

An open-label extension study, or OLE, is ongoing for patients who have completed the NEURO-TTR study, in which all patients are treated with inotersen. More than 95 percent of patients who have completed the NEURO-TTR study elected to participate in the OLE.

The TEGSEDI expanded access program (EAP) (NCT03400098) has been initiated in the U.S. and is currently enrolling eligible patients. Click here for more information on the TEGSEDI EAP.

For full prescribing information, please visit TEGSEDI.com (U.S.) and TEGSEDI.eu (EU).

See the press release about the U.S. regulatory approval here, the EU regulatory approval here, the Canadian approval here, the collaboration with PTC here and the EAP here.

About TTR Amyloidosis (ATTR)

ATTR amyloidosis is a systemic, progressive and fatal disease in which patients experience multiple overlapping clinical manifestations 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 approved for the treatment of TTR amyloidosis.

Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with polyneuropathy due to hATTR 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 patients with polyneuropathy due to hATTR worldwide.

ATTR 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. ATTR cardiomyopathy includes both the genetic and wild-type form of the disease. There are an estimated 240,000 patients with ATTR cardiomyopathy 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.

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
 
 
 
 
 

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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WAYLIVRATM (volanesorsen)

ApoCIII

Akcea

Familial Chylomicronemia Syndrome

Generation 2+ antisense drug

Indication*:

Familial Chylomicronemia Syndrome (FCS)

Description/Summary

Volanesorsen is a Generation 2+ antisense drug designed to reduce apoC-III protein production and reduce triglycerides for the treatment of patients with familial chylomicronemia syndrome (FCS) and familial partial lipodystrophy (FPL). 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.

Volanesorsen is currently under regulatory review for marketing authorization in the U.S., EU and Canada for the treatment of FCS, and has been granted priority review in Canada. The U.S. and European regulatory agencies have granted Orphan Drug Designation to volanesorsen for the treatment of patients with FCS. The European regulatory agency has also granted Orphan Drug Designation to volanesorsen for the treatment of FPL.

Clinical Data

In March of 2017, we announced that the pivotal Phase 3 APPROACH study of volanesorsen met its primary endpoint of reducing triglyceride levels in patients with familial chylomicronemia syndrome (FCS). The APPROACH study, a one-year, randomized, placebo-controlled study in 66 patients with FCS (average baseline triglycerides of 2,209 mg/dL) achieved its primary endpoint of reduction in triglycerides at three months, with a 77% mean reduction in triglycerides from baseline, which translated into a 1,712 mg/dL mean absolute triglyceride reduction in volanesorsen-treated patients. Treatment with volanesorsen was associated with a statistically significant reduced rate of on-study pancreatitis attacks in the group of patients who had multiple pancreatitis events during the 5 years prior to screening. In addition, reduced abdominal pain was observed in patients treated with volanesorsen who reported pain during the screening period.

In the study, there were no treatment-related liver adverse events, including no increases in liver fat. There were no treatment-related renal adverse events. The most common adverse event in the volanesorsen-treated group of patients was injection site reactions (ISRs), which were mostly mild. Reductions in platelet counts were observed in many patients and were generally well managed with dose adjustment. Infrequent serious platelet events (grade 4 thrombocytopenia), which resolved without incident following cessation of dosing, were observed in three volanesorsen-treated patients. In the entire volanesorsen clinical program, 294 individuals have been treated with volanesorsen, including 87 FCS patients, some for more than two years.

For more information on the results of the APPROACH study, please see our press release here. For more Information about APPROACH, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

In December of 2016, we announced that the Phase 3 COMPASS study met its primary endpoint. COMPASS was a randomized (2:1), double-blind, placebo-controlled, 26-week Phase 3 study evaluating volanesorsen in 113 patients with severe hypertriglyceridemia. Of the 113 patients enrolled, there was a subset of seven patients with FCS enrolled in the study.

In the COMPASS study, volanesorsen-treated patients (n=75) achieved a statistically significant (p<0.0001) mean reduction in triglycerides of 71.2% from baseline after 13 weeks of treatment, compared with a mean reduction of 0.9% in placebo-treated patients (n=38). In a subset of seven patients with FCS, volanesorsen-treated patients (n=5) achieved a mean reduction in triglycerides of 73% from baseline after 13 weeks of treatment, compared with a mean increase of 70% in placebo-treated patients (n=2). The mean absolute reduction in triglycerides in all volanesorsen-treated patients was 869 mg/dl; in the subset of patients with FCS, the mean absolute reduction in triglycerides was 1,511 mg/dl. The treatment effect observed was sustained through the end of the 26 week treatment period. The majority of patients treated with volanesorsen achieved triglyceride levels less than 750 mg/dL, which is below the risk level for acute pancreatitis. Additionally, there was a lower incidence of pancreatitis in the volanesorsen-treated patients compared to placebo.

The most common adverse event in volanesorsen-treated patients were ISRs, which were mostly mild. There was one potentially related SAE on the drug-treated arm that occurred two weeks after the last study dose and resolved without treatment. In addition, there were no serious platelet events in the study.

For more information on the results of the COMPASS study, please see our press release here. For more Information about COMPASS, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

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 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

Volanesorsen is currently under regulatory review for marketing authorization in the U.S., EU and Canada for the treatment of FCS.

For more information about the regulatory filings for volanesorsen: In the U.S. click here. In the EU click here. In Canada click here.

In November 2015, we initiated a randomized, double-blind, placebo-controlled 12-month, Phase 3 study (BROADEN) evaluating volanesorsen in patients 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. Patients in the BROADEN study are also eligible to roll over into an open-label extension study upon completing dosing in the study. Akcea plans to have data from the pivotal BROADEN study in patients with FPL in 2019.

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 a severe, rare genetic disorder characterized by extremely high levels of triglycerides and the risk of recurrent, potentially fatal pancreatitis. People with FCS are unable to effectively clear large, triglyceride-rich lipid particles called chylomicrons due to a deficiency of lipoprotein lipase, an enzyme that helps to break down triglycerides. FCS is estimated to affect 3,000 to 5,000 patients worldwide. There is no effective therapy available. Additional information on FCS is available at www.fcsfocus.com and through the FCS Foundation at www.livingwithfcs.org and the LPLD Alliance at www.lpldalliance.org.

Partner

Akcea Therapeutics, Ionis' affiliate, is responsible for developing and commercializing volanesorsen. Volanesorsen is part of Akcea's and Ionis' franchise of drugs to treat patients with serious cardiometabolic diseases caused by lipid disorders.

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
 
 
 
 

WAYLIVRATM (volanesorsen)

ApoCIII

Akcea

Familial Partial Lipodystrophy

Generation 2+ antisense drug

Indication*:

Familial Chylomicronemia Syndrome (FCS)

Description/Summary

Volanesorsen is a Generation 2+ antisense drug designed to reduce apoC-III protein production and reduce triglycerides for the treatment of patients with familial chylomicronemia syndrome (FCS) and familial partial lipodystrophy (FPL). 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.

Volanesorsen is currently under regulatory review for marketing authorization in the U.S., EU and Canada for the treatment of FCS, and has been granted priority review in Canada. The U.S. and European regulatory agencies have granted Orphan Drug Designation to volanesorsen for the treatment of patients with FCS. The European regulatory agency has also granted Orphan Drug Designation to volanesorsen for the treatment of FPL.

Clinical Data

In March of 2017, we announced that the pivotal Phase 3 APPROACH study of volanesorsen met its primary endpoint of reducing triglyceride levels in patients with familial chylomicronemia syndrome (FCS). The APPROACH study, a one-year, randomized, placebo-controlled study in 66 patients with FCS (average baseline triglycerides of 2,209 mg/dL) achieved its primary endpoint of reduction in triglycerides at three months, with a 77% mean reduction in triglycerides from baseline, which translated into a 1,712 mg/dL mean absolute triglyceride reduction in volanesorsen-treated patients. Treatment with volanesorsen was associated with a statistically significant reduced rate of on-study pancreatitis attacks in the group of patients who had multiple pancreatitis events during the 5 years prior to screening. In addition, reduced abdominal pain was observed in patients treated with volanesorsen who reported pain during the screening period.

In the study, there were no treatment-related liver adverse events, including no increases in liver fat. There were no treatment-related renal adverse events. The most common adverse event in the volanesorsen-treated group of patients was injection site reactions (ISRs), which were mostly mild. Reductions in platelet counts were observed in many patients and were generally well managed with dose adjustment. Infrequent serious platelet events (grade 4 thrombocytopenia), which resolved without incident following cessation of dosing, were observed in three volanesorsen-treated patients. In the entire volanesorsen clinical program, 294 individuals have been treated with volanesorsen, including 87 FCS patients, some for more than two years.

For more information on the results of the APPROACH study, please see our press release here. For more Information about APPROACH, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

In December of 2016, we announced that the Phase 3 COMPASS study met its primary endpoint. COMPASS was a randomized (2:1), double-blind, placebo-controlled, 26-week Phase 3 study evaluating volanesorsen in 113 patients with severe hypertriglyceridemia. Of the 113 patients enrolled, there was a subset of seven patients with FCS enrolled in the study.

In the COMPASS study, volanesorsen-treated patients (n=75) achieved a statistically significant (p<0.0001) mean reduction in triglycerides of 71.2% from baseline after 13 weeks of treatment, compared with a mean reduction of 0.9% in placebo-treated patients (n=38). In a subset of seven patients with FCS, volanesorsen-treated patients (n=5) achieved a mean reduction in triglycerides of 73% from baseline after 13 weeks of treatment, compared with a mean increase of 70% in placebo-treated patients (n=2). The mean absolute reduction in triglycerides in all volanesorsen-treated patients was 869 mg/dl; in the subset of patients with FCS, the mean absolute reduction in triglycerides was 1,511 mg/dl. The treatment effect observed was sustained through the end of the 26 week treatment period. The majority of patients treated with volanesorsen achieved triglyceride levels less than 750 mg/dL, which is below the risk level for acute pancreatitis. Additionally, there was a lower incidence of pancreatitis in the volanesorsen-treated patients compared to placebo.

The most common adverse event in volanesorsen-treated patients were ISRs, which were mostly mild. There was one potentially related SAE on the drug-treated arm that occurred two weeks after the last study dose and resolved without treatment. In addition, there were no serious platelet events in the study.

For more information on the results of the COMPASS study, please see our press release here. For more Information about COMPASS, click here to go to clinicaltrials.gov or click here to go to the volanesorsen study website.

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 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

Volanesorsen is currently under regulatory review for marketing authorization in the U.S., EU and Canada for the treatment of FCS.

For more information about the regulatory filings for volanesorsen: In the U.S. click here. In the EU click here. In Canada click here.

In November 2015, we initiated a randomized, double-blind, placebo-controlled 12-month, Phase 3 study (BROADEN) evaluating volanesorsen in patients 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. Patients in the BROADEN study are also eligible to roll over into an open-label extension study upon completing dosing in the study. Akcea plans to have data from the pivotal BROADEN study in patients with FPL in 2019.

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

Akcea Therapeutics, Ionis' affiliate, is responsible for developing and commercializing volanesorsen. Volanesorsen is part of Akcea's and Ionis' franchise of drugs to treat patients with serious cardiometabolic diseases caused by lipid disorders.

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
 
 
 

AKCEA-ANGPTL3-LRx

ANGPTL3

Akcea

Rare Hyperlipidemias

Generation 2+ LICA antisense drug

Indication*:

Rare Hyperlipidemias

Description/Summary:

AKCEA-ANGPTL3-LRx is a Generation 2+ ligand conjugated antisense (LICA) drug designed to reduce angiopoietin-like 3 protein, or ANGPTL3. Studies have shown that elevated levels of the ANGPTL3 protein are associated with an increased risk of premature heart attacks, increased arterial wall thickness and multiple metabolic disorders, such as insulin resistance. In contrast, people with lower levels of ANGPTL3 have lower LDL-C and triglyceride levels and thus lower risk of heart attacks and multiple metabolic disorders. We and Akcea are developing AKCEA-ANGPTL3-LRx to treat multiple lipid disorders including rare hyperlipidemias and nonalcoholic fatty liver disease (NAFLD) and metabolic complications as well as rare diseases such as homozygous familial hypercholesterolemia (HoFH) and familial chylomicronemia syndrome (FCS).

Clinical Data

In November 2016, at the American Heart Association Meeting, we and Akcea reported results from the initial cohort from an ongoing Phase 1/2 study of AKCEA-ANGPTL3-LRx in people with elevated triglycerides. We observed that the people with elevated triglycerides achieved dose-dependent, statistically significant mean reductions in ANGPTL3 of up to 83%. Treatment with AKCEA-ANGPTL3-LRx was also associated with statistically significant mean reductions in triglycerides of up to 66%, in LDL-C of up to 35% and in total cholesterol of up to 36%. AKCEA-ANGPTL3-LRx has displayed a favorable safety and tolerability profile in this study.

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

Development Plan

AKCEA-ANGPTL3-LRx is in Akcea's pipeline of novel drugs for the treatment of multiple lipid disorders. Akcea plans to complete the ongoing Phase 1/2 study and then conduct a Phase 2 study of AKCEA-ANGPTL3-LRxin patients with hyperlipidemia with metabolic complications, such as insulin resistance and fatty liver, including patients with nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH). Akcea also plans to conduct a Phase 2 study of AKCEA-ANGPTL3-LRx in patients with rare hyperlipidemias, including patients with FCS.

Current Status

We are conducting a Phase 1/2 study for AKCEA-ANGPTL3-LRx in people with elevated triglycerides.

Study Description

The Phase 1/2 study of AKCEA-ANGPTL3-LRx is a placebo-controlled, dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of AKCEA-ANGPTL3-LRx administered by a subcutaneous injection to people with elevated triglycerides.

About Rare Hyperlipidemias

Rare hyperlipidemias are genetic diseases characterized by high levels of lipids or lipoproteins in the blood. Function or levels of various lipid clearing enzymes, like LPL and hepatic lipase, are decreased in patients with rare hyperlipidemias. These patients may also have a reduced ability to clear other lipids, including LDL, leading to very high lipid levels. Examples of diseases in this category include FCS and familial hypercholesterolemia. Despite existing and emerging therapies, there remains an unmet need to reduce multiple lipid parameters in these patients, including LDL and triglycerides.

Partner

Akcea Therapeutics is responsible for the development and commercialization of AKCEA-ANGPTL3-LRx as part of its lipid franchise.

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
 
 

IONIS-GHR-LRx

GHr

-

Acromegaly

Generation 2+ LICA antisense drug

Indication*:

Acromegaly

Description/Summary

IONIS-GHR-LRx is a LICA Generation 2.0+ antisense drug designed to reduce the production of the growth hormone receptor (GHr) to decrease the circulating level of insulin-like growth factor-1 (IGF-1). IGF-1 is a hormone primarily produced in the liver that plays an important role in childhood growth and has anabolic effects in adults. Several different diseases result from abnormally low or high levels of IGF-1, or an inappropriate response to this hormone. When produced in excess, IGF-1 results in acromegaly, a chronic, slowly progressing and life-threatening disease.

Current Status

IONIS-GHR-LRx is being evaluated in a Phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers.

About GHr and Acromegaly

Acromegaly is a chronic, slowly progressing and life-threatening disease most often caused by oversecretion of growth hormone (GH) by benign pituitary tumors. Elevated levels of GH can overstimulate growth hormone receptors (GHr) and induce excess production of insulin-like growth factor-1 (IGF-1). High levels of circulating GH and IGF-1 lead to this multisystem disease characterized by organ overgrowth and physical disfigurement, such as enlarged hands, feet, and facial features. Patients with acromegaly also experience multiple comorbidities, such as type 2 diabetes, hypertension, and respiratory complications, as well as premature mortality. Because IGF-1 mediates the majority of the growth-promoting action of GH, reducing GHr production could in turn decrease levels of IGF-1 and provide a potential treatment to patients with acromegaly. Current treatments to block IGF-1 include surgical removal of the pituitary gland, which is often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.

Select Publications

  1. Tachas, G. et. al. (2006) A GH receptor antisense oligonuceotide 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 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
 

IONIS-PKK-LRx

PKK

-

Hereditary Angioedema

Generation 2+ LICA antisense drug

Indication*:

Hereditary Angioedema

Description/Summary:

IONIS-PKK-LRx is a Generation 2+ ligand-conjugated antisense (LICA) 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.

Current Status

We are developing IONIS-PKK-LRx as a prophylactic treatment for patients with HAE. IONIS-PKK-LRx is being evaluated in a Phase 1, randomized, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. The Phase 1 study is evaluating single and multiple doses of IONIS-PKK-LRx administered subcutaneously.

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
 

IONIS-TMPRSS6-LRx

TMPRSS6

-

β-Thalassemia

Generation 2+ LICA antisense drug

Indication*:

Beta-thalassemia and Iron Toxicity

Description/Summary:

IONIS-TMPRSS6-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce the production of transmembrane protease, serine 6, or TMPRSS6, to treat anemia and iron toxicity in patients with beta-thalassemia; a disease caused by mutations in the beta globin gene. TMPRSS6 is a protein produced in the liver that plays an important role in the regulation of the body's iron homeostasis through the control of the iron regulatory protein hepcidin. Inhibition of TMPRSS6 leads to increased production of hepcidin, which results in more effective red blood cell production (erythropoiesis) in the bone marrow and reduced iron toxicity in the liver as a result of improved control of iron availability. Results from preclinical and clinical studies suggest that reducing levels of TMPRSS6 may be an effective strategy to control iron availability, improve liver iron toxicity and increase red blood cell production under conditions of beta-thalassemia.

Current Status

The ongoing Phase 1 study, initiated in June, 2017, is a randomized, double-blind, placebo-controlled, dose-escalation study in healthy volunteers evaluating single and multiple doses of IONIS-TMPRSS6-LRx. Plans are in progress to evaluate IONIS-TMPRSS6-LRx in patients with various forms of beta-thalassemia in the future, including, beta-thalassemia intermedia.

About Beta-thalassemia

Beta-thalassemia is an inherited blood disorder caused by a genetic mutation in the beta globin gene resulting in defective red blood cell production. Patients with beta-thalassemia can experience severe anemia, splenomegaly, marrow expansion, bone deformities, as well as iron toxicity. While the severity of anemia varies between patients, iron toxicity is a common complication leading to high rates of mortality as a result of iron accumulation in major organs, such as the heart and liver. Currently there are no effective therapies for patients with beta-thalassemia. The current standard of care is managing patients' symptoms with blood transfusions, hydroxyurea, iron chelation and splenectomy.

Beta-thalassemia can be further subdivided into patients with transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT), such as beta-thalassemia intermedia. Although transfusions are not needed to support life in patients with NTDT, the associated complications of the disease are severe and often fatal.

Selected Publications

  1. Guo, S., et al.(2013) Reducing TMPRSS6 ameliorates hemochromatosis and ?-thalassemia in mice. J Clin Invest. 123(4):1531-41.
  2. Finberg, K. E.(2013) Striking the target in iron overload disorders. J Clin Invest. 123:1424-1427.
  3. Camaschella, C.(2013) Treating Iron Overload. N Engl J Med 2013; 368:2325-2327.
  4. Musallam, K.M., et al.(2013) Non-Transfusion-Dependent Thalassemias. Haematologica. June 2013; 98:833-44.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
Cardiometabolic & Renal

In 2015, cardiovascular disease (CVD) was the number 1 cause of death globally, accounting for 31 percent of deaths that year, according to the World Health Organization. The drugs in our cardiovascular franchise target the key components of CVD, including various atherogenic lipids, inflammation and thrombosis. There is also a significant need for new therapies to treat the millions of people with metabolic disorders. The Centers for Disease Control and Prevention has stated that diabetes affects more than 29 million people in the U.S., or nine percent of the population, with type 2 diabetes constituting 90 to 95 percent of those cases.

A subset of our cardiovascular drugs — ones that address lipid risk factors — are being developed and commercialized by our commercial affiliate, Akcea Therapeutics. We are also developing anticoagulant agent, IONIS-FXIRx, and its LICA follow-on, IONIS-FXI-LRx, in partnership with Bayer.

Drug
Target
Partner
Indication
P1
P2
P3
R
C

AKCEA-ANGPTL3-LRx

ANGPTL3

Akcea

NAFLD/Metabolic Complications

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Complications

Description/Summary:

AKCEA-ANGPTL3-LRx is a Generation 2+ ligand conjugated antisense (LICA) drug designed to reduce angiopoietin-like 3 protein, or ANGPTL3. Studies have shown that elevated levels of the ANGPTL3 protein are associated with an increased risk of premature heart attacks, increased arterial wall thickness and multiple metabolic disorders, such as insulin resistance. In contrast, people with lower levels of ANGPTL3 have lower LDL-C and triglyceride levels and thus lower risk of heart attacks and multiple metabolic disorders. We and Akcea are developing AKCEA-ANGPTL3-LRx to treat multiple lipid disorders including rare hyperlipidemias and NAFLD and metabolic complications as well as rare diseases such as homozygous familial hypercholesterolemia (HoFH) and familial chylomicronemia syndrome (FCS).

Clinical Data

In November 2016, at the American Heart Association Meeting, we and Akcea reported results from the initial cohort from an ongoing Phase 1/2 study of AKCEA-ANGPTL3-LRx in people with elevated triglycerides. We observed that the people with elevated triglycerides achieved dose-dependent, statistically significant mean reductions in ANGPTL3 of up to 83%. Treatment with AKCEA-ANGPTL3-LRx was also associated with statistically significant mean reductions in triglycerides of up to 66%, in LDL-C of up to 35% and in total cholesterol of up to 36%. AKCEA-ANGPTL3-LRx has displayed a favorable safety and tolerability profile in this study.

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

Development Plan

AKCEA-ANGPTL3-LRx is in Akcea's pipeline of novel drugs for the treatment of multiple lipid disorders. Akcea plans to complete the ongoing Phase 1/2 study and then conduct a Phase 2 study of AKCEA-ANGPTL3-LRx in patients with hyperlipidemia with metabolic complications, such as insulin resistance and fatty liver, including patients with nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH). Akcea also plans to conduct a Phase 2 study of AKCEA-ANGPTL3-LRx in patients with rare hyperlipidemias, including patients with FCS.

Current Status

We are conducting a Phase 1/2 study for AKCEA-ANGPTL3-LRx in people with elevated triglycerides.

Study Description

The Phase 1/2 study of AKCEA-ANGPTL3-LRx is a placebo-controlled, dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of AKCEA-ANGPTL3-LRx administered by a subcutaneous injection to people with elevated triglycerides.

Non-Alcoholic Fatty Liver Disease

While some fat in the liver is normal, a significant percentage of individuals have elevated levels of liver fat. Individuals with excessive fat accumulation in the liver also have elevated risk of developing insulin resistance and metabolic syndrome, type 2 diabetes, and cardiovascular disease. These risks are further elevated in patients with hyperlipidemia, especially those with elevated triglyceride levels. The most common form of fatty liver disease is NAFLD, which is associated with obesity-related disorders even in patients who drink little or no alcohol and is characterized by the gradual accumulation of fat in the liver, or steatosis. One of the key causes of this condition is the Western diet, which is rich in processed foods with high fat and sugar content. In the early stages of NAFLD, patients typically experience steatosis that is slow-progressing. Over time, a subset of these patients progress to steatohepatitis, a more severe and progressive form of NAFLD characterized by chronic inflammation and liver-cell damage, called NASH. Over time, the chronic inflammation caused by NASH can lead to the formation of scar tissue in the liver, known as fibrosis. As scar tissue gradually replaces healthy liver tissue, blood flow is restricted, which can lead to the loss of normal liver function, cirrhosis, portal hypertension, liver cancer and ultimately liver failure. Currently, there are no approved treatments specifically for NAFLD or NASH. If the disease ultimately progresses beyond NASH, the only alternative is a liver transplant.

Partner

Akcea Therapeutics is responsible for the development and commercialization of AKCEA-ANGPTL3-LRx as part of its lipid franchise.

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
 
 

AKCEA-APO(a)-LRx

Apo(a)

Akcea/Novartis

CVD

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

CVD

Description/Summary:

AKCEA-APO(a)-LRx is a LICA Generation 2+ antisense drug designed to reduce apolipoprotein(a) in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a), a very atherogenic and thrombogenic form of LDL. Elevated Lp(a) is recognized as an independent, genetic cause of coronary artery disease, heart attack, stroke and peripheral arterial disease. Currently, there is no effective drug therapy to specifically and robustly lower elevated levels of Lp(a). Lp(a) levels are determined at birth and, therefore, lifestyle modification, including diet and exercise, do not impact Lp(a) levels. Even patients who can control their LDL-C remain at high-risk of cardiovascular events if they have high levels of Lp(a).

We and Akcea are developing AKCEA-APO(a)-LRx for patients who are at significant risk of CVD because of their elevated Lp(a). We believe AKCEA-APO(a)-LRx is the first and currently only drug in clinical development designed to selectively and robustly inhibit the production of Lp(a).

Clinical Data

In November 2015, we reported results from a Phase 1/2a study evaluating AKCEA-APO(a)-LRx in subjects with high Lp(a). In this clinical study, we observed significant and sustained reductions in Lp(a) of up to 97 percent with a mean reduction of 79 percent after a single, small volume dose of AKCEA-APO(a)-LRx. With multiple doses of AKCEA-APO(a)-LRx, we observed even greater reductions of Lp(a) of up to 99 percent with a mean reduction of 92 percent. AKCEA-APO(a)-LRx was equally effective regardless of starting Lp(a) levels. The safety and tolerability profile of AKCEA-APO(a)-LRx supports continued development.

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-APO(a)-LRx is in Akcea's pipeline of novel drugs for the treatment of cardiometabolic diseases. Akcea is conducting a Phase 2 dose-ranging study with ACKEA-APO(a)-LRx to choose the optimal dose and dose schedule for the Phase 3 cardiovascular outcome study. At the completion of Phase 2 development, Novartis has an option to license the drug and continue to develop and commercialize AKCEA-APO(a)-LRx. If Novartis exercises its option and pays Akcea $150 million license fee, Novartis plans to conduct a Phase 3 cardiovascular outcome study in a high-risk patient population and will be responsible for the worldwide development and commercialization activities for AKCEA-APO(a)-LRx. Akcea retains the right to co-commercialize AKCEA-APO(a)-LRx through its specialty sales force focused on lipid specialists on terms and conditions to be agreed with Novartis.

Current Status

We and Akcea completed a Phase 1/2a study for AKCEA-APO(a)-LRx in subjects with high Lp(a). In March 2017, Akcea initiated a Phase 2 dose-ranging study with AKCEA-APO(a)-LRx in patients with hypolipoproteinemia(a) and established CVD to determine the dose level and frequency for use in a future cardiovascular outcome study.

Study Description

The Phase 2 dose-ranging study is a randomized, double-blind, placebo-controlled study evaluating AKCEA-APO(a)-LRx in patients with hypolipoproteinemia(a) and established CVD. The goal of the study is to determine the dose level and frequency for use in a future cardiovascular outcome study

About Lp(a)

Lp(a) is a lipoprotein particle assembled in the liver that consists of an LDL-C-like particle and apolipoprotein(a). Lp(a) is considered a key driver for cardiovascular disease due to its association with an increased risk of coronary heart disease. There is evidence that elevated Lp(a) levels may contribute directly to heart attacks. Lp(a) levels in blood can vary greatly between individuals primarily due to genetic variations. 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 reduce Lp(a) to recommended levels in patients who have high Lp(a). 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

AKCEA-APO(a)-LRx is part of our lipid franchise and, as such, our subsidiary, Akcea Therapeutics, is responsible for developing and commercializing AKCEA-APO(a)-LRx. In January 2017, we and Akcea entered into a strategic collaboration with Novartis to co-develop and co-commercialize globally AKCEA-APO(a)-LRx and AKCEA-APOCIII-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
 
 

AKCEA-APOCIII-LRx

ApoCIII

Akcea/Novartis

CVD

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

CVD

Description/Summary:

AKCEA-APOCIII-LRx is a LICA Generation 2+ antisense drug designed to inhibit the production of apoC-III, the same protein inhibited by volanesorsen, for the broad population of patients who are at risk for cardiometabolic disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood. ApoC-III levels and elevated triglycerides have been linked to increased cardiovascular risk. People who have low levels of apoC-III or reduced apoC-III function have lower levels of triglycerides and a lower incidence of CVD. In contrast, people with elevated levels of apoC-III have high triglycerides associated with multiple metabolic abnormalities, such as insulin resistance and metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides.

Clinical Data

In January 2017, we reported single dose data from a Phase 1/2a study evaluating AKCEA-APOCIII-LRx in healthy volunteers. Treatment with single doses of AKCEA-APOCIII-LRx resulted in robust, dose-dependent reductions in apoC-III. The safety and tolerability profile of AKCEA-APOCIII-LRx in the Phase 1/2a study supports continued development.

Development Plan

AKCEA-APOCIII-LRx is in Akcea's pipeline of novel drugs for the treatment of cardiometabolic diseases. Akcea plans to complete the ongoing Phase 1/2a study and then conduct a Phase 2 dose-ranging study to choose the optimal dose and dose schedule for the Phase 3 cardiovascular outcome study. At the completion of Phase 2 development, Novartis has an option to license the drug and continue to develop and commercialize AKCEA-APOCIII-LRx. If Novartis exercises its option and pays Akcea $150 million license fee, Novartis plans to conduct a Phase 3 cardiovascular outcome study in a high-risk patient population and will be responsible for the worldwide development and commercialization activities for AKCEA-APOCIII-LRx. Akcea retains the right to co-commercialize AKCEA-APOCIII-LRx through its specialty sales force focused on lipid specialists on terms and conditions to be agreed with Novartis.

Current Status

Akcea initiated a Phase 1/2a study of AKCEA-APOCIII-LRx in the second half of 2016 in people with elevated triglycerides.

About ApoC-III and Triglycerides

ApoC-III is an important emerging target linking hypertriglyceridemia with cardiovascular disease (CVD). In several studies, apoC-III levels are an independent risk factor for CVD. Further, its presence on lipoproteins may increase their atherogenicity. A study in the New England Journal of Medicine reported that out of a sample of over 100,000 people, individuals with an apoC-III loss-of-function mutation had a reduced risk of clinical coronary heart disease. Each decrease of 1mg/dL in plasma levels of apoC-III was associated with a 4% decrease in the risk of incident coronary heart disease. Triglycerides may also play a role in cardiovascular risk. In two separate studies encompassing nearly 20,000 patients, as triglyceride levels increased, so did the risk of a cardiovascular event. In summary, apoC-III impacts triglyceride levels and may also increase inflammatory processes. This combination of effects makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled.

Partner

AKCEA-APOCIII-LRx is part of our lipid franchise and, as such, our subsidiary, Akcea Therapeutics, is responsible for developing and commercializing AKCEA-APOCIII-LRx. In January 2017, we and Akcea entered into a strategic collaboration with Novartis to co-develop and co-commercialize globally AKCEA-APO(a)-LRx and AKCEA-APOCIII-LRx.

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. 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.
  3. 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.
  4. Kathiresan et al. (2014) Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. N Engl J Med. 371, 22-31.
  5. Scherer, J., Singh, V.P., Pitchumoni, C.S. & Yadav, D. (2014) Issues in hypertriglyceridemic pancreatitis: an update. J. Clin Gastroenterol. 48, 195-203.
  6. 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
 
 

IONIS-GCGRRx

GCGR

-

Diabetes

Generation 2+ antisense drug

Indication*:

Type 2 Diabetes

Description/Summary:

IONIS-GCGRRx is a Generation 2+ 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 January 2017, we reported results from the Phase 2 dose optimization study evaluating IONIS-GCGRRx in 79 patients with type 2 diabetes uncontrolled on stable, maximal metformin therapy. In this study, patients treated with IONIS-GCGRRx achieved robust and sustained, statistically significant improvements in hemoglobin A1c (HbA1c) and other measures of glucose control after 26 weeks of treatment. Patients treated with 50 mg and 75 mg weekly doses achieved mean reductions in HbA1c of 0.7 percentage points (p < 0.05) and 1.4 percentage points (p < 0.001) from baseline, respectively, compared to a reduction of 0.1 percentage points for placebo-treated patients, in an intent to treat (ITT) analysis. IONIS-GCGRRx-treated patients experienced a mean increase in total GLP-1 from baseline compared to a decline in placebo-treated patients. IONIS-GCGRRx was generally safe and well tolerated in the study.

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

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 100mg and 200mg weekly doses of 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 have completed two Phase 2 studies with IONIS-GCGRRx: 1) a 13-week study in patients with type 2 diabetes who are poorly controlled on stable metformin therapy and 2) a 26-week study to identify the optimal dose and schedule to achieve glucose control with manageable glucagon receptor-related liver enzyme elevations.

We are now evaluating partnership opportunities for IONIS-GCGRRx.

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-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, 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 blood clot formation inside blood vessels (thrombosis), which can cause heart attacks and strokes. Alternatively, individuals deficient in Factor XI have a lower incidence of thrombosis-related events and little to no increase in bleeding risk. This makes Factor XI an attractive target for an antithrombotic drug because of the potential to separate antithrombotic activity from bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, these anticoagulants are associated with increased bleeding risk at therapeutic doses, which can lead to major, sometimes fatal bleeding events. In clinical studies, IONIS-FXIRx has demonstrated dose-dependent inhibition of Factor XI activity, which was associated with significant reductions in clotting events and no increase in major bleeding events. These data coupled with data in humans with little to no Factor XI activity provide evidence that IONIS-FXIRx has the potential to be used broadly as an anti-thrombotic in different therapeutic settings for which additional safe and well tolerated anti-thrombotic drugs are needed, especially in patient populations that are at high risk for thrombosis and are also at high risk for bleeding.

Clinical Data

In November 2016, we announced positive data from a Phase 2 placebo-controlled study evaluating IONIS-FXIRx in patients with end-stage renal disease (ESRD) on hemodialysis. In this Phase 2 study patients treated with IONIS-FXIRx achieved statistically significant, dose-dependent reductions in Factor XI activity. In patients treated with 200 mg and 300 mg of IONIS-FXIRx, a mean percent reduction in FXI activity of 56% (p=<0.001) and 71% (p=<0.001), respectively, was achieved at week 13, compared to a mean percent reduction of 4% for placebo-treated patients. Furthermore, a decrease in severe clots in the dialysis circuit after six weeks compared to baseline was observed. IONIS-FXIRx displayed a favorable safety and tolerability profile in this study. There were no clinically meaningful reductions in platelet levels and no treatment-related major or clinically relevant non-major bleeding events.

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

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

We are currently preparing to conduct a Phase 2b study evaluating IONIS-FXIRx in approximately 200 patients with ESRD on hemodialysis to finalize dose selection. At the conclusion of this study, our partner, Bayer, will be responsible for all subsequent global clinical development activities as well as worldwide regulatory and commercialization activities for IONIS-FXIRx.

For more Information about the current status of this program, please see our press release, here

About Thrombosis

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, Factor Xa inhibitors and thrombin inhibitors. Although these drugs are effective at lowering the risk of thrombosis, these drugs place patients at significant risk of serious bleeding because they target factors required for normal coagulation.

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 February 2017, we announced the advancement of IONIS-FXIRx in clinical development under an existing exclusive agreement with Bayer. Under this agreement, Ionis will also initiate development of the LICA drug, IONIS-FXI-LRx. In conjunction with Bayer's decision to advance these programs, Ionis received a $75 million payment from Bayer.

For more information about our partnership with Bayer for our FXI program, please see our press release here.

Selected Publications

  1. Buller, 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. Lowenberg, 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-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 November 2016, we announced the completion of a randomized, placebo-controlled, dose-escalation Phase 1 study of IONIS-DGAT2Rx in healthy overweight volunteers (body mass index between 29 and 38 kg/m2). NASH is most commonly found in persons who are overweight or obese. This study in overweight subjects was designed to give us valuable insights on the effects of IONIS-DGAT2Rx in a patient population who are closely matched to patients with NASH. In this study, volunteers received doses of up to 300 mg/week, administered for 6 weeks. The safety and tolerability profile of IONIS-DGAT2Rx as demonstrated in this study supports continued development.

We are currently evaluating IONIS-DGAT2Rx in a Phase 2 randomized, placebo-controlled, dose-escalation study in patients with type 2 diabetes and NAFLD.

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
 
 

IONIS-AGT-LRX

AGT

-

Treatment-Resistant Hypertension

Gen. 2.0+ LICA-conjugated antisense drug

Indication*:

Treatment Resistant Hypertension

Description/Summary:

IONIS-AGT-LRx is a LICA Generation 2+ antisense drug designed to reduce the production of angiotensinogen to decrease blood pressure in patients with treatment resistant hypertension (TRH). Despite availability of generic antihypertensive agents, TRH is a major contributor to cardiovascular and renal disease.

Inhibiting the renin-angiotensin-aldosterone system (RAAS) is a well-established method of treating hypertension and complications of hypertension. While angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely used, many patients with high blood pressure are not well controlled by these treatment options. Angiotensinogen, the target of IONIS-AGT-LRx, is upstream of ACE inhibitors and ARBs in the RAAS pathway. Therefore, reducing angiotensinogen levels has the potential to decrease blood pressure in patients whose blood pressure is not adequately controlled by currently available treatment options. Furthermore, inhibiting angiotensinogen, which is made in the liver, may maintain renal compensatory mechanisms, which could lead to fewer side effects compared to current standard of care.

Current Status

In March 2017, we initiated a Phase 1 study of IONIS-AGT-LRx in healthy volunteers and hypertensive patients with blood pressure controlled on ACE inhibitors or ARBs.

About Treatment Resistant Hypertension (TRH)

Approximately 70 million adults in the United States have hypertension, half of which have uncontrolled hypertension. About 12-15 percent of patients with uncontrolled hypertension have resistant hypertension, defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. Current estimates approximate that there are up to three million patients with TRH in the U.S. Patients with TRH have been found to have 3-fold increased odds of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.

Selected Publications

  1. Williams, B. (2016) Drug discovery in renin-angiotensin system intervention: Past and future. Ther Adv Cardiovasc Dis. ;10:118-125.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described Back to top
 

IONIS-AZ4-2.5-LRx

Undisclosed

AstraZeneca

Cardiovascular Disease

Generation 2.5 LICA antisense drug

Indication*:

Cardiovascular Disease

Description/Summary

IONIS-AZ4-2.5-LRx, also referred to as AZD8233, is a Generation 2.5 LICA antisense drug designed to inhibit an undisclosed target to treat cardiovascular disease.

Current Status

AstraZeneca is evaluating IONIS-AZ4-2.5-LRx in a Phase 1, randomized, single-blind, placebo-controlled study in healthy male subjects with elevated LDL-C levels. This study will assess the safety, tolerability and pharmacokinetics, following subcutaneous administration of single ascending dose of IONIS-AZ4-2.5-LRx. This study will also investigate the pharmacodynamics of IONIS-AZ4-2.5-LRx by investigating the effect of IONIS-AZ4-2.5-LRx on levels of cholesterol and related biomarkers.

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

Partner

IONIS-AZ4-2.5-LRx is a development candidate identified under a collaboration agreement with AstraZeneca to discover and develop antisense drugs for cardiovascular, renal and metabolic diseases. In December 2016, we received $25 million from AstraZeneca when we advanced IONIS-AZ4-2.5-LRx into preclinical development and AstraZeneca exercised its option to license IONIS-AZ4-2.5-LRx. AstraZeneca is responsible for all global development, regulatory and commercialization activities for IONIS-AZ4-2.5-LRx. In addition, we are eligible to receive up to $300 million in additional development and regulatory milestone payments, as well as tiered, low double-digit royalties from sales of the drug.

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

IONIS-FXI-LRx

Factor XI

Bayer

Clotting Disorders

 
Cancer

Cancer is a complex disease involving many targets. Using our antisense technology, we can validate and rapidly identify anti-cancer drugs, which allow us to preferentially 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. We have partnered with AstraZeneca to develop and, if successful, commercialize two anti-cancer drugs: IONIS-STAT3-2.5Rx and IONIS-KRAS-2.5Rx. AstraZeneca brings significant experience that enables the identification of novel genetic and epigenetic targets for cancer. We also have a collaboration agreement with University of Texas MD Anderson Cancer Center to identify cancer targets and create novel antisense drugs to treat people with cancer.

Drug
Target
Partner
Indication
P1
P2
P3
R
C

IONIS-AR-2.5Rx

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.

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
 
 

Danvatirsen
(IONIS-STAT3-2.5Rx)

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 September 2017, at the European Society for Medical Oncology (ESMO) Annual Congress, AstraZeneca presented results from a Phase 1b/2 study of IONIS-STAT3-2.5Rxin combination with Imfinzi (durvalumab), a programmed death ligand (PD-L1) blocking antibody, in patients with advanced solid tumors and recurrent metastatic head and neck cancer. The treatment combination demonstrated a 29% (8/28) objective response rate with four partial responses (PR) and four complete responses (CR), of which one was a CR in target lesions only. An additional eight patients on the treatment combination had stable disease (SD) at 12 weeks, resulting in an overall disease control rate of 57% (16/28). Complete response was seen in a patient with R/M-SCCHN that was refractory to previous PD-L1 treatment.

IONIS-STAT3-2.5Rx in combination with Imfinzi demonstrated a manageable safety profile. The most common drug-related adverse events occurred infrequently and were similar to those observed with other drugs targeting the JAK/STAT pathway, including mild liver enzyme increases, mild platelet count decreases and mild anemia.

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

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

AstraZeneca is evaluating IONIS-STAT3-2.5Rx in combination with MEDI4736, AstraZeneca's investigational anti-PD-L1 drug, in two studies, in patients with head and neck cancer and 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
 
 

IONIS-KRAS-2.5Rx
(AZD4785)

KRAS

AstraZeneca

Cancer

Generation 2.5 antisense drug

Indication*:

Cancer

Description/Summary

IONIS-KRAS-2.5Rx, also referred to as AZD4785, is a Generation 2.5 antisense drug designed to selectively inhibit KRAS, one of the most frequently mutated genes in cancer. KRAS mutations are thought to underlie the pathogenesis of up to 30% of human tumors. The KRAS protein is involved in regulating cell division and tumor cell survival.

Current Status

AstraZeneca is evaluating IONIS-KRAS-2.5Rx in a Phase 1/2, open-label, multicenter, dose-escalation study in patients with advanced solid tumors for whom KRAS may be an important driver of tumor survival.

About KRAS and Cancer

KRAS, one of the most frequently mutated genes in cancer, is thought to underlie the pathogenesis of up to 30% of human tumors. The KRAS protein is involved in regulating cell division and tumor cell survival. Developing therapeutics using traditional drug modalities to block KRAS activity has proven difficult. Antisense technology may provide a novel solution for such difficult targets because antisense drugs can be designed to selectively inhibit the RNA sequence for a target with high specificity.

Partner

IONIS-KRAS-2.5Rx is a development candidate identified under a collaboration agreement with AstraZeneca to discover and develop antisense drugs for cancer. In December 2016, we received $28 million from AstraZeneca when we advanced IONIS-KRAS-2.5Rx into development and AstraZeneca licensed IONIS-KRAS-2.5Rx. AstraZeneca is responsible for global development, regulatory and commercialization activities for IONIS-KRAS-2.5Rx. In addition, we are eligible to receive up to $137 million in additional development and regulatory milestone payments and up to low double-digit royalties from sales of the drug.

Select Publications

  1. Ross, S. et. al. (2015) Targeting KRAS dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci. Transl. Med. Published online June 14, 2017.
  2. Hong, D. et. al. (2015) AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl. Med. 7: 185-197.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described. Back to top
 
 
Other

By exploiting the broad applicability of our antisense technology, we can develop novel drugs designed to treat many diseases outside of our core areas of development such as IONIS-FB-LRx for complement-mediated diseases, and the antiviral drugs we are developing with GSK.

Drug
Target
Partner
Indication
P1
P2
P3
R
C

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

In March 2017, our partner GSK initiated a Phase 2 study of IONIS-HBVRx in treatment-naive patients with chronic HBV infection. We have completed a Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of single and multiple doses of IONIS-HBVRx in healthy volunteers. The safety and tolerability profile of IONIS-HBVRx demonstrated in this study supports continued development.

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 collaboration that provides GSK an option to develop and commercialize IONIS-HBVRx. 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 May 2017, we announced that our partner GSK initiated a Phase 2 study of IONIS-HBV-LRx in patients with chronic HBV infection. We have completed a Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of single and multiple doses of IONIS-HBV-LRx in healthy volunteers. The safety and tolerability profile of IONIS-HBV-LRx demonstrated in this study supports continued development.

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 the development of IONIS-HBV-LRx to the collaboration we 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
 
 

IONIS-FB-LRx

Complement Factor B

-

Complement-Mediated Diseases

Generation 2+ LICA antisense drug

Indication*:

Complement-Mediated Diseases, including Dry Age-related Macular Degeneration (AMD)

Description/Summary

IONIS-FB-LRx is a Generation 2+ ligand conjugated antisense (LICA) drug designed to reduce the production of complement factor B (FB). FB is produced predominantly in the liver and circulates at high levels throughout the vascular system where it plays a pivotal role in an innate immunogenic cascade. Genetic association studies have shown that overaction of this cascade has been associated with the development of several complement-mediated diseases, including dry age-related macular degeneration (AMD). FB, which plays a pivotal role in this cascade, is produced predominately in the liver and circulates at high levels throughout the vascular system, including in capillaries in the eye. 1-5

Clinical Data

In May 2017, we presented results from a randomized, placebo-controlled, dose-escalation Phase 1 study evaluating IONIS-FB-LRx in 54 healthy volunteers. Healthy volunteers treated with a single dose of IONIS-FB-LRx achieved dose-dependent reductions in plasma FB of up to a 50%. Treatment with multiple doses of IONIS-FB-LRx during a six-week period resulted in greater reductions in circulating FB levels. The safety and tolerability profile of IONIS-FB-LRx supports further clinical development.

Current Status

We have completed a Phase 1 study evaluating IONIS-FB-LRx in healthy volunteers. We are currently preparing to initiate a Phase 2 study in patients with dry AMD.

About AMD

AMD is the leading cause of central vision loss in developed countries. It is estimated that more than three million people in the United States will be affected by the disease by 2020.6 AMD is believed to be a systemic disease with local disease manifestation at the aging retinal macula. AMD gradually destroys vision in the center of the visual field due to progressive damage of the retina.7

Partner

In August 2017, GSK declined its option to license IONIS-FB-LRx as part of a reprioritization of its pipeline and strategic review of its Rare Diseases business.

For more information about this announcement, please see our press release here.

Select Publications

  1. Ricklin D and Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007; 25(11): 1265-1275.
  2. Silva AS, Teixeira AG, Bavia L, Lin F, Velletri R, Belfort Jr R, Isaac L. Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of Complement Factor H Tyr402His polymorphism. Mol Vision 2012; 18: 2288-2299. Koskimies et al. Complement In_amm. 1991;8(5-6):257-60.
  3. Grossman et al. Reduction in Ocular Complement Factor B Protein in Mice and Monkeys by Systemic Administration of Factor B Antisense Oligonucleotide. IOVS. 2016; 57:5000.
  4. Loyet et al. Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. IOVS 2012; 53(10): 6628-6637.
  5. Gold et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genetics. 2006; 38:458-462.
  6. Friedman et al. Eye diseases prevalence research group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564-572.
  7. Sunness et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999; 106: 1768-1779.
* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.Back to top
 
 

IONIS-JBI1-2.5Rx

Undisclosed

Janssen

GI Autoimmune Disease