Generation 2⁺ antisense drug

ION716 is an antisense oligonucleotide (ASO) targeting prion protein (PrP) messenger ribonucleic acid (mRNA). ION716 is designed to inhibit the production of cellular PrP protein (PrPC) and is being developed as a potential therapy for Prion diseases. ASO-mediated reduction of PrPC has the potential to ameliorate, prevent, or even reverse Prion diseases.

About Prion Diseases

Prion disease is a fatal, incurable neurodegenerative disease that typically presents as a rapidly progressive dementia. Regardless of etiology – sporadic, genetic, or acquired, and regardless of clinical name – Creutzfeldt-Jakob disease, fatal familial insomina, or Gerstmann-Straussler-Scheinker syndrome, all prion diseases are caused by conformational change of PrP from its native fold to a self-propagating misfolded form (PrPSc), which is an abnormal, pathogenic agent that causes brain damage.

Generation 2⁺ antisense drug

ION581 is an antisense oligonucleotide (ASO) that targets Ubiquitin Protein Ligase E3A-Antisense Transcript (UBE3A-ATS), which is a long non-coding ribonucleic acid (lncRNA). ION581 reduces the levels of UBE3A-ATS and is being developed as a potential therapy for Angelman Syndrome (AS). Angelman Syndrome is caused by maternal deficiency of the Ubiquitin Protein Ligase E3A (UBE3A). The paternal copy of the UBE3A gene is usually intact but is silenced by the UBE3A-ATS. It has been shown in iPSC neurons derived from AS patients and in an AS mouse model that ASO-mediated suppression of UBE3A-ATS results in UBE3A unsilencing and robust expression from the paternal allele. ASO-mediated up-regulation of UBE3A mRNA has the potential to restore the levels of UBE3A protein in neurons in patients with AS.

About Angelman syndrome

Angelman syndrome is a rare neurogenetic disorder caused by the loss of function of the maternally inherited UBE3A gene and affects approximately 1 in 15,000 individuals. Angelman syndrome presents early in life with profound and severe developmental delays in motor, language and cognitive functioning, seizures and ataxia. It is a non-degenerative, life-long disorder that generally remains clinically unchanged, resulting in complete dependence on a caregiver throughout their life. Some symptoms can be managed with existing drugs; however, there is no disease modifying therapy.

Generation 2⁺ antisense drug

Generation 2⁺ antisense drug

ION283 is an antisense drug designed to reduce the accumulation of glycogen by inhibiting the production of brain glycogen synthase type 1 (GYS1), the enzyme that makes glycogen in the brain. Mutations that are the genetic cause of Lafora disease (LD) result in the accumulation of excess glycogen and result in the formation of Lafora Bodies in the brain and spinal cord, which results in neurodegeneration.  In animal models of LD, reduction of GYS1 reduced glycogen accumulation and prevented the formation of Lafora Bodies and neurodegeneration.

About Lafora Disease

Lafora disease (LD) is an inherited and very severe epilepsy syndrome.  Although children are born with LD, the disease does not manifest itself until adolescence when seizures begin.

LD is characterized by a progressive increase in intensity of seizures, a rapid cognitive decline (dementia) and motor incoordination (ataxia).  Patients who suffer from this devastating disease have difficulty walking, speaking and eating and will eventually become wheelchair bound, and lose the ability to speak and feed themselves.  Lafora patients typically die within 10 years.

LD is autosomal recessive disease caused by mutations in the laforin or malin genes. The underlying pathology is the result of glycogen accumulation in neurons and glial cells that form toxic Lafora Bodies. Currently, there is no disease-modifying therapy and seizures are poorly managed with anti-epileptic drugs.

Generation 2⁺ antisense drug

ION373 is an antisense oligonucleotide (ASO) targeting glial fibrillary acidic protein (GFAP) messenger ribonucleic acid (mRNA). ION373 is designed to inhibit the production of GFAP and is being developed as a potential therapy for Alexander disease (AxD). Nearly all cases of AxD are caused by gain-of-function mutations in GFAP that lead to spontaneous overproduction and toxic accumulation of GFAP into abnormal protein deposits called Rosenthal fibers in the brain. ASO-mediated reduction of GFAP has the potential to ameliorate the underlying cause of disease pathology and reverse or prevent disease progression.

About Alexander disease

Alexander disease (AxD) is a rare neurological condition characterized as a leukodystrophy, or a disease affecting the myelin sheath (the fatty insulation that protects a nerve fiber and supports signal conduction). Two major types of AxD have been defined. Type I onset typically occurs before 4 years of age and patients can experience head enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of 4 and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most often fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.

Clinical trials Posting

Not yet posted

Generation 2⁺ antisense drug

ION464, formerly known as IONIS-BIIB6_Rx.

Generation 2⁺ antisense drug

ION541, formerly known as IONIS-BIIB8_Rx.

Generation 2.5 antisense drug

Generation 2.5 LICA antisense drug

Generation 2.5 LICA antisense drug

Generation 2⁺ LICA antisense drug

IONIS-DGAT2_Rx 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.

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.

Generation 2.5 antisense drug

Generation 2.5 antisense drug

Generation 2.5 antisense drug

ION251, formerly known as IONIS-IRF4-2.5_Rx.

Interferon Regulatory Factor 4 (IRF4) is a transcription factor expressed in lymphocytes, where it directs terminal differentiation of B-cells to plasma cells and also has roles in T cell functions such as T cell exhaustion. IRF4 has emerged as a key regulator of multiple genes controlling the survival of multiple myeloma (MM) tumor cells as well as other B-cell malignancies. IRF4 is overexpressed in MM as a result of several mechanisms including activating mutations in the DNA binding domain and translocations. Even limited depletion of IRF4 leads to rapid cell death of MM tumor cells, and as such MM is considered to be “addicted” to IRF4. Taken together, selective inhibition of IRF4 with a therapeutic antisense oligonucleotides (ASO) is an attractive strategy for the treatment of MM with the potential for potent MM cell kill with limited effects on normal cells.​

About Multiple Myeloma

Multiple Myeloma (MM) is an incurable cancer characterized by uncontrolled proliferation of bone marrow plasma cells. Despite their initial responses to current therapies, almost all MM patients eventually relapse with a median overall survival time of 13 months following relapse, presenting a strong need for new treatments. Interferon Regulatory Factor 4 (IRF4) is a transcription factor involved in immune cell development and is essential for plasma cell differentiation. IRF4 has emerged as a key regulator of multiple genes controlling the survival of MM and other B-cell malignancy such as c-Myc and is aberrantly expressed in MM as a result of activating mutations and translocations.

Generation 2.5 antisense drug

ION674, formerly known as IONIS-EZH2-2.5_Rx, is an epigenetic modulator as the catalytic subunit of the polycomb repressive complex 2 (PRC2). It functions as a histone methyltransferase which catalyzes the mono- through tri-methylation of lysine 27 residue of histone 3 (H3K27me3) and suppresses the transcription of specific genes. It is involved in early embryogenesis, self-renewal and proliferation of embryo and adult stem cells. Increased expression or activity of EZH2 has been reported in multiple solid tumors as well as hematological malignancies, which associates with poor prognosis. Aberrant expression of EZH2 can be caused by multiple mechanisms in a variety of cancer types. For example, activating mutations leading to enhanced catalytic activity of EZH2 are found in certain types of B-cell lymphoma including GCB-DLBCL and follicular lymphoma. There is also evidence that solid tumors with a loss of function in tumor suppressor genes such as SWI/SNF complex, BAP1, and UTX are highly dependent on EZH2 for their growth. Finally, EZH2 can promote tumor growth by creating immune-suppressive tumor microenvironment such as T cell exhaustion. Collectively, selective depletion of EZH2 by ASO is expected to be highly efficacious in treating tumors with aberrant expression of EZH2.

GCB-DLBCL and Follicular Lymphoma

GCB-DLBCL and follicular lymphoma belong to B-cell non-Hodgkin lymphoma (NHL), a lymphoproliferative disorder originating in B lymphocytes. Even though the initial response rate to the standard of care treatment composed of chemotherapy in combination with anti-CD20 antibody (R-CHOP) is relatively good, the disease either relapses or becomes refractory to the therapy. Heterozygous somatic mutations leading to increased EZH2 activity have been found in approximately 20% of patients with GCB-DLBCL and follicular lymphoma, where EZH2 plays an important role in promoting tumor growth, suggesting that these tumor types might be sensitive to antisense inhibition by EZH2 production.

Generation 2.5 antisense drug

ION736, formerly known as IONIS-AZ7-2.5_Rx.

Generation 2.5 antisense drug

ION253, formerly known as IONIS-JBI2-2.5_Rx.