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Antisense oligonucleotides are essentially short, single-stranded synthetic fragments of DNA or RNA that bind specifically to the target RNA sequence inside cells and modulate protein expression through several different mechanisms, blocking the ability of the RNA to make a protein or function in other ways. In recent years, these drugs have gained popularity among drug developers, as they are a highly specific, targeted treatment that can treat a wide range of diseases. In this article, we take a look at six antisense oligonucleotide companies leading the way in this emerging field.
Table of contents
Ionis Pharmaceuticals
- Pipeline consists of more than 40 antisense drugs
- Partnership with AstraZeneca for drug development across several indications
- Priced a $500 million IPO in September 2024
As the first company to ever have an antisense oligonucleotide drug approved by the U.S. Food and Drug Administration (FDA), Ionis Pharmaceuticals is now seen as a pioneer in the field. Its drug, called fomivirsen, was given the green light in 1998 to treat cytomegalovirus (CMV) retinitis – a serious infection of the retina that can lead to blindness – in immunocompromised patients with AIDS.
Historically, Ionis worked with other biotech companies as a partner to deliver medicines to patients who needed them. But, in 2020, it made the decision to shift to directly serving patients by launching its products independently as a fully integrated biotech company. Now, the company has an antisense pipeline of more than 40 drugs designed to treat a broad range of diseases spanning various therapeutic indications. It currently has three ongoing phase 3 programs in neurology, four in cardiology, and one in specialty and rare diseases, as well as two phase 3 programs listed under the bracket of “other medicines” – one of these is for hepatitis B virus infection and the other is for complement factor B IgA nephropathy.
The antisense oligonucleotide company has also formed extensive partnerships over the years, including with AstraZeneca for the development of several of its drugs for indications such as nonalcoholic steatohepatitis (NASH), amyloid transthyretin cardiomyopathy (ATTR-CM), and amyloid transthyretin polyneuropathy (ATTR-PN).
Furthermore, in September 2024, Ionis announced the pricing of a $500 million initial public offering (IPO) and said that it intended to use the proceeds from this to fund its independent commercial launches, late-stage clinical programs, earlier pipeline programs, and research and development activities, as well as for working capital and general corporate purposes.
Isarna Therapeutics
- Drug target: TGF-β, which plays an important role in key biological processes
- Lead antisense candidate: ISTH0036, for ophthalmic conditions
- ISTH0036 being tested in phase 2 trial for wet AMD and DME
Isarna Therapeutics is developing a portfolio of antisense oligonucleotide therapies targeting an emerging therapeutic field in human biology: transforming growth factor beta (TGF-β) signaling. TGF-β plays an important role in key biological processes such as cell proliferation, cell differentiation, immune response, and tissue modeling. Due to the fact that TGF-β is chronically elevated in many diseases, including ophthalmic and fibrotic diseases and cancer, and involved in their pathophysiology, it is thought to be an extremely versatile drug target throughout the body.
Isarna’s lead candidate, called ISTH0036, is currently being tested in a phase 2 study for wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME) – both ophthalmic indications that cause major problems with people’s vision. According to the antisense oligonucleotide company, in ophthalmology, certain gene variants affecting the TGF-β pathway potentially lead to a higher risk of patients suffering from more severe forms of AMD during their lifetime, which suggests that TGF-β might contribute to disease progression.
To date, the phase 2 trial for ISTH0036 has reported a good safety profile and efficacy for the candidate. The morphological data, analyzed using the artificial intelligence (AI)-powered discovery platform from RetinAI, which Isarna has an ongoing collaboration with, showed the prevention of fibrosis and epithelial-mesenchymal transition together with a drying effect as a key differentiator to currently approved anti-angiogenic therapies.
Regulus Therapeutics
- Developing antisense oligonucleotides to target microRNAs
- Lead candidate: RGLS8429, for autosomal dominant polycystic kidney disease (ADPKD)
- Regulus raised $100 million in private placement in March 2024
Regulus Therapeutics is developing antisense oligonucleotide drugs designed to target microRNAs, which are essentially small, naturally occurring, non-coding RNAs that function as important regulators of gene expression of messenger RNA (mRNA) and play a role in multiple cellular processes. MicroRNA expression or function is significantly altered in numerous diseases including cancer and fibrosis, as well as in central nervous system (CNS), metabolic, and inflammatory disorders. Regulus is currently focused on treating genetic kidney diseases, centering specifically on orphan kidney diseases with high unmet needs.
The company’s lead candidate is called RGLS8429 and is currently being evaluated in a phase 1b trial for the treatment of autosomal dominant polycystic kidney disease (ADPKD) – a life-threatening condition that causes fluid-filled cysts to develop and enlarge in both kidneys, eventually leading to kidney failure. ADPKD is caused by a mutation in either the Pkd1 or Pkd2 genes, which are associated with an increase in the expression of a specific microRNA called miR-17. Therefore, RGLS8429 is designed to inhibit miR-17 and to preferentially target the kidney.
Administration of RGLS8429 has shown clear improvements in kidney function, size, and other measures of disease severity in preclinical models, as well as in a phase 1 trial that was completed in 2022. Moreover, Regulus recently announced positive topline data from multiple cohorts of patients in its phase 1b trial of the drug candidate. At the time of the announcement, Jay Hagan, chief executive officer (CEO) of Regulus, said that the company anticipates requesting an end-of-phase 1 meeting with the FDA in the fourth quarter of this year.
The antisense oligonucleotide company also received a big cash injection in March 2024 after a $100 million private placement.
Sarepta Therapeutics
- PPMO therapies based around PMOs, a class of antisense oligonucleotides
- Three approved PPMO therapies for DMD: Exondys 51; Vyondys 53; Amondys 45
- Most recent collaboration: $1 billion-plus deal with Arrowhead Pharmaceuticals
Sarepta Therapeutics has a pipeline of programs in various stages of development across three technologies – RNA, gene therapy, and gene editing – and multiple therapeutic areas, including neuromuscular, CNS, and cardiology. Currently, Sarepta has one gene therapy and three RNA-based therapies on the market in the U.S.
The company’s RNA platform is based around phosphorodiamidate morpholino oligomers (PMOs), which are a class of synthetic antisense oligonucleotides modeled after the natural framework of RNA that are especially stable, highly soluble, and non-toxic. Sarepta’s proprietary next-generation PMO-based therapies are known as peptide phosphorodiamidate morpholino oligomers (PPMOs) and are specifically designed to increase tissue penetration compared with PMOs.
Sarepta already has three approved PPMO therapies for the treatment of Duchenne muscular dystrophy (DMD): Exondys 51, Vyondys 53, and Amondys 45. All of these treatments concentrate on exon-skipping; DMD is caused by a genetic mutation in the dystrophin gene and, most commonly, one or more exons (parts of the gene) are missing, causing errors in the instructions for making dystrophin. This results in the body not being able to produce enough – or any – working dystrophin protein. But, by hiding certain exons, Sarepta are able to “skip” their location to link with an exon with the right connector. This would allow for the production of a shortened and potentially functional dystrophin protein.
Sarepta has inked several partnerships over the years. For example, it announced a collaboration in 2019 with Roche, which obtained the exclusive right to launch and commercialize Sarepta’s gene therapy SRP-9001 outside the U.S. And, just this week, Sarepta announced a $1 billion-plus global license and collaboration deal with Arrowhead Pharmaceuticals for multiple preclinical and clinical programs.
Secarna Pharmaceuticals
- Lead preclinical program: SECN-15, for oncology indications
- SECN-15 targets NRP1, which is involved in various tumor-promoting functions
- Secarna has formed several collaborations, most recently with Orbit Discovery
Secarna Pharmaceuticals is focusing its efforts on developing antisense oligonucleotides in the fields of immuno-oncology, inflammatory, fibrotic, and cardiometabolic diseases, as well as CNS disorders. It currently has a pipeline of both partnered and proprietary antisense oligonucleotide candidates in preclinical and clinical development.
The antisense oligonucleotide company’s proprietary lead program is called SECN-15, which is currently progressing toward Investigational New Drug (IND)-enabling studies. Intended for use in oncology, SECN-15 works by targeting Neuropilin 1 (NRP1), a protein that is involved in various tumor-promoting functions such as angiogenesis, suppression of effector immune responses, cancer cell migration, and metastasis. In particular, NRP1 contributes to the suppressive capacity of tumor-associated macrophages and regulatory T cells – both cell types that can be efficiently targeted with antisense oligonucleotides. According to Secarna, SECN-15 has the potential to break resistance to checkpoint therapy in cancer patients and is promising in a range of solid tumors.
The company also has several collaborations with other companies. For example, in 2020, it partnered with Denali Therapeutics to develop novel antisense therapies in the field of neurodegenerative diseases, from which it is able to leverage Denali’s blood-brain barrier technology, and it formed a collaboration with Evotec for the development of novel antisense therapies across a broad range of diseases. Plus, more recently, in May 2024, Secarna entered into a partnership with Orbit Discovery to discover and develop peptide-conjugated targeted antisense oligonucleotides.
Wave Life Sciences
- Lead antisense program: WVE-003, for Huntington’s disease
- WVE-003: Being tested in phase 1b/2a trial; positive results recently reported
- Wave has formed partnerships with GSK and Takeda
RNA editing company Wave Life Sciences is developing antisense oligonucleotide therapies across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization, and production of oligonucleotides, which are designed to engage mRNA strands inside human cells to repair, restore, or reduce proteins to treat diseases.
As well as Wave’s lead RNA editing candidate, which recently became the first-ever RNA editing candidate to be tested in clinical trials, Wave Life Sciences also has an antisense oligonucleotide candidate called WVE-003 being tested in a phase 1b/2a trial for Huntington’s disease, an indication for which there is a high unmet need for effective therapies. Wave’s allele-selective antisense drug is designed to lower mutant huntingtin (mHTT) protein and preserve healthy, wild-type huntingtin (wtHTT) protein. In June 2024, Wave reported positive results from the trial, as it demonstrated an mHTT lowering of 46% with preservation of wtHTT.
Wave has formed multiple partnerships over the last few years, including one with GSK for its RNA editing candidate. The initiation of the trial for WVE-006 saw Wave achieve its first milestone in its collaboration with GSK, which resulted in a $20 million payment to the RNA editing company. The company also had a collaboration with Takeda for the development of WVE-003, formed in 2018; however, Takeda recently decided to walk away from this pact. But after the positive results of the phase 1b/2a trial, Wave says that the program has caught the attention of other drug developers, meaning it could land a new deal for the program very soon.
Antisense oligonucleotide market on an upward trajectory
According to Future Market Insights, the global antisense oligonucleotides market is projected to amass a revenue of around $5,519 million by 2033, up from $2,913 million in 2023, meaning that it will move forward with a compound annual growth rate (CAGR) of 6.6% during the forecast period.
The rising demand for antisense oligonucleotides is reportedly attributed to its ability to modify the immune system, which means it can facilitate the treatment of a wide range of autoimmune disorders that cannot be treated with available drugs. Plus, it is easy to scale up the commercial scale GMP production of these medicines compared to other biologic therapies, and the market is enhanced by the minimal side effects caused by antisense drugs, which are controlled with ease as compared to other classes of drugs.
So, with more companies slowly entering the field, it is likely that we will soon see more antisense oligonucleotides reaching the market.
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