Although antisense therapy — using antisense oligonucleotides (ASOs) to control protein function — has generated controversy and skepticism over the years, it is now considered a promising strategy for treating a variety of disorders. This blog will look back at the steps leading up to this point and review current ASOs in the market and the pipeline.
ASOs are short, single-stranded synthetic, chemically modified chains of nucleotides that are designed to strategically bind to messenger RNA (mRNA) and thereby reduce, restore, or modify protein expression. Stanley Crooke founded Isis Pharmaceuticals in 1989 (renamed Ionis in 2015) with the goal of commercializing antisense therapy. At the time, there was a lot of excitement about the new gene therapy approach.
Checkmate Pharmaceuticals CSO Art Krieg, who devoted his career to antisense, was a postdoctoral researcher at the US National Institutes of Health during this time. He recalled an incredible optimism and excitement that this drug design could work for the most challenging targets and diseases. “The idea is it was going to be God’s gift to drug development,” said Krieg. However, there were some growing pains.
Does Antisense Make Sense?
It proved difficult to design ASOs that could have the intended effect on the protein target without degrading or hitting other targets. “Very few people actually had a grip on how difficult it would be to make modified oligonucleotides,” said Karl-Heinz Altmann, who led chemistry at Ciba-Geigy during its partnership with Isis Pharmaceuticals.
By the early 1990s, the glow around antisense had dimmed. Although academic research was published describing the use of antisense to understand the function of specific genes, it was later revealed that the findings misinterpreted off-target effects as antisense effects. This had a chilling effect on funding and research interest as attention turned to other approaches, including RNA interference. “No one in the world believed that antisense worked,” says Arthur Levin, who is now executive vice president of R&D at Avidity Biosciences.
Levin noted that the skepticism extended to the US Food and Drug Administration (FDA). In 1998 during a meeting seeking approval for Isis Pharmaceuticals’ first drug, fomivirsen, a reviewer said, “I’m wasting my time here because everybody knows that antisense doesn’t work.”
ASOs Find Acceptance (And Eventual Success)
Vitravene® (fomivirsen) did, however, become the first ASO approved by the FDA. It was co-developed by Isis and Novartis Ophthalmics to treat cytomegalovirus (CMV) retinitis. At the time, there was a high unmet need for a therapeutic option. However, with the development of high-activity anti-retroviral therapy, the number of CMV cases dropped dramatically and Vitravene® was pulled from the market.
In 2008, Genzyme paid Isis $325 million for access to Kynamro® (mipomersen), a treatment for a rare, inherited form of high cholesterol. In 2013 it became the first systemically delivered ASO approved by the FDA. Kynamro is currently only available in the US through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) due to hepatoxicity.
Today, Ionis’ pipeline of antisense therapies includes more than 40 medicines for a range of diseases that show great potential, and approved drugs include:
- Spinraza® (nusinersen), the first-ever FDA-approved treatment for spinal muscular atrophy.
- Tegsedi® (inotersen), approved by the FDA in 2018 for treating hereditary ATTR amyloidosis with polyneuropathy, a rare nerve disease.
- Waylivra® (volanesorsen), approved in the EU in 2019 for the treatment of familial chylomicronemia syndrome (FCS), a rare genetic condition that gives rise to high levels of triglycerides in the blood.
Other companies have also found success with ASOs. Since 2016, three of Sarepta Therapeutics’ ASO drugs received accelerated FDA approval for the treatment of specific types of Duchenne muscular dystrophy (DMD), a progressive genetic neuromuscular disorder. Exondys 51® (eteplirsen) was the first-ever drug approved for DMD, and now Vyondys 53™ (golodirsen) and Amondys 45™ (casimersen) are a part of their DMD portfolio. In addition, Viltepso® (viltolarsen), from Nippon Shinyaku and NS Pharma, received accelerated FDA approval for DMD in 2020. Clinical trials continue to evaluate each of these drugs.
Future Potential
Single-patient studies are measuring the potential of ASO technology. Researchers at the UMass Chan Medical School reported on the development of an ASO to treat a patient with amyotrophic lateral sclerosis (ALS) in 2021. Biogen and Ionis are also co-developing ASOs to treat ALS.
In another single-patient study, researchers at Boston College reported positive results from the custom oligonucleotide therapy designed to treat a patient with Batten disease, a rare neurodegenerative genetic disorder.
As ASO technology continues to evolve, it has the potential to transform the therapeutic landscape for many conditions into the future. Although he retired from Ionis in 2021, Crooke continues to focus on helping patients through his nonprofit, the n-Lorem Foundation, which provides free individualized antisense treatments to patients living with ultra-rare diseases.
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