Recent advances in antisense oligonucleotide therapy development

Our work at Headland covers a wide range of diseases and therapeutic areas, and we try to stay abreast of recent news and developments in the biopharma world. Below, we’ll share our thoughts on some recent news in antisense oligonucleotide (ASO) therapy.


ASOs alter RNA splicing to produce functional proteins or target aberrant mRNA for degradation, making them ideal candidates to treat genetic neuromuscular diseases. While first reported in 1978 to be a potential laboratory tool for gene regulation, advances have allowed for tailored ASO molecules with increased potency, therapeutic safety, and specificity.


In late 2016, ASO therapy established itself as a clinical success. The FDA approved nusinersen and eteplirsen, two of the first antisense oligonucleotide therapies, to treat spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Nusinersen targeted exon-inclusion for SMA, while eteplirsen targeted exon-exclusion for DMD. Nusinersen improved motor milestones in 51% of infants with SMA (n=122) compared to 0% in the placebo group. The eteplirsen approval was based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some treated patients, which the FDA concluded was likely to predict clinical benefit in patients.


Huntington’s disease (HD) has been another recent disease target for ASOs due to the ability to target the mutated form of the huntington protein (mHTT). The wildtype protein (wtHTT) is important for neuronal function and may be neuroprotective in an adult brain, while mHTT may drive the progression of HD; patients with HD have 3-fold higher concentrations of mHTT in their cerebrospinal fluid. In 2017, Roche sought to capitalize on ASO’s potential to tackle Huntington’s disease by licensing Ionis’s novel ASO therapy IONIS-HTTRx, now tominersen, for $45M following positive Phase I/IIa trials. Given the high unmet medical need in the disease, investors were cautiously optimistic that the drug could reach up to $5B in peak annual sales if approved. A Jefferies analyst acknowledged the drug was a “potential high risk but blockbuster reward asset in Roche’s pipeline.” However, in late March, Roche halted the ongoing Phase 3 study and open-label GEN-EXTEND extension after an interim review reported a lack of efficacy.


Similarly, Wave Life Sciences recently canceled early-stage studies on two experimental drug candidates (WVE-120102 and WVE120101) from their ASO program for the treatment of HD. In one study, a high dose of WVE-120102 reduced mHTT by 9.9% in the cerebrospinal fluid compared to a 0.8% decrease for placebo. However, pharmacokinetic modeling suggested additional dose escalation would unlikely reach dose concentrations required for therapeutic mHTT knockdown. A separate trial observed that a high dose of WVE-120101 only reduced mHTT by 11.6% compared to 10% for placebo, demonstrating an inconsistent hit on mHTT, also prompting termination.


Even with the recent setback, Ionis is still marching ahead with ASO development, with plans to build upon their platform for neurological, renal, cardiovascular and rare diseases. Additionally, ASOs are seeing momentum in other areas, with Stoke Therapeutics beginning an open-label Phase I/IIa ADMIRAL study of STK-001 for treating Dravet syndrome, a progressive form of epilepsy. In an effort to combat viruses such as SARS-CoV-2, recent ASO studies have explored targeting toll-like receptors (TLRs) to produce protective interferons (TLRs are hypothesized to be involved in the initial failure of viral clearance and in the subsequent development of the deadly clinical manifestations of severe COVID-19). In addition, there are active antisense drug-discovery platforms underway in ALS, Alzheimer’s disease, Angelman syndrome, and infantile seizure disorders.


While ASO prospects in Huntington’s are on shaky ground given the recent clinical efficacy setbacks, research on improved biophysical and biological attributes of the ASOs and their targets may allow for further advancements in the treatment of disorders once deemed untreatable by small-molecule therapies. Despite the challenges of off-target toxicity associated with accumulation in organs and the inability to diffuse across membranes, ASOs are chemically flexible enough in design, allowing for optimized synthesis controls and target specificity. ASOs are typically dosed by an invasive procedure (e.g., lumbar puncture), driving adoption of the technology in more severe, rapidly progressive diseases. With the advancements of more convenient drug delivery platforms, ASOs hold enormous potential for treating genetic neuromuscular and neurodegenerative diseases. With a large pipeline of drugs in clinical development, we look forward to further validation of ASO therapy in the next decade.

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