Eteplirsen Similar Drugs: Emerging Exon-Skipping Therapies

Eteplirsen was the first exon-skipping therapy approved for Duchenne muscular dystrophy (DMD), a severe genetic disorder that leads to progressive muscle degeneration. Since its approval, research has expanded to develop similar drugs targeting different exons, offering potential benefits to more patients with specific mutations.

With advancements in RNA-based therapies, new exon-skipping compounds continue to emerge, each designed to restore partially functional dystrophin protein.

Mechanism Of Action

Eteplirsen and similar therapies work by modifying pre-messenger RNA (pre-mRNA) splicing to bypass mutations in the dystrophin gene. DMD results from mutations that disrupt the reading frame, preventing functional dystrophin production. Exon-skipping compounds restore the frame by excluding specific exons during mRNA processing, enabling the synthesis of a truncated but functional dystrophin protein. This approach mimics Becker muscular dystrophy, a milder form of the disease where dystrophin retains partial functionality.

These therapies use synthetic antisense oligonucleotides (AONs), short chemically modified RNA-like molecules that bind to pre-mRNA sequences. AONs interfere with the spliceosome, the cellular machinery that processes pre-mRNA into mature mRNA. By blocking splice sites, they prevent the inclusion of a specific exon, restoring the reading frame and allowing ribosomes to produce a functional dystrophin variant.

The effectiveness of exon-skipping therapies depends on AON binding efficiency, modified mRNA stability, and the ability of truncated dystrophin to integrate into the dystrophin-associated protein complex (DAPC). Studies have shown that even low dystrophin levels provide clinical benefits. Longitudinal data from clinical trials, such as those published in JAMA Neurology and The Lancet Neurology, indicate that sustained treatment slows disease progression, improving ambulation and respiratory function.

Exon 51-Targeting Compounds

Eteplirsen’s approval marked the start of exon 51-targeting therapies for DMD, leading to the development of additional compounds aimed at improving efficacy and pharmacokinetics. These therapies share the exon-skipping mechanism but differ in chemical modifications, dosing regimens, and clinical outcomes.

Golodirsen, developed by Sarepta Therapeutics, incorporates phosphorodiamidate morpholino oligomer (PMO) chemistry similar to eteplirsen. Approved by the FDA in 2019, it demonstrated increased truncated dystrophin levels in muscle biopsies during the ESSENCE trial. However, concerns about renal toxicity led to a reassessment of its long-term safety.

Casimersen, another Sarepta therapy, was evaluated in a broader patient population, including younger individuals. Clinical trials showed dystrophin increases similar to eteplirsen and golodirsen, leading to its FDA approval in 2021.

Viltolarsen (NS-065/NCNP-01), developed by Nippon Shinyaku, introduced a distinct PMO backbone for enhanced cellular uptake. Approved in Japan and the U.S., it demonstrated a more rapid dystrophin increase in clinical trials. A JAMA Neurology study reported a mean dystrophin increase of ~5.9% of normal levels after 24 weeks, correlating with functional improvements in motor assessments.

Exon 53-Targeting Compounds

Exon 53-skipping therapies expand treatment options for DMD patients with specific mutations. These therapies follow the same molecular principles but require optimization for maximum clinical benefit.

Viltolarsen was one of the first exon 53-skipping therapies to receive approval. Early trials demonstrated a notable dystrophin increase, with a JAMA Neurology study reporting levels reaching ~5.9% of normal after 24 weeks. Patients also showed stabilization in motor function tests, reinforcing its potential for early intervention.

Sarepta Therapeutics’ casimersen, the exon 53-targeting counterpart to golodirsen, received FDA approval based on its ability to induce exon skipping and increase dystrophin production. Clinical trials showed a statistically significant rise in truncated dystrophin expression, though long-term functional benefits are still being evaluated.

Phosphorodiamidate Morpholino Platforms

Phosphorodiamidate morpholino oligomers (PMOs) are a key technology in exon-skipping therapies due to their stability, specificity, and resistance to enzymatic degradation. Unlike traditional antisense oligonucleotides (ASOs), PMOs use a synthetic backbone of morpholine rings linked by phosphorodiamidate groups. This structure enhances stability, prolongs activity, and reduces the frequency of dosing. PMOs also have low immunogenicity, an advantage over other exon-skipping platforms that may trigger immune responses.

A major challenge for PMOs is penetrating muscle cells, given the dense extracellular matrix surrounding myofibers. To improve uptake, researchers have developed peptide-conjugated PMOs (PPMOs), which incorporate cell-penetrating peptides. Preclinical studies have shown that PPMOs significantly boost exon-skipping efficiency and dystrophin restoration. A Nature Communications study reported that PPMOs increased dystrophin levels more than tenfold in murine DMD models, highlighting their potential for future therapies.

Administration Modalities For Exon-Skipping Agents

Effective delivery of exon-skipping therapies requires optimizing pharmacokinetics, biodistribution, and long-term tolerability. Because these therapies rely on synthetic oligonucleotides, their administration must ensure sufficient uptake while minimizing systemic toxicity.

Intravenous infusion is the standard delivery method for approved exon-skipping therapies, including eteplirsen, golodirsen, casimersen, and viltolarsen. This allows systemic circulation to reach skeletal muscle, though the extracellular matrix limits penetration, requiring repeated high-dose infusions. Despite this, systemic administration has been shown to increase dystrophin in muscle biopsies, correlating with functional improvements. Researchers are exploring extended infusion schedules and combination approaches to enhance drug stability and uptake.

Localized delivery methods, such as intramuscular injections, are being investigated to improve exon-skipping efficiency in specific muscle groups. Preclinical models suggest potential benefits for targeting respiratory and cardiac muscles, which are less accessible through systemic delivery. Additionally, peptide-conjugated morpholinos (PPMOs) have demonstrated improved muscle uptake and exon-skipping efficiency. These advancements suggest that future therapies may incorporate targeted delivery mechanisms to maximize dystrophin restoration while reducing systemic exposure.