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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the following ten years, due to a number of technological advances, including improved chemistries (to limit sensitivity to nucleases) and delivery systems, several new antisense agents were developed and progressed to clinical trials, not just in the cancer area, but also for diabetes, amyotrophic lateral sclerosis (ALS), and diseases such as asthma, arthritis, and pouchitis with an inflammatory component. For example, an antisense agent targeted to the gene responsible for Duchenne muscular dystrophy (DMD) was developed. Eteplirsen (brand name Exondys 51) is a medication to treat, but not cure, some types of Duchenne muscular dystrophy, caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen was designed and developed by Sarepta Therapeutics. After a controversial debate surrounding the efficacy of the drug, during which two FDA review panel members resigned in protest, eteplirsen received accelerated approval from the US Food and Drug Administration in late 2016. A one-year treatment package is priced at $300,000.
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Antisense oligonucleotides can restore a disrupted reading frame and lead to the expression of a shortened but functional dystrophin protein.42 Eteplirsen (Exondys 51) is the first approved antisense therapy for Duchenne's dystrophy in United States designed to skip exon 51 and provides treatment option for 14% of all DMD patients.43 It is given as 30 mg/kg intravenously once a week. Other exon-skipping therapies targeting exons 53 and 45 are in early phase of clinical trials.
Emerging Topics
Published in Demissie Alemayehu, Birol Emir, Michael Gaffney, Interface between Regulation and Statistics in Drug Development, 2020
Demissie Alemayehu, Birol Emir, Michael Gaffney
Approvals have also been granted based on historical controls. An example is the accelerated approval of eteplirsen for Duchenne muscular dystrophy. The approval of eteplirsen used data on a historic control arm from a registry database (Mendell et al. 2016). In another case, label expansion was granted for blinatumomab based on the results of a single-arm trial supported by RWE to include indication for patients with minimal residual disease in which cancer cells are present at a low level that cannot be detected microscopically (Gokbuget et al. 2018).
Next steps for the optimization of exon therapy for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2023
Galina Filonova, Annemieke Aartsma-Rus
Additional clinical trials of eteplirsen have been focusing on endpoints that could confirm the clinical benefits of eteplirsen treatment on DMD boys aged 7–16 years. In the first trial, 30 DMD patients not amenable to exon 51 skipping were enrolled as an untreated control group (https://clinicaltrials.gov/ct2/show/NCT02255552). However, half of the control group discontinued the trial mostly to be involved in other clinical trials. Moreover, since mutations of DMD patients from the untreated control group did not match to mutations of the exon 51 skippable group, these groups are not clinically equal, e.g., the untreated group contained also exon 44 skippable patients known to have a slower disease progression [41]. These factors impede group comparison and receiving a statistically significant result. Therefore, external NH patients and patients from the phase 2 clinical study of eteplirsen were chosen as a comparator for analysis. The level of dystrophin proteins measured by western blot (WB) increased by 0.516% after 96 weeks of eteplirsen treatment. Analysis of the 6MWT data demonstrated that patients from eteplirsen-treated cohorts walked 67.3 m less from the baseline, while NH patients walked 133.8 m less suggesting a beneficial functional effect of eteplirsen [42].
Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19
Published in Pediatric Hematology and Oncology, 2021
Satoru Takafuji, Takeshi Mori, Noriyuki Nishimura, Nobuyuki Yamamoto, Suguru Uemura, Kandai Nozu, Kiminori Terui, Tsutomu Toki, Etsuro Ito, Hideki Muramatsu, Yoshiyuki Takahashi, Masafumi Matsuo, Tomohiko Yamamura, Kazumoto Iijima
Recently, splicing abnormalities have gained attention as a potential target of treatment. Splice alteration, through the use of antisense oligonucleotides, has emerged as an effective approach for the treatment of inherited diseases caused by splicing abnormalities. Eteplirsen and Nusinersen have already been approved by the FDA as splicing modulation drugs for Duchenne muscular dystrophy and spinal muscular atrophy, respectively.48,49 Additionally, our group developed exon skipping therapy using antisense oligonucleotides for Alport syndrome, one of the most common inherited kidney diseases.50 In the future, splicing targeted therapy may be applied to the treatment of other inherited diseases. For this reason, it is critically important to determine the pathogenicity of intronic variants with unknown significance.
Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2021
Anne-Fleur E. Schneider, Annemieke Aartsma-Rus
Current phase 3 registration trials generally last 96 weeks, with weekly hospital visits, which is a burden on patients and families (Table 2). Efforts are made to find alternatives for the use of placebo groups, e.g. using historic controls. However, this poses many risks, since the standards of care are improving with time, and steroid regimens vary between different sites. Finding a perfect contemporary match for each patient, with similar baseline parameters for the primary endpoint, comparable care and similar steroid regimen is very challenging. Creative solutions have been used, such as the described clinical trial for eteplirsen, where patients not eligible for eteplirsen treatment from the same clinics were followed up with the same functional outcome measures and checked for the occurrence of ‘adverse events.’ However, the challenge here is that while these ‘controls’ are not eligible for eteplirsen, they are eligible for many of the other therapies currently tested for DMD. It is therefore in hindsight not unexpected, that the majority of the control group dropped from the trial prematurely. A shared placebo-group as is happening for the currently ongoing clinical trials for golodirsen and casimersen is probably a more workable solution. Furthermore, the models generated by cTAP and D-RSC will also facilitate optimal matching between contemporary natural history controls.