Kyndrisa (drisapersen) / BioMarin - LARVOL DELTA

Safety of Different Pharmacological Treatments in Boys with Duchenne Muscular Dystrophy: A Systematic Review and Bayesian Network Meta-analysis of Randomized Controlled Trials (AAN 2024) - "Our study indicates a differential safety profile among the analyzed treatments for boys with DMD, drisapersen and vamorolone exhibit a promising safety profile."

Retrospective data • Review • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Pediatrics

Next Generation Exon 51 Skipping Antisense Oligonucleotides for Duchenne Muscular Dystrophy. (PubMed, Nucleic Acid Ther) - "Pioneering first generation exon 51 skipping AONs like drisapersen and eteplirsen have more recently been followed up by AONs for exons 53 and 45, with, to date, a total of four exon skipping AON drugs having reached (conditional) regulatory US Food and Drug Administration (FDA) approval for DMD. These dystrophin levels allowed for normalization of creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and improved motor function in hDMDdel52/mdx mice. As no major safety observation was obtained, the improved therapeutic index of these next generation AONs is encouraging for further (pre)clinical development."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • HSP90AA1

Consistency of changes in percent-predicted forced vital capacity between real-world data and trial placebo arms in ambulatory Duchenne muscular dystrophy (WMS 2022) - "Placebo arm data came from phase 3 trials of tadalafil and drisapersen, and one phase 2 trial of drisapersen. These findings are encouraging for use of external controls for FVC%p outcomes in this population. Additional research is needed to assess consistency of FVC%p over longer-time frames, and among older and non-ambulatory boys."

Clinical • Real-world evidence • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Evaluation of DNA segments in 2'-modified RNA sequences in designing efficient splice switching antisense oligonucleotides. (PubMed, RSC Adv) - "Notably, three among them (Exondys 51, Vyondys 53 and Viltepso) are based on phosphorodiamidate morpholino (PMO) chemistry whereas Spinraza is based on 2'-O-methoxyethyl phosphorothioate (2'-MOE PS) chemistry. Although systemic delivery of PMOs has displayed a good safety profile even at high doses, the 2'-O-methyl phosphorothioate modified (2'-OMe PS) ASO drug candidate (drisapersen) failed due to safety issues...Our results demonstrated that 2'-modified RNA PS ASOs containing four or less PS DNA nucleotides at the 3'-end yielded improved exon 23 skipping efficacy in line with fully modified ASO controls. Based on these results, we firmly believe that the present study opens new avenues towards designing splice modulating ASOs with limited chemical modifications for enhanced safety and therapeutic efficacy."

Journal

Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis. (PubMed, PLoS One) - "This study provides a current summary of prognostic indicators of disease progression in DMD, which will help inform the design of comparative analyses and future data collection initiatives in this patient population."

Biomarker • Journal • Review • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update. (PubMed, Arch Toxicol) - "Issues faced by eteplirsen and SRP-5051, including efficacy and safety, are identified. Lastly, the current state of eteplirsen and exon-skipping therapy in general as a strategy for the treatment of DMD are discussed."

Journal • Review • Cardiovascular • Congestive Heart Failure • Dermatology • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy • Otorhinolaryngology • Respiratory Diseases

[VIRTUAL] Twenty Years of Clinical Trials in Duchenne Muscular Dystrophy- A Low Clinical Drug Development Success (ISPOR 2021) - "The most frequently studied compounds were Ataluren, Drisapersen, Eteplirsen and Tadalafil. We found a very low trial success rate. There is a significant gap between drug discovery and development success rates that warrants improvement and careful appraisal of this life-threatening disease."

Clinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Restorative treatments of dystrophin expression in Duchenne muscular dystrophy: A systematic review. (PubMed, Ann Clin Transl Neurol) - "In the systematic review, analyzing individually the clinical trials using Ataluren and Drisapersen showed a nonsignificant effect on 6MWD. Eteplirsen and Ataluren could modestly reduce disease progression. However, more trials are needed to confirm its efficacy, as well as quality of life and cost-utility studies."

Journal • Review • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

"$SRPT Maybe $SLDB will call it Drisapersen II" (@DeanIrving2)

The Pharmacokinetics of 2'-O-Methyl Phosphorothioate Antisense Oligonucleotides: Experiences from Developing Exon Skipping Therapies for Duchenne Muscular Dystrophy. (PubMed, Nucleic Acid Ther) - "This article presents a detailed review of absorption, distribution, metabolism, and excretion of 2OMe PS AONs, compiled from publicly available data and previously unpublished internal data on drisapersen and related exon skipping candidates in preclinical species and DMD patients...A level of detail on muscle as a target tissue is provided, which was not previously available. Furthermore, muscle biopsy samples taken in DMD clinical trials allowed confirmation of the applicability of interspecies scaling approaches commonly applied in the absence of clinical target tissue data."

Journal • PK/PD data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Nonclinical Exon Skipping Studies with 2'-O-Methyl Phosphorothioate Antisense Oligonucleotides in mdx and mdx-utrn-/- Mice Inspired by Clinical Trial Results. (PubMed, Nucleic Acid Ther) - "The morpholino phosphorodiamidate oligomer eteplirsen has been approved by the Food and Drug Administration, whereas clinical development with the 2'-O-methyl phosphorothioate (2OMePS) AON drisapersen was recently stopped. We further report that treadmill running increases AON uptake and dystrophin levels in mdx/BL10 mice. Finally, we show that even low levels of exon skipping and dystrophin restoration are sufficient to significantly increase the survival of mdx-utrn-/- mice from 70 to 97 days."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Atrophy • Muscular Dystrophy

Drisapersen associated with elevated serum factor VIII levels in Duchenne muscular dystrophy. (PubMed, Neurology) - No abstract available

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Magnetic resonance imaging characteristics of injection site reactions after long-term subcutaneous delivery of drisapersen. (PubMed, Eur J Pediatr) - No abstract available

Journal • Lipodystrophy

Open Label Study of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (clinicaltrials.gov) - P3; N=233; Terminated; Sponsor: GlaxoSmithKline; Active, not recruiting -> Terminated ; Trial primary completion date: Dec 2014 ->Mar 2014

Trial primary completion date • Trial termination • Biosimilar

A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. (PubMed, Neuromuscul Disord) - P3; "A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects."

Journal

Therapy with 2'-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption. (PubMed, Mol Ther Nucleic Acids) - "Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with drisapersen, a modified 2'O-methyl phosphorothioate antisense oligonucleotide (6 mg/kg)...In conclusion, phosphorothioate oligonucleotides appear to directly compete for receptor-mediated endocytosis in proximal tubules. We postulate that oligonucleotide-induced low molecular weight proteinuria in patients is therefore a transient functional change and not indicative of tubular damage."

Journal

Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne. (PubMed, Sci Rep) - "...We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3...The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients."

Biomarker • Journal

"Sounds like Drisapersen (Disastersen) repackaged to me." (@greyzone513)

Injection site reactions after long-term subcutaneous delivery of drisapersen: a retrospective study. (PubMed, Eur J Pediatr) - "We discuss some possible underlying mechanisms. The exact mechanism however is still not known."

Journal • Retrospective data