AVI-7288 for Marburg Virus in Nonhuman Primates and Humans

Heald, Alison E.; Charleston, Jay S.; Iversen, Patrick L.; Warren, Travis K.; Saoud, Jay; Al-Ibrahim, Mohamed S.; Wells, Jay; Warfield, Kelly L.; Swenson, Dana L.; Welch, Lisa S.; Sazani, Peter; Wong, Michael; Berry, Diane; Kaye, Edward M.; Bavari, Sina

doi:10.1056/nejmoa1410345

Cited by 55 publications

(44 citation statements)

References 19 publications

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“…Notably, adverse events frequently seen with other RNA analogs, including administration site reactions, flulike symptoms, coagulopathies, inflammatory response, and renal or hepatic toxicity,20, 33 were observed rarely, if at all 20, 33. This is consistent with the safety profile and tolerability of eteplirsen and other PMO‐based oligomers seen in animals41, 42, 43 and in other human studies 44. This lack of toxicity is attributed to PMO chemistry, which is charge‐neutral, largely unmetabolized, and not linked to immune activation,10, 45 platelet activation, or hepatotoxicity.…”

Section: Discussionsupporting

confidence: 81%

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

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446

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ObjectiveTo continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).MethodsAmbulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.ResultsAt 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.InterpretationOver 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271

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Section: Discussionsupporting

confidence: 81%

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

Self Cite

446

392

View full text Add to dashboard Cite

show abstract

“…However, this thrust has been supplanted by the use of PMOs having positive piperazine residues incorporated into the backbone (252,253); these seem to be less toxic than the CPP-PMOs in the antiviral context and have shown impressive results in trials against Marburg virus in monkeys and were apparently well tolerated in phase I trials in man (254). …”

Section: Approaches To Deliverymentioning

confidence: 99%

The delivery of therapeutic oligonucleotides

2016

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The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

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“…[161] Eteplirsen ist z. [163] Peptid-Nukleinsäuren (PNAs) haben ein nicht-proteinogenes Peptidrückgrat, bei dem ein N-(2-Aminoethyl)glycin die Phosphodiesterverknüpfung ersetzt (Abbildung 9). [162] Um die Zellaufnahme von PMOs zu erhçhen, hat Sarepta Therapeutics eine neue Gruppe PMOs geprüft ("PMOplus").…”

Section: Angewandte Chemieunclassified

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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AVI-7288 for Marburg Virus in Nonhuman Primates and Humans

Abstract: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).

Cited by 55 publications

References 19 publications

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

The delivery of therapeutic oligonucleotides

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

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