COMPOUND AND METHOD FOR TREATING MYOTONIC DYSTROPHY
Application number: 20150080311
Abstract: An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3?UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is ?-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
Filed: April 24, 2014
Issued: March 19, 2015
Assignee: Sarepta Therapeutics, Inc.
Inventors: Hong M. Moulton, Ryszard Kole
you will see GILD grow in many other areas ...buyouts,new drugs''
Santhera reported positive results from the double-blind, randomized, placebo-controlled Phase III study (DELOS) in 65 Duchenne boys aged between 10 and 18 years who were not using concomitant corticosteroids. The outcomes provide clear evidence of a clinical benefit for Catena®/Raxone® in delaying the loss of respiratory function in patients with DMD compared to placebo.
The DELOS trial met the primary endpoint, the difference between Catena®/Raxone® and placebo in the change from baseline to week 52 in Peak Expiratory Flow (PEF as percent predicted, PEF%p). Peak Expiratory Flow is a measure of respiratory muscle strength, the decline of which is a major contributing factor to morbidity and mortality in DMD. Hospital-based spirometry assessments demonstrated that Catena®/Raxone® significantly reduced the annual decline in PEF%p by 66% compared to patients taking placebo.
Catena®/Raxone® also significantly reduced the annual decline in PEF%p by 80% compared to patients taking placebo as measured weekly by the patient at home using the hand-held ASMA-1 device (secondary endpoint). Furthermore, Catena®/Raxone® significantly reduced the annual decline of Forced Expiratory Volume in 1 second by 78% compared to patients taking placebo. Importantly, the outcome for Forced Vital Capacity, a measure of restrictive lung disease predictive of morbidity and mortality in DMD, also supported a treatment benefit of Catena®/Raxone®. The annual decline in FVC%p was reduced by 37% in Catena®/Raxone®-treated patients.
Catena®/Raxone® (900 mg/day) was safe and well tolerated with adverse event rates comparable to placebo.
For a description of the DELOS results, click here Buyse et al: Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet 2015; 385: 1748-57.
ptct had almost nothing as far as data and also showed very very little help in dmd improvement and they got approved ..huh
PTCT seems to have a very tiny positive effect for about a year but they got it approved...If ever Sarepta gets approved that stock ptct will drop like a rock.r
The so-called six-minute walk test was the primary outcome measure for this 174-person, 48-week trial. At the end of the trial, all participants had lost some walking ability, as measured by the distance they could cover in six minutes.
However, after about a year, those in the low-dose ataluren group were able to walk an average of 29.7 meters (about 97 feet) further than those in the placebo group. The high-dose group, by contrast, walked on average the same distance in six minutes as the placebo group.
Participants were ambulatory males who were at least 5 years old. Thirty-seven trial sites in North America, Europe, Australia and Israel were part of this study.
The low-dose group received oral ataluren at 10 milligrams per kilogram of body weight each morning and at midday and 20 milligrams per kilogram in the evening. The high-dose group received 20 milligrams per kilogram in the morning and at midday and 40 milligrams per kilogram in the evening. The placebo group received a look-alike, inert substance.
The six-minute walk test was the primary outcome measure, but other outcomes were also assessed, including safety, muscle function and strength, and muscle dystrophin levels.
Ataluren was generally well tolerated, and adverse events were similar across all treatment groups. Serious adverse events were infrequent, and none were considered related to the drug.
The trial results suggested "positive trends" in muscle function, as measured by timed function tests, in those receiving the low-dose regimen of ataluren compared to those receiving a placebo, PTC said.
PTC said dystrophin protein expression could not be properly assessed, in part because of technical limitations. The company said no relationship could be established between dystrophin levels and distance covered in the six-minute walk tes
Dystrophin was also restored in the diaphragm and other accessory respiratory muscles, intercostal (IM) and sternomastoid (SM) as well as tibialis anterior (TA) of the lower limb. Again immunohistological staining demonstrated extensive dystrophin protein restoration (Supplementary Fig. 3 A) with exceptionally high recovery scores between 74–104% (Supplementary Fig. 4). The RT-qPCR (Supplementary Fig. 3 B) and western blot quantification (Supplementary Fig. 3 C&6) exhibited similar results with very high dystrophin transcript levels (77–86%) and between 58–101% restoration of dystrophin protein in the diaphragm, TA, IM and SM muscles. RT-PCR also showed complete skipping of exon 23 in these muscles (Supplementary Fig. 5). This demonstrates that the repeated low-dose Pip6f-PMO administration protocol successfully restored high levels of dystrophin in skeletal and cardiac muscles.
Exercised mdx mice exhibit dilated cardiomyopathy
The cardiac phenotype in 6 month old mdx mice is mild, but may be aggravated by exercise33, 34. A forced exercise regimen was undertaken in control wild type C57BL/10 mice (n = 10) and mdx mice both untreated (n = 9) and treated with Pip6f-PMO (n = 10). From 12 weeks of age, mice were exercised on a treadmill 3 times every 2 weeks for 45 minutes (Supplementary Fig. 2). 10 mdx and 10 C57BL/10 unexercised mice were used as controls to monitor the effects of exercise alone. Mdx mice failed to run consistently, as they stopped intermittently and required constant encouragement (Supplementary Video 1). Indeed, 3 untreated mdx mice were removed from the study as they exhibited severe aversions to running, thereby reducing the sample size from 12 to 9 mice, which demonstrates their poor running capacity. C57BL/10 mice were markedly more active than their mdx counterparts (Supplementary Video 2).
All groups of mice underwent cine-MRI at 24 weeks of age, 5 days after the last exercise event in the exercised groups.
American Academy of Neurology [AAN] Washington D. C. April 18-25
From the program listing - site says over 2500 abstracts - these are one's I picked out using the search term "duchenne".
Meeting schedule - Thursday April 23
Developing Antisense Oligomers as a Genetic Therapy for Duchenne Muscular Dystrophy
Francesco Muntoni, MD University College London Institute of Child Health, London, United Kingdom
Poster Session II Tuesday April 21
P2.006 Utrophin Modulators to Treat Duchenne Muscular Dystrophy (DMD): Phase 1b Clinical Trial Results of SMT C1100 Jon Tinsley, Francesco Muntoni, Stefan Spinty, Helen Roper, Imelda Hughes, Valeria Ricotti, Alison Bracchi, Bina Tejura, David Roblin, Gary Layton, Kay Davies
P2.230 Drisapersen: An Overview of the Exon-51 Skipping Antisense Oligonucleotide Clinical Program to Date in Duchenne Muscular Dystrophy (DMD) Craig McDonald, Nathalie Goemans, Thomas Voit, Rosamund Wilson, Claire Wardell, Giles Campion
P2.238 Evaluating the Progression of Physical Impairment, Activity Limitation and Quality of Life in Duchenne Muscular Dystrophy (DMD): A Prospective Natural History Study Nathalie Goemans, Brenda Wong, Craig McDonald, Ali Jones, Caroline Mason, Giles Campion
P2.240 Pooled Analyses of Efficacy Parameters in Patients with Duchenne Muscular Dystrophy (DMD): Results from the Drisapersen (DRIS) Clinical Trial Program Nathalie Goemans, Thomas Voit, Craig McDonald, Rosamund Wilson, Claire Wardell, Giles Campion
Poster Session V Wednesday April 22
P5.052 Skeletal Muscle, Cardiac, and Pulmonary Imaging Biomarkers of Disease Activity in a Trial of Exon-skipping for Boys with Duchenne Muscular Dystrophy Ami Mankodi, Robert Janiczek, Noura Azzabou, Lasya Gaur, Courtney Bishop, Harmen Reyngoudt, Martijn Froeling, Rexford Newbould, Andrew Arai, Pierre Carlier, Kenneth Fischbeck
P5.061 In Vitro Pharmacokinetic Evaluation of Eteplirsen, SRP-4045, and SRP-4053;
Biotech is super growing and it is hard to get anyone these days.You will see many mergers and many biotechs will be bought out over the next few years even sarepta.
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OLIGONUCLEOTIDE ANALOGUES HAVING MODIFIED INTERSUBUNIT LINKAGES AND/OR TERMINAL GROUPS
Application number: 20150073140
Abstract: Oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3? and/or 5?-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.
Filed: June 6, 2014
Issued: March 12, 2015
Assignee: Sarepta Therapeutics, Inc.
''all belongs to Sarepta''