AAN Annual Meeting


Initial Efficacy and Safety Evaluation in Cynomolgus Monkeys of AVI-5038, a Peptide Conjugated Phosphorodiamidate Morpholino Oligomer (PPMO) Being Developed To Skip Exon 50 in Duchenne Muscular Dystrophy

Peter Sazani, Stephen Shrewsbury, Bothell, WA

To evaluate the efficacy of AVI-5038 at inducing skipping of dystrophin exon 50, as determined by RT-PCR, and also perform an initial toxicology assessment. BACKGROUND: AVI-5038 is a PPMO that induces dystrophin exon 50, and is designed to restore the reading frame and enable dystrophin expression in DMD patients. DESIGN/METHODS: Cynomolgus monkeys were dosed IV with 0, 3, or 9 mg/kg with AVI-5038, once weekly for 4 weeks. Following a 21 day recovery period, animals were sacrificed and a toxicological evaluation was performed. Selected muscle tissues were also evaluated by RT-PCR for evidence of skipping of dystrophin exon 50. RESULTS: AVI-5038 was well tolerated, with no adverse effects detected at doses up to 9 mg/kg. Toxicological findings were generally limited to the kidney, and included basophilic granules and instances of tubular degeneration / regeneration that was dose dependant. No clear evidence of kidney function change was detected, as shown by clinical chemistry and urinalysis evaluations. Significant levels of exon skipping were detected by RT-PCR in all major muscle groups evaluated, including diaphragm, heart, and quadriceps, at 9 mg/kg. CONCLUSIONS/RELEVANCE: AVI-5038, the first PPMO for DMD, was extremely well tolerated at all tested doses in primates. In addition, the safety data indicate that higher doses could be used to produce greater efficacy. Exon skipping was induced by the PPMO in healthy primate's muscles following systemic administration.
Category - Muscle Disease/Neuromuscular Junction - Therapeutics

Wednesday, April 14, 2010 3:15 PM

Poster Session: Integrated Neuroscience: Emerging Treatments in Neuromuscular Disease (3:15 PM-4:30 PM)

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Still waiting for the clinical trials here!! They were supposed to take place in March - I was told they've been put off a bit. I guess I'm just anxious but this is very good news that it's tolerable.
This is skipping 50 using PPMO not skipping 51 using PMO. This enters the heart, the PMO doesn't.


BOTHELL, WA — March 25, 2010 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based drugs, today announced that on April 14, 2010, at the American Academy of Neurology Annual Meeting (AAN), it will provide an update on the preclinical evaluation of AVI-5038, its lead peptide-conjugated morpholino-modified phosphorodiamidate oligomer (PPMO) drug candidate for Duchenne muscular dystrophy. PPMOs are based on AVI’s core phosphorodiamidate morpholino oligomers chemistry.

Previously presented data of a preclinical study found AVI-5038 to be generally well tolerated at doses up to 9 mg/kg administered once weekly by bolus intravenous injection for 4 weeks. Preliminary results from an ongoing, longer duration preclinical study at doses up to 15 mg/kg for 12 weeks, will also be presented at AAN. The 12 week preclinical study demonstrated significant toxicological findings in some groups following bolus intravenous administration. The in-life portion of the study is complete, but the collection and analysis of data from the study is still ongoing. We believe the data set is not yet sufficient for the company to make a decision on the future development of this drug candidate.

Is the latest finding applicable to PPMO only or PMO also?

Only PPMOs. PMOs are safe so far, in fact they just tested them in monkeys at high doses w/o problems.

Bains said:

Is the latest finding applicable to PPMO only or PMO also?


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