I have never bought into the "leaky membrane" hypothesis for one obvious reason. Once the cell membrane's integrity has been compromised the cell is no longer viable as in cell death. Who cares if the oligos enter via these membrane disruptions if they are passing the cell's organelles on their way out of the cell? There are numerous papers that address leaky membranes. There is a chemistry blog that i read called "Woodward's Whiskey". he lists his thought on this topic and lists the scientific papers to support his conclusions.
Sentiment: Strong Buy
tred, I use to believe what you believe but decades of experience paints a different story. Analysts use code words like adding "color" to an issue, "background" ,"granularity". It is very possible that management conveyed specific knowledge without unequivocally stated said information. No one can convince me that CG didn't have specific knowledge of the initial 36 week Phase II data before conducting their reverse split. Did he officially have knowledge of data, probably not. 3 days later data was released [officially] and the rest is history.
jrrt1, The mouse model is the more sensitive toxicological system for testing oligos, not the rat. Without looking up the exact target sequence used for the rat PMO it is very likely that it is target specific. Relating to the target sequence it is most likely that the patching over the target exonic sequence causes the toxicity itself or the binding of this rat sequence resulted in mismatch patching causing toxicity. This is only demonstrative at super high doses in the less then optimal model that tests for oligo toxicity. My previous comment regarding granulation is so unlikely even at the doses reported in the rat study that I shouldn't have mentioned it. Granulation has been reported in animal models with dosing over the gram/'kg dosing in the rat study and over long durations. It is no secret that oligos in general can accumulate in organs over time. This fact is well documented and not relevant in these studies.
Very interesting and revealing comment by Baird analyst. He reports that after spending time with SRPT management they provided "granularity" to upcoming new data points prior to adcom and risk is greatly mitigated hence upgrade to $47 pps. It sounds like dystrophin data and 6MWT scores were revealed in these meetings.
"The problem is that the Mercuri decline is 1/2 driven by the rare, but extreme, declines to non amb. Sarepta just had to get a little bit lucky (est 30% to 50% chance) in picking their 6 patients to avoid getting any declines-to-non-amb-in-3-years"…That is one explanation but I have a better one that is supported by a proven mechanism of action and quantifiable and qualifiable drug induced Dystrophin production correlating with 6MWT scores. What happens to the "30% to 50% chance" when the trial reaches 4 years and there are no additional wheelchair bound boys?
The exon 53 rat data did not experience toxicity until 1 gram/kg. This is an enormous dose. DMD animal models use different sequences to patch over sequence to ameliorate dystrophin functionality compared to human DMD patch sequence. there are only two possibilities for the PMO toxicity at such a large dose. First it is sequence specific which is very likely or organ granulation which has been reported in animal models at multiple gram'/kg weights over prolonged periods of time. The later finding does not appear in the literature but has been relayed to me in unpublished experiments
Ifxxx, Remember all the comments post 168 week 6MWT scores from analysts that they expected increased decline in these scores? At the time I thought it was more likely to stabilize then decrease significantly. This is all unchartered territory.
"Further loss of ambulation for 10 ambulant boys? NO, all boys are still ambulant." and I believed he stated that there has been no significant loss of ambulation in treatment cohort. Is this a stabilization of the 6MWT scores? If true would be significant step in gaining AA approval. Factor in the dystrophin rescores and the 4th biopsies, and the FDA will have a very difficult time in rejecting AA NDA.
Jon, Thanks. I read a paper by Hong many moons ago where she reported that nonspecific binding effects by cationics [PMOs] had much to due with PMO sequences then +charge in mouse model. Are you familiar with that observation?
Jon, I believe your hypothesis would be correct if the introduction of piper residues constituted up to 50% of the linkers on the oligo strand but when they occupy 2- 4 linkages on the entire strand off-target effects are similar to the naked PMO. If I'm incorrect maybe you could point me in the direction that proves this hypothesis. Thanks.
Your statement, "This chemistry will make the drug more promiscuous and increase off-target effects" is half right and half wrong. The drug has improved uptake dynamics [promiscuous] and the piperazine residues [+ charged]placed intermittently along the sublinkages improves the binding affinity to negatively charged RNA. The length of the PMO+ oligo is equal to the naked PMO so if it's not shorter and the binding affinity is greater how do we get to "More off-target effects?"….
Bruce Wentworth has conducted extensive research into Pompe Disease using the PPMO chemistry. Here's an excerpt from 2014 paper…"Systemic administration of GS-PPMO reduces glycogen synthase activity in the skeletal muscle and heart of Pompe mice
Treating Pompe mice with GS-PPMO led to complete correction of the elevated glycogen synthase activity in the quadriceps"…Complete Correction, how often can claim complete correction???
Yahoo will not allow completion. If interested go to NEJM Journal Watch…Drisapersen.They go on to say the company makes certain conclusions and offers no data to support these conclusions. Garbage.
Here's the critique of this dubious Phase II trial. "October 28, 2014
Phase II Exon-Skipping Trial in Duchenne Dystrophy Raises More Questions Than It Answers
John T. Kissel, MD, Michael Benatar, MD, MS, PhD reviewing Voit T et al. Lancet Neurol 2014 Oct.
The results of a recently completed phase II trial of drisapersen are difficult to interpret.
Duchenne muscular dystrophy (DMD) results from a heterogeneous group of mutations in the dystrophin gene that disrupt the transcriptional reading frame and lead to dystrophin protein deficiency. Antisense oligonucleotides (ASOs) may be used to induce “exon skipping,” thereby restoring the open reading frame and resulting in a truncated but functional dystrophin protein intended to yield a milder phenotype. Researchers conducted a phase II, randomized, placebo-controlled, manufacturer-sponsored study of drisapersen, which targets skipping of exon 51, a therapeutic strategy relevant to about 13% of DMD patients. Fifty-three patients were randomized to 48 weeks of placebo, drisapersen 6 mg/kg administered subcutaneously either continuously (once weekly), or intermittent drisapersen (on a set schedule for 9 doses every 10 weeks).
The continuous-treatment group, but not the intermittent-treatment group, had improved walking distance (by 31.5 meters, vs. a 3.6-meter decrease with placebo) on the 6-minute walking test at week 25, the prespecified primary outcome measure, but no effect at week 49. Measurement of pharmacodynamic markers of dystrophin expression showed minimal increases in half the active-treatment recipients (and no placebo recipients). Mild to moderate injection-site reactions were the most common treatment-related adverse event.
These interesting results are incredibly difficult to interpret. This study was conducted in parallel with an unpublished phase III 48-week trial that compared the continuous administration of the same dose of drisapersen against placebo but showed no difference on the same