PPS: Congrats to Peter Sarnow and Catherine Jopling who in 2005 made the mind-boggling discovery that HCV relies on a microRNA for its replication. I hope they will be handsomely rewarded for it.
Wednesday, October 22, 2014
Tuesday, October 21, 2014
Thursday, October 16, 2014
Wednesday, October 15, 2014
Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months. After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events. Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.
On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing. This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.
The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown. Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease. Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.
Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.
Monday, October 13, 2014
The data not only greatly de-risk ISIS-SMNRx, but open up phosphorothioate-based antisense technology for a whole range of other, largely severe CNS-based diseases of high unmet need, including Huntington's disease, the spinal cerebellar ataxias, Alzheimer's, Parkinston's- you name it!
Specifically, the data showed that despite only a focal, intrathecal infusion of the antisense drug into the lower spine, it readily distributed throughout the CNS up to the brain and at concentrations (10-30ug per gram tissue) that are strongly predicted to support both steric blocking and RNaseH antisense mechanism of actions in the CNS for 2' MOE chemistry. Further chemistry improvements such as cET are opening the therapeutic window even more so. What is more, these concentrations were maintained for months, thus further supporting the apparent therapeutic benefits seen in these open-label studies.
Note that the effective concentration for antisense mechanisms will differ according to target tissues; e.g. in the liver, largely due to competition from phagocytic Kupffer cells, the effective concentrations are 100ug/g and above with 2' MOE chemistry.
With the generous support of SMA families, the company was also able to look for the drug and the SMN protein in tissue sections from 3 deceased infants. These investigations showed that the phosphorothioate oligo had been taken up pretty much in every neuronal and non-neuronal cell types.
Such broad-based uptake may be quite important according to the opening keynote address of ISIS collaborator Don Cleveland last night at the annual OTS meeting in San Diego, given that expressions of disease-causing genes in various cell types, not just the neurons, seem to contribute to most neurodegenerative diseases.
In terms of drug action, the SMN protein was found to be re-expressed in the corresponding cells as intended for the splice-modulating approach of ISIS-SMNRx. This was shown by immunofluorescent analysis. Moreover, quantitative PCR showed that the expression of the intended full-length SMN2 mRNA was increased by 2 to 3-fold, consistent with the 2 to 3-fold increases in SMN2 proteins found from cerebrospinal fluid (CSF) samples in the child-onset studies.
No dose-limiting safety issues were seen and the intrathecal infusions which are predicted to be needed on a ~6 month-basis for many of the anticipated CNS-related antisense applications could be performed without having to resort to general anesthesia.
For SMA, genetically speaking all this essentially turns a type I infant-onset SMA baby into a less severe type II/III child, and a type II/III SMA child into a normal one, with the caveat that this benefit obviously only accrues from the time the drug is given which, unfortunately, may be too late for many type I SMA babies. I was e.g. somewhat disappointed that no apparent correlation was seen between onset of antisense administration and therapeutic outcomes in the infant study, although clearly the numbers may well have been too small (n=20). I am very hopeful, however, that those infants making it out to say 18 months and beyond with ISIS-SMNRx may see very good outcomes indeed.
Despite the caution, all this was accompanied by apparent therapeutic benefits in terms of survival and muscle strength. While highly intriguing, due to the open-label nature of the studies and the small patient numbers, it is not my intention to delve more into that aspect of the data and instead focus today on the truly mind-blowing pharmacodynamic data. These should provide hope for many patients and families with neurodegenerative diseases. If not, we might as well give up on rational drug development.
Wednesday, October 8, 2014
Disclosure: Long ARWR. I sold most of my holdings at $11 and change given the underwhelming results and increasingly negative market reaction, but got back in below $6 when I considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the potential to surprise the market to the upside from now much lowered expectations. Add to this ARC-AAT, the platform...
Tuesday, October 7, 2014
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