Last week at World Muscle, ISIS Pharmaceuticals provided an update on their phase II study results for ISIS-SMNRx for the infant- and child-onset forms of spinal muscular atrophy (SMA). Importantly, biomarker and biodistribution results were reported that clearly showed that ISIS-SMNRx is doing exactly at what it was designed to do, namely meaningfully increase target gene expression in the central nervous system (CNS).
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!
Biodistribution
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.
Biomarker
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.
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!
Biodistribution
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.
Biomarker
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.
4 comments:
What are the chances the phase 3 will be stopped early when the control group is seen faring consistent with the natural history study??
Although not designated a breakthrough drug, one has to ask given the natural history study the fairness to families of the afflicted having to endure a placebo control study for such a devastating disease.
New labels as "breakthrough" drugs mean little when the path to market for such diseases as this is not much quicker.
The pressure will no doubt only get worse as good ALS, Huntington's, Atxia and other treatments are developed only to run into the regulatory process which flows like molasses in cold weather.
It's a good point. I suspect part of the reason why ISIS Pharm did not 'hype' the results is that they do not want to impair enrolment in the phase III study.
How much value does this actually have for Isis though? Haven't you pointed out in the past that they have given away much of the value of their neurologic pipeline through partnering with Biogen? I fear they have given away the majority of any potential future revenue in this area leaving me uncertain how much value to ascribe to their neurologics.
Chris
Grant Compassionate Use of ISIS-SMNrx to Harper Olivia Singh and other children who don't qualify for clinical trial.
http://www.change.org/p/kristina-lemonidis-bowyer-grant-compassionate-use-of-isis-smnrx-to-harper-olivia-singh-and-other-children-who-don-t-qualify-for-clinical-trial
out of sight, out of mind, people better start writing in for help.
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