After I tried to focus attention on the Silence Therapeutics presentation this afternoon at the BIO CEO & Investor Conference, as soon as I had published my earlier blog I half regretted my decision to do so because more often than not positive news does not materialize when you expect it. This blog in particular is littered with such speculations. Fortunately, this time was different as Silence Therapeutics was able to present some really neat data from the ongoing phase I study with Atu-027 in the treatment of advanced solid cancer.
To date, at least 20 patients have received at least one Atu027 siRNA-lipoplex infusion. While the dose escalation is being conducted in a very cautious manner, i.e. slowly, dosages are now approaching levels of around 0.1mg/kg where therapeutic efficacy may be expected based on pre-clinical non-human primate data. Importantly, after 157 infusions administered, the drug seems to be very well tolerated. The only notable safety concern may be the complement activation likely related to the positive charge of Silence’s lipoplex formulation and that the Company characterized to be ‘limited’ and ‘transient’ in nature. This would be consistent with the fact that no dose limiting toxicity was reported,
There was also anecdotal evidence for anti-tumor efficacy of Atu-027. 5 out of 20 patients experienced stable disease during the 3 month study period with one patient in the sixth cohort (7th dose cohort now dosing) said to exhibit ‘remarkable shrinkage of target and non-target lesions’. There was also a mention of a reduction in lung metastases which could be clinically very meaningful for certain cancers (slide 16). Unfortunately, since this presentation was not webcast live, it is currently difficult for me to figure out the context in which this comment was made.
In sum, from today on, Atu-027 has to be considered one of the foremost RNAi clinical candidates and I look forward to data from the higher dose groups at ASCO. Congrats to the company for having come this far.
6 comments:
Dirk,
thank you for your comment about Marina's style of financing. I am a burnt Marina/MDRNA investor and totally appalled at their recent financing. Yes I understand that they desperately needed cash. But that is because they are oversized. Their cash burn is just not justified by their science.
Dirk,
I have a question regarding the Silence therapeutics presentation you've commented on.
Are you able to extract from the information they've provided anything that would indicate that ATU027 is silencing within the target cells, or could the reported tumour response be down to an immune system response?
Just thinking back to Alnylams recent release of data from their ongoing trial of their liver cancer compound where they took a biopsy of the tumour to measure levels of the drug within the tumour to prove it is in fact reaching the target.
RE the immune stimulation issue:
That's certainly a fair question, but based on the presentation, cytokine activation was looked for, but not detected. This is corroborated by the pre-clinical studies conducted with Atu-027. These were some of the more rigorous studies in the field to rule out interferon-related off-target anti-cancer efficacy, something also acknowledged by Dr. Ian MacLachlan (CSO of Tekmira) in a review. You can read a review on the preclinical studies with Atu027 in the following blog entry, a collaboration between Tobias Wolfram and myself: http://rnaitherapeutics.blogspot.com/2010/02/for-silence-therapeutics-atu-027-cancer.html
The notion of an absence of meaningful interferon stimulation makes particularly sense since Atu-siRNAs are heavily 2'-o-methylated which is predicted to abrogate TLR7/8 activation.
Lastly, based on slide 12 of the presentation, tumor sampling does not appear to be part of the study protocol so that Alnylam-type pharmacologic analyses such as drug concentrations in the tumor are unlikely to emerge. However, since Atu027 is a vascular endothelial-targeted formulation, determining drug plasma concentrations should have similar predictive value in terms of biodistribution.
Actually, I'm surprised that we are discussing this issue on this blog and that the company has not issued a press release to explain the results. It almost seems like the Company has an interest in the share price not to go up and instead would prefer a highly dilutive financing... just kidding ;)
Dirk,
Do you know if Atu-027 was dosed with any accompanying immune-modulating treatment, such as dexamethasone?
It seems unlikely that it would be tolerated so well without some sort of additional agents to help mitigate the complement cascades that tend to result from these types of charged particles.
Will you post on the US finalisation of the Graham ‘099 Patent Re-Examination Certificate for Benitec yesterday and it's implications for RNAi companies?
On whether Atu-027 involved some immuno-modulating pre-treatment: As far as I am aware, not. In fact, on page 14 they make a big deal around the fact that Atu027 did not require any pre-medication (hint, hint...).
RE Benitec '099 re-issuance: I had already blogged about it a few months ago: http://rnaitherapeutics.blogspot.com/2010/09/beniteccsiro-win-major-patent-battle-in.html
Will have to re-visit the claims though and whether anything has changed since. If not really, then I see no need for another post.
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