On Monday at ASCO 2011, Silence Therapeutics provided an extensive update on its ongoing phase I trial of Atu027 for the treatment of advanced solid tumors (additional background on Atu027 and the current study provided here and here). While there are a few signs already that the drug candidate may have some anti-tumor activity, the even more important message was that Atu027 has been remarkably safe and well tolerated, while reaching drug exposures in the ongoing dose escalation at which, based on the pre-clinical experience, bona fide RNAi knockdown of the targeted gene can be expected.
In cancer drug development in particular, the name of the game in phase I trials is to test how much drug can be given without causing severe, dose-limiting toxicities. Often, in studies like this one, patients of highly varied, late-stage cancers are enrolled and too few of them are treated at the high dose levels. In that regard, the trial progress can be called quite satisfactory in that no dose-limiting toxicities were reported and the SAEs judged as unrelated to study drug. The most commonly reported side-effect was minor grade 1 fatigue. It is possible that this is drug-related, although many cancer patients suffer from fatigue for many reasons. Also of note, and as indicated in the abstract, the observed complement activations were transient and not clinically significant.
Making the safety findings even more meaningful, the measured pharmacokinetic data indicate that the drug was safe at concentrations in the blood where RNAi knockdown can be expected based on the preclinical studies in rodents and monkeys and the known knockdown potency of the RNAi trigger in tissue culture cells.
There were also preliminary signs of anti-tumor efficacy. 9 of the 24 patients had stable disease one week after receiving the last of 9 doses 2 months after study initiation, 6 of which remained stable until the end of the study (3 months after initiation). Moreover, there were two cases where tumor masses were notably reduced. Particularly notable was the case of the individual with the neuroendocrine cancer where a 2-3cm tumor mass disappeared following the re-peat administration of Atu027 (see also my earlier blog on the abstract). However, none of these apparent responses could be scored as responses by stringent RECIST criteria. It is possible that this is because other masses present in those patients did not respond. Also, stable disease did not appear to be dose-related, which may not be surprising given that most of the 24 patients enrolled so far were not given pharmacologically relevant dosages.
Considering the safety profile so far, i.e. the absence of dose-limiting and other dose-proportional toxicities, I am hopeful that even higher dosages will be tolerated. Silence Therapeutics may even want to seek an extension of the study should the remaining 3 dose cohorts remain uneventful in terms of safety. As for Alnylam’s ALN-VSP02, the future development plan, especially a narrower patient selection and combination treatments, remain unclear and will be best explored in collaboration with a larger partner so that Atu027 can test and reach its full potential in a timely manner. Further investments seem more than justified and the main risk may be in the drug target.