It is 6 o’clock in the morning in my part of the world, have not slept all night, but am more awake now than I have been for a long time: The ASCO abstracts on Silence Therapeutics’ Atu027 (for advanced solid cancers) and Alnylam’s ALN-VSP02 (for cancers with liver involvement) have just been released and both surpassed my already optimistic expectations (copies of abstracts, see below).
For one, I fully expected to learn about additional warts with regards to the safety profile of the drug candidates, aspects that the companies may have chosen to ignore until now for obvious reasons. This, however, was not the case. Atu027 seems to be remarkably innocuous and well tolerated at doses where we can expect to see anti-tumor activity based on the pharmacological evidence. No dose-limiting toxicities (DLTs) and no cytokine inductions with this positively charged lipid-siRNA formulation! ALN-VSP02 also did very well in that only one additional DLT at the very high 1.5mg/kg dose (a case of hypokalemia, i.e. too little potassium) was disclosed that we had not heard of before. Together, Atu027 and ALN-VSP02 demonstrate that lipid-siRNA/nucleic acid formulations are clinically viable indeed.
On the efficacy front, Atu027 exceeded my expectations considerably. Keeping in mind that this has been a small phase I study (abstract relates to the first 21 patients and dose escalation still ongoing), the fact that one patient with highly advanced (an enrolment criteria) neuroendocrine cancer had disease stabilization for 9 months and another had a partial regression of pulmonary metastases sounds very encouraging already and would seem to justify a more targeted phase I study in this patient population, but considering that there was still another breast cancer patient that had regression of liver metastases (breast cancer patients die from such metastases, not the primary cancer) makes it even more impressive and almost more than just ‘anecdotal’ evidence of anti-tumor efficacy.
The clinical investigators of Alnylam’s ALN-VSP02 also had some new intriguing data to report with regard to efficacy: while only 1 of 12 patients up to 0.4mg/kg had stable disease for at least 2 months, 7 of 15 had stable disease for that time period if given more than 0.4mg/kg. This does not look like chance at all and maybe these mouse experiments tell us something about the potential of RNAi Therapeutics for cancers after all. The only clarification that I hope to get is whether some of that difference might be explained by a difference in baseline characteristics, especially in light of the fact that the enrolment criteria had been adjusted at 0.7mg/kg to limit the extent of liver metastases a trial participant could have.
With the abstracts released, all eyes are now on the data presentation at the actual Meeting in 2-3 weeks’ time. We should then learn of more details related to the data contained in today’s abstracts, and with the appetite thus wetted….updates from the more recent patients in the higher dose groups for Atu027 (every additional cohort is a significant plus) and the dose expansion phase of ALN-VSP02.
The sleep is finally over, lots more RNAi Therapeutics clinical data to come.
First-in-human phase I study of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3) in patients with advanced solid tumors.
Background: Atu027 is a novel RNAi therapeutic based on cationic lipoplexes containing chemically stabilized siRNAs, which targets PKN3 gene expression in the vascular endothelium. PKN3 acts as a downstream effector of PI3K-signaling pathway and is implicated in controlling cellular morphology and locomotion in endothelial and cancer cells. Preclinical data obtained in various cancer mouse models revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metastasis formation. Methods: Patients (pts) (ECOG PS 0-2) received Atu027 as a single 4h-infusion with 3wks follow-up, and were thereafter treated twice weekly over another four week period. Upon SD, pts were given the opportunity to continue until PD. Dose escalation was accompanied by assessment of data related to toxicity and pharmacokinetics (PK). Results: The study design comprises 11 escalating doses. To date, 21 pts have received Atu027 of seven dose levels up to 0.120 mg/kg. Mean age = 62.4 years (range 29-81), 12 female, 9 male. No premedication was required. No cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6) was observed. In some subjects transient activation of the complement system (C3a, Bb, sC5b-9) was found, but without any clinical relevance. Preliminary PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Across the dose levels tested, Atu027 was generally well-tolerated. Adverse events possibly related to Atu027 were fatigue grade (G)1 (4pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (1 pt, DL2) and diarrhea (1 pt, DL5). No dose limiting toxicities (DLTs) were seen so far. Stable disease after 3 months was observed in 6 pts. Two pts with neuroendocrine cancer had disease stabilization for 9 months, and partial regression of pulmonary metastases, respectively. Another patient with breast cancer had regression of liver metastases.Conclusions: Atu027 is well-tolerated and antitumor activity has been observed. Accrual is ongoing to determine the MTD of Atu027.