Thursday, May 17, 2012

ASCO 2012: Silence and Alnylam Provide Update on RNAi Therapeutics Candidates for Solid Cancer

It is this time of the year again when abstracts for the upcoming ASCO mega-cancer meeting are released (ASCO 2012 in Chicago, June 1-5).  Among the poster abstracts were phase I updates for Atu027 by Silence Therapeutics and ALN-VSP02 by Alnylam for advanced solid cancers and cancers with liver involvement, respectively.  Although the full details are yet to be presented at the meeting and the abstract date was in early February (this particularly means that critical data from the high-dose cohorts for Atu027 are missing), I will post here the abstracts as appetizers, each one followed by some brief comments. Highlights are mine.


Abstract No. e13597 by Silence Therapeutics

Antimetastatic activity of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3): Final results of a phase I study in patients with advanced solid tumors.

Developmental Therapeutics - Experimental Therapeutics

Author(s): Dirk Strumberg, Beate Schultheis, W Meyer-Sabellek, C. Vank, F Gebhardt, A. Santel, O. Keil, K. Giese, J. Kaufmann, Joachim Drevs; University of Bochum, Marienhospital Herne, Department of Internal Medicine III, Herne, Germany; Silence Therapeutics AG, Berlin, Germany; Tumorzentrum UniFontis am Eduarduskrankenhaus, Köln, Germany

Background: Atu027 contains siRNA-lipoplexes, which elicits RNAi mediated suppression on PKN3 in vascular endothelial cells. In various xenograft mouse models, silencing of PKN3 expression and significant inhibition of invasive growth, lymph node and pulmonary metastasis formation was shown. Methods: Atu027 was applied to patients (pts) as a single 4h-infusion with subsequent follow-up for 3 wks. Thereafter pts were treated twice weekly for 4 weeks. In case of SD, pts were treated until PD. Dose escalation was associated with assessment of toxicity, pharmacokinetics (PK), and multiplex biomarker analyses in plasma from treated pts. Results: A total of 33 pts have received Atu027 of 11 dose levels (DL) up to 0.336 mg/kg. No pre-medication 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. PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Among various biomarkers tested, sVEGFR-1 plasma levels decreased significantly upon treatment. Across all dose levels, Atu027 was well-tolerated. Adverse events possibly related to Atu027 were fatigue grade G1 (6pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (2 pts, DL2+DL10) and diarrhea (1 pt, DL5). So far, no DLTs were seen in the last DL. Stable disease after 3 and 6 months was observed in 10 and 3 pts, respectively. Two pts with neuroendocrine cancer had disease stabilization for 9 and 12 months, respectively, including partial regression of pulmonary metastases in 1 pt. Another patient with breast cancer had regression of liver metastases.Conclusions: Atu027 is well-tolerated and anti-metastatic activity has been observed. Soluble VEGFR-1 might serve as a biomarker. So far, 0,336 mg/kg is the recommended dose for further phase II trials.

Comments: Importantly, dose escalation in this dose-finding study could proceed to the second highest planned dose level (0.336mg/kg), which at least based on the previously presented PK data should be well above the dose necessary (~0.25mg/kg) for obtaining solid target gene knockdown in endothelial cells.  As 0.336mg/kg was dose cohort 10 (up to 11 planned) and 33 patients have been dosed, this means that one cohort probably included 6 instead of 3 the subjects. I am curious to learn the reason for this in June and particularly will be looking for more insight on the complement activations which have been described to be ‘without any clinical relevance’.  Also of interest is that the soluble version of the VEGF-receptor 1 was found to decrease significantly upon treatment (maybe as an adaptation to an anti-angiogenic mechanism of Atu027?) leading the company to speculate that this could serve as a biomarker in future trials.  On the efficacy front, still nothing really conclusive can be said and there were no additional ‘hints’ of efficacy in the higher dose cohorts as one might have hoped.   Overall, however, I look forward to the updated and fleshed-out data in 2 weeks.

For a discussion of the Atu027 results at last year’s ASCO meeting, click here.

Abstract No. 3062 by Alnylam Pharmaceuticals

Developmental Therapeutics - Experimental Therapeutics

Author(s): Maria Alsina, Josep Tabernero, Geoffrey Shapiro, Howard Burris, Jeffrey R. Infante, Glen J. Weiss, Andres Cervantes-Ruiperez, Mrinal M. Gounder, Luis Paz-Ares, Rick Falzone, Jamie Hill, Jeffrey Cehelsky, Akshay Vaishnaw, Jared Gollob, Patricia LoRusso; Molecular Therapeutics Research Unit, Vall d'Hebron University Hospital, Barcelona, Spain; Dana-Farber Cancer Institute, Boston, MA; Sarah Cannon Research Institute, Nashville, TN; Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Memorial Sloan-Kettering Cancer Center, New York, NY; University Hospital - Virgen del Rocio, Seville, Spain; Alnylam Pharmaceuticals, Cambridge, MA; Karmanos Cancer Institute, Detroit, MI

Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.

Comments: Final results for this study were presented at last year’s ASCO meeting (for a discussion click here). The new data relate to the open-label extension phase which is of particular interest as it relates to the longer-term safety and tolerability of ALN-VSP02, and possibly first-generation SNALP delivery technology in general.  It is too early to tell to what extent siRNA sequence and modification-dependent effects played a role, but the apparent spleen toxicity is consistent with what one might expect from such formulations. Although the spleen is not an essential organ and most of us will do just fine without one, this could become a dicey issue for a chronically dosed drug like ALN-PCS02 in a ‘lesser’ disease such as many types of hypercholesterolemia.  Overall, however, this is an encouraging start for the longer-term safety of SNALP delivery technology.  Based on the indications of efficacy, another more focused study may be warranted before a final determination as to the viability of ALN-VSP02 for the treatment of cancers with liver involvement.


Anonymous said...

From the sound of it you're sceptical about the Silecne trial wrt the 33 vs 10 cohorts and the lack of any additional comments re possible efficacy in ATU027?

Dirk Haussecker said...

I'd like to see the ASCO poster first before revisiting the issue of whether Atu027 deserves further support or not. I'm also curious whether the next Financing will come before or after ASCO.

Anonymous said...

This is all ground breaking data, looks like the beginning of these drugs becoming the new treatment modality at last something really new to treat sick patients. We so need to get away from the current mindset

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