First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement.
RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer.


CONCLUSIONS
The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.
Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net
Josep
J
Tabernero
Geoffrey I
GI
Shapiro
Patricia M
PM
LoRusso
Andres
A
Cervantes
Gary K
GK
Schwartz
Glen J
GJ
Weiss
Luis
L
Paz-Ares
Daniel C
DC
Cho
Jeffrey R
JR
Infante
Maria
M
Alsina
Mrinal M
MM
Gounder
Rick
R
Falzone
Jamie
J
Harrop
Amy C Seila
AC
White
Iva
I
Toudjarska
David
D
Bumcrot
Rachel E
RE
Meyers
Gregory
G
Hinkle
Nenad
N
Svrzikapa
Renta M
RM
Hutabarat
Valerie A
VA
Clausen
Jeffrey
J
Cehelsky
Saraswathy V
SV
Nochur
Christina
C
Gamba-Vitalo
Akshay K
AK
Vaishnaw
Dinah W Y
DW
Sah
Jared A
JA
Gollob
Howard A
HA
Burris
D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D016207:Cytokines; C470243:KIF11 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016547:Kinesins