Corporate Banner
Satellite Banner
RNAi
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Alnylam and Collaborators Publish Results from Phase I Clinical Trial with RNAi Therapeutic

Published: Thursday, January 31, 2013
Last Updated: Thursday, January 31, 2013
Bookmark and Share
Results published in Cancer Discovery document most comprehensive human experience to date for RNAi therapeutics delivered with lipid nanoparticles (LNPs).

Alnylam Pharmaceuticals, Inc. and collaborators announced the publication of complete study results from a Phase I trial with ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. The paper, titled “First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement” appears as an OnlineFirst publication in the journal Cancer Discovery (Tabernero et al., Cancer Discovery CD-12-0429; Published OnlineFirst January 2013). The study results document anti-tumor activity for ALN-VSP in a heavily pre-treated and advanced patient population, including a complete response in an endometrial cancer patient who had multiple hepatic metastases. In addition, this study provided proof of RNAi mechanism in man based on molecular analysis of biopsy samples from patients. Finally, in this study – the most comprehensive study of a systemically administered RNAi therapeutic to date – chronic dosing of ALN-VSP for up to 26 months was found to be generally safe and well tolerated.

“Our ALN-VSP Phase I clinical trial defines the most comprehensive human experience for RNAi therapeutics delivered with lipid nanoparticle formulations. Results from this study highlight safety and tolerability of multiple doses of ALN-VSP, proof of RNAi activity in man, and evidence for anti-tumor activity in a very advanced, heavily pre-treated cancer patient population,” said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. “We are encouraged by the anti-tumor activity observed in this study in multiple patients who achieved stable disease or better; this includes a patient with endometrial cancer metastatic to the liver who achieved a complete response. Results from the extension study also give us increased confidence in long-term chronic dosing for RNAi therapeutics delivered with lipid nanoparticle formulations, as patients received an average of over 11 months of treatment overall, including one patient who received treatment for over two full years.”

ALN-VSP is a systemically delivered RNAi therapeutic using first-generation lipid nanoparticle (LNP) or “SNALP” delivery technology that comprises two siRNAs targeting two genes critical for the growth and development of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP). The ALN-VSP Phase I trial was designed as a multi-center, open-label, dose-escalation study in patients with advanced solid tumors with liver involvement who failed to respond to or had progressed after standard treatment. A total of 41 patients were enrolled. The primary objective was to evaluate the safety, tolerability, and pharmacokinetics of intravenously administered ALN-VSP given every two weeks. Other secondary and exploratory objectives included: assessment of tumor response using Response Evaluation Criteria for Solid Tumors (RECIST); quantitation of change in tumor blood flow and vascular permeability as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and, analysis of pharmacodynamic effects of ALN-VSP on tumors as measured in patients electing to proceed with voluntary pre- and post-treatment biopsies.

Results of the Phase I study in 41 patients were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2011 and demonstrated proof of RNAi mechanism based on liver biopsy samples and disease control (stable disease or better after first two months) in 13/31 (42%) patients treated at doses greater than or equal to 0.4 mg/kg. ALN-VSP was generally safe and well tolerated up to a dose of 1.0 mg/kg. The most common adverse events were grade 1-2 fatigue (24% of patients), nausea (17% of patients) and fever (17% of patients), with no clear dose relationship. There were also no dose-dependent changes in liver function tests. Grade 2 infusion-related reactions were observed in 15% of patients, or 3% of total doses administered; these reactions responded to slowing of the infusion of drug, and no patients discontinued therapy because of an infusion reaction. Dose-limiting toxicities included: liver failure and death in one patient with extensive hepatic metastases involving greater than 70% of liver mass and prior splenectomy/partial hepatectomy at 0.7 mg/kg; transient grade 3 thrombocytopenia in two patients at 1.25 mg/kg; and grade 3 hypokalemia in one patient at 1.5 mg/kg.

The ALN-VSP extension study was designed to enable continued dosing with ALN-VSP in patients who had achieved stable disease or better after completing four months of treatment on the Phase I trial. Patients enrolled onto the extension study were permitted to receive bi-weekly ALN-VSP at the same dose level that they had been safely treated with in the Phase I study until disease progression or unacceptable toxicity; a total of seven patients were enrolled. The primary objective was to collect long-term safety data. The secondary objective was to assess tumor response.

Results from the extension study were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2012 and demonstrated that chronic dosing with ALN-VSP up to 1.0 mg/kg was generally safe and well tolerated in this setting. On average, patients received bi-weekly treatments for 11.3 months. An endometrial cancer patient achieved a complete response (CR) after 20 months of treatment at 0.7 mg/kg and remained in remission upon completion of 26 months of therapy. A patient with pancreatic neuroendocrine tumor (PNET) treated at 1.0 mg/kg remained on study with stable disease (SD) for 18 months, and two patients with renal cell carcinoma (RCC) treated at 1.0 mg/kg remained on study with SD for approximately 8-12 months. No new toxicities were reported among the patients enrolled onto the extension study. A PNET patient and an RCC patient who achieved SD at 1.0 mg/kg came off the study after 5.5 and 8.5 months, respectively, for adverse events that included grade 3 elevated alkaline phosphatase or grade 2 fatigue deemed possibly related to study drug. A decrease in spleen volume, likely an on-target anti-KSP effect and not associated with any adverse events, occurred to a greater degree on the extension study than in the Phase I trial and was most pronounced in patients receiving 12 or more doses.

“Both primary liver cancer and metastatic disease of the liver are associated with poor prognosis for patients, and new therapies are clearly needed,” said Josep Tabernero, M.D., Chairman of the Medical Oncology Department and Phase I Program at Vall d’Hebron University Hospital in Barcelona, Spain. “This Phase I trial and extension study with ALN-VSP represents, to our knowledge, the most comprehensive clinical trial of a systemically delivered RNAi therapeutic and also the most extensive experience with RNAi therapeutics in cancer. The safety data and anti-tumor activity with ALN-VSP, including a complete response in a patient with multiple liver metastases who had failed multiple prior therapies, are very encouraging and I look forward to the further development of this promising agent.”

In 2012, Alnylam and Ascletis Pharmaceuticals (Hangzhou) Co., Ltd., a privately held U.S.-China joint venture pharmaceutical company, formed a strategic collaboration for the development of ALN-VSP in China. Alnylam will retain all rights in the rest of the world, and is eligible to receive milestones and royalties from Ascletis based on product sales.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Alnylam Receives Notice of Allowance from USPTO
Allowed claims of Manoharan '478 application cover GalNAc-conjugates independent of length, sequence, and disease target.
Saturday, July 26, 2014
Alnylam Reports Positive Phase II Data for Patisiran (ALN-TTR02)
New results in ATTR patients show up to 96% knockdown of TTR with activity toward both wild-type and mutant TTR.
Tuesday, November 12, 2013
Alnylam Reports Positive Phase II Data for ALN-TTR02, an RNAi Therapeutic
Interim results in ATTR patients show up to 93% knockdown of TTR with activity toward both wild-type and mutant TTR.
Monday, July 01, 2013
Alnylam and PBL Sign License Agreement for Baulcombe & Hamilton RNAi Patent
PBL has granted Alnylam a world-wide, non-exclusive license to the Baulcombe patent for use in the field of human therapeutics.
Thursday, May 24, 2012
Alnylam and Arrowhead Form Collaboration and Licensing Agreement
Alnylam has granted Arrowhead a license under its intellectual property that enables the discovery, development, and commercialization of an RNAi therapeutic targeting the hepatitis B virus (HBV).
Thursday, January 05, 2012
Alnylam Reports Positive Preliminary Clinical Results for RNAi Therapeutic
The company achieved positive preliminary results from its ongoing clinical trial of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. ALN-PCS demonstrated statistically significant RNAi silencing of PCSK9 of up to 66% and reductions of up to over 50% in levels of low-density lipoprotein cholesterol (LDL-C), a clinically validated endpoint.
Wednesday, January 04, 2012
Alnylam and MIT Collaborators Discover Novel “Core-Shell” Nanoparticles for Systemic Delivery of RNAi Therapeutics
Development of novel nanoparticles that have optimal chemical and physical properties for effective intracellular delivery of RNAi therapeutics.
Tuesday, July 26, 2011
Alnylam, MIT Team Up for 'Binary' Approach to Delivering siRNA
New data describes new approach for systemic delivery of RNAi therapeutics using combinations of lipid-like materials called "lipidoids.”
Monday, July 25, 2011
Alnylam Biotherapeutics Presents Data on new Applications of RNAi Technology for Biologics Manufacturing
siRNAs targeting vesivirus potently block CHO cell infection, highlighting uses of RNAi technologies to prevent or treat viral infections in bioprocessing.
Friday, November 19, 2010
Alnylam Grants new InterfeRx™ Intellectual Property License to Tekmira
Agreement aims to develop and commercialize of TKM-Ebola, an RNAi therapeutic for the treatment of Ebola Virus Infection.
Monday, November 08, 2010
Alnylam and Collaborators Publish new Pre-clinical Research on Therapeutic Silencing of Parkinson's Disease Gene
New Research shows silencing of alpha-synuclein in the Substantia Nigra of non-human primates with an RNAi therapeutic.
Tuesday, August 31, 2010
Alnylam and Collaborators Discover Key Mechanism for Delivery of RNAi Therapeutics
Data Reveals an endogenous targeting mechanism for systemic delivery of RNAi therapeutics to liver using lipid nanoparticles.
Monday, January 11, 2010
Alnylam and Collaborators at MIT Report New Pre-clinical Research on Systemic Delivery of RNAi Therapeutics
Findings published in PNAS highlight discovery of novel “Lipidoids,” lipid-like materials, for low dose in vivo gene silencing.
Wednesday, December 30, 2009
Alnylam Presents Pre-Clinical Data on ALN-TTR for the Treatment of Transthyretin-Mediated Amyloidosis
New data demonstrate durable in vivo efficacy for ALN-TTR at the 60th Annual Meeting of the American Association for the Study of Liver Diseases.
Tuesday, November 03, 2009
Alnylam Grants KOKEN License to Kreutzer-Limmer Patents for the RNAi Research Products Market
The non-exclusive worldwide license enables KOKEN to manufacture and provide RNAi research products and services under the Kreutzer-Limmer patent family.
Wednesday, October 28, 2009
Scientific News
Microscopic Fish are 3D-Printed to do More Than Swim
Researchers demonstrate a novel method to build microscopic robots with complex shapes and functionalities.
Inciting an Immune Attack on Cancer Cells
A new minimally invasive vaccine that combines cancer cells and immune-enhancing factors could be used clinically to launch a destructive attack on tumors.
Reprogramming Cancer Cells
Researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.
New Strategy for Combating Adenoviruses
Using an animal model they developed, Saint Louis University and Utah State university researchers have identified a strategy that could keep a common group of viruses called adenoviruses from replicating and causing sickness in humans.
Surprising Mechanism Behind Antibiotic-Resistant Bacteria Uncovered
Now, scientists at TSRI have discovered that the important human pathogen Staphylococcus aureus, develops resistance to this drug by “switching on” a previously uncharacterized set of genes.
Fat in the Family?
Study could lead to therapeutics that boost metabolism.
Imaging Software Could Speed Up Breast Cancer Diagnosis
Researchers use high speed optical microscopy of intact breast tissue specimens to analyze breast tissue.
A Metabolic Master Switch Underlying Human Obesity
Researchers find pathway that controls metabolism by prompting fat cells to store or burn fat.
Synthetic DNA Vaccine Against MERS Shows Promise
A novel synthetic DNA vaccine can, for the first time, induce protective immunity against the Middle East Respiratory Syndrome (MERS) coronavirus in animal species.
How Small RNA Helps Form Memories
In a new study, a team of scientists at Scripps Florida has found that a type of genetic material called "microRNA" (miRNA) plays surprisingly different roles in the formation of memory in animal models.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!