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

Alnylam Presents New Pre-clinical Data on ALN-AT3

Published: Tuesday, December 10, 2013
Last Updated: Tuesday, December 10, 2013
Bookmark and Share
New results demonstrate an expanded therapeutic index for AT knockdown and complete correction of aPTT in models of hemophilia.

Alnylam Pharmaceuticals, Inc. has announced that it has presented new pre-clinical data with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD), at the 55th Annual Meeting of the American Society of Hematology (ASH) held December 7 - 10, 2013 in New Orleans.

In these new studies, repeat administration of ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than levels required to achieve 50% AT knockdown.

Further, the new studies demonstrate that ALN-AT3 administration achieves complete correction of the activated Partial Thromboplastin Time (aPTT) - an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia - in HA mice. ALN-AT3 is a key program in the company’s “Alnylam 5x15” product strategy, which is aimed at advancing five RNAi therapeutic programs directed toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015.

“Hemophilia and other rare bleeding disorders are characterized by deficiencies in specific clotting factors that ultimately lead to inadequate thrombin generation and a bleeding diathesis. ALN-AT3 is aimed at correcting these bleeding disorders by knockdown of AT - an endogenous anticoagulant - thus, increasing thrombin generation and improving hemostasis,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “These new data presented at ASH demonstrate that repeat administration of ALN-AT3 is well tolerated in animal models of hemophilia, and suggest that our RNAi therapeutic has the potential for a wide therapeutic index in subjects with hemophilia. With MHRA approval of our recently filed CTA, we look forward to the advancement of ALN-AT3 in our Phase I clinical trial that we expect to start in early 2014, with data from hemophilia subjects expected by the end of next year.”

“The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients that develop inhibitory antibodies to their replacement factor. Indeed, availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis,” said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. “I continue to be encouraged by Alnylam’s pre-clinical progress to date with ALN-AT3, including these new data demonstrating a wide therapeutic index and correction of aPTT for ALN-AT3 in animals with hemophilia. I look forward to the advancement of this innovative therapeutic candidate in clinical studies in the months to come.”

In a presentation titled “Expanded Therapeutic Index of Antithrombin Silencing and Correction of APTT in a Hemophilia A Mouse Model,” Alnylam scientists presented data demonstrating that, in contrast to wild type (WT) mice, repeat administration of ALN-AT3 was very well tolerated in HA mice. Specifically, HA mice treated with ALN-AT3 exhibited no adverse events up to 100 mg/kg – a dose that is 200-fold greater than the mouse ED50 and that essentially ablates AT protein levels in blood.

In fact, 100% of the treated HA mice survived, with no adverse clinical signs or changes to body weight parameters. In WT mice (with intact coagulation systems), repeat administration of over 10 mg/kg ALN-AT3 led to greater than 90% knockdown of plasma AT, and resulted in the expected procoagulant phenotype and poor tolerability. This result was expected since AT knockout in mice and homozygous AT deficiency in humans are known to be embryonic lethal (J. Clin. Invest. (2000) 106:873-878; Blood (2008) 112:19-27). To evaluate the potential reversal of ALN-AT3 efficacy, WT mice treated with 100 mg/kg ALN-AT3 were also treated with exogenous human AT protein.

Co-administration of human AT conferred complete protection from prothrombotic adverse events observed in WT mice receiving ALN-AT3 alone, demonstrating that human AT protein could serve as a potential reversal agent for ALN-AT3, if needed. In addition, HA mice treated with ALN-AT3 exhibited significant reductions in aPTT relative to control HA mice.

Specifically, the aPTT in HA mice, which is significantly prolonged, was corrected back to aPTT values observed in WT mice. Collectively, these data suggest a substantially expanded therapeutic index of AT knockdown in the hemophilia disease condition, and confirm the active effects for ALN-AT3 that are expected to reset insufficient thrombin generation in people with hemophilia.

Alnylam remains on track to begin a Phase I trial with ALN-AT3 early in 2014. Alnylam has announced that it has received CTA approval from the MHRA for the initiation of the Phase I clinical study. The study will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. Only low doses of ALN-AT3 will be administered in this part of the study with stopping rules at greater than 40% AT knockdown, which is believed to be a well tolerated level of AT knockdown based on pre-clinical studies, in addition to data from people with heterozygous AT deficiency. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels.

The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation.


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 3,700+ 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 Elects Amy Schulman to its Board of Directors
Appointment of industry leader brings broad strategic, commercial, and legal experience to board.
Saturday, July 05, 2014
Alnylam Announces USPTO Issues Patent Covering RNAi Therapeutics
New '277 McSwiggen patent includes broad, sequence-independent claims for chemically modified siRNAs targeting the HBV genome.
Saturday, June 14, 2014
Alnylam Presents New Pre-Clinical Data with Development Candidate for ALN-CC5
Company on track to file IND application in late 2014 and now guides to report initial clinical results in mid-2015.
Thursday, June 12, 2014
Alnylam Initiates Phase II Clinical Trial with ALN-TTRsc
Company expects to present data in late 2014, and start pivotal phase III trial with ALN-TTRsc in TTR cardiac amyloidosis in late 2014.
Monday, December 30, 2013
Alnylam Files CTA to Initiate a Phase I Study for ALN-AT3
Company expects to initiate phase I study in early 2014 with interim data from hemophilia subjects by year-end 2014.
Friday, November 01, 2013
Alnylam Scientists Present Pre-clinical Data with ALN-CC5, an RNAi Therapeutic
New research demonstrates potent, dose-dependent, and durable silencing of serum C5 for the treatment of complement-mediated diseases.
Friday, June 21, 2013
Alnylam Reports Positive ALN-TTR02 Clinical Data
Results of clinical study demonstrate rapid, dose-dependent, durable, and specific knockdown of TTR, the disease-causing protein in TTR-mediated Amyloidosis (ATTR).
Tuesday, July 24, 2012
Alnylam and Collaborators Publish New Pre-clinical Results
New paper published in blood shows potent and selective induction of liver erythropoietin through silencing of EglN genes.
Wednesday, June 13, 2012
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
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!