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

Alnylam Files CTA to Initiate a Phase I Study for ALN-AT3

Published: Friday, November 01, 2013
Last Updated: Friday, November 01, 2013
Bookmark and Share
Company expects to initiate phase I study in early 2014 with interim data from hemophilia subjects by year-end 2014.

Alnylam Pharmaceuticals, Inc. has announced that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia, including people with “inhibitors.”

Hemophilia is a hereditary disorder caused by genetic deficiencies in various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs.

By knocking down AT, ALN-AT3 administration is expected to increase thrombin generation and reduce disease burden, including annualized bleeding rate, severity of bleeding, and requirement for replacement factor or bypass agent, and to potentially improve quality of life.

ALN-AT3 is a key program in the company’s “Alnylam 5x15” product development and commercialization strategy, in which the company aims to advance five RNAi therapeutic programs toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015.

“Hemophilia is characterized by a genetic deficiency in clotting factors that ultimately leads to inadequate thrombin generation and a bleeding disorder. ALN-AT3 aims to correct the hemostatic imbalance in hemophilia by knocking down AT - an endogenous anticoagulant – thus increasing thrombin generation and improving hemostasis, and reducing disease burden. This innovative approach is strongly supported by clinical cases in people with hemophilia who have co-inherited prothrombotic traits, including AT deficiency, and are characterized by a milder bleeding phenotype,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer at Alnylam.

Vaishnaw continued, “This CTA for ALN-AT3 marks our second for an RNAi therapeutic that utilizes our proprietary GalNAc conjugate delivery platform, which we have now shown to be clinically validated. Our pre-clinical data with ALN-AT3 have demonstrated normalization of thrombin generation and improvement of hemostasis in hemophilia models. We have also demonstrated that ALN-AT3 has a wide therapeutic index in the context of hemophilia. We very much look forward to the continued advancement of ALN-AT3, including the start of our Phase I clinical trial in early 2014 with data from hemophilia subjects expected by the end of that year.”

ALN-AT3 is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand. GalNAc-siRNA conjugates are a proprietary, clinically validated delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor.

Pre-clinical studies have shown that subcutaneous administration of ALN-AT3 can normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model.

A single subcutaneous dose of ALN-AT3 that resulted in plasma AT reduction of approximately 90% led to normalization of thrombin generation and improvement in hemostasis in hemophilia mice. In wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible silencing of plasma AT.

Weekly subcutaneous doses of 0.50 mg/kg resulted in 90% AT knockdown, while an ED50 knockdown was achieved at a dose as low as 0.125 mg/kg. Furthermore, in an NHP “inhibitor” model, in which a hemophilia A (HA) phenotype was induced via administration of a polyclonal anti-factor VIII antibody, ALN-AT3-treated animals showed the expected level of AT knockdown but also showed a statistically significant (p<0.01) dose-dependent increase in thrombin generation, fully restoring this hemostatic parameter back to normal levels. We believe these results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key proof of concept for the program. In addition, single doses of ALN-AT3 as high as 500 mg/kg - over 100-fold greater than doses that result in essentially complete ablation of AT - were well tolerated in HA mice: 100% of animals survived, and there were no toxicologically significant findings in clinical or pathology exams.

As per the filed CTA, the Phase I trial of ALN-AT3 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.

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 3,800+ 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 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 Presents New Pre-clinical Data on ALN-AT3
New results demonstrate an expanded therapeutic index for AT knockdown and complete correction of aPTT in models of hemophilia.
Tuesday, December 10, 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
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!