Corporate Banner
Satellite Banner
Pharma Outsourcing
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 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 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
Scientific News
Liquid Biopsies: Utilization of Circulating Biomarkers for Minimally Invasive Diagnostics Development
Market Trends in Biofluid-based Liquid Biopsies: Deploying Circulating Biomarkers in the Clinic. Enal Razvi, Ph.D., Managing Director, Select Biosciences, Inc.
Study Questions Presence in Blood of Heart-Healthy Molecules from Fish Oil Supplements
A new study from the Perelman School of Medicine at the University of Pennsylvania questions the relevance of fish oil-derived SPMs and their purported anti-inflammatory effects in humans.
Experimental MERS Vaccine Shows Promise in Animal Studies
A two-step regimen of experimental vaccines against Middle East respiratory syndrome (MERS) prompted immune responses in mice and rhesus macaques, report National Institutes of Health scientists who designed the vaccines.
Young South African Women can Adhere to Daily PrEP Regimen as HIV Prevention
NIH-funded study finds men in Bangkok, Harlem also successful in taking daily dose.
Key Player in Diabetic Kidney Disease Revealed
Discovery could lead to new and better diagnostic marker for chronic kidney disease.
Immunotherapy Shows Promise for Myeloma
A strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
Santhera Announces First Patient Dosing with Omigapil in CMD
Company announces full patient recruitment of CALLISTO study.
Study Shows Promise of Precision Medicine for Most Common Type of Lymphoma
The study appeared online July 20, 2015, in Nature Medicine.
HIV Control Through Treatment Durably Prevents Heterosexual Transmission of Virus
NIH-funded trial proves suppressive antiretroviral therapy for HIV-infected people effective in protecting uninfected partners.
Adaptimmune's Novel Cancer Therapeutics Show Positive Clinical Trial Results
The company has announced that positive data from its Phase I/II study of its affinity enhanced T-cell receptor (TCR) therapeutic targeting the NY-ESO-1 cancer antigen in patients with multiple myeloma has been published.
Scroll Up
Scroll Down
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!