Rare Disease Report

Hemophilia Treatment Candidate Posts Promising Results

JULY 07, 2015
ALN-AT3’s Potent AT Knockdown Punch Tied to Several Statistically Significant Endpoints

According to recently presented interim Phase 1 data,1 ALN-AT3 - an investigational RNA interference (RNAi) therapy manufactured by Cambridge, Massachusetts-based Alnylam Pharmaceuticals - has demonstrated robust potential as a future treatment option for hemophilia and other rare bleeding disorders (RBDs).

The international, multi-site (Bulgaria, Russia, Switzerland and the UK) ongoing Phase 1 trial was segmented into 3 components. Parts A and B are now complete. Part C, currently underway, is slated for completion later this year.

The study is being conducted to evaluate the safety and tolerability of utilizing multiple doses of subcutaneous ALN-AT3 to treat hemophilia. Its other primary goal is assessment of the agent’s clinical activity, utilizing metrics such as circulating antithrombin (AT) levels and thrombin generation.

AT is a liver-expressed plasma protein that acts as an anticoagulant by inactivating Factor Xa and thrombin.1 Thrombin is an enzyme which promotes blood clotting.2

ALN-AT3 belongs to a therapeutic class that harnesses the natural cellular process of gene silencing, employing small interfering RNA (siRNA).3

Interim Results Provide Evidence of Safety, Efficacy

Reported data focused upon outcomes observed in the Part B population. The Part B component of the study was an open-label, multi-dose, dose-escalation study of 12 subjects with severe hemophilia A or B. Patients were dosed subcutaneously with an escalating dose of ALN-AT3 (15, 45 and 75 mcg/kg) at a frequency of once per week over a duration of 3 weeks.

  < 33%
AT knockdown
33 - 66%
AT knockdown
 > 66%
AT Knockdown
Subjects (n) 12 9 2
Cumulative Days 509 414 106
Peak Thrombin Generation (PTG) (mean) 18 + 8 nM 35 + 24 nM 120 + 81 nM *
% Increase PTG (mean) 25 + 72% 69 + 92% 350 + 239%*
Cumulative Bleeds 33 + 5 14 + 5 0
Estimated ABR (mean)** 22 14 0
* P < .05 (compared to >33% group)
** P < .001

To date, there have been no serious adverse events or discontinuations in this or any of the studies. Akshay Vaishnaw, MD, PhD, Executive Vice President of R&D and Chief Medical Officer, Alnylam Pharmaceuticals stated, “ALN-AT3 has continued to be generally well tolerated, including no clinically significant increases in D-dimer levels.” D-dimer is an established marker of pathological clot formation.4

Findings further indicated that ALN-AT3 affected a dose-dependent and statistically significant (P < .05) AT knockdown of up to 86%. Moreover, this AT knockdown effect was discovered to be highly durable. Effects lasted for more than 2 months after subjects received their final dose of the drug.

The relationship between levels of AT knockdown and thrombin generation was analyzed by means of a post hoc analysis which segregated AT knockdown levels into 3separate categories or “tertiles.” In the highest tertile (greater than 66% AT knockdown), ALN-AT3 administration resulted in mean increases in thrombin generation of 350 ± 239% (P < .05). In fact, the levels of thrombin generation (120 ± 81 nM peak thrombin) in the highest tertile were comparable to levels observed in the healthy subjects (120 ± 33 nM peak thrombin) who participated in Part A of the Phase 1 study. 

“The ability of ALN-AT3 to potentially increase thrombin generation in severe hemophilia subjects toward normal levels is an important finding,” noted Claude Negrier, MD, PhD, Professor of Medicine, Claude Bernard University and Chairman of the Hematology Division at Edouard Herriot University Hospital and Louis Pradel Cardiology Hospital, Lyon, France. Thrombin generation is a known biomarker for bleeding frequency and severity in people with hemophilia.5

Although the Phase 1 study was not designed to evaluate the effects of ALN-AT3 on bleeding, a post hoc analysis was performed which examined the frequency of bleeding events in all Part B study subjects. Once AT knockdown exceeded 66%, the mean estimated annualized bleeding rate (ABR) was decreased to 0. The reduced ABR associated with increased AT knockdown was found to be statistically significant (P < .001). The study subject who experienced the highest degree of AT knockdown remained bleed-free for an interval of 114 days.

Further Research Planned

“We regard these new results as very promising,” concluded Dr. Vaishnaw. Final data from the study reported upon herein is expected by the end of the year. Dr. Vaishnaw also reported that the company has set a date (mid-2016) for the initiation of a Phase 3 clinical trial.

Rare Disease Pearls - Hemophilia

  • Hemophilia A and B are hereditary disorders caused by genetic deficiencies which impact the functionality of various blood clotting factors (Factors VIII and IX respectively). Other RBDs, exponentially more rare, are defined by deficiencies of other blood coagulation factors. Hemophilia and hemophilia-type RBDs can result in recurring bleeds into joints, muscles and other major internal organs.6
  • Currently, the number of people with hemophilia in the United States (which overwhelmingly afflicts men but also, in extremely rare cases, presents in women) is estimated to be about 20,000.7 Worldwide, roughly 1 in 5,000 male births is impacted by hemophilia.7 The prevalence of other RBDs is even more rare: Approximately 1,000 people worldwide possess a severe bleeding phenotype.3


  1. Sorensen B, Mant T, Georgiev P, et al. A subcutaneously administered investigational RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment in hemophilia: phase 1 study results in subjects with hemophilia A and B. Presented on June 23, 2015, at the 2015 International Society on Thrombosis and Haemostasis Congress, Toronto, Canada.
  2. Merriam Webster Dictionary website. http://www.merriam-webster.com/dictionary/thrombin Accessed on July 8, 2015.
  3. Alnylam Reports New Positive Clinical Data for ALN-AT3, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders (press release). Published June 23, 2015. http://investors.alnylam.com/releasedetail.cfm?ReleaseID=919144 Accessed July 6, 2015.
  4. Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009:113(13)2878-2887.
  5. Dargaud Y, Beguin S, Lienhart A, et al: Evolution of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 2005;93:475-480.
  6. National Human Genome Research Institute website. Learning about hemophilia.   https://www.genome.gov/20019697 Accessed July 8, 2015.
  7. Centers for Disease Control and Prevention web site. Hemophilia homepage (Data and Statistics). http://www.cdc.gov/ncbddd/hemophilia/data.html Updated August 26, 2014. Accessed July 7, 2015.

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