Date: 2015-07-27
Type of information: Initiation of the trial
phase: 1-2
Announcement: initiation of the trial
Company: Alnylam Therapeutics (USA - MA)
Product: ALN-AAT
Action
mechanism: RNAi. ALN-AAT is a subcutaneously administered investigational RNAi therapeutic that utilizes Alnylam\'s proprietary ESC-GalNAc-siRNA conjugate delivery technology. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Disease: AAT deficiency-associated liver disease (alpha-1 liver disease)
Therapeutic area: Rare diseases - Genetic diseases - Liver diseases
Country: UK
Trial
details: The Phase 1/2 trial of ALN-AAT is a randomized, single-blind, placebo-controlled study being conducted in three parts. Parts A and B are single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 48 healthy adult volunteers. Part C will be a multi-dose study designed to enroll up to a total of 24 adults with alpha-1 liver disease and mild-to-moderate liver fibrosis. The primary objective of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AAT. Secondary objectives include evaluation of pharmacokinetics and clinical activity for ALN-AAT as measured by knockdown of serum AAT. In addition, biopsies will be obtained from subjects with alpha-1 liver disease to quantify the effects of treatment on levels of periodic acid-Schiff (PAS)-stained globules, a measure of misfolded AAT accumulation observed in the livers of alpha-1 liver disease patients. (NCT02503683)
Latest
news: * On July 27, 2015, Alnylam Pharmaceuticals, a leading RNAi therapeutics company, announced that it has initiated a Phase 1/2 clinical trial with ALN-AAT, a subcutaneously administered investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease (alpha-1 liver disease). The Phase 1/2 trial will be conducted initially in normal healthy volunteers, and, then, in patients with alpha-1 liver disease. Initiation of this trial is based on encouraging pre-clinical data presented at the Digestive Disease Week (DDW) meeting May 16 - 19, 2015. The company expects to present initial clinical data from this trial in early 2016. * On May 17, 2015, Alnylam Pharmaceuticals 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 1/2 clinical trial with ALN-AAT, a subcutaneously administered investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease (alpha-1 liver disease). As per the CTA filing, the intended clinical study of ALN-AAT will be performed in normal healthy volunteers, and, then, in subjects with alpha-1 liver disease. As per the filed CTA, the Phase 1/2 trial of ALN-AAT will be a randomized, single-blind, placebo-controlled study conducted in three parts. Parts A and B will be single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 48 healthy adult volunteers. Part C will be a multi-dose study in adults with the PiZZ mutation in their AAT gene and with mild-to-moderate liver fibrosis. The primary objective of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AAT. Secondary objectives include evaluation of pharmacokinetics of ALN-AAT and clinical activity for ALN-AAT as measured by knockdown of serum AAT. In addition, biopsies will be obtained from subjects with alpha-1 liver disease to quantify the effects of treatment on levels of periodic acid-Schiff (PAS)-stained globules, a measure of AAT misfolding observed in the livers of alpha-1 liver disease patients. Consistent with previous guidance, the company expects that following approval of the CTA, it will initiate the Phase 1/2 study in late 2015, with initial data expected to be reported in early 2016. In addition, Alnylam scientists presented new pre-clinical data in an oral presentation at the Digestive Disease Week (DDW) meeting, held May 16 - 19, 2015 in Washington, D.C. In an oral presentation at DDW, Alnylam scientists presented new data demonstrating an up to 93% knockdown of serum AAT (mean 90 ± 2%) following monthly subcutaneous dosing with ALN-AAT in NHPs at a dose of 3 mg/kg. This level of knockdown was highly durable, lasting for greater than 30 days following the final dose. Further, ALN-AAT was found to have a wide therapeutic index based on results from GLP toxicology studies. Specifically, 13-week studies were performed in the rat and NHP with q2W doses and showed No Adverse Effect Levels (NOAELs) of greater than or equal to 50 mg/kg and 150 mg/kg, respectively; these dose levels were the top doses in both studies. In addition, study results were reported from a transgenic mouse model of alpha-1 liver disease, where mice overexpress the human Z-AAT protein. A single subcutaneous dose of ALN-AAT led to dose-dependent, durable and reversible knockdown of Z-AAT, with an ED50 of ~0.5 mg/kg, with mean Z-AAT knockdown of greater than 90% achieved following a single subcutaneous dose of 3mg/kg. As previously presented, sustained reduction of Z-AAT in aged transgenic mice with established liver disease led to improvement in tissue pathology, decrease in fibrosis, decrease in number of proliferating hepatocytes, and reduction in tumor burden as measured by both number and size of tumors.
