Arrowhead Research Corporation a biopharmaceutical company that develops targeted RNAi therapeutics, recently announced that they have completed dosing in healthy volunteers and will now start dosing patients in an on-going Phase 1 clinical trial of the company lead candidate, ARC-AAT, for the treatment of Alpha-1 Antitrypsin Deficiency (AATD).
Alpha-1 Antitrypsin Deficiency is a genetic condition that affects and damages the lungs and liver. The trial began dose escalation of healthy volunteers and is now transiting into patients (Part B) because the predefined knockdown target was achieved. The knockdown target was set at a minimum of 30% reduction in the levels of AAT serum, in 3 subjects or higher than 60% reduction in one participant. The researchers achieved this target during the third cohort. In terms of tolerability and safety, all three dose levels were found to be positive which prompted the researchers to transit to the study Part B, with AATD patients which will received the highest Part A dose levels and will continue dose escalation. The Phase 1 is expected to be complete by the end of 2015.
“We are excited that Part A of the phase 1 study is complete and that we can now begin studying ARC-AAT directly in patients with PiZZ genotype AATD,” said Bruce D. Given, M.D., Arrowhead’s Chief Operating Officer in a recent news release. “The lung disease associated with AATD is frequently treated with AAT augmentation therapy. However, there is a great need in the field to identify new treatment options for the AATD-related liver disease. Currently, the only option for severe cases is liver transplant, with all of its attendant risks and availability issues. We think ARC-AAT is a very promising program that may potentially provide a better option for patients and physicians.”
The drug includes novel unlocked nucleobase analog with RNAi triggering molecules (UNA) co-administered with Dynamic Polyconjugates (DPCs) to allow UNA to escape from endosomes.
The ratio of UNA to DPC is 2:1 by weight. In the study Part A, a total of three cohorts comprising of six participants in which each received ARC-AAT at doses of 0.38 mg/kg, 1.0 mg/kg, and 2.0 mg/kg of UNA, and 0.19 mg/kg, 0.5 mg/kg, and 1.0 mg/kg of DPC, respectively.
This Phase 1 study is a randomized, placebo-controlled, double-blind, multi-center, single dose-escalation, and is the first trial conducted in human evaluating the ARC-AAT pharmacokinetics safety and tolerability and its effects on circulating levels of AAT. Participants at randomly assigned participants at a ratio of 2:1 to receive a single intravenous injection of either ARC-AAT or placebo.
Part B of the study will be conducted in patients with PiZZ genotype AATD. The study evaluates participants for 28 days following dosing, with additional follow-up if needed every 2 weeks until AAT levels return to baseline.
“The Alpha-1 Foundation and the entire Alpha-1 community are excited to see this program move forward,” said John Walsh, president and chief executive officer of the Alpha-1 Foundation. “We and The Alpha-1 Project, the Foundation’s venture philanthropy arm, will continue to work closely with Arrowhead on clinical trial recruitment and provide additional assistance to get this potentially life saving therapy to adults and children with liver disease due to Alpha-1.”