May 7th, 2015
"We see factor 12 as an extremely attractive target to add to our pipeline. There is clear unmet need in thrombosis and angioedema and the biology of factor 12 as part of the coagulation cascade and the kinin-kallikrein system suggest that its reduction through RNAi may present opportunities in both disease areas," said Christopher Anzalone, Ph.D., president and chief executive officer. "We will be conducting additional studies in relevant disease models shortly to provide us with further data to decide on the advancement of ARC-F12 as a clinical candidate and initiation of IND enabling studies."
David Lewis, Ph.D., chief scientific officer, presented initial data from wild type mice, showing that various RNAi triggers selected from in vitro screening sets and co-administered with DPCs achieved significant and sustained knockdown of F12 levels of greater than 99% at nadir for most triggers. Strategic incorporation of various modifications to the most potent RNAi trigger increased the depth and duration of F12 knockdown activity as shown in dose response studies. In a study in mice, these modified triggers exhibited a dose-dependent increase in F12 knockdown. A single intravenous dose of 0.5 mg/kg reduced F12 by greater than 80%. When the dose was increased to 2 mg/kg, the reduction increased to greater than 95% at nadir, with greater than 70% knockdown observed at the one month time point. The lead RNAi trigger was also highly active in multiple dose nonhuman primate studies. With four intravenous doses of 2 mg/kg given once every four weeks, approximately 90% F12 knockdown was achieved after the first dose with even greater knockdown following subsequent doses. Knockdown was also highly durable with greater than 80% reduction maintained between monthly doses. The combination of RNAi trigger and DPC appeared to be generally well-tolerated and no drug-related changes in toxicity markers were observed as measured by clinical chemistry and hematologic parameters.
Dr. Lewis also presented data from a relevant disease model on the lead RNAi trigger and DPC combination. In this mouse model, thromboembolism is induced by exposure of carotid artery to ferric chloride. The time to blood flow occlusion is then measured as a clinically relevant indicator of physiological response to F12 knockdown. Animals were treated with saline or the lead RNAi trigger and DPC combination 15 days prior to ferric chloride challenge. Treated animals showed approximately 99% knockdown in serum F12 levels at Day 15 relative to baseline, while animals receiving saline showed no reduction. A dramatic increase in occlusion times as a measure of the inhibition of thrombus formation was observed in treated mice.
Arrowhead believes that ARC-F12 may present opportunities to target multiple diseases, including in thrombosis. The company is currently planning to investigate ARC-F12 in hereditary angioedema (HAE) as the first target indication. HAE is a rare genetic disorder with a prevalence of approximately 1/5,000-1/10,000 that is most commonly caused by mutations in the complement factor 1 esterase inhibitor gene (C1INH). Patients with HAE can experience recurrent and dangerous acute inflammatory attacks in multiple tissues, with attacks of laryngeal edema being particularly serious and potentially fatal. Current treatments seek to reduce the severity, duration, and frequency of acute HAE attacks, but frequent intravenous dosing of 1-3 times weekly is required and many patients do not respond adequately. Arrowhead believes the novel mechanism of ARC-F12 may fill an unmet need for patients and physicians who desire long term prophylaxis and may view intravenous dosing every 4-6 weeks as a significant advance.
The company is currently planning additional evaluation of ARC-F12 in relevant HAE disease models including C1INH knockout animals and captopril-induced vascular leak, among potential other studies to support advancement of ARC-F12 into IND enabling studies.