Anadys Pharmaceuticals, Inc. announced that patient dosing has commenced in a phase I study of ANA773, the company's oral TLR7 agonist prodrug, in patients with advanced solid tumours. This first-in-human trial is a safety and tolerability study designed to identify pharmacologically active doses and preliminary anti-tumour activity as well as to select the dose and schedule for phase II trials.
The phase I trial is a multiple, ascending dose study conducted at several sites in the United States. In addition to safety and tolerability, patients will be monitored for pharmacodynamic responses indicative of immunological stimulation. Initially, patients will be dosed every other day. The company also expects to investigate additional schedules during this first clinical trial and anticipates that up to 60 patients will be enrolled in the study.
"The extensive preclinical investigation Anadys has conducted with ANA773 over the last 18 months has taught us much about the pharmacology of orally administered TLR7 agonists, including the importance of schedule in sculpting the profile of immune activation," said James Freddo, M.D., Anadys' Chief Medical Officer. "We believe ANA773 holds promise for the treatment of a range of malignancies and may have utility when combined with targeted agents, therapeutic antibodies and/or chemotherapy. We are excited about having initiated this first clinical study."
Steve Worland, Ph.D., Anadys' President and Chief Executive Officer, said, "This is an important milestone for Anadys. The initiation of this trial marks the resumption of our clinical investigation of oral TLR7 agonists and moves us closer toward our objective of developing ANA773 as a novel therapy for patients with cancer. We anticipate identifying the dose and schedule for Phase II investigation by the end of this year."
ANA773 is an orally administered prodrug of a novel TLR7-specific agonist. Pharmacology studies have shown that ANA773 can elicit desired immune responses and components of the response can be modulated by both dose and schedule of administration.
Data presented at the AACR-NCI-EORTC meeting in October 2007 showed that activation of TLR7 by the biologically active metabolite of ANA773 initiates a cascade of immune stimulatory events that has the potential to mediate anti-tumour activity by the induction of cytolytic activity by CD8 T cells against tumour cells and cytolytic activity of NK cells against tumour cells directly or through antibody-dependent cellular cytotoxicity (ADCC). Anadys also demonstrated that the immunostimulatory responses can be modulated by schedule of administration. Earlier in 2007, data presented at the AACR meeting showed that ANA773 and its active metabolite stimulate secretion of interferon alpha and other cytokines as well as enhance rituximab-mediated ADCC against transformed B cells.
The potential benefits of the TLR7 mechanism in cancer therapy arise from the fundamental role of this receptor in immune activation. The host immune system, once activated, plays an essential role in controlling the ability of cancer cells to grow, invade and metastasize. Immunotherapy has had some success in treating selected tumours, and the potential to harness the immune system as a therapeutic modality remains of great interest to many oncologists.
TLR7 agonists are of particular interest because there is precedent for their use in cancer. Small molecule ligands for this receptor have been identified, including topical imiquimod (Aldara) which is approved for the treatment of basal cell carcinoma in the United States. Imiquimod and other TLR7 agonists have also demonstrated early clinical activity against other tumour types, including melanoma and chronic lymphocytic leukaemia.
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines in the areas of hepatitis C and oncology.