Eidos Therapeutics announced dosing of the first patient in the Phase 2 clinical trial of AG10 in patients with ATTR cardiomyopathy.
The Phase 2 trial will enroll approximately 45 symptomatic ATTR cardiomyopathy patients in a randomized, double-blind, placebo-controlled design. The trial will include a minimum of 30% of patients with mutant ATTR cardiomyopathy, with the remainder having wild type ATTR cardiomyopathy. Patients will be randomized in a 1:1:1 fashion to placebo or one of two different doses of AG10 on a background of stable heart failure therapy. If all doses are well-tolerated, patients will be treated for 28 days.
"ATTR cardiomyopathy represents a significant unmet need with a poor prognosis and limited existing treatment options, and further, the prevalence of the disease is increasing dramatically with improved awareness and novel, non-invasive diagnostic techniques," said Rodney Falk, M.D., director of the cardiac amyloidosis program at Brigham and Women's Hospital and associate professor of medicine at Harvard Medical School. "The preclinical and Phase 1 data describing AG10 indicate that it could be a valuable treatment option for these patients, and I am eager to participate in the trial and learn more about AG10's potential."
The primary objective of this trial is to evaluate the safety and tolerability of AG10. The trial will also characterize the pharmacokinetics of AG10 administered twice daily. Finally, the trial will measure and confirm TTR stabilization by validated ex vivo assays, namely fluorescent probe exclusion and immunoblotting. As previous clinical studies have demonstrated that increasing levels of TTR stabilization lead to improved clinical benefit, the trial aims to provide clinical proof of concept to support potential subsequent pivotal trials.
This Phase 2 trial follows the successful completion of a Phase 1 trial of AG10 in healthy volunteers, reported at the 16th International Symposium on Amyloidosis in Kumamoto, Japan on March 29, 2018. The Phase 1 trial included single ascending dose, multiple ascending dose (MAD) and food effect components. AG10 was found to be well-tolerated at all doses. No serious adverse events were observed in the trial, vital signs and cardiac safety measures revealed no findings of clinical concern, and liver, kidney and hematological parameters were all within normal limits.
Pharmacokinetic measurements demonstrated that AG10 is rapidly and consistently absorbed with a terminal half-life of approximately 25 hours. Ex vivo pharmacodynamic assays demonstrated 100% TTR stabilization at peak plasma concentrations and >95% stabilization on average in the final MAD cohort. TTR stabilization measurements were highly correlated between assays and a clear dose-dependency of stabilization was observed.
The company expects to report topline results from this Phase 2 trial by the end of 2018. Eidos expects to launch a second Phase 2 trial in patients with ATTR polyneuropathy later this year.