Phase 2 for ATTR Cardiomyopathy Therapy Underway

Dosing of the first patient in the Phase 2 clinical trial of AG10 in patients with transthyretin (TTR) amyloidosis (ATTR) cardiomyopathy, Eidos Therapeutics, Inc. has announced.

The company intends to enroll approximately 45 symptomatic ATTR cardiomyopathy patients in a randomized, double-blind, placebo-controlled design. Discovered and initially developed by Eidos' co-founders Isabella Graef, M.D. and Mamoun Alhamadsheh, Ph.D., AG10 was the result of research funded by the SPARK program of Stanford Medicine.

"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 in a press release.

The trial will include a minimum 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 1 of 2 different doses of AG10 on a background of stable heart failure therapy.

If all doses are well-tolerated by those enrolled, treatment will continue for 4 weeks.

"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,” said Dr Falk.

Safety and tolerability of AG10 will serve as the primary endpoint of the study, and the trial will also characterize the pharmacokinetics of the drug administered twice daily.

TTR stabilization will be measured and confirmed by validated ex vivo assays, namely fluorescent probe exclusion and immunoblotting. Historical clinical studies have demonstrated that increasing levels of TTR stabilization lead to improved clinical benefit, and this Phase 2 aims to provide clinical proof of concept to support potential subsequent pivotal trials.

The Phase 2 trial follows the successful completion of a Phase 1 trial of AG10 in healthy volunteers. It included single ascending dose, multiple ascending dose, and food effect components. The drug was found to be well-tolerated at all doses, and no serious adverse events (AEs) 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.

"The positive results of our Phase 1 trial of AG10 in healthy volunteers encouraged our rapid advancement into a Phase 2 trial in patients with ATTR cardiomyopathy," said Jonathan Fox, M.D., Ph.D., the company's president and chief medical officer. "Our preclinical and Phase 1 data provide evidence that AG10 could be beneficial for both wild type and mutant ATTR cardiomyopathy patients, and this Phase 2 trial aims to provide additional information in these specific populations."

Pharmacokinetic measurements exhibited that AG10 is rapidly and consistently absorbed with a terminal half-life of approximately 25 hours. Ex vivo pharmacodynamics 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.

An estimated 250,000 people suffer from the neurological and cardiac consequences of this disease worldwide, and the prevalence of the disorder is inclining with the aging population. Earlier diagnoses and increased awareness are the primary goals of the development of potential new therapies.

Edios has stated its intentions to report topline results from the Phase 2 trial by the end of 2018. The company anticipates launching a second Phase 2 trial in patients with ATTR polyneuropathy later this year.

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