Phase 3 Trial of Acoramidis in ATTR-CM Patients Fully Enrolled, Trial in FAP Underway

Eidos Therapeutics announced that the Phase 3 clinical trial evaluating its lead candidate acoramidis (formerly known as AG10) in treating adults with transthyretin amyloidosis cardiomyopathy (ATTR-CM) is fully enrolled.

Top-line results from part A of the trial, called ATTRibute-CM (NCT03860935), are expected in late 2021 or early 2022, and from part B in 2023.

If part A is successful, the company plans to file for regulatory approval of acoramidis as a treatment for ATTR-CM in 2022.

“The completion of enrollment in our Phase 3 ATTRibute-CM clinical study marks the next milestone in the accelerated development of acoramidis for patients with transthyretin (TTR) amyloidosis (ATTR),” Neil Kumar, PhD, the CEO of Eidos, a  BridgeBio Pharma subsidiary, said in a press release.

“Since originally licensing acoramidis from Stanford University in 2016, we have endeavored to advance the molecule as quickly as possible, knowing that every moment matters for the patients and families suffering from this devastating disease. We look forward to our top-line Phase 3 readout in just over a year and are preparing to commercialize acoramidis globally if the trial is successful,” Kumar added.

A separate Phase 3 study (NCT04418024), called ATTRibute-PN, testing acoramidis in people with familial amyloid polyneuropathy (FAP; also known as hereditary ATTR polyneuropathy or ATTR-PN) has already launched, the release stated. More information on contacts and locations can be found here; it is not clear whether this trial has started enrolling patients. 

A small molecule, acoramidis works by binding and stabilizing the TTR protein, which is misfolded (altered in shape) in people with ATTR, promoting the formation and buildup of toxic protein clumps in several tissues and organs.

Of note, a functional TTR comprises four identical TTR protein molecules bound together. But mutations or a spontaneous destabilization of this protein cause a dissociation of the tetramers into single proteins, which can then form insoluble protein clumps.

The therapy is designed to mimic the TTR protein that is produced from the T119M variant of the TTR gene. This is regarded as a rescue mutation because individuals who inherit it, along with a disease-causing mutation in TTR, were shown to have either no disease or a milder form.

In this way, acoramidis is thought to address the root cause of ATTR and prevent the formation of the toxic clumps, slowing disease progression. According to Eidos, the therapy is the only TTR stabilizer in development to mimic the stabilizing structure of this rescue mutation.

Data from previous Phase 1 and 2 trials showed that acoramidis was well tolerated, and led to a greater than 90% TTR stabilization in both healthy volunteers and ATTR-CM patients, who have an accumulation of TTR toxic clumps in the walls of the heart’s left ventricle.

These positive findings supported the launch of the ATTRibute-CM and ATTRibute-PN Phase 3 trials.

The global, two-part ATTRibute-CM is evaluating acoramidis’ safety and effectiveness in more than 600 adults with ATTR-CM, either associated with TTR mutations or with older age, enrolled across more than 80 sites in 18 countries.

Participants will be randomly assigned to receive a tablet, twice daily, of either acoramidis (800 mg) or a placebo for 30 months (two and a half years).

The study’s part A will assess changes in patients’ exercise capacity (as determined with the 6-minute walk test) after one year of treatment, while part B will determine changes in mortality and frequency of cardiovascular-related hospitalizations at 30 months.

ATTRibute-PN will evaluate the safety and effectiveness of 18 months of treatment with acoramidis against a placebo in up to 145 adults with FAP. Its main goal is to assess changes in the modified Neuropathy Impairment Score +7, a validated measure of neurological impairment, at the end of treatment. The trial is expected to finish by 2024.

Patients completing either trial will have the option of entering an open-label extension, in which all will receive the therapy over a longer period of time.

Eidos entered a partnership agreement with Alexion Pharmaceuticals that provides the latter with exclusive rights to develop and commercialize acoramidis in Japan. Alexion plans to initiate a Phase 3 bridging study of acoramidis in people with ATTR-CM in Japan by the end of December.