Alexion Obtains Japanese Rights to Potential FAP Therapy AG10; Phase 3 Trial Planned

Alexion Pharmaceuticals has obtained exclusive rights in Japan to develop and market AG10, an oral treatment candidate for familial amyloid polyneuropathy (FAP), also called ATTR polyneuropathy (ATTR-PN).

AG10 is a small molecule developed by Eidos Therapeutics, a subsidiary of BridgeBio Pharma. It is intended to address the root cause of transthyretin amyloidosis — misfolded (altered shape) TTR — by binding to and stabilizing that protein in the blood, which ultimately prevents the formation of amyloid fibrils.

Specifically, AG10 was developed to mimic 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, have shown it prevented or lessened disease. According to the pharmaceutical companies, AG10 is the only TTR stabilizer in development that mimics the structure of this rescue mutation.

Eidos is planning a Phase 3 trial of AG10 in FAP this year.

A Phase 3 study in the U.S. and Europe — called ATTRibute-CM (NCT03860935, still enrolling) — is already testing this therapy in patients with ATTR cardiomyopathy (ATTR-CM), another form of transthyretin amyloidosis characterized by the accumulation of TTR amyloid deposits in the walls of the heart’s left ventricle.

Part A of ATTRibute-CM will assess improvements in exercise capacity and health-related quality of life over 12 months (as determined with the 6-minute walk distance test); part B will analyze mortality and the frequency of cardiovascular-related hospitalizations at 30 months, comparing twice-daily treatment with 800 mg AG10 to a placebo. This trial plans to enroll 510 participants.

“We believe AG10 holds promise in its ability to stabilize TTR and halt disease progression,” John Orloff, MD, Alexion’s executive vice president and head of research & development, said in a press release.

“We are excited by the potential to grow our amyloidosis portfolio by partnering with Eidos to expand the development of AG10 to Japan,” Orloff said. “Alexion has more than 10 years of experience operating there, and we look forward to applying our expertise to bring AG10 to Japanese patients.”

A Phase 2 trial in patients with symptomatic ATTR-CM showed that treatment with AG10 was well-tolerated and led to a greater than 90% TTR stabilization at day 28, which is correlated with disease severity in these patients. Also, it normalized serum levels of TTR in a dose-dependent manner. Such increases in protein concentrations had been linked previously with longer survival in ATTR-CM patients.

“The Phase 2 study in ATTR-CM suggested that AG10 has the potential to become an important treatment option for the underserved ATTR-CM population,” said Jonathan Fox, MD, PhD, president and chief medical officer at Eidos. “We have now begun our Phase 3 program to evaluate the safety and efficacy of AG10 in larger studies.”

Under the terms of the agreement, Alexion will make an upfront payment of $25 million to Eidos. An equity investment of $25 million will be made when the deal is completed, as well as potential additional payments based on milestone royalties.

“This agreement provides the potential opportunity to help even more patients globally,” Fox said.