Shanghai-based YolTech Therapeutics has dosed the first patient with YOLT-201 in the Phase I trial evaluating the therapy as a treatment for hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

The open-label Phase I trial (NCT06082050) will assess the therapy's safety, tolerability, pharmacokinetics, and pharmacodynamics. The study will also aim to identify an optimal biologically active dose.

A genetic mutation of the gene for transthyretin (TTR) protein causes ATTR, which leads to the production of an abnormal form of the protein causing protein build-up in the organs. ATTR-CM is caused by TTR protein build-up in the heart muscle causing thickening and stiffening of the muscle. This impairs the heart’s ability to function properly and can lead to stroke or death.

YOLT-201 is an in vivo genome editing candidate which consists of lipid nanoparticles (LNP), formed with ionisable lipids as primary excipients to encapsulate messenger ribonucleic acid (mRNA) and single guide RNA (sgRNA) raw materials. The sgRNA component is responsible for preventing transcription of the TTR gene, as such stopping the production of the TTR protein.

ATTR-CM treatment landscape

Multiple companies are developing therapies for ATTR-CM. One of the more clinically advanced therapy programmes includes Alnylam Pharmaceuticals’s Onpattro (patisiran).

The Phase III trial (NCT03997383) for the RNA interference (RNAi) therapy met its primary endpoint but despite positive results, the US Food and Drug Administration (FDA) refused to approve the therapy. In October, the agency issued a complete response letter (CRL) stating that the drug “could not be approved in its present form”. Following the CRL, Alnylam stated that it would no longer seek US approval for the therapy in ATTR-CM indication.

Ionis Pharmaceutical’s antisense therapy eplontersen is being evaluated in a Phase III trial (NCT04136171). The placebo-controlled study enrolled more than 1,400 participants, with data expected in H1 2025.

Eplontersen is being developed as part of a development and commercialisation agreement with AstraZeneca. The companies are also seeking FDA approval for the therapy as a treatment of transthyretin-mediated amyloid polyneuropathy. The Prescription Drug User Fee Act (PDUFA) action date for the approval was set for 22 December 2023.

The early clinical stage therapies being developed to treat ATTR-CM include Intellia Therapeutics and Regeneron Pharmaceuticals’ CRISPR/Cas9 genome editing therapy NTLA-2001. The therapy is currently in Phase I trial (NCT04601051). Neurimmune’s monoclonal antibody therapy NI006 demonstrated a positive safety profile in the Phase I trial. NI006 is being developed in partnership with AstraZeneca.

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