Eloxx Plans to Advance ZKN-013 as Oral Treatment for RDEB and JEB

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Eloxx Pharmaceuticals announced ZKN-013 as its lead oral treatment candidate for recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) caused by nonsense mutations in the COL7A1 gene.

Preclinical safety and toxicology studies, required to secure U.S. Food and Drug Administration (FDA) approval for clinical trials of ZKN-013, are expected to begin by year’s end. Eloxx anticipates to file such a request to the FDA in 2022.

ZKN-013 was originally developed by Zikani Therapeutics, which was acquired by Eloxx in April. The combined company aims to be leader in ribosomal RNA-targeted therapies for rare diseases and cancers due to nonsense mutations.

According to Eloxx, nonsense mutations cause approximately 10–12% of rare inherited diseases. They refer to a type of mutation that causes a premature “stop” signal in protein production, resulting in a shorter, non-functional protein.

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Both companies are focused on developing ribosomal-targeting therapies that can overcome nonsense mutations in a disease-specific fashion, and restore the production of full-length and working proteins.

These therapies work by binding to ribosomes — the cells’ protein-making machinery — allowing them to ‘read through’ or ‘ignore’ the aberrant stop signal to generate a fully working protein.

“Since the acquisition of Zikani Therapeutics in early April, we have made tremendous progress across our portfolio of novel therapeutic programs,” Sumit Aggarwal, Eloxx’s president and CEO, said in a press release regarding the company’s 2021 second quarter financial and business update.

Besides its lead clinical program in cystic fibrosis (CF), Eloxx continues to advance its preclinical programs to demonstrate the potential of its newly acquired oral ribosomal modulating agents (RMAs), Aggarwal emphasized.

“We intend to provide additional insight into these programs in the coming quarters,” Aggarwal added.

ZKN-013, generated through Zikani’s unique proprietary TURBO-ZM platform, is an orally available RMA designed to treat people with RDEB and JEB caused by nonsense mutations in the COL7A1 gene.

This gene contains the instructions to produce type VII collagen, a major component of adhesion between layers of skin. Its deficiency results in very fragile skin, severe blistering, and skin erosion in response to minor injury or friction.

Nonsense mutations in both copies of the COL7A1 gene have been associated with a severe form of RDEB and with a milder form of JEB, one of the most severe types of EB.

By restoring the production of a full-length, functional type VII collagen protein, ZKN-013 is expected to lessen disease severity in patients with these forms of EB, potentially representing the first oral disease-modifying therapy for this patient population.

In preclinical studies, ZKN-013 was shown to restore, to clinically relevant levels and in a dose-dependent manner, the production of functional type VII collagen in skin cells derived from RDEB patients with different nonsense mutations.

The therapy was also found to be generally safe, with therapeutic levels found in the skin after chronic dosing in an animal toxicity study.