First In-human Trial of XCUR-FXN Planned for 2022

Exicure recently discussed preclinical research data and the next steps in developing XCUR-FXN, its investigational antisense oligonucleotide (ASO) therapy for Friedreich’s ataxia (FA), in a live webcast.

After initiating investigational new drug (IND)-enabling studies of XCUR-FXN in late 2020 — intended to support regulatory clearance of clinical trials — the company plans to file an IND application to the U.S. Food and Drug Administration (FDA) by the end of the year, with the first-in-human trial planned for 2022.

ASOs are small molecules that can be designed to suppress or boost the production of a specific protein by binding to particular regions of its messenger RNA (mRNA) — the molecule derived from DNA and used as a template for protein production.

To date, this strategy has been applied successfully to develop approved therapies for genetic neuromuscular diseases such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy.

Being developed in collaboration with the Friedreich’s Ataxia Research Alliance (FARA), XCUR-FXN is an ASO designed to increase the production of the frataxin protein, which is lacking in FA patients due to a mutation in the FXN gene.

Since frataxin is essential for the normal functioning of mitochondria, the cells’ powerhouses, its deficiency results in mitochondrial abnormalities and impaired energy production in several organs, mainly affecting the nervous system and the heart.

XCUR-FXN is meant to be delivered directly into the spinal canal (intrathecal injection) to reach the central nervous system (CNS, the brain and spinal cord) and thereby address key neurological symptoms.

In the webcast, Bart Anderson, PhD, the director of Exicure’s research and development, explained that XCUR-FXN comprises two ASOs with two distinct targets and mechanisms.

One works by preventing FTX mRNA from being degraded in the cell’s nucleus (where the genetic info is stored), and the other stabilizes the mRNA outside the nucleus, where protein production takes place, allowing more protein copies to be generated per mRNA molecule.

The combination of both mechanisms is thought to strongly increase frataxin levels in mitochondria, which was confirmed in lab-grown nerve cells derived from two FA patients. Notably, this restoration of frataxin levels was found to result in an increase in mitochondrial energy metabolism, suggesting improved mitochondrial health, Anderson noted.

“We were thrilled to see these preclinical results that connect the anticipated mechanism of action to increased mRNA, protein, localized protein, and ultimately to the cellular function that is needed to correct the molecular deficit that drives Freidreich’s ataxia,” Anderson said.

Further analyses also showed that the multi-targeting SNA resulted in greater frataxin levels than the sum of the effects of individual single-targeting SNAs at equivalent doses, and that the twofold to threefold increase in FXN mRNA levels observed in lab-grown cells are expected to be “highly efficacious” if recapitulated in patients.

Notably, XCUR-FXN is delivered through Exicure’s innovative technology, called spherical nucleic acids (SNAs), in which oligonucleotides are very tightly packed around a nanoparticle core, providing them improved properties to enter cells.

Grant Corbett, PhD, head of Exicure’s neuroscience research, presented substantial data from studies in rodents and non-human primates highlighting SNAs’ advantages over standard ASOs — including Biogen’s SMA-approved therapy Spinraza — that are delivered in their natural form.

Results showed that SNAs are more easily taken in by cells and persist longer in the CNS, leading to higher potency and prolonged efficacy. In addition, SNA intrathecal administration was found to result in an effective distribution to all brain regions, including those relevant in FA, and to all CNS cell types.

Susan Perlman, MD, a neurologist at University of California Los Angeles (UCLA), said that, based on its mechanism of action, XCUR-FXN may result in equivalent or greater effects in mitochondria than Reata Pharmaceuticals’ omaveloxolone, potentially leading to similar or more pronounced clinical improvements.

But “we have to wait until clinical trials begin to compare them,” she added. Perlman also is the director of clinical trials and ataxia clinic of UCLA’s neurogenetics program and a member of Exicure’s scientific advisory board.

The potential design of the first-in-human trial of XCUR-FXN, expected to begin next year, was shared by the company’s chief medical officer, Douglas Feltner, MD.

The Phase 1b study will evaluate the safety, pharmacokinetics (uptake, distribution, and elimination in the body) and pharmacodynamics (effects on the body), and preliminary effectiveness of multiple ascending doses of XCUR-FXN in people with FA.

Feltner said that the company expects to include patients with a broad age range, from children to young adults — plans that will be discussed with the FDA in an already planned pre-IND meeting.

The levels of several biomarkers will be measured in the patients’ blood and cerebrospinal fluid (CSF, the liquid that surrounds the brain and spinal cord). These likely will include frataxin in the CSF, nerve cell damage biomarkers in the CSF and blood, and ferritin in the blood to analyze iron metabolism, which is abnormal in FA.

The researchers also will assess the levels of other molecules and nerve fibers health in patients’ brains through imaging tests, and exploratory goals will include clinical measures such as the modified Friedreich’s Ataxia Rating Scale.

The design and site selection of the trial are being defined in close collaboration with FARA, and its results are expected to inform future Phase 2/3 trials, including the optimal dose to be tested in such studies, Feltner noted.