AMX0035 Alters Activity of Various Genes Relevant to ALS, Study Finds

Experiments in patients' cells show changes due to potential therapy's combination

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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AMX0035 — Amylyx Pharmaceuticals’ experimental combination therapy for amyotrophic lateral sclerosis (ALS) now under review for approval in the U.S. — alters the activity of genes involved in several disease-relevant pathways, according to a study in lab-grown cells.

Notably, the two-compound oral treatment was seen to change the activity of many more genes than either of its components alone, with most of these changes unique to the combination.

“While AMX0035 has been shown to meaningfully slow the loss of function and extend survival in people living with ALS in a randomized, placebo-controlled clinical trial, this study is the first to explore the molecular effects of the combination of AMX0035 versus the individual compounds in ALS patient-derived cells,” Hibiki Kawamata, PhD, and Giovanni Manfredi, MD, PhD, the study’s co-senior authors, said in a press release from Amylyx.

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“These findings may underlie the benefits that AMX0035 has been shown to have on individuals living with ALS,” added Kawamata and Manfredi, both with the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

The study, “Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts,” was published in the Annals of Clinical and Translational Neurology. The work was funded in part by Amylyx.

AMX0035 combines compounds thought to protect nerves

AMX0035 contains a fixed-dose combination of two compounds thought to help protect nerve cells from stress-related damage: sodium phenylbutyrate (PB) and taurursodiol (known as TUDCA or TURSO).

In the Phase 2 CENTAUR clinical trial (NCT03127514), which involved 137 adults recently diagnosed with ALS, the therapy outperformed a placebo at slowing functional decline and extending survival.

These findings supported Amylyx’s applications with regulatory authorities in several countries and regions seeking the approval of AMX0035 for treating ALS.

A decision in the U.S., where an evaluation committee recently favored the approval, is expected by month’s end. The therapy is also under review in Europe, and it recently became available in Canada after gaining conditional approval there.

AMX0035 is being evaluated in a larger Phase 3 trial called PHOENIX (NCT05021536), which is still enrolling recently diagnosed ALS patients at dozens of European sites.

In the current study, Manfredi and his team evaluated the effects of PB, TUDCA, or their combination in lab-grown skin fibroblasts from 12 people with sporadic ALS and an average age of 62.6 and 12 age-matched healthy people as controls.

Fibroblasts are structural cells that can be easily isolated from the skin and that show disease-associated features similar to those seen in motor neurons, the movement-controlling nerve cells that become dysfunctional and die in ALS.

These cells were used in this study because they “are accessible and easily manipulated to study drug effects,” the researchers wrote.

Gene and metabolite changes seen as ‘unique’ to combination

The team conducted global analyses of how the treatments affected the cells’ metabolic profiles and gene activity.

When looking at all fibroblasts, regardless of disease state, treatment with PB alone was found to alter the activity of 186 genes, while TUDCA treatment alone changed the activity of 16 genes. Treatment with both compounds, by contrast, resulted in activity changes in 1,838 genes.

Similarly, the AMX0035 combination altered the levels of many more metabolites — intermediate or end products of metabolism — relative to either TUDCA or PB alone (27 vs. 8 to 10 metabolites).

Most of these significant metabolic and gene activity changes were unique to the combination treatment, highlighting that AMX0035’s effects “are not simply additive effects of PB and TUDCA,” the team wrote.

Closer analysis of the specific genes affected by AMX0035 revealed that many of them were involved in pathways that have been implicated in ALS. These included those related to the function of mitochondria (the cells’ powerhouses) and the immune system, transport within cells, and processes that help cells survive under stress conditions.

Further analysis showed that all metabolites significantly changed by the combo therapy in patient-derived cells were also changed in those from controls. However, AMX0035 treatment significantly changed the activity of twice the number of genes in patient-derived cells than in control cells.

Many of these changes also were found to be unique to patient-derived cells. Specifically, genes involved in transport inside cells, stress responses, and RNA-related processes were altered only in cells from ALS patients.

“We propose that the modulation of these pathways could underlie the neuroprotective effects of TURSO–PB in ALS,” the researchers wrote.

When analyzing changes in ALS patients’ gene activity and available data on their disease severity, the team identified a set of highly activated genes that are strongly associated with several measures of ALS severity and were modified by AMX0035.

Further studies are needed to confirm these findings in lab-grown motor neurons from ALS patients, the researchers noted, and to assess the long-term molecular effects of this combination treatment.

As more patient samples and treatment response data become available, these metabolic and gene activity changes may be associated with or predict responses to AMX0035, the researchers added.