Science and Pipeline2019-04-09T19:44:49+00:00

Science and Pipeline


Preclinical Validation

IND Enabling Studies

Phase I

Phase II

Phase III

Amyotrophic Lateral Sclerosis (ALS)
Alzheimer’s Disease
Wolfram Syndrome

AMX0035 is a combination therapy of two active small molecules: tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate (PB). TUDCA ameliorates mitochondrial deficits in cellular and animal models and PB relieves endoplasmic reticulum (ER) stress through upregulation of heat shock proteins in a number of models. Both mitochondrial and ER stress have been strongly implicated in neuronal death and degradation pathways. The combination of these two agents is synergistically effective in preventing neuronal death from bioenergetic, metabolic and oxidative insult models.

TUDCA has been demonstrated to recover mitochondrial bioenergetic deficits through its incorporation into the mitochondrial membrane, resulting in reduced Bax translocation to the mitochondrial membrane, increasing the apoptotic threshold of the cell [Rodrigues 2003]. TUDCA has exhibited efficacy in in vivo oxidative insult models, including models of stroke, Alzheimer’s Disease, retinal disease, cardiac disease, brain lipopolysaccharide (LPS) insult, the MPTP mouse model of Parkinson’s, and ALS in vitro models of poly(GA)-induced toxicity [Rodrigues 2003; Castro-Caldas 2012;  Zhang 2014].

TUDCA has also demonstrated early evidence of clinical efficacy in a year-long clinical trial in ALS patients.

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PB is a pan-histone deacetylase (HDAC) inhibitor that ameliorates ER stress through upregulation of the master chaperone regulator DJ-1 and through potent recruitment of other chaperone proteins [Suaud 2011; Zhou 2011]. The large increase in chaperone production reduces activation of canonical ER stress pathways and has been shown to increase survival in vivo in models of ALS (SOD1 G93Amouse) [Del Signore 2009; Petri 2006; Ryu 2005], Huntington’s disease [Gardian 2005], Alzheimer’s disease [Ricobaraza 2009], and Parkinson’s disease [Roy 2012].

PB has also been studied in a open label study in ALS showing early signs of biological activities and tolerability.

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Amylyx combined these agents and demonstrated synergistic benefit in multiple models. Shown below is the synergistic effects of AMX0035 on cell viability following hydrogen peroxide insult in rat primary cortical neurons. In this study, both TUDCA and PB show efficacy, however the combination is significantly more effective in preventing neuronal death.

Our hope is that with the combination therapy, AMX0035, we will see synergistic benefit across multiple neurodegenerative diseases.