Background Pridopidine is a drug in clinical development for HD and ALS. It has selective agonistic activity at the Sigma-1 Receptor (S1R). The S1R is enriched in brain areas implicated in HD (basal ganglia and cortex) and plays a key role in cellular pathways vital to neuronal function and survival. S1R activation by pridopidine induces beneficial effects in HD and other neurodegenerative disease models. Activation of the S1R is characterized by a biphasic dose response, in which greater biologic activity is present at optimal doses and diminishes with higher doses.

Consistent with S1R agonism, pridopidine demonstrates a biphasic profile in preclinical and clinical studies. In HD models, pridopidine elicits a biphasic effect on neurotrophin release (BDNF), upregulation of mitochondrial function and rescue of synaptic plasticity, among others.

In PRIDE-HD, 45 mg bid was most efficacious dose for maintaining Total Functional Capacity (TFC) and quantitative Q-motor testing. To further explore the biphasic response, we evaluated the pridopidine exposure-response relationship for TFC.

Method Plasma exposure (area under curve in mg*h/ml, AUC) was plotted (PK) against ΔTFC at Week 52 per individual in PRIDE-HD (PD).

Results We show a correlation between exposure levels and ΔTFC from baseline. Plasma concentrations of AUC 7-19 mg*h/ml associate with no deterioration or improvement of TFC (ΔTFC≥0). In the 45 mg bid treatment group, 94% (34/36) of patients had AUC 7-19 mg*h/ml, and of these, 82% (28/34) show ΔTFC ≥ 0. Higher doses were associated with exposures greater than 19 mg*h/mL [70% (19/27), 88% (30/34) and 96% (22/23) of the 67.5, 90 and 112.5 mg bid groups, respectively]. In all groups, among patients with TFC worsening (TFC < 0), 82% (36/44) had AUC ≥ 20 mg*h/ml. Regardless of dose, most patients (77%, 36/47) with AUC 7-19 mg*h/ml show ΔTFC ≥ 0.

Conclusion The 45 mg bid dose of pridopidine yields the optimal exposure for clinical efficacy measured by TFC.