Pre-clinical studies with OP-101 have shown normalization of microglia, prevention of neuronal loss, and restoration of motor function. OP-101 is currently being evaluated for safety and pharmacokinetics in a healthy volunteer study in the United States (view on clinicaltrials.gov).
OP-101 consists of N-acetyl cysteine (NAC) linked to a hydroxyl dendrimer via a disulfide bond. NAC prevents activation of the NF-κB pathway under oxidative and inflammatory stress conditions. NF-κB inhibition decreases expression of pro-inflammatory cytokines and chemokines (IL-6, IL-1β, TNFα, and CCL2).
NAC is approved by FDA for the treatment of treat paracetamol (acetaminophen) overdose and has demonstrated potent anti-oxidant properties. Orpheris is leveraging the drugs' favorable safety profile and anti-inflammatory/anti-oxidant properties. By chemically linking NAC to the hydroxyl dendrimer dendrimer, we are able to avoid previous challenges of delivering NAC across the BBB to target neuroinflammation. Free-NAC is taken up by cells through the XCT transporter causing glutamate release (excitotoxicity). NAC also binds to plasma proteins and has limited BBB penetration. The pharmacology of NAC is altered to address these limitations by linking it to a hydroxyl dendrimer via a disulfide bond causing release primarily inside cells by intracellular glutathione (GSH). OP-101 selectively and efficiently delivers 20 NAC molecules per molecule of OP-101 inside activated microglia returning the cells to their normal state (Navath 2008, 2010; Kurtoglu 2009; Wang 2009).
The differences in pharmacology and efficacy between OP-101 and NAC alone have been demonstrated in multiple animal models of neuroinflammation. For example, in a rabbit model of neonatal inflammation (similar to human chorioamnionitis), OP-101, but not NAC restores motor function after single dose (Kannan 2012). By restoring microglia to their normal state in this acute inflammation model, the rabbits are able to mature normally and return to normal function with no notable differences in function or histology from normal healthy controls at adulthood. The dramatic effect of OP-101 therapy in this model is illustrated in videos of treated and untreated rabbits (Download "supplemental video 2" – untreated; Download "supplemental video 3" – treated).
ccALD is a rare disease caused by the accumulation of very long chain fatty acids (VLCFA) and children with ALD present with severe neuroinflammation driven by activation of microglia (Eichler 2008; click here for more on ccALD).
While no preclinical model of the cerebral form of ALD exists, ex vivo studies with blood samples from ccALD patients have been tested to evaluate the effects of OP-101 and NAC alone. In a collaboration with Kennedy Krieger Institute, monocytes were isolated from the blood of normal volunteers, AMN (spinal form of ALD) and ccALD patients (n=4). Macrophages derived from the isolated monocytes were activated with the molar equivalent of VLCFA burden in ccALD - mimicking activated microglia in patients. No effect of VLCFA stimulation was observed in macrophages from normal or AMN patients, as expected. In contrast, OP-101 restores ccALD specific macrophages - stimulated with VLCFA - to the normal state.