Effects of the Next Generation TNF Inhibitor (XPro1595) on Inflammation-related Deficits in Reward Circuitry and Motivation in Depression

PROJECT SUMMARY Treatment resistant depression (TRD) is a devasting condition affecting ~30% of depressed patients and significantly contributing to the personal and societal burden of the disease including suicide. Unfortunately, few treatments are available for TRD patients, representing a major unmet clinical need. One pathophysiologic pathway that may contribute to TRD is inflammation. TRD patients exhibit increased inflammatory markers, including the inflammatory cytokine tumor necrosis factor (TNF) and the acute phase reactant C-reactive protein (CRP). In addition, increased inflammatory markers prior to treatment predict poor response to conventional antidepressants. Work by our group suggests that inhibition of TNF may improve depressive symptoms in TRD patients but only in patients with high inflammation as indexed by plasma CRP. The most responsive symptom to TNF inhibition was anhedonia, a core symptom of depression that reflects reduced motivation and contributes to the disability of the disorder. This observation is consistent with a rich literature demonstrating that peripheral inflammation impacts reward-related brain regions and disrupts functional connectivity in reward circuitry in association with anhedonia. Unfortunately, currently available TNF antagonists have limited viability as antidepressants given their significant risk of infection and potential precipitation/exacerbation of autoimmune diseases especially demyelinating disorders such as multiple sclerosis (MS). Thus, new TNF inhibitors are needed to leverage the potential of anti-TNF therapy to improve depressive symptoms like anhedonia in patients with TRD and increased inflammation. One such candidate compound is XPro1595, a novel next-generation, dominant-negative inhibitor of TNF. Unlike available TNF inhibitors, XPro1595 was designed to selectively neutralize the pathological, inflammatory species of TNF [soluble TNF (sTNF)] while sparing neuroprotective aspects of TNF conveyed by transmembrane TNF (tmTNF) signaling. Interestingly, XPro1595 has demonstrated robust anti-inflammatory and anti-depressant-like activity in laboratory animal models of depression including TRD, while exhibiting an excellent safety profile in animal models of infection and MS. In Phase I testing in patients with cancer or Alzheimer’s Disease, subcutaneous (SC) XPro1595 1.0 mg/kg was safe and well- tolerated, exhibiting steady state blood concentrations 3 logs higher than plasma TNF concentrations seen in TRD patients, while reducing CRP by ~43%. The Aims of this SBIR proposal are to use a biomarker-driven approach to determine whether XPro1595 (1.0 mg/kg SC) can reduce inflammation (Aim 1) and improve functional connectivity in reward-related brain circuitry (Aim 2) in association with improved motivation and anhedonia (Aim 3) in a randomized, double-blind, placebo-controlled Phase IIa study in TRD patients with CRP andgt;3 mg/L and significant anhedonia. Reduced CRP (Target Engagement: Peripheral Inflammation) and increased connectivity in reward circuitry (Target Engagement: Brain) will inform a Go/No-Go decision on XPro1595 as a potential therapy for TRD and possibly other psychiatric illnesses with high inflammation and anhedonia.PROJECT NARRATIVE Inflammation is believed to contribute to treatment resistant depression (TRD), which affects ~30% of depressed patients and significantly contributes to the personal and societal burden of the disease including suicide. Drugs that block the inflammatory molecule tumor necrosis factor (TNF) have shown promise in treating TRD patients with high inflammation, but the currently available TNF blockers have a serious risk of infection and other complications. XPro1595 is a next generation TNF inhibitor that is more selective and potentially safer and more effective than older TNF inhibitors, and in this study, we will determine whether XPro1595 can reduce inflammation and its effects on the brain to improve depressive symptoms in patients with TRD.