Major Depression Disorder (MDD) is a debilitating and extremely common disease. In the US, approximately 17 Million people suffer from depression annually and it is estimated that 1 out of every 5 people will have depression at some time in their life.  MDD is the leading cause of disability worldwide and a leading cause of death^1-3. 

Approximately 33% of MDD patients do not respond to conventional antidepressant therapy and are classified as Treatment Resistant Depressed (TRD). These 7 million patients with TRD have more severe disease, more hospitalizations, and twice the healthcare costs of treatment responsive depressed patients. 

Management of patients with TRD is a major challenge for mental health professionals.  The obvious problem is failure of existing therapies.  A more frustrating problem is the inability to predict who will respond to conventional therapy for depression.  That is, diagnosis of TRD depends on trial-and-error.  The MDD patient is treated with one type of anti-depressive drug for 3 months, if no improvement, they received a second anti-depressant therapy for 3 months.  Only when they fail the second course of therapy are they defined as TRD.  This diagnostic period lasts 6 months!  During that 6 months, the patient’s depression persists, their family suffers, their job performance deteriorates.  A solution is to this problem is needed.

A biomarker predicting which patient with MDD will have TRD is needed.  Patients with TRD are often found to have elevated biomarkers of inflammation in their blood, have more severe symptoms, and a longer course of depression⁴.  The elevated biomarkers of inflammation in the blood suggests that neuroinflammation plays a role in the resistance to conventional therapies of MDD.  Put another way, neuroinflammation is an important cause of TRD and elimination of neuroinflammation may be an important step in converting patient’s disease from treatment resistant to treatment responsive. 

Although there are many inflammatory factors involved in depression, Tumor Necrosis Factor (TNF) may play a unique role in TRD. TNF is reliably increased in TRD patients and TNF levels are associated with the number of failed treatments and poorer treatment outcomes⁵. Anti-TNF therapy has been shown to improve mood in patients suffering from inflammatory diseases such as psoriasis⁶ and Crohn’s disease⁴. Finally, a proof of concept clinical trial demonstrated that blocking TNF improved mood in a subset of TRD patients that had elevated biomarkers of inflammation (c-reactive protein; CRP)⁷.  The last point is important.  Elevated CRP in the blood is a biomarker predicting TRD in patients with depression suggesting that a simple and widely available laboratory test could change the management of patients with TRD⁸.

Pre-clinical studies support the use of XPro1595 in the treatment of depression.  XPro1595 has been shown to ameliorate depressive-like behaviors in several animal models including social predatory stress, environmental stress, a genetic model of depression, and a rodent model of treatment resistant depression (chronic Adrenocorticotropic hormone (ACTH) treatment)^9-11.   

The Phase 2 clinical trial is a placebo-controlled blinded study of XPro1595 in patients with TRD and biomarkers of inflammation. This 6-week study will enroll 90 patients at Emory University and University of Alabama- Birmingham.  To be eligible, patients must meet the criteria for TRD (i.e., failed 2 courses of anti-depressant treatment) and have biomarkers of inflammation defined as a CRP greater than 3 mg/L and symptoms of anhedonia, a core symptom of depression that is sensitive to inflammation.  

Although the reversal of the clinical symptoms of depression in patients is an important goal of the Phase II study, the primary goal of the study is to understand the pathophysiology. Consistent with this approach and the reason INmune Bio was awarded an NIMH grant which may be as much as  $2.9M  to perform the Phase II study, trial includes endpoints to define the biology of TRD.  The team at Emory University has used novel neuroimaging technology to show changes in functional connectivity within the reward circuitry in patients with TRD.  This study will assess whether XPro1595 can restore the functional connectivity between two areas of the brain that subserve motivation and reward and determine the extent to which early changes in these biomarkers can predict clinical effectiveness as determined by traditional measures.

Forward Looking Statements

Clinical trials are in early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this statement that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. INB03™, XPro1595, LIVNate, Quellor™ and INKmune are still in clinical trials or preparing to start clinical trials and have not been approved and there cannot be any assurance that they will be approved or that any specific results will be achieved. Our two platforms are beginning clinical trials and there cannot be any assurance of the success of these trials. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Company’s ability to produce more drug for clinical trials; the availability of substantial additional funding for the Company to continue its operations and to conduct research and development, clinical studies and future product commercialization; and, the Company’s business, research, product development, regulatory approval, marketing and distribution plans and strategies. These and other factors are identified and described in more detail in the Company’s filings with the Securities and Exchange Commission, including the Company’s Annual Report on Form 10-K, the Company’s Quarterly Reports on Form 10-Q and the Company’s Current Reports on Form 8-K. The Company assumes no obligation to update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this statement.

_References

_{1              Substance Abuse and Mental Health Services Administration. (2019). Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health (HHS Publication No. PEP19-5068, NSDUH Series H-54). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/} 

_{2              Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, Grant BF (2018): Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry 75: 336–346.}

_{3              Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization; 2017.}

_{4              Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.}

_{5              Haroon E, Daguanno AW, Woolwine BJ, et al. Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology. 2018;95:43-49. doi: 10.1016/j.psyneuen.2018.05.026. PubMed PMID: 29800779; PMCID:}

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_{6              Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet (London, England). 2006;367(9504):29-35.}

_{7              Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn's disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22(2):101-110.}

_{8              Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41. doi: 10.1001/2013.jamapsychiatry.4. PubMed PMID: 22945416; PMCID: PMC4015348..}

_{9              Bedrosian TA, Weil ZM, Nelson RJ. Chronic dim light at night provokes reversible depression-like phenotype: possible role for TNF. Mol Psychiatry. 2013;18(8):930-936.}

_{10           Aguilar-Valles A, Haji N, De Gregorio D, et al. Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nat Commun. 2018;9(1):2459.}

_{11           unpublished data}