EVX-101 - Therapeutic Rationale

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Depression symptomatology is uniquely human and difficult to model in animal behavioral models. All clinically effective antidepressants were developed based on initial clinical pilot trials and observations. The EVX-101 rationale is similar, based on convergent multi-pronged clinical data.

1. Elevating extracellular serotonin (5-HT) beyond the SSRI/SNRI effect enhances antidepressant efficacy. Multiple clinical reports find that adding a second 5-HTergic compound to antidepressant therapy, to enhance extracellular 5-HT additionally, treats additional patients. Such second 5-HTergic compounds include tryptophan, monoamine oxidase inhibitors, 5-HTP, and methylfolate. Based on available clinical evidence, all such compounds appear effective in augmenting antidepressant efficacy. However, all have drawbacks related to safety, pharmacokinetics, and/or mechanism, which precludes their general clinical use.

2. Evidence that 5-HT deficiency is causal in SSRI/SNRI non-response. CNS metabolomics biomarkers of 5-HT deficiency segregate with poor antidepressant response to SSRI/SNRIs. Conversely, suicidality and co-morbid borderline personality disorder, two conditions associated with CNS 5-HT deficiency, predict poor antidepressant response to SSRI/SNRIs.     

3.  PET imaging: SSRI/SNRIs elevate extracellular 5-HT inconsistently in humans. The serotonin transporter, the main target of SSRI/SNRIs, is just one of many regulators of extracellular 5-HT. In fact, recent human PET imaging data show that chronic SSRI treatment only elevates brain extracellular 5-HT modestly, on average,and not at all in some humans. Further, PET imaging finds that SSRIs short-term may even decrease extracellular 5-HT in the human frontal cortex, likely due to auto-inhibitory feedback. These latter findings could help explain early adverse events and the delayed onset of therapeutic efficacy.       

4.  5-HTP and SSRI synergizes in elevating extracellular 5-HT in humans. Neuroendocrine (cortisol, prolactin) biomarker studies consistently finds that 5-HTP alone is modestly effective in elevating brain extracellular 5-HT. In contrast,  adjunctive 5-HTP strongly augments the extracellular 5-HT elevation produced by SSRIs.

5.  Reports of adjunctive 5-HTP + carbidopa antidepressant effects in humans. Several pilot reports, totalling ~200 subjects, report that adjunctive 5-HTP/carbidopa augments the antidepressant effect of SSRI-like or other 5-HTergic antidepressants.  

6.  5-HTP has a good human safety record. Experimental clinical studies with 5-HTP has been pursued since the 1950s. Thousands of subjects have been dosed with 5-HTP, in doses often exceeding 1g/day, with or without carbidopa, and with or without another 5-HTergic drug. Yet, there are no reports of serotonin syndrome, other serious events, or death associated with 5-HTP (NIH, FDA).       

7.  5-HTP's human half-life and Tmax are too short for a drug. As a rule of thumb, drugs must be dosed at least every two half-lives to maintain steady exposure and efficacy. With a half-life of 2h, 5-HTP would have to be dosed 6 times per day, which is unattaintable in a real-life clinical setting. Further, 5-HTP's rapid absorption (Tmax = 1.5h) and resultant 5-HT spikes is associated with gastrointestinal and other side effects. 

8.  Extracellular 5-HT elevation must be sustained for antidepressant efficacy in humans. In previously depressed patients treated to remission with an SSRI, SNRI, or another 5-HTergic antidepressant, acutely reversing the extracellular 5-HT elevation causes acute relapse,  within hours. This demonstrates that the antidepressant effect is directly sustained in real time by the elevation in extracellular 5-HT.

9.  Advanced SR delivery technologies can transform the drug-properties of fast pharmacokinetics compounds. Over the last decades, slow-release drug delivery technologies have been implemented that can markedly improve the therapeutic potential of short-acting compounds. Examples of such compounds include nifedipine, L-DOPA/carbidopa, venlafaxine, dimethyl fumarate, minocycline, methylphenidate, and niacin.