Pharmaceutical Approach

5-hydroxytryptophan (5-HTP)

5-HTP And Serotonin Biology

5-HTP is the natural endogenous immediate precursor of serotonin. In the body, 5-HTP is produced intracellularly from dietary tryptophan. 5-HTP synthesis is the rate-limiting step in serotonin synthesis. Endogenous 5-HTP levels are therefore low, as the 5-HTP is quickly converted to serotonin.

 

Serotonin, aka 5-hydroxytryptamine (5-HT), is a neurotransmitter in the brain. Serotonin released from the pre-synaptic nerve terminal into the extracellular synaptic space is the “active” serotonin, often referred to a as extracellular serotonin. Extracellular serotonin binds to post-synaptic serotonin receptors, which elicits the serotonin neurotransmission. Hence, elevated extracellular serotonin equals stronger serotonin neurotransmission. In humans and primates, among several functions, serotonin neurotransmission promotes mood, sociability, and cognitive flexibility, and attenuates aggression and impulsivity.

Exogenous 5-HTP And Brain Serotonin

5-HTP can also be administered directly to the body. Such “exogenous” 5-HTP for human use is usually botanical, extracted from the seeds of the African shrub Griffonia Simplicifolia. EVX-101 and EVX-301 contain botanical 5-HTP. Numerous human and animal studies demonstrate that 5-HTP administered to the body, orally or intravenously, reaches the brain and is converted to serotonin by serotonergic neurons. At suffcient levels, exogenous 5-HTP will elevate extracellular serotonin and strengthen serotonin neurotransmission, as demonstrated by multiple biomarker and brain imaging studies. Thus,
exogenously administered 5-HTP can amplify brain serotonin levels and strengthen serotonin neurotransmission.

5-HTP Human Safety

5-HTP has a remarkable good human safety record. 5-HTP has been administered to thousands of human subjects in hundreds of studies since the 1950s. Many studies administered high (>1 gram/day) 5-HTP doses, often for long durations (months, years), and often with other drugs, including SSRI or SSRI-like drugs. 5-HTP has not been found to cause any severe side effects, human disease, or deaths.

5-HTP Therapy For Human Diseases – Promise & Limitations

5-HTP has shown therapeutic potential in a wide spectrum of human disorders, most notably depression, but also in obesity, myoclonus, movement disorders, pain disorders, and some rare diseases. Despite these promising findings, no 5-HTP drug candidate has ever entered regulatory-grade clinical trials. No FDA- or EMA-approved drug product exists. Likely, this is because native 5-HTP is impractical as a drug treatment.

 

While 5-HTP appears to have good safety, the tolerability of native 5-HTP is often poor. 5-HTP is very rapidly absorbed from the intestine. This can cause transient 5-HTP and hence serotonin spikes and overdose manifest usually as nausea, vomiting, and diarrhea. Such CMax-effects are common for fast-absorbed compounds. Conversely, as native 5-HTP has a short half-life—2h in humans—blood levels drop off between administrations, necessitating three or more daily doses, to maintain a just reasonably sustained serotonin amplifying effect. Further, native 5-HTP, when taken orally, is mostly degraded by the intestine. Hence, normally only a fraction of orally ingested 5-HTP reaches the blood stream and the brain. Thus, as a drug treatment, native 5-HTP is limited by the triple shortcomings of fast absorption, short half-life, and low bioavailability. A novel drug delivery technology that overcame the triple shortcomings of 5-HTP could, for the first time, realize the full therapeutic potential of 5-HTP, in depression, and in other mental and central nervous system disorders. EVX-101 is one such drug candidate.

Therapeutic Rationale

Sustained Amplification Of Brain Endogenous Serotonin By 5-HTP Slow-release

Dosing with native 5-HTP is associated with intermittent overdose and poor tolerability alternating with loss of pharmacological effect. These shortcomings, along with poor absorption, makes native 5-HTP a poor drug. The 5-HTP slow-release (5-HTP SR) hypothesis posits that if the 5-HTP plasma spikes and valleys are eliminated or minimized, the drug properties
of 5-HTP will be transformatively improved. Research by Evecxia’s founders Drs. Jacobsen and Caron confirmed this hypothesis in translational pre-clinical models.

Mechanism Of Action Of 5-HTP SR Vs Common Antidepressants

The most widely used antidepressant class for mood and anxiety disorders are the SSRIs. SSRIs (and SNRIs) treat these disorders by elevating extracellular serotonin, which activates post-synaptic serotonin receptors, and hence serotonin neurotransmission. SSRIs work by blocking the serotonin reuptake transporter, one of several regulators of extracellular serotonin. However, in human studies SSRIs elevate extracellular serotonin modesty and inconsistently across subjects, and with a delay. This pharmacology could contribute to the generally modest, inconsistent, and delayed therapeutic effect of
SSRIs. 5-HTP SR elevates extracellular serotonin via a mechanism distinct from the SSRIs. 5-HTP SR increases endogenous serotonin synthesis and levels, thereby amplifying dynamic serotonin neurotransmission.

Adjunctive 5-HTP SR Synergizes With Common Antidepressants To Enhance The Serotonergic Therapeutic Mechanism

“Adjunctive” means adding-on a second treatment to an already ongoing treatment to augment clinical efficacy. Adjunctive drug therapy is common in Psychiatry. Evecxia’s pre-clinical research has demonstrated that adjunctive 5-HTP SR interacts synergistically with ongoing SSRI treatment to elevate extracellular serotonin and amplify serotonin neurotransmission beyond the effect of SSRI monotherapy. This antidepressant-augmentation like pharmacological effect of 5-HTP SR was not associated with any apparent side effects. Evecxia’s recent pre-clinical data fits with several clinical pilot studies
conducted over the years with native 5-HTP. These studies reported that adjunctive 5-HTP can augment antidepressant efficacy in depressed patients, albeit often with significant side effects, and a requirement for multiple daily doses.

Adjunctive 5-HTP SR Could Treat Patients Treated Inadequately By Antidepressant Monotherapy

Multiple lines of evidence support that one cause of inadequate antidepressant response to SSRI/SNRI monotherapy is insuffcient elevation of extracellular serotonin in the brain. Thus, when antidepressant monotherapy brings insuffcient relief to the patient, adjunctive treatment with an appropriate 5-HTP SR drug could bring the needed relief, by amplifying serotonin neurotransmission beyond the SSRI effect. Convergent clinical and preclinical evidence suggest that the adjunctive 5-HTP SR therapy would be safe and tolerable. Thus, adjunctive 5-HTP SR could emerge as a critical new therapy for patients suffering from depression and other mood and anxiety disorders, for whom today good therapeutic options are unavailable.

The Serotonin Synapse

5-HTP

Serotonin

SSRI

Serotonin

Serotonin Transporter

Baseline

Serotonin is continuously released extracellularly into the synaptic cleft. Extracellular serotonin activates post-synaptic receptors that mediates serotonin neurotransmission. Pre-synaptic serotonin transporters work as a break on serotonin neurotransmission, by pumping extracellular serotonin back into the pre-synaptic neuron terminal.

SSRI treated

Blocking the serotonin transporter with an SSRI is intended to elevate extracellular serotonin. SSRI treatment depends on baseline serotonin release, which limits how much and how reliably an SSRI (or SNRI) can enhance serotonin neurotranmission.

Adjunctive 5-HTP SR to SSRI treatment

Adjunctive 5-HTP SR amplifies neuronal serotonin production and release, thereby synergizing with SSRI treatment in elevating extracellular serotonin and strengthening serotonin neurotransmission.

Technology Rationale

Overcoming 5-HTP’s Limitation As A Therapeutic

Native 5-HTP has 3 shortcomings as a therapeutic:

  1. Fast absorption associated with side effects and poor tolerability.
  2. Short half-life, necessitating multiple daily doses.
  3. Poor absorption, necessitating large doses.

In addition, 5-HTP has a narrow absorption window restricted to the upper intestine. Evecxia is employing proven drug delivery technologies and combinations with other compounds to remedy the short-comings of 5 HTP as a therapeutic.

Overcoming 5-HTP’s Fast Absorption And Short Half-Life

Evecxia is developing drug delivery technologies that secures sustained 5-HTP plasma levels and consequently sustained brain serotonin amplification. These technologies optimize the therapeutic effect of 5-HTP and minimize side effects.

Overcoming 5-HTP’s Narrow Absorption Window

In humans 5-HTP is substantially absorbed only by the upper intestine, and not by the colon. This narrow absorption window occludes using conventional drug delivery technologies to achieve 5-HTP SR. Evecxia employs novel proprietary embodiments of validated technologies, to either deliver 5-HTP over a prolonged period to the upper intestine [EVX-101], or to deliver 5-HTP parenterally, bypassing the intestine [EVX-301]. These approaches enable for the first time to achieve 5-HTP SR in humans.

Overcoming 5-HTP’s Poor Absorption With Low-Dose Carbidopa

Evecxia has discovered that extremely small doses of the drug carbidopa can many-fold enhance 5-HTP’s absorption from the intestine. (Carbidopa has previously been reported to enhance 5-HTP’s absorption, but in orders of magnitude higher doses.) This unexpected pharmacological phenomenon requires that 5-HTP and carbidopa are delivered in close spatial and temporal juxtaposition to the site of 5-HTP absorption, the upper intestine. The low-dose carbidopa approach is used in EVX-101.

 

In another approach, 5-HTP is delivered via a constant IV infusion. This provides complete dose control, to optimize the rate of brain serotonin amplification, and to personalize the dose to the needs of the individual patient. This approach is used in EVX-301.