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TriRima: An Antidepressant

Summary:
TriRima® is an optimized, specific, high affinity, reversible inhibitor of monoamine oxidase-A (RIMA) potentially useful as monotherapy in the treatment of major depressive disorder, anxiety and ADHD. TriRima was designed and developed specifically to maximize RIMA efficacy while minimizing traditional MAOI-class tolerability issues. There is a clear unmet medical need for a robust, well tolerated alternative antidepressant with a proven mechanism of action for non-responders to SSRIs. TriRima is targeted to severe, atypical and treatment-resistant depression patients and has been tested in more than 450 subjects in Phase 1 and Phase 2 clinical trials, showing a good tolerability profile, pharmacodynamic proof of concept, and preliminary efficacy.

Mechanism of Action:
Triple acting RIMAs inhibit the activity of monoamine oxidase-A, known to be elevated in major depression patients, thus preventing the breakdown and increasing the availability of the neurotransmitters serotonin, norepinephrine, and dopamine. Unlike irreversible MAO-A inhibitors, TriRima has shown no propensity to induce hypertensive crisis after ingestion of tyramine-rich food. This mechanism offers an effective, whole-brain strategy for restoring natural neurotransmitter balance to treat major depression. While increased serotonin is associated with improved mood and reduced anxiety, improved energy and motivation are associated with normalized levels of norepinephrine, addressing depression-associated fatigue and low energy. Previous MAO-A inhibitors have been proven effective in the past, but their use has been limited by safety concerns.  TriRima’s specific MAO-A affinity is 100x higher than moclobemide which has been launched in major markets outside the US. Due to negligible anticholinergic and antihistaminic actions, RIMAs have been shown to be better tolerated than tri- or heterocyclic antidepressants and atypical antipsychotics.  Gastrointestinal side effects and sexual dysfunction have been shown to be much less frequent with RIMAs than SSRIs.

Development Program Status:
  • IND filed; full preclinical pharmacological, toxicological and CMC package completed.
  • Phase 1 dose ranging and pharmacology package completed
    • PET scan study to validate whole-brain pharmacology
    • CNS penetration, MAO-A binding & reversibility demonstrated
    • Tyramine challenge study confirmed favorable safety profile
  • Phase 2a depression study completed (early formulation)
    • PK/PD relationship showed clinically significant drop in MADRS score in compliant patients
    • High response rates seen in severe depression patients
    • Favorable safety and tolerability profile demonstrated; no tyramine interaction
  • Phase 2b treatment resistant depression study completed (commercial formulation).
    • Responder analysis showed significant improvement compared to placebo in MADRS.
    • Sub-population evaluations showed efficacy in severe depression and non-smoker patients
  • Dosage and administration: TriRima is available as an oral, sustained release tablet with BID dosing
  • Cost of goods is forecast to be standard for an oral, small molecule drug

Commercial Status:
TriRima has been licensed for development to Cennerv Pharma (S) Pte Ltd. However, KPI has retained the rights to develop or license TriRima in North and Central America. Two comprehensive market research studies have confirmed the utility and acceptance of an effective, well tolerated RIMA as an alternative to SSRIs in the treatment of severe depressive disorder. Peak sales are projected to exceed 8% of the overall prescription pharmaceutical depression market in major market areas.  Treatment of ADHD is of interest but remains to be demonstrated.

Intellectual Property:
Three issued patents offer market exclusivity in the United States to 2030.
TriRima is a registered trademark of KPI.

 

 
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