A Phase 1 Randomized Single Oral Dose Four Period Cross-Over Study Investigating Omnitram Dose Proportionality and Food Effect in Normal Human Subjects - From 2009-2013 the utilization of the Schedule II opioids codeine, OxyContin and fentanyl declined
significantly, down about 14.0% for all three drugs. In sharp contrast, the use of tramadol, a Schedule IV
controlled substance, increased 32.5%. Schedule IV substances have low potential for abuse and harm
relative to Schedule II substances, and the fortuitous trend to tramadol has reduced the use of the relatively
unsafe Schedule II opioids dramatically. Tramadol is a weak opioid-adjunct combination that is recognized as
having a better safety profile and less abuse potential than Schedule II opioids (e.g., oxycodone, tapentadol).
Unfortunately, tramadol suffers from a critical shortcoming. Tramadol requires metabolic activation for efficacy,
and individuals who are CYP2D6 poor metabolizers (PMs) fail to obtain pain relief. The “real world” incidence
of CYP2D6 PM status in clinical practice has been shown to be as high as 1 in 3. Tramadol resistance due to
CYP2D6 PM status is a shortcoming that results in a significant negative impact on patient care, and that
erodes the entire utility of tramadol as a safer alternative to Schedule II opioids. There exists a significant need
for an “improved tramadol” that would have the same inherent safety but be effective in all patients irrespective
of their metabolic status. Omnitram is a novel mixed-mechanism analgesic developed by Syntrix that is an
opioid-adjunct analgesic combination consisting of the enantiomers of O-desmethyltramadol, the active
metabolite of tramadol. Omnitram provides the same net pharmacology as tramadol, but in contrast to
tramadol, does not require metabolism by CYP2D6 for its activity. Omnitram broadly increases the utility of
tramadol, and would leverage and accelerate the shift in prescribing trends away from the relatively unsafe
Schedule II opioids. A Phase 1b randomized, double-blind, placebo-controlled, double cross-over trial in 40
healthy subjects that compared the safety, oral steady-state pharmacokinetics, and analgesic activity of 20 mg
Omnitram and 50 mg tramadol was recently completed. The Phase 1b trial successfully demonstrated that 20
mg Omnitram was bioequivalent to 50 mg tramadol, and that Omnitram produced significant analgesia
compared to placebo, being as effective as tramadol. A recent meeting with the FDA provided clear guidance
towards NDA approval, which requires clinical evidence of Omnitram dose-proportionality, and the evaluation
of food intake on systemic Omnitram plasma levels following oral administration. In this SBIR Fast-Track,
Omnitram dose-proportionality and food-effect will be evaluated as mandated by the FDA. This SBIR Fast-
Track proposal will conduct a Phase 1 randomized single oral dose, four period cross-over study investigating
Omnitram dose-proportionality (10 mg, 20 mg and 30 mg) and food-effect (30 mg) in normal human subjects.
Success in this in-patient Phase 1 clinical trial will provide direct support for Omnitram's continued clinical
development as a novel mixed-mechanism analgesic.
