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. Desmetramadol is a novel mixed-mechanism analgesic developed by Syntrix that is an opioid-adjunct analgesic combination consisting of the enantiomers of the active metabolite of tramadol. Desmetramadol provides the same net pharmacology as tramadol, but in contrast to tramadol, does not require metabolism by CYP2D6 for its activity. Desmetramadol 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 desmetramadol and 50 mg tramadol was recently completed. The Phase 1b trial successfully demonstrated that 20 mg desmetramadol was bioequivalent to 50 mg tramadol, and that desmetramadol 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 desmetramadol dose-proportionality, and the evaluation of food intake on systemic desmetramadol plasma levels following oral administration. In this SBIR Fast-Track, desmetramadol 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 desmetramadol 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 desmetramadolandapos;s continued clinical development as a novel mixed-mechanism analgesic.Opioids are among the most widely prescribed analgesics for treatment of chronic pain despite significant adverse effects that include death. More than 16,600 persons die every year, or about 45 a day, from an opiate pain medication overdose – more than cocaine and heroin combined. This proposal would clinically advance a safer mixed-mechanism (weak opioid + adjunct) analgesic (desmetramadol) with the aim that desmetramadol would supplant relatively unsafe opioids in the clinic for the treatment of pain.