We have completed two phase 1 clinical studies in healthy volunteers, examining the impact that deuteration has on drug behavior. We have shown that drug plasma levels have been favorably impacted through strategic deuteration of venlafaxine, enhancing the levels of the parent molecule while reducing the levels of the major metabolite (ODV, or O-desmethyl venlafaxine).
The first adjacent graph shows the blood plasma levels for each of the deuterated vs. non-deuterated forms of venlafaxine, represented as their time vs concentration profiles.
The second graph shows the time vs concentration profile observed in healthy volunteers for the deuterated vs. non-deuterated versions of the major metabolite, ODV. It is readily observed that when human subjects are dosed with the deuterated version of venlafaxine, they benefit from higher and more consistent blood concentrations of non-metabolized parent drug relative to the non-deuterated version. The treated subjects also exhibit lower levels of the major metabolite ODV in their bloodstream, as would be expected. We are confident these phase 1 results will translate into meaningful efficacy and safety benefits in patients treated with deuterated venlafaxine (SD-254).
The above plot demonstrates how treatment with SD-254 results in less subject-to-subject variation with respect to the rate of metabolic conversion of venlafaxine. The red dots represent the metabolic rate of individuals treated with non-deuterated venlafaxine and the blue dots represent the metabolic rate of the same individuals treated with deuterated venlafaxine (SD-254). It is evident that administration of deuterated venlafaxine leads to a slower and more homogeneous metabolic conversion rate, thus offering the potential to avoid undesirable dose titrations and leading to the most desirable concept of “one dose fits all.” Since these findings are a direct consequence of attenuating the rate of metabolism due to deuteration, this concept may prove to be applicable to many other important drugs.
Finally, the above graph demonstrates that deuterated venlafaxine exhibits model pharmacokinetic and pharmacodynamic properties. We are encouraged by these data from healthy human volunteers, and look forward to continuing to advance this program through accelerated clinical development.
