EXXUA™ for Generalized Anxiety Disorder
Therapeutic Area: Generalized Anxiety Disorder: Phase II
- Phase of Development: One Phase II Trial with extended release formulation. 5-25 mg needed prior to entering Phase III Trials Two-year carcinogenicity studies have been completed. CMC is complete.
EXXUA™ is a 5HT1A partial agonist. This means it is an agonist at the serotonin 1A receptor site but its potency is less than endogenous serotonin. This ability to occupy the 5HT1A receptor sites and have an effect less than that of serotonin allows EXXUA™ to function as an inhibitor. Inhibition at the 5HT1A site results in anxiolytic activity.
There is an optimal dose of EXXUA™ which competes with endogenous serotonin to effect anxiolytic activity. A dose below the optimal dose would have less anxiolytic activity. A dose higher than the optimal dose would also result in less anxiolytic activity.
EXXUA™ is a significantly stronger anxiolytic than buspirone, with no dopaminergic effects.
Early in the development of EXXUA™ 7 studies of an immediate release formulation were carried out in subjects with GAD.
Two studies in GAD of immediate release EXXUA™ with mean modal doses of 15 and 16 mg/day showed statistically significant improvement at endpoint (p<0.01, and p<0.04) on the Hamilton Anxiety Rating Scale (HAMA) change from baseline compared to placebo, with comparable or superior efficacy to benzodiazepines diazepam, bromazepam, and lorazepam. An additional IR study in the proper dose range (23 mg/day) also showed positive results.
Safety in these 7 studies was of no concern with minor adverse events of nausea and dizziness which resolve with continued dosing. The efficacy and safety data from studies in MDD were submitted to the FDA as the basis of an IND for EXXUA™ for GAD. Summary of Pre-IND FDA Meeting
The potential issues raised and resolved with no further action needed include the following: The GAD IND can cross-reference other EXXUA™ INDs. For the initial NDA, no long term efficacy data in GAD, additional pediatric or geriatric data are required. The previous preclinical pharmacology program for EXXUA™ is acceptable, with no further studies required. The toxicology program is also acceptable, with no further studies needed for the initial NDA.
The only action needed to complete the initial IND is the manufacture of 5 mg tablets and a clinical pharmacology study.
Fabre-Kramer agreed to conduct an open-label maintenance efficacy study as a phase 4 commitment for long term safety at low doses of EXXUA™. Because of the potential for off-label use in the treatment of children and adolescents, a pediatric GAD indication is appropriate. For such an indication, a pediatric safety and efficacy study will be required, as well as a toxicology study in juvenile rats. The Agency stated that these studies would not be required for the original NDA.
The GAD market in the United States is difficult to quantify because most approved medications are generic, i.e. benzodiazepines, SSRIs, and buspirone. Further, the SSRIs are counted in the antidepressant market, not the GAD market. Nonetheless, the GAD market is substantial. Last year in the US, there were 85.3 million prescriptions for benzodiazepines. A novel, differentiable anxiolytic could potentially achieve peak annual sales over $1 billion.
EXXUA™ is a safe drug which has met all FDA safety requirements. The remaining issues for an NDA for GAD can be accomplished in 2-3 years. The cost is relatively low, a fraction of the cost for an NCE. The market is large and EXXUA™ should be distinguishable from the competitor anxiolytics.
Development and commercialization partnering opportunities are available.