Therapeutic Area: Generalized Anxiety Disorder
Phase of Development: Phase II
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.
Dose becomes a very big concern, since at higher doses EXXUA is an agonist and has antidepressant activity.
Therefore, 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 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 (p<0.01).
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 FDA issued IND 104,229 as a new IND for EXXUA treatment of GAD. The Agency accepted the EXXUA data as evidence of EXXUA efficacy in GAD, as well as accepting the proposed dose range of 10 – 25 mg/day EXXUA for GAD. There was agreement on a flexible dose opening study of EXXUA for GAD, which will include a) escitalopram as an active comparator, b) sexual functioning measures (to demonstrate non-inferiority to placebo, c) prospective assessment for suicidality, and d) inclusion criteria for ages 18 – 80 to achieve 10% of subjects that are more than 64 years old. A fixed dose EXXUA study that will depend on results of the flexible dose study is the second trial. The Agency specified that patients with prior benzodiazepine use will be included in at least one trial.
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. Although the FDA agrees that no QTc prolongation signal is present, they request a hERG assay be performed for completeness.
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.
Differentiation of EXXUA from Competitor Anxiolytics
At present, SSRIs are widely used in the treatment of GAD, with sexual dysfunction a significant side effect. The issue of sexual dysfunction is the same in GAD patients as in MDD patients. EXXUA has a distinct advantage of not causing sexual dysfunction. EXXUA does not cause the amnesia, dependency, and withdrawal seen with the benzodiazepines. EXXUA is a stronger anxiolytic than buspirone and also relieves somatic anxiety, which buspirone does not address.
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.