Assessing the Success of AVP-786 for Patients with Treatment Resistant Major Depressive Disorder

Assessing the success of a clinical trial depends on many factors.  Trial design, primary endpoint, prior drug trials, safety and tolerability, competitor success with similar drug, and what is deemed successful by FDA standards, are just a few factors to consider.  Avanir Pharmaceuticals is nearing the end of a phase 2 clinical trial for AVP-786 as Adjunctive Therapy in Patients with Major Depressive Disorder With Inadequate Response to Anti-Depressant Treatment in clinical trial NCT02153502.

The first important factor to consider is that AVP-786 is the deutered version of AVP-923.  Both drugs were tested in a Phase 1, Single-center, Randomized, Double-blind, Double-dummy, 2-way Crossover Study Comparing AVP-786 with AVP-923 here NCT02336347.  The two drugs exhibited a similar PK and safety profile.  This is important because we will be using data from two AVP-923 clinical studies that had a subset of patients tested for depression, with either the BDI-2 (Beck Depression Inventory-II) or the Cornell Depression Scale.

Avanir ran a phase 3 clinical trial with AVP-923 evaluating the safety and efficacy of AVP-923 in PBA (Pseudobulbar Affect) patients with ALS or MS, trial named (STAR) here NCT00573443. The mean change from baseline at day 84 in the Beck Depression Inventory (BDI-II) Total Score was used as a secondary endpoint.  Patients with moderate depression on the BDI-II scale, greater than 18, scored a significant p=0.03 while taking AVP-923, 30mg dextromethorphan / 10mg quinidine.  Below is the Avanir, JP Morgan Healthcare Conference presentation in January 2014.

2014 JP Morgan Healthcare Conference
Treatment-Resistant MDD Clinical Rationale
The Beck Depression Inventory-II (BDI-II) was included as a secondary efficacy endpoint in the pivotal phase 3 trial in PBA patients
Major Depression Excluded
Among patients with baseline BDI-II scores >10, AVP-923 treatment was associated with a reduction in depression symptoms
STAR Trial; Avanir data on file

Endpoint BDI-II
(n=50)  -3.36  AVP-923 30/10
(n=55)    -2.3   AVP-923 20/10
(n=52)    -1.1    Placebo

P Value
0.065   AVP-923 30/10
0.378   AVP-923 20/10

"Among a subset of patients with baseline BDI-II scores > 18, AVP-923 30/10 was
associated with statistically significant improvement (p=0.03)".

Using the description below for the (p=0.03) subset, the trial had patients classified primarily in the moderate depression range, as the presentation listed major depression as excluded. The following is a breakdown of the BDI-II, which is a 21-item self-report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3.

BDI-II Depression Scale
0-13 is considered minimal range 
14 to 19 mild depression
20 to 28 moderate depression
29 to 63 severe depression
  

In a phase 2 clinical trial for Alzheimer's patients experiencing agitation. Trial NCT01584440 utilized a secondary endpoint called the Cornell Scale for Depression in Dementia (CSDD): which a statistical p=0.02 was observed. 

Bottom Line:
Although the number of patients were relatively small in the two above trials showing benefits of AVP-923 for depression, it does give us some guidelines to the probabilities for potential success in the current clinical trial coming to completion.  Thank you for reading.

NMDA Receptor Modulators for Depression

NMDA (N-mythel-D-asparate) roots track back to a drug known as Ketamine or street name Special K, with hallucination effects.  Ketamine is an NMDA receptor antagonist originally used as an anaesthetic.  The glutamate receptor subtype known as (NMDA) plays a central role of modulating brain activity in the central nervous system, such as synaptic transmission, synaptic plasticity, and excitotoxicity. Pharmaceutical firms have been developing NMDA type drugs for over two decades, and a few including Memantine, and Nuedexta are being marketed for other indications outside of depression.
There have been several studies modulating the NMDA receptor, that have shown efficacy in patients with treatment-resistant depression.  A trial performed by Avanir Pharmaceuticals for pseudobulbar affect with drug AVP-923 (Nuedexta), showed efficacy in a subset of patients for depression using the Beck Depression Inventory II or BDI-II. Data showed that the dextromethorphan (an NMDA receptor antagonist, sigma 1 agonist) / quinidine combination was effective in patients with BDI-II scores greater than 18 at inclusion with AVP-923 30/10, and was associated with a statistically significant improvement of (p=0.03). What's also significant is that major depression was an exclusion into the trial.  Avanir is now in a phase 2 clinical trial with AVP-786, for major depressive disorder patients as adjunct to current antidepressant here NCT02153502.  I think the chances of success are high, based on how the dextromethorphan/quinidine combination performed in the subset of patients in prior trials.
Private company Naurex, is also working on NMDA drugs for depression patients. The company has displayed good data in early clinical trials using IV, and soon to be launched an oral NMDA drug for depression.  Thank you for reading.

AVP-786 is Concert Pharmaceutical's deutered enhanced version of AVP-923.