Background

This investigational therapeutic is a deuterated, second-generation version of AVP-923/Nuedexta, a fixed-dose combination of two approved drugs.

Both AVP-923 and AVP-786 contain dextromethorphan, the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, and an agonist of sigma 1 receptors, molecular chaperones located in membranes of the endoplasmic reticulum. Both AVP-923 and AVP-786 also contain quinidine. Otherwise prescribed to treat irregular heartbeat, quinidine in this combination increases the bioavailability of dextromethorphan by slowing its oxidative metabolism by the liver enzyme cytochrome P450-2D6 and by inhibiting the blood-brain barrier protein pump P-glycoprotein.

AVP-786 differs from its predecessor in that it contains deuterium, a naturally occurring, heavier isotope of hydrogen. As developed by Sun Pharma, formerly Concert Pharmaceuticals, deuterium chemistry leaves a drug's mechanism of action fundamentally unchanged but can alter its pharmacokinetic properties, for example by slowing its liver metabolism, prolonging exposure in the blood, or reducing its side effect profile.

Avanir engineered AVP-786 together with Concert Pharmaceuticals. In 2014, Otsuka Pharmaceutical Co. acquired Avanir.

Findings

AVP-786's clinical development began in October 2012 with a Phase 1 trial in 48 young, healthy volunteers. It tested safety, tolerability, and pharmacokinetics of deuterated dextromethorphan only. In September 2013, Avanir started a second Phase 1 trial in 56 young, healthy people of deuterated dextromethorphan with a low dose of quinidine sulfate added back in, and compared a one-week course of this combination to AVP-923. Both trials took place in Australia. The company reported that AVP-786 achieved the same steady-state plasma concentrations of dextromethorphan as AVP-923, at a lower quinidine dose (Feb 2013 press release). All subsequent trials use the deuterated combination.

In 2014 and early 2015, Avanir ran three additional Phase 1 trials. One directly compared AVP-786 to AVP-923 in 62 slightly older healthy volunteers in the U.S.; one looked for drug interactions between AVP-786 and two antidepressant medications, paroxetine and duloxetine, in 56 healthy volunteers in Australia; the third trial compared AVP-786 and AVP-923 for their respective interactions with the antifungal itraconazole in 24 healthy adults in Kansas. 

In November 2015, the FDA fast-tracked AVP-786 for agitation.

Also that month, Avanir/Otsuka started enrolling for TRIAD-1 and TRIAD-2, two Phase 3 trials to evaluate the combination's efficacy in 325 and 380 patients, respectively, who have moderate Alzheimer's disease with clinically significant agitation. Both trials enrolled the same patient population, both evaluated a 12-week course of twice-a-day AVP-786 administration, and both are conducted in the United States and Canada.

Both trials used the same outcome measures. The primary outcome was the Cohen Mansfield Agitation Inventory (CMAI); secondary outcomes included the neuropsychiatric inventory (NPI), the agitation component of the ADCS-CGIC, and other global, quality of life, resource utilization, and cognitive measures. The trials compared two different doses of drug to placebo, but with slightly different designs. TRIAD-1 used a sequential design aimed at minimizing the influence of placebo responders on the outcomes. A sequential design was used in the previous Phase 2 trial of AVP-923, where the drug improved AD-related agitation (Cummings et al., 2015). TRIAD-2 uses a traditional, three-arm parallel comparison.

A third Phase 3 trial began in October 2017. A worldwide version of TRIAD-2, it aimed to enrolling 550 people at 118 study locations in the U.S., Europe, and South Africa, and was planned to run through July 2022.

In March 2019, Avanir announced that the TRIAD-1 sequential design trial met its primary endpoint. According to the company press release, one of the two dose groups improved their scores on the CMAI and on "the key" secondary endpoint, though Avanir did not disclose which secondary endpoint. A trend for a treatment benefit in the other dose group missed statistical significance. Most common adverse effects in the 410-patient study were falls, urinary tract infection, headache, and diarrhea; there were no deaths related to treatment.

In September 2019, the company disclosed negative results for TRIAD-2. In this study of 522 patients in three parallel arms, AVP-786 did not improve agitation compared with placebo (Oct 2019 news). Again, adverse events included falls and urinary tract infection, as well as somnolence, with no deaths related to AVP-786. Soon after, Avanir announced plans to continue clinical development of AVP-786, including the ongoing worldwide Phase 3 (Nov 2019 press release).

A 52-week extension trial of AVP-786 began in 2015 for people who had completed an earlier Phase 2 study of AVP-923, and people who completed any of the Phase 3 trials. It administers one of three doses; all participants know they are on drug, but the trial is blinded to dose. This trial was to enroll 1,000 people, and run until October 2023. It was later enlarged to 1,200 participants, and extended to July 2025.

In 2020, Avanir began two additional Phase 3 trials of AVP-785 in people with AD-associated agitation. In each, 750 participants will be randomized to twice-daily drug or placebo for 12 weeks. CMAI is the primary outcome, and Clinical Global Impression of Severity of illness (CGI-S) is the sole secondary measure. The trials are being conducted at 110 centers worldwide, through December 2024.

On February 12, 2024, the company announced negative topline results of the worldwide TRIAD Phase 3 study (press release). CMAI did not differ between drug and placebo. Falls were more common in the treated group than among patients on placebo.

APV-786 was also being studied in schizophrenia, but a Phase 2/3 trial was terminated for futility. A trial in intermittent explosive disorder (Rynar and Coccaro, 2018) was stopped due to difficulty recruiting. Trials were completed for behavioral disinhibition (aggression, agitation, and irritability) in patients with traumatic brain injury, and treatment-resistant depression.

For all trials on this medication, see clinicaltrials.gov.