Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Phase 2)
Company: Avanir Pharmaceuticals, Concert Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd.
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 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 and, in 2014, was acquired by Otsuka Pharmaceutical Co.
AVP-786's clinical development began in October 2012 with a Phase 1 trial in 48 young, healthy volunteers, testing safety, tolerability, and pharmacokinetics of deuterated dextromethorphan only. In September 2013, Avanir switched to 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. All subsequent trials use the deuterated combination. Both trials took place in Australia.
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 United States; 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 enroll the same patient population, both evaluate a 12-week course of twice-a-day AVP-786 administration, and both are conducted in the United States and Canada. Both trials use the same outcome measures. The primary outcome is the Cohen Mansfield Agitation Inventory (CMAI); secondary outcomes include the neuropsychiatric inventory (NPI), the agitation component of the ADCS-CGIC, and other global, quality of life, resource utilization, and cognitive measures. The trials compare two different doses of drug to placebo, but with slightly different designs. TRIAD-1 uses a traditional, three-arm comparison, while TRIAD-2 uses a sequential design aimed at minimizing the influence of placebo responders on the outcomes.
A third Phase 3 trial began in October 2017. A worldwide version of TRIAD-1, it is enrolling 412 people at 118 study locations in the United States, Europe, and South Africa, and will run through June, 2021.
In March 2019, Avanir announced that the TRIAD-2 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, diarrhea; there were no deaths related to treatment.
In September 2019, the company disclosed negative results for TRIAD-1. 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 is to enroll 1,000 people, and run until June 2022.
APV-786 is also being studied in schizophrenia and to treat behavioral disinhibition (aggression, agitation, and irritability) in patients with traumatic brain injury.
For all trials on this medication, see clinicaltrials.gov.
Last Updated: 25 Feb 2020
- Garay RP, Grossberg GT. AVP-786 for the treatment of agitation in dementia of the Alzheimer's type. Expert Opin Investig Drugs. 2017 Jan;26(1):121-132. Epub 2016 Dec 11 PubMed.