Therapy Type: 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 being conducted in the United States at a total of 110 centers. 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 mainly differ in that one compares one dose, the other two different doses, to placebo.
In December 2015, a long-term extension trial started for people who had completed an earlier Phase 2 study of AVP-923, and people who completed of TRIAD-1/-2. It administers a 52-week course of either the low dose of AVP-786 (i.e., 18 mg dextromethorphan with 4.9 mg quinidine), or the high dose (28 mg dextromethorphan with 4.9 mg quinidine). All participants know they are on drug, but the trial is blinded as to dose. This trial is to enroll 550 people, and run until July 2019.
Also in December 2015, a small Phase 2 trial started evaluating a six-week course of AVP-786 on the disinhibition component of the NPI. It enrolls 12 patients across a range of neurodegenerative diseases who exhibit symptoms of disinhibition.
APV-786 is also being studied in schizophrenia and depression. For all trials on this medication, see clinicaltrials.gov.
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