Ingrezza engages with therapeutic target more strongly than Austedo
Study: It may better address cause of uncontrolled movements in Huntington's
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Ingrezza (valbenazine) engages with its VMAT2 target more strongly than extended-release Austedo XR (deutetrabenazine), which may translate into better control of chorea by more effectively reducing excess dopamine, the cause of these uncontrolled movements in Huntington’s disease and tardive dyskinesia, according to a study.
Both medications are approved for the two diseases.
In a head-to-head study by Neurocrine Biosciences, which markets Ingrezza, occupancy of VMAT2 was nearly twice as high with Ingrezza as with Austedo XR in eight healthy men after a single dose of each medication. Occupancy is a measure of how much of the VMAT2 protein, which packs dopamine for release from nerve cells, is being blocked.
“INGREZZA demonstrated approximately two-fold higher target occupancy compared with AUSTEDO XR at therapeutic doses,” Sanjay Keswani, MD, Neurocrine’s chief medical officer, said in a company press release. “The significantly higher VMAT2 occupancy observed with INGREZZA adds to the already established differences between VMAT2 inhibitors in pharmacologic and clinical profiles.”
The data were presented at this year’s American College of Neuropsychopharmacology meeting, held earlier this month in the Bahamas. An abstract, “A Head-To-Head Assessment of VMAT2 Target Occupancy of Therapeutic Doses of Ingrezza Compared to Therapeutic Doses of Austedo Extended Release,” was published in Neuropsychopharmacology.
Average occupancy of Ingrezza twice as high as that of Austedo XR
Chorea, characterized by sudden, uncontrollable movements, is a common symptom of Huntington’s disease. It is linked to high levels of dopamine, a brain chemical. Similar to Ingrezza, Teva Pharmaceuticals’ Austedo and its extended-release formulation, Austedo XR, work by blocking VMAT2 to reduce excess dopamine and help control chorea.
For a direct comparison of how strongly each medication engages with VMAT2, eight healthy men received a single dose of Ingrezza (40 mg or 80 mg) and Austedo XR (24 mg or 48 mg), with a washout period of 14 to 21 days between each. These volunteers underwent four brain scans using positron emission tomography, which allowed the researchers to assess how much of the target protein was being occupied.
At doses considered therapeutic, the average occupancy of Ingrezza was twice as high as that of Austedo XR (76.5% vs. 38.3%). Higher occupancy suggests a medication may have a greater effect.
“The high occupancy of INGREZZA may contribute to the robust early and sustained clinical efficacy consistently demonstrated in multiple tardive dyskinesia and Huntington’s disease chorea clinical trials,” Keswani said.
The researchers also used exposure modeling to estimate what happens when the medication is taken regularly and levels stabilize in the body. Based on a measure of the amount of medication needed to achieve half its maximum effect, Ingrezza was expected to reach 83% occupancy at 40 mg and 92% at 80 mg; Austedo XR was estimated to reach 54% at 24 mg and 70% at 48 mg.
According to the scientists, one possible reason for this difference is how the medications are processed in the body. Ingrezza primarily produces one active breakdown product that strongly engages VMAT2. Austedo XR produces several breakdown products, some of which bind less strongly to VMAT2. Both medications were generally well tolerated in the study, and the safety profile was consistent with what is already known.
