A T-type calcium channel blocker reduced tremor in a rat model of the disorder, according to a presentation at the AAN Annual Meeting.
The results with the channel blocker may also serve as a biomarker for a safe and effective dose in people.
Research suggests that T-type calcium channels play a key role in essential tremor, because they modulate neural activity in the cerebellum, thalamus, and cortex circuitry, where increased burst firing coincides with tremor.
“It's thought that there's excessive bursting activity throughout the circuit that is driving tremor," said Corey Puryear, PhD, director of translational sciences at Boston-based Praxis Precision Medicines. With the drug, called PRAX-944, which blocks T-type calcium channels, researchers are trying to dampen the bursting activity within these circuits in order to decrease the severity of tremor.
The T-type calcium channel blocker is the latest in a series of drugs under development aimed at targets thought to be involved in essential tremor.
In a rat model, PRAX-944 had a dose-dependent effect, reducing tremor by 50 percent at a 1 mg/kg dose and by 72 percent at a 3 mg/kg dose. Importantly, at these doses, rats showed no locomotor side effects, indicating that the reduction in tremor was not due to general suppression of movement.
Researchers also worked to establish a biomarker to measure the drug's effects on T-type calcium channels, by assessing the effects on sigma-band EEG power during non-REM sleep. These channels are known to regulate this EEG activity and researchers hypothesized that PRAX-944 would reduce sigma-band EEG power. In rats, they showed that sigma power was reduced by 30 percent to 50 percent at the same doses that reduced tremor.
“Since we're able to suppress sigma-band EEG power, we are confident that we are functionally blocking T-type calcium channels in relevant circuits at doses that show efficacy in the animal model," Dr. Puryear said.
Now they are hoping to see similar results in people.
In an EEG study in healthy volunteers, they were able to show a reduction of non-REM sigma power similar in magnitude to what was seen in the preclinical work. At 10 mg to 100 mg, sigma power was reduced 34 percent to 50 percent, with no further reduction at 120 mg. All of those doses were well-tolerated, the researchers reported.
“Administration of PRAX-944 in rats and humans produced strong and consistent effects on sigma-band EEG power, which may represent a robust and translatable biomarker of T-type calcium channel blockade," researchers wrote.
“That gives us confidence that those doses that we were testing showed real promise in suppressing tremor," Dr. Puryear said.
In open-label data shared late last year, researchers reported results for six patients with essential tremor and showed a reduction in tremor severity with PRAX-944 at doses of 20 mg and 40 mg. Topline results are expected to be reported in May 2022. Studies at higher doses, including a randomized withdrawal meant to gauge the durability of the response, are ongoing, said Alex Kane, vice president of investor relations and corporate communications at Praxis.
Neepa Patel, MD, associate professor of neurological sciences at Rush University, said a new therapy could help patients who don't respond to existing medications, including propranolol, primidone, topiramate, and gabapentin.
“Some people's tremors respond very well to the medication with minimal side effects," Dr. Patel said. “However, many others do not have meaningful tremor reduction or cannot tolerate the side effects of the medications to reach a meaningful dose."
Hopefully, the new medication will have a stronger level of evidence to support it, she said, adding, “Because it is a novel mechanism, it may be better tolerated and benefit more patients."
But she said more evidence is needed. “The early studies were tried in a small population and this needs to be replicated in a larger population in a blinded fashion to ensure that it is effective and also to better understand the incidence of side effects," she said.
She said she would like to see data on the improvement of quality-of-life measures that are assessed over a longer period of time, demonstrating a sustained benefit.
“Sometimes," Dr. Patel said, “objective measures of tremors do not always provide meaningful benefits in our patients' day-to-day lives."
Link Up for More Information
AAN Abstract S32.009: Puryear C, Scott L, Belfort G, et al. Translational pharmacology of PRAX-944. A novel T-type calcium channel blocker for the treatment of essential tremor.