Dr Margaret LeeMargaret Lee, PhD
Significant improvements across a number of clinical measures were observed in patients with essential tremor who were treated with CX-8998, an investigational agent developed by Cavion, according to the results of a phase 2 study (NCT03101241).1

Patients who received CX-8998 saw positive changes in the investigator-rated The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale (P = .017), TETRAS-Activities of Daily Living (TETRAS-ADL; P = .049), TETRAS total score (P = .007) and Clinician Global Impression of Improvement (P = .001). The data from the double-blind, placebo-controlled T-CALM trial were presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania.

“I am pleased to present the results of our Phase 2 T-CALM proof-of-concept study of CX-8998 in essential tremor at the annual Academy meeting,” said Margaret Lee, PhD, senior vice president, Preclinical and Translational Sciences, Cavion, in a statement.2 “We look forward to discussing our clinical path forward as we work to address the unmet need in this devastating disorder that can rob people of their quality of life and has not seen any new approved drug therapies in more than 3 decades.”

The first-in-class potent, selective, and state-dependent small molecule modulator of T-Type calcium channels was assessed in a cohort of 95 patient with essential tremor at 25 US-based sites. A majority of subjects in the trial (64%) took study drug on top of a few standard of care anti-tremor medications. The study drug was administered twice daily in a titrated dose to 10 mg for 28 days. Patient outcomes were collected at baseline, and then on day 15 and day 28.

The significance achieved on TETRAS-ADL was confirmed by goal attainment scaling (P = .034), with additional support from the patient impressions of improvement (P = .089).

Although the aforementioned measures showed significance from placebo, the primary end point of centrally video-rated TETRAS Performance Subscale did not at Day 28 (P = .696), which Lee and the other investigators noted was due to methodological issues.

Spyros Papapetropoulos, MD, PhD, executive vice president, Research & Development, and chief medical officer, Cavion, said when the data were presented at the 2018 International Congress of Parkinson’s Disease and Movement Disorders in Hong Kong that CX-8998 provides hope to patients with essential tremor.

“The data are particularly compelling given that about two-thirds of patients in the study were on standard of care treatment and significant improvement was achieved with CX-8998 on several measures in a study lasting just one month,” Papapetropoulos, who was also one of the study authors, said in a statement.3

Currently, the only FDA-approved medication for essential tremor is propranolol, highlighting a need for additions to the movement disorder’s medication armamentarium. The subthreshold oscillations and extreme rhythmicity of pathophysiologic states which occur in tremor are facilitated by the T-type calcium channel. Cavion stated that due to tremor-related oscillations being a neuronal signature for essential tremor, the role T-type calcium channels play in their initiation is critical. As such, CX-8998 was designed to act on this channel.

Cavion has also explored the investigational product in genetic rodent models of absence epilepsy, in which it demonstrated dose-dependent efficacy. Lee, who authored this study as well, noted with colleagues that the results highlighted the potential for selective Cav3 antagonists as a therapeutic option in absence epilepsy and supported further investigation.4

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REFERENCES
1. Papapetropoulos S, Lee M, Boyer S, et al. Efficacy Result from a Phase 2, Double-Blind, Placebo-Controlled Study of CX-8998 a State-Dependent T-Type Calcium (Cav3) Channel Modulator in Essential Tremor Patients (T-CALM). Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.
2. Cavion to Present Results of Phase 2 Essential Tremor Clinical Trial in Platform Presentation at the American Academy of Neurology [press release]. Charlottesville, VA, and Cambridge, MA: Cavion Inc; Published April 24, 2019. apnews.com/Business%20Wire/8b6edfe8d6f0437f961f527937606cdc. Accessed May 8, 2019.
3. Cavion Announces Promising Phase 2 Data for Essential Tremor in T-CALM Proof-of-Concept Study [press release]. Hong Kong: Cavion Inc; Published October 5, 2018. businesswire.com/news/home/20181005005117/en. Accessed May 8, 2019.
4. Papapetropoulos S, Lee M. CX-8998, a potent, selective T-type calcium channel antagonist dose-dependently suppresses seizures in the WAG/Rij genetic model of absence epilepsy. Neurology. 2018;90(15 Suppl). Published online April 26, 2018. neurology.org/content/90/15_Supplement/P5.281.