Objective: KINETIC2 is a multicenter, randomized, placebo-controlled, dose-response Ph2b study evaluating SAGE-324/BIIB124 for treatment of essential tremor (ET).

Background: ET is a common movement disorder^1,2 associated with altered γ-aminobutyric acid (GABA) neurotransmission in cerebellar-thalamo-cortical circuits.^3,4 A high density of benzodiazepine insensitive δ-subunit-containing GABA_A receptors can be found at extrasynaptic sites of cerebellar granule cells.⁵ Neuroactive steroid (NAS) GABA_A receptor positive allosteric modulators (PAMs) bind to synaptic γ-containing and extrasynaptic δ-containing GABA_A receptors, potentiating phasic and tonic inhibition, respectively [Figure 1].^6-8 SAGE-324/BIIB124 is an investigational NAS GABA_A receptor PAM. In the Ph2a KINETIC trial, participants with ET who received SAGE-324/BIIB124 demonstrated significant improvement in upper limb (UL) tremor vs those who received placebo at Day 29 (primary endpoint).⁹

Method: KINETIC2 (NCT05173012) enrolled participants from US sites. Eligibility criteria included: ages 18−80 years; ET diagnosis​ (isolated bilateral UL action tremor ≥3 years with/without tremor in other locations); no other relevant neurological signs; The Essential Tremor Rating Assessment Scale (TETRAS)-Performance Scale (PS) Subscale Item 4 (UL) score ≥12 (≥6 dominant UL) at screening/baseline; at screening TETRAS Activities of Daily Living (ADL) Subscale score ≥20; willingness to discontinue ET medications except propranolol (≤320 mg/day). Participants randomized 1:1:1:1 to oral placebo or SAGE-324/BIIB124 15, 30, or 60 mg (up-titrated from 15 mg over 42 days). Stratified by baseline propranolol use (adjunct therapy), study drug is administered once nightly for 90 days. Primary and secondary endpoints are change from baseline in TETRAS-PS Subscale Item 4 score and TETRAS ADL Subscale composite score (items 1 to 11 ADL Subscale; PS Item 6), respectively, at Day 91 in the monotherapy cohort. Safety and tolerability are assessed.

Results: Current ET treatments may not provide optimal tremor control. SAGE-324/BIIB124 may increase inhibition of cerebellar cortical activity via activation of extrasynaptic GABA_A receptors and represents a novel potential treatment for ET.

Conclusion: KINETIC2 was designed to evaluate SAGE-324/BIIB124 dose response on clinically relevant endpoints and safety/tolerability. Enrollment is complete and results from KINETIC2 will be presented.

Figure 1.

References: Prior Presentations (Trial in Progress)
[1] Pahwa R, et al. International Congress of Parkinson’s Disease and Movement Disorders; 2022 Sep 15-18; Madrid, Spain.
[2] Pahwa R, et al. IAPRD 2023 World Congress; 2023 May 13-16; Chicago, IL, USA.
[3] Pahwa R, et al. 2nd International Tremor Congress; 2023 May 18-19; New York, NY, USA.
References
[1] Crawford S, et al. Presented at: 3rd Pan American Parkinson’s and Movement Disorders Congress; 2020 Feb 14-16; Miami, FL, USA. Poster 192.
[2] Haubenberger D, Hallett M. N Engl J Med. 2018;378(19):1802-1810.
[3] Paris-Robidas S, et al. Brain. 2012;135(pt 1):105-116.
[4] Gironell A. Tremor Other Hyperkinet Mov (N Y). 2014;4:254.
[5] Chuang S-H, Reddy DS. J Pharmacol Exp Ther.2018;364(2):180-197.
[6] Martinez Botella G, Salituro FG, Harrison BL, et al. J Med Chem. 2015;58(8):3500-3511.
[7] Reddy DS, Estes WA. Trends Pharmacol Sci. 2016;37(7):543-561.
[8] Jacob TC, Moss SJ, Jurd R. Nat Rev Neurosci. 2008:9(5):331-343.
[9] Bankole K, et al. Presented at: MDS Virtual Congress 2021; 2021 Sep 17-22. Abstract LBA 10.

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