Investigating Codabakalner in a Phase 2b/3 Trial for the Treatment of Fragile X Syndrome: The CLARITY Study

Welcome to NeurologyLive's Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. In honor of Fragile X Syndrome Awareness Day, held annually on July 22, this month’s spotlight is the phase 2b/3 CLARITY trial (NCT07439510) testing codabakalner (Spinogenix), formally known as SPG601, for the treatment of patients with Fragile X syndrome (FXS).¹

“FXS presents a heavy burden on patients, one that involves not just intellectual disability, but also symptoms such as anxiety, attention deficit and others that compound overall impairment and have a major impact on quality of life,” Stella Sarraf, PhD, CEO and founder at Spinogenix, told NeurologyLive^®. “Many parents and clinicians point to a lack of effective treatments for these additional symptoms – i.e. anxiety and attention deficit – as the biggest unmet need because reducing them would greatly improve quality of life. Codabakalner has the potential to treat both intellectual disability and these compounding symptoms, and the CLARITY trial is designed to capture efficacy in these domains.”

Mechanism of Action

Codabakalner is a first-in-class, oral, small-molecule positive modulator of large-conductance, calcium-activated potassium (BK) channels being developed for FXS.^1,2 In FXS, loss of the fragile X messenger ribonucleoprotein (FMRP), is associated with downstream reduction in BK channel activity, contributing to cortical hyperexcitability, disrupted excitation-inhibition balance, and synaptic dysfunction.^2,3 By selectively enhancing BK channel function, codabakalner is designed to correct this circuit-level abnormality rather than broadly modulate neurotransmission.

Study Design

Led by principal investigator Craig A. Erickson, MD, professor of psychiatry at Cincinnati Children's Hospital and chief medical advisor at Spinogenix, CLARITY is a 2-part, randomized, double-blind, placebo-controlled, adaptive phase 2b/3 trial evaluating the efficacy, safety, and tolerability of codabakalner in adult patients with FXS, specifically men. The design allows for direct progression from the phase 2b dose-selection stage into a phase 3 registration-directed stage, an approach reached in agreement with the FDA.¹

In the phase 2b stage, up to 48 men with genetically confirmed, fully methylated FMR1 full mutations will be randomized to 1 of 3 codabakalner dosing regimens, 400 mg once daily, 800 mg once daily, or 800 mg twice daily or placebo, for 28 days. Co-primary end points are the NIH Toolbox Total Cognition Composite Change-Sensitive Score and change from baseline in electroencephalogram (EEG) resting-state relative power across the alpha, theta, and gamma frequency bands. Secondary end points include the Fluid Cognition Composite of the NIH Toolbox Cognition Battery, the NIH Toolbox Flanker Inhibitory Control and Attention Test, and change in everyday functioning as measured by the FXS Functional Rating Scale.

If phase 2b results support advancement, the trial will proceed to a phase 3 stage evaluating a single selected dose regimen against placebo over 12 weeks in approximately 200 adult and adolescent males with FXS, incorporating the same neurophysiological and cognitive-behavioral framework alongside a broader panel of validated cognitive and behavioral measures. Total planned enrollment across both stages is approximately 248 participants with FXS.

“The CLARITY trial is ground-breaking in several respects. From a therapeutic perspective, the clinical evaluation of codabakalner represents a novel approach – boosting BK channel activity to normalize specific synaptic and neural circuit level deficits – that has been backed by over a decade of preclinical research in the field and by positive results from Spinogenix’s phase 1 trial,” Sarraf added.

“From an execution standpoint, the CLARITY trial is unique in its utilization of EEG as an objective and quantitative measure of target engagement and efficacy alongside standard outcome measures. FXS is characterized by signature changes in the EEG that reflect an underlying dysfunction of neural circuits that contribute to, and correlate with, symptoms,” Sarraf continued. “In the completed phase 1/2a trial, codabakalner normalized these EEG signatures while also improving performance on cognitive measures of attention.”

Inclusion and Exclusion Criteria

Eligible participants must be a man with a genetically confirmed diagnosis of FXS involving a fully methylated FMR1 full mutation. The phase 2b stage enrolls adults, whereas the phase 3 stage broadens eligibility to include adolescent boys; reported age parameters for the overall program span approximately 18 to 45 years, consistent with the age range used in the preceding phase 2a study. Participants are required to have an identified caregiver able to support study participation and to be in generally good overall health, without significant uncontrolled medical conditions that could confound assessment of safety, tolerability, or efficacy.

Prior Data Supporting Further Study

The CLARITY program builds on a phase 2a, randomized, double-blind, placebo-controlled, 2-period crossover study (NCT06413537) in 10 adult men with genetically confirmed full-mutation FXS, in which participants received single doses of codabakalner 800 mg and placebo separated by a 1-week washout period.² Overall, codabakalner was well tolerated, with no evidence of sedation or clinical impairment, and produced significant modulation of resting-state EEG power spectral density relative to placebo, including effects on gamma-band power (F=5.20, P = .023), alpha2-band power (F=17.43, P <.001), and theta-band power (F=7.06, P = .008), as well as significant modulation of the aperiodic EEG slope (F=5.28, P =.022), a marker of cortical excitation-inhibition balance.

“[Our] reaction [to these findings] was one of cautious optimism. Ironically, there was also some degree of surprise because, while we were confident in the therapeutic approach, the strong efficacy signals observed stood out against the backdrop of a very challenging history of therapeutic development in FXS. Moreover, no other therapeutic had moved the needle so far in the EEG biomarkers assessed,” Sarraf told NeurologyLive. “With both neurophysiological and behavioral evidence of efficacy, our reaction was also one of compounded resolve to advance codabakalner as rapidly and rigorously as possible.”

On cognitive testing, codabakalner treatment was associated with significant improvement on the NIH Toolbox Flanker Inhibitory Control and Attention Test (P = .027), with a directional trend toward improvement also observed on the Fluid Cognition Composite and Total Cognition Composite indices; no significant effect was observed on auditory-evoked gamma measures.² Investigators have described the convergence of neurophysiological and cognitive signal after a single dose as unusually robust for the FXS field, providing rationale for evaluation of repeated dosing in CLARITY.⁴ Codabakalner has previously received fast track and orphan drug designations from the FDA and orphan designation from the European Medicines Agency for FXS.^5,6

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REFERENCES
1. Spinogenix announces CLARITY: a phase 2b/3 trial of SPG601 for the treatment of fragile X syndrome. News release. Spinogenix, Inc. April 23, 2026. Accessed July 21, 2026. https://spinogenix.com/press-release/spinogenix-announces-clarity-a-phase-2b-3-trial-of-spg601-for-the-treatment-of-fragile-x-syndrome/
2. Pedapati EV, Vanderklish PW, Sarraf ST, et al. SPG601-associated modulation of resting-state EEG and improvement in executive function in a fragile X syndrome randomized controlled crossover study. Sci Rep. 2026;16(1):11705. Published 2026 Apr 7. doi:10.1038/s41598-026-46928-6
3. Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X syndrome. Nat Rev Dis Primers. 2017;3:17065. Published 2017 Sep 29. doi:10.1038/nrdp.2017.65
4. New peer-reviewed research demonstrates neurophysiological efficacy of Spinogenix’s SPG601 in patients with fragile X syndrome. News release. Spinogenix, Inc. April 9, 2026. Accessed July 21, 2026. https://spinogenix.com/press-release/new-peer-reviewed-research-demonstrates-neurophysiological-efficacy-of-spinogenixs-spg601-in-patients-with-fragile-x-syndrome/
5. FDA Grants Fast Track Designation to Spinogenix's SPG601 for Treatment of Fragile X Syndrome, a Common Inherited Form of Autism. News Release. Spinogenix. Published January 13, 2025. Accessed July 21, 2026. https://www.spinogenix.com/fda-grants-fast-track-designation-to-spinogenixs-spg601-for-treatment-of-fragile-x-syndrome-a-common-inherited-form-of-autism/
6. Spinogenix Announces U.S. FDA Orphan Drug Designation Granted to SPG601 for the Treatment of Fragile X syndrome. News Release. Spinogenix. Published May 20, 2024. Accessed July 21, 2026. https://www.spinogenix.com/spinogenix-announces-u-s-fda-orphan-drug-designation-granted-to-spg601-for-the-treatment-of-fragile-x-syndrome