Advances in Fragile X Syndrome Therapeutics: Overviewing the Pipeline

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading known single gene cause of autism spectrum disorder. There is still no FDA approved, disease targeted therapy. Families and clinicians rely on off label, symptom focused medications instead.

The past year tested the field. Two of the most advanced candidates, zatolmilast and ZYN002, both missed their primary endpoints in Phase 3 trials. Even so, the broader pipeline remains active and mechanistically diverse. Below is a round up of seven notable investigational agents in development for FXS.

Emerging Agents

Zatolmilast (BPN14770), Shionogi

Zatolmilast is a first in class, allosteric phosphodiesterase 4D (PDE4D) inhibitor. It targets the dimeric, PKA activated form of the enzyme. In FXS, reduced FMRP expression is linked to low cyclic AMP (cAMP) signaling, and zatolmilast is designed to restore that signaling. The compound was originally developed by Tetra Discovery Partners before Shionogi acquired the program in 2020.

An earlier Phase 2 trial (NCT03569631) randomized 30 adult men with FXS to zatolmilast or placebo for 12 weeks. The drug was generally safe and showed improvement over placebo on measures of language and daily functioning.¹ That signal supported two Phase 3 studies under the EXPERIENCE program, enrolling 334 participants total. Neither trial met its primary endpoint of improving the NIH Cognition Crystallized Composite score.²

Still, the adult study showed a significant improvement in a caregiver reported measure of language and daily function, though the adolescent study did not replicate that finding. Shionogi has said it plans further analyses of the Phase 3 data, alongside follow up in the four year open label extension study, EXPERIENCE-302, and continued discussions with the FDA.

ZYN002 (Cannabidiol Transdermal Gel), Harmony Biosciences

ZYN002 is a pharmaceutically synthesized, THC free formulation of cannabidiol delivered as a transdermal gel. It was developed on the premise that FXS involves dysregulated endocannabinoid signaling. Zynerba Pharmaceuticals originally advanced the program, and Harmony Biosciences acquired it in 2023. ZYN002 targets behavioral symptoms like social avoidance, irritability, and anxiety rather than cognition directly.

In the Phase 3 CONNECT-FX trial, 212 children and adolescents with FXS were randomized to 12 weeks of ZYN002 or placebo. Unfortunately, the primary endpoint in the full mutation cohort was not met. A prespecified subgroup with at least 90% methylation of the FMR1 promoter, where symptom severity tends to be greatest, did show significant improvement in social avoidance.³ Long term open label extension data presented at the 2025 American Academy of Neurology meeting showed sustained improvement in irritability related symptoms.⁴

Building on that signal, Harmony launched the registrational Phase 3 RECONNECT trial in patients with complete FMR1 methylation. Results announced in September 2025 showed RECONNECT did not meet its primary endpoint, which the company attributed to an unexpectedly high placebo response rate.⁵ ZYN002 holds FDA Fast Track and orphan drug designations, and Harmony has said it will conduct further analyses of the full dataset.

SPG601, Spinogenix

SPG601 is an oral, first in class modulator of large conductance, calcium activated potassium (BK) channels. It is designed to correct synaptic dysfunction and neuronal hyperexcitability, both considered core drivers of FXS symptoms. Its development has leaned heavily on objective neurophysiological biomarkers rather than behavioral rating scales alone.

In a Phase 2a crossover study in 10 adult men with FXS, a single dose of SPG601 significantly reduced excessive high frequency gamma band activity on EEG, an abnormality that correlates with symptom severity.⁶ The drug was also associated with significant improvement on the NIH Toolbox Flanker task, a measure of attention and inhibitory control. Following a positive FDA meeting in September 2025, Spinogenix initiated CLARITY, an adaptive Phase 2b/3 trial, in April 2026.⁷

The Phase 2b portion will enroll up to 48 adult men with fully methylated FMR1 mutations. A subsequent Phase 3 stage is planned to enroll roughly 200 adult and adolescent males. SPG601 holds FDA Fast Track and Orphan Drug designations, along with EMA Orphan Disease designation.

MRM-3379, Mirum Pharmaceuticals

MRM-3379 is an orally available, highly brain penetrant, selective PDE4D inhibitor. Like zatolmilast, it is designed to enhance cAMP signaling, but with pharmacological properties meant to differentiate it from the earlier generation compound. It was originally discovered at Dart Neuroscience and advanced by Enthorin Therapeutics before Mirum acquired global rights in October 2024.

In preclinical work, including studies in an Fmr1 knockout mouse model, MRM-3379 was reported to improve cognition and reduce behavioral deficits across multiple domains.⁸ Brain drug levels were roughly five fold higher than blood levels, supporting strong CNS penetration.

Mirum enrolled its first participant in the Phase 2 BLOOM study in December 2025.⁹ Males ages 16 to 45 are randomized across three oral dose levels or placebo for 12 weeks, while a younger cohort ages 13 to under 16 receives open label drug for exploratory assessment.¹⁰ Topline data are anticipated in 2027.

CTH120, CONNECTA Therapeutics

CTH120 is a first in class, oral small molecule that targets tropomyosin receptor kinase B (TrkB), a central regulator of neuroplasticity, the brain's capacity to form and reorganize synaptic connections. Rather than targeting a single downstream symptom, CONNECTA has positioned CTH120 as a potentially disease modifying approach aimed at restoring the underlying neuronal architecture disrupted in FXS.

Backed by preclinical data and a completed Phase 1 safety study in healthy volunteers, CONNECTA initiated a Phase IIa trial in June 2026, its first evaluation in patients with FXS.¹¹ The randomized, placebo controlled study is being conducted at sites in the Barcelona area and is evaluating twice daily CTH120 in adult men with FXS, the population in which the X linked disorder is typically most severe.¹²

The company has said it intends to extend the program into pediatric populations, supported by the EU co funded FRAXCURE project, pending results from the adult study.

KER-0193, Servier (originally Kaerus Bioscience)

KER-0193 is an oral small molecule modulator of BK channels, developed to directly address a channel level dysfunction tied to the genetic cause of FXS. That places it alongside SPG601 as one of two BK channel directed programs now in the pipeline. Kaerus Bioscience discovered the molecule before Servier acquired global rights in September 2025, in a deal worth up to $450 million.¹³

KER-0193 completed a Phase 1 trial in March 2025 that enrolled 56 healthy volunteers. The compound was safe and well tolerated with dose proportional pharmacokinetics. A pharmaco EEG biomarker substudy showed significant effects on multiple relevant parameters of brain activity, an early proof of mechanism signal ahead of patient studies.¹⁴

In preclinical genetic models of FXS, KER-0193 has shown effects across behavioral, sensory, and cognitive domains.¹⁵ The compound holds FDA Orphan Drug and Rare Pediatric Drug designations, and Servier has indicated plans to advance into a Phase 2 study in adults with FXS.

SRX246, Azevan Pharmaceuticals

SRX246 takes a distinct approach from the other agents on this list, targeting a specific behavioral domain rather than a broad cognitive or synaptic endpoint. It is an orally available, CNS penetrant, highly selective vasopressin 1a (V1a) receptor antagonist, designed to reduce pathological aggression by dampening vasopressin driven activity in brain circuits that modulate emotional and fear responses.

The rationale draws on prior clinical experience. In an exploratory Phase 2 study in Huntington disease, SRX246 reduced aggressive behaviors in patients with irritability and aggression, with a favorable safety profile and no effect on water balance.16

Azevan is now evaluating SRX246 specifically in FXS through a Department of Defense funded Phase 2 trial focused on irritability, agitation, aggression, and self injury in adult men with FXS.17 The study uses a home based, crossover design, with participants taking study drug or placebo for up to eight months, supported by weekly remote check ins and periodic in home nursing visits.18 The trial is expected to begin enrolling in 2026.

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