Neuroplasticity modulators as innovative potential disease-modifying treatments for Fragile X Syndrome and other CNS disorders

In September last year, we reported Servier had advanced its emerging neurology pipeline into the clinical trials stage by licensing a drug for the rare genetic disorder Fragile X syndrome (FXS) from UK biotech Kaerus Bioscience. That same month, Philadelphia-based Harmony announced the failure of its synthetic cannabidiol (CBD) gel candidate ZYN002 in the RECONNECT study for FXS.

Fragile X syndrome is a neuropsychiatric disorder with no FDA-approved therapies and is a leading cause of inherited intellectual disability and autism spectrum disorder (ASD). It occurs in both sexes, but with boys generally more severely affected than girls.

Kaerus’ drug, KER-0193, addresses the abnormal function of BK channels that leads to hyperexcitability of neurons, which is a feature of FXS symptoms such as hyperactivity, anxiety, sensory hypersensitivity, and seizures that afflict some patients with the disorder. KER-0193 was set up by life sciences venture capital specialist Medicxi in 2016.

Indeed, Q3 2025 was an active period for the FXS field, and in our Q3 clinical trials round-up we reported that CONNECTA Therapeutics received EIC Accelerator funding to advance CTH120, a neuroplasticity modulator, into paediatric trials for Fragile X Syndrome. With strong Phase I safety data and a scalable platform, CONNECTA is positioned to address multiple neurodevelopmental disorders.

Neuroplasticity is not a fixed process. It is influenced by a variety of factors, including genetic predisposition, environmental factors, experience-dependent learning, and pharmacological interventions. To find out more about neuroplasticity modulators in both FXS and other CNS disorders, pharmaphorum spoke with CONNECTA Therapeutics’ Jordi Fàbrega, co-founder and CEO, and Dr Josep Prous Jr, co-founder and CSO.

Q. What makes CNS and neurodevelopmental disorders like Fragile X Syndrome (FXS) so difficult to treat effectively today?

Jordi Fàbrega [JF]: CNS conditions, including neurodevelopmental disorders such as FXS, are difficult to treat because they involve widespread dysfunction across neural circuits. Genetic mutations, developmental disruptions, or environmental factors affect common and multiple interconnected pathways and proteins, making it challenging for target-selective therapies to correct the underlying biology. This selective approach often triggers compensatory mechanisms, as the brain finds alternative circuits to maintain network stability. While this may provide short-term symptomatic relief, efficacy frequently diminishes over time, limiting durable clinical benefit and leading to undesirable side-effects.

This challenge highlights the importance of network pharmacology approaches focusing on the pathophysiology of disease. For example, restoring neuroplasticity, the brain’s ability to adapt to internal and external stimuli, which is impaired in many of these disorders, offers a way to improve cognitive, behavioural, and functional outcomes. CONNECTA Therapeutics is advancing innovative neuroplasticity modulators, including its lead asset CTH120, to restore neuroplasticity balance and deliver sustained improvements across key domains.

Q. Why is restoring neuroplasticity, rather than targeting a single downstream symptom, a more promising approach for disorders like FXS?

Josep Prous [JP]: Neuroplasticity balance, which is disrupted in many CNS disorders, is essential for learning, memory, and behaviour. Restoring neuroplasticity offers a promising approach for CNS disorders like FXS by addressing the core biological dysfunction, rather than merely managing symptoms.

Traditional therapies targeting individual symptoms or specific pathways provide modest, short-term relief, but fail to correct circuit-level dysfunction, as the brain adapts through compensatory mechanisms. In contrast, restoring neuroplasticity balance recovers neural circuit function at a systems level, simultaneously improving cognition, behaviour, and daily functioning.

CONNECTA Therapeutics’ small molecule CTH120 restores neuroplasticity balance through the allosteric modulation of TrkB, a key regulator of neuroplasticity pathways. CTH120 has shown robust preclinical efficacy, a favourable safety profile in regulatory toxicology and Phase I studies, and is now entering Phase II clinical development in adults with FXS to confirm its safety and evaluate its functional benefits across multiple domains.Inici del formulari

Q. How does TrkB modulation differ from earlier single‑target strategies that have struggled to deliver meaningful clinical benefit in CNS diseases?

JP: TrkB (Neurotrophic Receptor Tyrosine Kinase 2, NTRK2) is the receptor for endogenous BDNF (Brain-Derived Neurotrophic Factor) and a key regulator of activity-dependent neuronal plasticity. TrkB regulates multiple pathways that govern neuronal survival, neurite outgrowth, and dendritic spine density and maturity. By modulating these processes, it enables the restoration of normal neuronal connectivity, ultimately improving cognition, behaviour, and daily functioning.

CTH120’s TrkB allosteric modulation activity represents a fundamentally different approach from traditional target-selective therapies aiming to correct specific imbalances in excitatory or inhibitory signalling. In such cases, the brain often compensates through parallel pathways, limiting both the magnitude and durability of clinical benefit and leading to side-effects.

Q. What would true disease modification look like for individuals and families living with Fragile X Syndrome?

JP: For individuals with FXS, true disease modification goes beyond managing symptoms, delivering sustained improvements in core daily functioning. This includes measurable gains in cognition (learning, memory, attention) alongside behavioural improvements such as reduced anxiety, stronger social engagement, and better daily life navigation.

Disease modification also means greater independence. Currently, only about 10% of adult males and 44% of females with FXS live independently. Meaningful progress would enable reduced support in school, smoother transitions to vocational or community settings, and fuller societal participation, with developmental trajectories closer to typical learning and behavioural patterns.

For families and caregivers, disease-modification benefits include reduced behavioural challenges, lower stress, more stable routines, and decreased economic and emotional burden.

A hallmark of true disease modification is durability: improvements that persist beyond treatment, reflecting restoration of underlying neural circuits, rather than temporary symptomatic relief, especially when intervention occurs early in development.

Q. How can small‑molecule neuroplasticity modulators expand treatment possibilities across both rare and more prevalent CNS conditions?

JP: Small-molecule neuroplasticity modulators, such as CTH120, have the potential to transform the treatment landscape across both rare and more prevalent CNS conditions, including autism spectrum disorder or attention-deficit/hyperactivity disorder. Neuroplasticity imbalance is a common feature across this wide range of conditions, making it a compelling target for therapeutic intervention.

Small molecules are particularly well-suited for this approach because they can penetrate the blood–brain barrier, be administered orally, and allow flexible dosing. This scalability makes them practical for long-term use and easier to integrate into existing health care procedures.

This multiple-indication strategy accelerates development by sharing safety studies, enabling common biomarkers and clinical strategies to be leveraged across CNS conditions. It improves the efficiency of clinical translation, reduces duplication of effort, streamlines regulatory pathways, and supports more rapid delivery of innovative therapies to patient populations that currently have limited treatment options.

Q. What role do public‑private partnerships play in accelerating innovation for rare neurodevelopmental disorders?

JF: Public–private partnerships (PPPs) are especially crucial for advancing therapies for rare neurodevelopmental disorders like FXS. By combining resources, expertise, and data from biotech companies, academic institutions, clinical research units, regulatory agencies, and patient advocacy groups, PPPs reduce risk and cost throughout drug development.

PPPs support all stages, from early discovery to clinical translation, optimising the use of infrastructures, sharing knowledge and expertise that accelerate trial readiness and improve data quality. They foster iterative feedback among stakeholders, aligning regulatory expectations, study design, and patient-centric outcomes to ensure trials are both scientifically rigorous and meaningful to patients and families.

CONNECTA Therapeutics has leveraged PPPs in developing CTH120, collaborating with academic institutions, hospitals, and their clinical research units, patient advocacy groups, and regulatory partners to advance the programme efficiently while maintaining alignment with patient priorities.Inici del formulari

Q. As these therapies move toward the clinic, what are the biggest access and adoption challenges that still need to be addressed?

JF: As neuroplasticity-targeting therapies like CTH120 advance toward the clinic, key challenges must be addressed to ensure access and adoption. Demonstrating clear clinical benefit is critical for patients, families, regulators, and payers. Functional endpoints (improvements in cognition, behaviour, or daily functioning) must be validated and show real-life impact. This is particularly challenging in rare disorders like FXS, given heterogeneity in clinical presentation and developmental trajectories.

Expanding clinician and caregiver awareness is essential, along with establishing dedicated hospital reference units, as these can centralise expertise, standardise care, and support clinical trial readiness.

Pricing and reimbursement are also sensitive, as rare disease therapies are costly. Payers require robust evidence of durable benefit, supported by health economics models that quantify long-term value, including reduced caregiver burden and improved quality of life.

References

• Enkavi, M. Girych, R. Moliner, I. Vattulainen, and E. Castrén, “TrkB transmembrane domain: bridging structural understanding with therapeutic strategy,” Trends Biochem Sci, vol. 49, no. 5, pp. 445–456, May 2024, doi: 10.1016/J.TIBS.2024.02.001/ASSET/27102A2B-20F8-428E-AAF0-4DED871EF1B3/MAIN.ASSETS/GR3.JPG.

• Dahlström et al., “Identification of novel positive allosteric modulators of neurotrophin receptors for the treatment of cognitive dysfunction,” Cells, vol. 10, no. 8, Aug. 2021, doi: 10.3390/CELLS10081871.

• Yates, J. L. Kruse, J. B. Price, A. A. B. Robertson, and S. J. Tye, “Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics,” Curr Treat Options Psychiatry, vol. 8, no. 4, pp. 229–257, Dec. 2021, doi: 10.1007/S40501-021-00249-9.

• K. Gupta, S. Gupta, S. Mehan, Z. Khan, G. Das Gupta, and A. S. Narula, “Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders,” Mol Neurobiol, 2025, doi: 10.1007/S12035-025-05001-5.

• Hartley SL, Seltzer MM, Raspa M, Olmstead M, Bishop E, Bailey DB. Exploring the adult life of men and women with fragile X syndrome: results from a national survey. Am J Intellect Dev Disabil. 2011 Jan;116(1):16-35. doi: 10.1352/1944-7558-116.1.16. PMID: 21291308; PMCID: PMC3238098.

• Project “DEVELOPMENT OF A THERAPY FOR FRAGILE X SYNDROME”, file number RTC2019-007230-1. The project is funded by the Spanish Ministry of Science, Innovation and Universities, and the State Investigation Agency (MCIN/AEI /10.13039/501100011033) within the RETOS-COLABORACIÓN Subprogram, 2019 Call. The project is co-financed by the European Union with the aim of promoting technological development, innovation and quality research.

• Project “ENSAYO CLÍNICO DE FASE IIA DE UNA TERAPIA INNOVADORA PARA PACIENTES CON SÍNDROME DE X FRÁGIL”, file number CPP2022-009659. The project is funded by the Spanish Ministry of Science, Innovation and Universities, and the State Investigation Agency (MCIN/AEI /10.13039/501100011033) within the Colaboración Público-Privada Subprogram, 2022 Call.

• Project “FRAXCURE: FRAgile X syndrome Clinical trial: Unravelling the science behind this Rare disease in Europe”, with grant agreement number GA 101217931. This project is part of the EIC Accelerator (call HORIZON-EIC-2024-ACCELERATOR-02 — EIC Accelerator Open 2024), an European Union funding programme to support companies (SMEs, start-ups, spin-outs and in exceptional cases small mid-caps) to bring their innovations to market and scale up.

About the interviewees

Jordi Fàbrega is co-founder and CEO of CONNECTA Therapeutics. Fàbrega has held various positions in the pharmaceutical industry and has several years of consultancy experience in the pharma and Med Tech sectors. As a consultant, he was responsible for the execution and development of over 100 projects. Prior to CONNECTA, Fàbrega was director of business development at Biocat. He was responsible for the definition and progress of the cluster initiatives to develop and promote the life sciences sector in Catalonia. He has broad experience in strategy, business development, marketing, market access, and regulatory. Fàbrega holds a BSc in Pharmacy and a BSc in Food Science and Technology, an MSc in Pharmaceutical and Parapharmaceutical Industries, and an MBA from the ESADE Business School.

Dr Josep Prous Jr is co-founder and CSO of CONNECTA Therapeutics, as well as co-founder and executive director of the Prous Institute for Biomedical Research, and strategic advisor to life sciences organisations, where he is responsible for the design and implementation of in silico drug discovery and safety technologies. Previously, he served as co-founder and executive director of Bionfofate, which was acquired by Clarivate Analytics in 2021, and VP and chief scientific officer of the Healthcare and Science business of Thomson Reuters, following the acquisition of his former company Prous Science by Thomson Scientific in 2007. Dr Prous Jr has longstanding experience in establishing fruitful collaborations with biomedical research organisations. He holds a BSc in Chemistry and an MBA from the ESADE Business School, and completed his PhD doctoral thesis, spearheading a medicinal chemistry project for the discovery of new drugs for Alzheimer's disease.