Feature|Articles|September 25, 2026

What's Next in Ataxia: Pipeline Overview of Investigational Therapeutics

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Key Takeaways

FDA approvals now include omaveloxolone for Friedreich ataxia and levacetylleucine for ataxia-telangiectasia, the latter improving SARA by −1.9 points versus placebo in IB1001-303.
Breakthrough designation for nomlabofusp leverages skin frataxin as a proposed surrogate for accelerated approval, with open-label mFARS improvement tempered by anaphylaxis-related discontinuations.
Cardiomyopathy-focused LX2006 AAV gene therapy showed dose-related cardiac frataxin increases and LVMI/troponin reductions; SUNRISE-FA 2 will use LVMI at 6 months as primary endpoint.
Allele-preferential intrathecal ASO VO659 targets expanded CAG repeats across polyglutamine disorders; radiculitis has recurred, prompting a shift to twice-yearly dosing with follow-up through 2028.
Externally controlled real-world evidence constrained troriluzole’s SCA filing after an FDA CRL, while fampridine enters randomized testing for SCA27B after strong observational response signals.

In recognition of International Ataxia Awareness Day, observed annually on September 25, NeurologyLive® reviews 6 investigational agents in clinical development across ataxia-related disorders.

International Ataxia Awareness Day, held annually on September 25, draws attention to a heterogeneous group of disorders marked by progressive loss of coordination, balance, and speech.¹ For most of these conditions, care remains supportive. Omaveloxolone (Skyclarys; Biogen) became the first approved therapy for Friedreich ataxia (FA) in February 2023, for patients aged 16 years and older.²

More recently, the FDA approved levacetylleucine (Aqneursa; IntraBio) oral suspension for ataxia in adults and pediatric patients with ataxia-telangiectasia (A-T) weighing at least 15 kg, the first treatment for ataxia in this population.³ The approval rested on the phase 3 IB1001-303 crossover trial (NCT06673056), in which levacetylleucine produced a treatment difference of −1.9 points on the Scale for the Assessment and Rating of Ataxia (SARA) compared with placebo (95% CI, −2.7 to −1.1; P <.001).⁴

The past year also brought setbacks. In the phase 3 NEAT trial of dexamethasone sodium phosphate encapsulated in autologous erythrocytes (eDSP) for A-T, neither the primary end point nor the key secondary end point reached statistical significance, and Quince Therapeutics said it would stop clinical development of the agent in January 2026.⁵ In spinocerebellar ataxia (SCA), the FDA declined to approve troriluzole in Novemeber 2025, which is further discussed below.

Against that backdrop, the following 6 programs illustrate the range of approaches under clinical investigation, from protein replacement and gene therapy to allele-preferential RNA targeting:

Friedreich Ataxia

Nomlabofusp (CTI-1601), Larimar Therapeutics

Nomlabofusp is an investigational frataxin (FXN) protein replacement therapy administered by daily subcutaneous injection, designed to deliver FXN to cells of patients whose disease stems from its deficiency. In February 2026, the FDA granted it breakthrough therapy designation for adults and children with FA, and the agency agreed that skin FXN concentration is likely adequate as a novel surrogate end point to support a biologics license application (BLA) seeking accelerated approval.⁶

Updated data from the ongoing open-label extension were reported in June 2026. As of that update, 43 adolescent and adult participants had received at least 1 dose, 22 remained on study, and roughly half were nonambulatory at baseline. Mean skin FXN rose from 3.7 pg/µg at baseline to 12.1 pg/µg at 1 year, and all 9 evaluable participants at that time point had levels above the threshold reported in asymptomatic heterozygous carriers. Clinically, the 13 participants treated for 1 year showed a mean 1.0-point improvement in modified Friedreich Ataxia Rating Scale (mFARS) score, compared with a 1.6-point worsening in a matched reference population from the FACOMS natural history study.⁷ Hypersensitivity is a notable safety consideration: 10 participants discontinued after anaphylaxis, 9 of whom had prior exposure to nomlabofusp in an earlier study, and all returned to their usual health after standard treatment.⁸

Larimar submitted the first module of a rolling BLA in June 2026 following a pre-BLA meeting with the FDA,⁷ and expects to complete the submission in the second half of 2026 and to dose the first patient in its global confirmatory phase 3 study in the third quarter.⁸ That study will use change in the Upright Stability Score, a subscale of mFARS, as its primary end point.⁶

LX2006, Lexeo Therapeutics

Cardiomyopathy is the leading cause of death in FA and is not directly addressed by current therapy. LX2006 (AAVrh.10hFXN) is an adeno-associated virus gene therapy intended to deliver a functional frataxin gene to cardiomyocytes and restore mitochondrial function.

Pooled phase 1/2 results were published in JAMA Cardiology in June 2026. Across 2 open-label, dose-ranging trials that together enrolled 17 patients, intravenous administration was associated with minimal toxic effects and reductions in left ventricular mass index (LVMI) on cardiac MRI and in high-sensitivity troponin I.⁹ In patients who underwent biopsy, mean cardiac frataxin increased by 20%, 81%, and 123% at 3 months across the low-, mid-, and high-dose cohorts, and troponin I fell by at least 10% in 15 of 17 patients.⁹ The authors characterized the efficacy findings as preliminary, and 4 serious adverse events occurred, all of which resolved.

The pivotal SUNRISE-FA 2 trial (NCT07721025) began enrolling in June 2026, shortly after its protocol was finalized. The open-label study will randomly allocate 26 participants aged 16 years and older with abnormal baseline LVMI to high-dose LX2006 or an untreated control arm without placebo or sham, with LVMI at 6 months as the primary end point.^10,11 Key secondary end points include mFARS, the Kansas City Cardiomyopathy Questionnaire, high-sensitivity troponin I, and lateral wall thickness, and control participants may cross over to treatment after 6 months. Lexeo anticipates topline data in the second half of 2027 and an accelerated approval BLA submission in the first half of 2028.¹⁰

Spinocerebellar Ataxias

VO659, Vico Therapeutics

VO659 is an intrathecally administered, allele-preferential antisense oligonucleotide (ASO) that targets expanded CAG repeats in mutant transcripts and inhibits their translation, an approach that could in principle apply across polyglutamine disorders. It is being tested in a basket design in Huntington disease (HD), SCA1, and SCA3 in a phase 1/2a trial (NCT05822908).¹²

Published pharmacodynamic data to date come from HD rather than the ataxia cohorts: interim results showed a 38% reduction in cerebrospinal fluid mutant huntingtin at 4 months after dosing. Radiculitis has been a recurring safety signal; it was reported in 1 participant with HD, 2 with SCA1, and 1 with SCA3.¹³ In February 2026, Vico began dosing a new cohort at 20 mg and 40 mg every 6 months, rather than every 4 weeks, with 12 months of follow-up, and announced FDA clearance of an investigational new drug application with plans to open US sites.^12,13 Primary completion is estimated for April 2028.¹⁴

Troriluzole, Biohaven

Troriluzole is a third-generation prodrug of riluzole intended to modulate glutamate by increasing its synaptic uptake. Its new drug application for adults with SCA across genotypes relied on the BHV4157-206-RWE study, in which oral troriluzole 200 mg met the primary end point of change in functional SARA at 3 years compared with an external control arm, with a reported 50% to 70% slower rate of decline.¹⁵

In November 2025, the FDA issued a complete response letter. The agency cited issues that can be inherent to real-world evidence and externally controlled studies, including potential bias, lack of prespecification, and unmeasured confounding. The FDA recommended that Biohaven meet with the division to discuss the evidence needed for a future application, while the company restructured its portfolio to prioritize other late-stage programs.¹⁶ Earlier, Biohaven withdrew its marketing application to the European Medicines Agency after the Committee for Medicinal Products for Human Use found insufficient supporting evidence.¹⁷ The program's trajectory will likely hinge on whether a prospectively controlled study is required.

CACNA1A-Related Disorders and SCA27B

Levacetylleucine, IntraBio

Beyond its approvals in Niemann-Pick disease type C (NPC) and A-T, levacetylleucine is being evaluated in CACNA1A-related disorders, which include SCA6 and episodic ataxia type 2. Although its precise mechanism has not been established, preclinical data suggest levacetylleucine may normalize glucose metabolism, enhance cerebellar activity, and improve lysosomal and mitochondrial function.³

The phase 3 IB1001-304 trial (NCT07221292) is a randomized, double-blind, placebo-controlled crossover study assessing safety, tolerability, and efficacy over a 12-week treatment period.¹⁸ It enrolls participants aged 4 years and older with genetically confirmed CACNA1A-related disorders at sites in Austria, Germany, Greece, Italy, Switzerland, the United Kingdom, and the United States, and uses the same design that supported approval in NPC. IntraBio anticipates completing recruitment in October 2026.¹⁹ As with the A-T data, a 12-week crossover design is suited to detecting symptomatic benefit; longer-term effects on progression would require separate evaluation.

Fampridine (4-Aminopyridine), Investigator-Initiated

SCA27B, caused by an intronic GAA repeat expansion in FGF14, has been identified as one of the most common genetic causes of late-onset ataxia. The potassium channel blocker 4-aminopyridine, already approved as dalfampridine for walking impairment in multiple sclerosis, has emerged as a candidate on the basis of observational data. In a cohort study of 50 patients, 86% of those treated reported a response relevant to daily living, and 3 prospective n-of-1 on/off experiences showed marked reductions in daily symptomatic time and symptom severity.²⁰

Because these observations are open-label and small, a controlled trial is now underway. Sponsored by Assistance Publique–Hôpitaux de Paris, the randomized, double-blind, multicenter, placebo-controlled study compares sustained-release fampridine 10 mg twice daily with placebo over 3 months, with functional handicap as the focus of assessment. The trial began in October 2025, with primary completion estimated for May 2027.²¹ A positive result would provide the first randomized evidence for a genotype-guided symptomatic therapy in SCA27B.

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