STK-002 completes first two phase 1 dose cohorts in ADOA

Dosing is complete in the first two cohorts of the phase 1 OSPREY study of STK-002, an intravitreal antisense oligonucleotide (ASO) for autosomal dominant optic atrophy (ADOA), according to Stoke Therapeutics.¹ The company presented natural history and preclinical data supporting the program at the American Academy of Ophthalmology (AAO) 2026 Annual Meeting, held October 9-12 in New Orleans.¹ No human safety or efficacy results have been released, and initial data are expected in the first half of 2027.¹

OSPREY is the first-in-human study of STK-002 in OPA1-associated ADOA, a condition with no approved treatment.¹ The agent builds on Stoke's TANGO splice-modulating platform, which uses ASOs to increase protein output from the wild-type allele.² The FDA has granted STK-002 orphan drug designation.¹

OSPREY phase 1 design: intravitreal STK-002 dose escalation in OPA1-associated ADOA

OSPREY (ISRCTN41725621) is an open-label, single-ascending-dose study enrolling patients aged 6 to 55 years with a confirmed disease-causing OPA1 variant.¹ Primary objectives are safety, tolerability, and serum exposure. Secondary objectives include changes in visual function, ocular structure, and quality of life.¹

Patients receive a single intravitreal injection in the more affected eye, or in the nondominant eye when both eyes are equally affected, according to a study design poster presented earlier this year.³ Part A enrolls adults aged 18 to younger than 55 years at planned doses of 0.1, 0.3, 0.5, and 0.7 mg/eye, with three patients per cohort and optional expansion.³ Part B enrolls patients aged 6 to younger than 18 years.³

Eligibility requires best-corrected visual acuity (BCVA) of 35 to 70 ETDRS letters in each eye, with an exception for the first 2 patients dosed.³ Patients with gain-of-function variants, ADOA-plus, or Behr syndrome are excluded.³ Secondary end points include peripapillary RNFL and macular ganglion cell layer thickness on OCT, BCVA, low-contrast acuity, perimetry, and photopic negative response ERG.3

Cohort 3 dosing is expected to finish by year-end 2026, with cohort 4 to follow pending safety review.¹ All eight planned sites are active in the United Kingdom, Germany, Denmark, Italy, and Austria.¹

AAO 2026 natural history and preclinical data, with OSPREY safety results pending

Stoke has not disclosed safety findings from the 2 completed cohorts, including rates of intraocular inflammation, endophthalmitis, IOP elevation, or retinal detachment.¹ Planned safety assessments include inflammation and lens grading, immunogenicity, and retinal toxicity or thinning, with follow-up through week 48.³

From the FALCON natural history study, the company reported higher mitochondrial oxidative stress in patients with ADOA than in healthy individuals, with levels strongly correlating with lower visual acuity.¹ The release did not report the analysis sample size, correlation coefficients, or P values. FALCON followed 47 untreated patients aged 8 to 60 years for 24 months at 10 sites.¹

Two-year FALCON results presented at AAO 2025 showed 24% of patients lost at least five letters of low-contrast visual acuity.⁴ Preclinically, STK-002 produced dose-dependent increases in retinal exposure, target engagement, and OPA1 protein and improved mitochondrial function in patient-derived cells.¹ After intravitreal dosing in cynomolgus monkeys, the ASO and increased OPA1 immunofluorescence localized to retinal ganglion cells.²

Patrick Yu-Wai-Man, MD, PhD, professor of ophthalmology at the University of Cambridge and the UCL Institute of Ophthalmology and lead OSPREY investigator, called the early data "an important step" in a statement.¹ He said the work will help determine whether an RNA-based medicine can address the underlying OPA1 deficiency and improve visual outcomes.¹ Yu-Wai-Man has provided consulting services to Stoke Therapeutics, according to published FALCON study disclosures.

Barry Ticho, MD, PhD, Stoke's chief medical officer, said in a statement cohorts 3 and 4 are designed to show measurable effects on visual function.¹ The company has not defined what it considers a therapeutic dose level. Stoke's lead TANGO asset, zorevunersen, is in phase 3 development for Dravet syndrome.¹

References

1. Stoke Therapeutics presents data supporting the disease-modifying potential of STK-002 in autosomal dominant optic atrophy (ADOA) at the American Academy of Ophthalmology (AAO) 2026 Annual Meeting. News release. Stoke Therapeutics; October 12, 2026. Accessed October 15, 2026. https://www.businesswire.com/news/home/20261012027670/en/

2. Venkatesh A, et al. Antisense oligonucleotide STK-002 increases OPA1 in retina and improves mitochondrial function in autosomal dominant optic atrophy cells. Nucleic Acid Ther. 2024;34(5):221-233. doi:10.1089/nat.2024.0022

3. Yu-Wai-Man P, Barboni P, Larsen M, et al. OSPREY: a phase 1, open-label study evaluating the safety and tolerability of the antisense oligonucleotide STK-002 in patients with OPA1 autosomal dominant optic atrophy. Poster presented at: European Neuro-Ophthalmology Society 2026; Milan, Italy. Accessed October 15, 2026. https://www.stoketherapeutics.com/wp-content/uploads/EUNOS-2026-OSPREY.pdf

4. Stoke Therapeutics presents two-year natural history data from patients with autosomal dominant optic atrophy (ADOA). News release. Stoke Therapeutics; October 20, 2025. Accessed October 15, 2026. https://www.businesswire.com/news/home/20251020363125/en/