Privosegtor earns EMA PRIME designation for optic neuritis

A neuroprotective investigational candidate for optic neuritis (ON) has received Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), adding European regulatory momentum to a drug program that already holds US Food and Drug Administration (FDA) Breakthrough Therapy designation for the same indication.

The dual designations signal that regulators on both sides of the Atlantic have determined that privosegtor (Oculis Holding AG) has the potential to offer a meaningful therapeutic advantage over existing options—a threshold that, in the context of ON, reflects the absence of any approved neuroprotective treatment rather than incremental improvement over a robust field of competitors.

For the practicing neuro-ophthalmologist and neurologist, the regulatory milestones are clinically relevant primarily because they are tethered to phase 2 data suggesting that structural optic nerve protection—not just accelerated visual recovery—may be achievable in the acute setting. Confirming that signal in adequately powered registrational trials is the pivotal next step, and Oculis has now initiated the first of three global phase 3 studies under the PIONEER program.

Regulatory context

The EMA grants PRIME designation selectively each year to medicines deemed likely to offer a major therapeutic advantage or to address patients with no current treatment options. The designation is intended to optimize development plans through early dialogue with regulators and to expedite evaluation timelines. Privosegtor also holds Orphan Drug designation from both the EMA and FDA for ON—a classification that confers regulatory incentives including market exclusivity and fee reductions, and that reflects the relatively low prevalence of the condition within the broader demyelinating disease landscape.

The FDA Breakthrough Therapy designation, announced in January 2026, similarly provides for intensive FDA guidance and organizational commitment to expedite development and review.¹ That designation was granted on the strength of phase 2 efficacy data from the ACUITY trial, which the EMA has now independently determined to be consistent with a magnitude of effect that could significantly address unmet need in ON.

The phase 2 ACUITY trial: Design and efficacy results

The ACUITY trial (Acute OptiC NeUrITis of DemYelinating Origin; NCT04762017) was a randomized, double-masked, placebo-controlled, multicenter phase 2 study designed primarily to evaluate the safety, tolerability, and preliminary efficacy of privosegtor in acute ON.² Thirty-six patients aged 18–60 years with recent-onset (within approximately 10 days of visual loss onset) unilateral acute ON of demyelinating origin were enrolled; 33 were evaluable in the modified intention-to-treat analysis. Sixty-one percent of participants had a confirmed diagnosis of multiple sclerosis (MS) at entry. Mean disease duration at baseline was 9.8 (±2.5) days.

Participants were randomized to intravenous (IV) privosegtor at 2 mg/kg/day or 3 mg/kg/day, or matching placebo, administered once daily for 5 days as adjunctive therapy on top of standard-of-care IV methylprednisolone. The primary endpoint was safety, assessed by changes in electrocardiographic parameters over the first 15 days. The study met this endpoint: no clinically significant cardiac differences were observed between active and placebo arms, no drug-related serious adverse events were reported, and no participants withdrew due to adverse events.³ The most frequently reported drug-related adverse events in the combined privosegtor arms were headache and acne, each occurring in approximately 10.5% of active-treated patients.

Pre-specified secondary efficacy endpoints provided the basis for the subsequent regulatory designations. Among patients receiving privosegtor 3 mg/kg/day plus IV methylprednisolone, improvement in low-contrast visual acuity (LCVA), measured by 2.5% Early Treatment Diabetic Retinopathy Study (ETDRS) letter scoring, was approximately 18 letters greater than placebo plus methylprednisolone at 3 months (least-squares mean difference 18.2 [SE, 5.7] letters; 90% CI, 8.4–27.9; P = .004), and approximately 15 letters greater at 6 months (least-squares mean difference 14.8 [SE, 5.5] letters; 90% CI, 5.4–24.1; P = .012).³ Structural outcomes were also favorable: ganglion cell and inner plexiform layer (GCIPL) thinning was reduced by 43% relative to placebo at month 3 (LS mean difference, 9.2 [SE, 5.4] µm; 90% CI, 0.0–18.3), a difference maintained at month 6, and retinal nerve fiber layer (RNFL) thinning was reduced by 28–30% at 3 and 6 months, respectively.³ Results were presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025 Congress.

Clinical context: The unmet need in optic neuritis

Optic neuritis affects predominantly young women in their third and fourth decades of life, with an estimated annual incidence of 5–6.4 cases per 100,000 in the United States and a female-to-male ratio of approximately 3:1.⁴ The condition is the initial clinical manifestation of MS in approximately 20% of patients and occurs at some point in the disease course in up to 50% of individuals with MS.⁵ Long-term follow-up data from the landmark Optic Neuritis Treatment Trial (ONTT), the foundational randomized clinical trial of corticosteroid treatment in ON, demonstrated that the 15-year cumulative probability of developing clinically definite MS following a first episode of ON is approximately 50%, with risk strongly modulated by the presence of white matter lesions on brain MRI at the time of the acute event.⁶

The standard of care for acute ON has remained substantially unchanged since the ONTT established IV methylprednisolone as the preferred acute treatment in 1992.⁷ High-dose IV corticosteroids accelerate the speed of visual recovery but have not been shown to improve long-term visual outcomes or to prevent permanent structural loss of optic nerve fibers and retinal ganglion cells—the cellular substrate of persistent visual deficits including reduced contrast sensitivity, impaired color vision, and residual visual field loss that many patients carry indefinitely. Oral corticosteroids alone are not recommended, as the ONTT demonstrated they increased the rate of recurrent ON attacks without meaningful benefit on visual recovery.⁷ There are no currently approved or clinically established neuroprotective treatments for ON or for optic neuropathies more broadly.

Mechanism of action and drug-class background

Privosegtor (formerly designated OCS-05) is a novel peptoid small molecule that acts as an activator of serum-glucocorticoid kinase-2 (SGK-2), a signaling pathway component linked to the activation of trophic factor pathways including insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF).³ Both IGF-1 and BDNF play established roles in the development and survival of neurons, including retinal ganglion cells—the projection neurons whose axons form the optic nerve and whose loss underlies permanent visual disability in ON and other optic neuropathies.

A key structural feature of privosegtor is its capacity to cross both the blood-brain barrier and the retinal barrier, a property that enables systemic administration to achieve therapeutic concentrations in retinal and optic nerve tissue. No approved drug for ON exploits this neuroprotective mechanism; available disease-modifying therapies approved for MS act primarily on the adaptive immune response to reduce relapse frequency but do not target neuroaxonal survival directly. Agents approved for the prevention of relapses in neuromyelitis optica spectrum disorder (NMOSD)—including eculizumab, inebilizumab, and satralizumab—address the distinct pathophysiology of aquaporin-4 antibody–mediated disease and are not indicated for acute ON outside of that context.

Expert interpretation and limitations

The ACUITY results represent a genuine advance in ON research: this is among the first trials to demonstrate simultaneous improvements in both functional visual outcomes and objective structural markers (GCIPL and RNFL thickness by optical coherence tomography) in a randomized, controlled setting. The parallel improvement in LCVA and in retinal structure is biologically coherent and strengthens the mechanistic plausibility of a neuroprotective effect. Mark Kupersmith, MD, of the Icahn School of Medicine at Mount Sinai—who also served as an investigator in the original ONTT—has noted that the ACUITY results represent the first time a candidate drug has demonstrated concurrent functional, imaging, and biological evidence of neuroprotective benefit within a single controlled trial.¹

That said, clinicians should interpret these data with appropriate caution. The ACUITY trial enrolled only 33 evaluable patients, was not powered for definitive efficacy conclusions, and did not include a prespecified primary efficacy endpoint. The functional differences observed with the 3 mg/kg dose were not replicated at the 2 mg/kg dose to the same magnitude, raising dose-response questions that will need resolution in larger studies. Because 61% of the cohort had MS—and outcomes in MS-associated ON may differ from idiopathic or other-etiology ON—the generalizability of these findings across the broader ON population also warrants scrutiny. LCVA on the 2.5% ETDRS chart, while more sensitive to subtle visual dysfunction than standard high-contrast acuity, is not universally adopted as a primary endpoint in ON trials, and its relationship to patient-reported functional outcomes in daily life remains an area of active research. Longer-term follow-up data beyond 6 months are not yet reported.

The PIONEER program and next steps

Following a productive FDA end-of-phase 2 meeting in autumn 2025, Oculis launched the PIONEER program (Privosegtor Investigation in Optic Neuropathies Efficacy Evaluation Research), a three-trial global registrational program.¹ PIONEER-1, targeting acute ON in a broad MS and non-MS population, was initiated in Q4 2025, with PIONEER-2 (same indication) planned for the first half of 2026. PIONEER-3 will evaluate privosegtor in non-arteritic anterior ischemic optic neuropathy (NAION), a distinct non-inflammatory ischemic optic neuropathy for which no neuroprotective treatment is currently approved, with initiation planned for mid-2026. The primary endpoint across the ON trials is LCVA at 3 months, with dosing and enrollment criteria intended to mirror the ACUITY design.

Enrollment in registrational ON trials has historically proved challenging given the relatively low incidence of the condition, the need for rapid enrollment within a narrow acute window, and the heterogeneity of ON etiology. The degree to which PIONEER-1 and -2 will include patients with NMOSD-associated or MOG-antibody–associated ON—conditions with a distinct pathophysiology and historically worse visual prognosis than MS-associated ON—will be a critical design element affecting generalizability. Whether the structural and functional benefits observed in ACUITY will be confirmed in a larger, adequately powered population, and whether these translate into durable improvement in patient-reported outcomes and reduced disability, remain the central unanswered questions.

References

1. Oculis Holding AG. Oculis announces U.S. FDA Breakthrough Therapy designation granted to privosegtor for treatment of optic neuritis. Press release. January 6, 2026. https://investors.oculis.com/news-releases/news-release-details/oculis-announces-us-fda-breakthrough-therapy-designation-granted

2. ClinicalTrials.gov. OCS-05 in patients with optic neuritis (ACUITY). NCT04762017. https://clinicaltrials.gov/study/NCT04762017

3. Oculis Holding AG. Oculis announces positive OCS-05 phase 2 ACUITY trial in acute optic neuritis, met primary safety endpoint and key secondary efficacy endpoints. Press release. January 6, 2025. https://investors.oculis.com/news-releases/news-release-details/oculis-announces-positive-ocs-05-phase-2-acuity-trial-acute

4. ScienceDirect Topics. Optic neuritis: epidemiology overview. In: Ophthalmology Reference Series. Elsevier. https://www.sciencedirect.com/topics/neuroscience/optic-neuritis

5. Karaarslan E, Uysal S, Mutluer N. Optic neuritis as an early sign of multiple sclerosis. EPMA J. 2011;2(2):195–200. doi:10.1007/s13167-011-0065-9. https://pmc.ncbi.nlm.nih.gov/articles/PMC5398757/

6. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final Optic Neuritis Treatment Trial follow-up. Arch Neurol. 2008;65(6):727–732. doi:10.1001/archneur.65.6.727. https://pmc.ncbi.nlm.nih.gov/articles/PMC2440583/

7. Beck RW, Cleary PA, Anderson MM Jr, et al; Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326(9):581–588. doi:10.1056/NEJM199202273260901. https://www.nejm.org/doi/full/10.1056/NEJM199202273260901

8. Oculis Holding AG. Oculis accelerates privosegtor into registrational trials in acute optic neuritis, pioneering the path for a potential first-in-class neuroprotective therapy. Press release. October 6, 2025. https://investors.oculis.com/news-releases/news-release-details/oculis-accelerates-privosegtor-registrational-trials-acute-optic

9. Bennett JL. Optic neuritis. Continuum (Minneap Minn). 2019;25(5):1236–1264. doi:10.1212/CON.0000000000000768. https://continuum.aan.com/doi/10.1212/CON.0000000000000768

10. Oculis Holding AG. Oculis announces European Medicines Agency PRIME designation for privosegtor, advancing a potential first-in-class neuroprotective candidate for optic neuritis. Press release. March 31, 2026. https://investors.oculis.com (Note: Direct EMA PRIME decision document link could not be independently verified at time of publication; readers are directed to the EMA website at ema.europa.eu for formal documentation.)

Disclosure: This article was prepared with artificial intelligence using publicly available press releases, peer-reviewed publications, and regulatory documentation.