Ultevursen

Usher syndrome combines hearing loss with retinitis pigmentosa, and it is the most common form of retinitis pigmentosa that comes with other symptoms, according to MedlinePlus Genetics^[16]. In retinitis pigmentosa the retina's light-sensing cells break down, so night vision usually goes first and side vision then narrows into tunnel vision^[16].

The USH2A gene makes usherin, a protein in the inner ear and retina that helps light-sensing cells develop and work, and USH2A changes are also the most common cause of the recessive form of retinitis pigmentosa without hearing loss^[17].

The 2 most common USH2A changes both sit in exon 13, 1 section of the gene^[13]. Ultevursen is an antisense oligonucleotide designed to stick to the USH2A message and make the cell skip exon 13, so the cell can make a slightly shortened usherin protein^[13]. In lab work by ProQR and Radboud University researchers, skipping this exon with a research molecule restored retinal function in zebrafish, and a mouse version of the drug reached the light-sensing cell layer after 1 injection into the eye^[13].

Whether ultevursen protects vision in people is what LUNA is testing^[1]. LUNA does not measure hearing, and its registry record defines Usher syndrome type 2a as retinitis pigmentosa with hearing loss present from birth^[1].

LUNA (NCT06627179) is a Phase 2, randomized, double-masked, sham-controlled trial that lasts 2 years^[1]. Sepul Bio calls it a Phase 2b study, and it randomizes people 2 to 1 to ultevursen or a sham procedure^[8][9]. LUNA is for people aged 8 and older with retinitis pigmentosa from Usher syndrome type 2a or without hearing loss, who have disease-causing changes in both copies of USH2A with at least 1 in exon 13^[1].

Both eyes must still have a measurable band of working light-sensing cells on a retinal scan and visual acuity of 20/80 or better^[1]. People who have had any injection into the eye before are excluded^[1].

Sepul Bio said the first participant was dosed in December 2024^[8]. LUNA plans 81 participants at 26 sites, 10 of them in the US (San Francisco, Miami, Atlanta, Boston, Ann Arbor, Portland in Oregon, Philadelphia, Dallas, Houston and Madison), with others in Belgium, Brazil, Canada, Denmark, France, Germany, Italy, the Netherlands and the UK^[1]. LUNA is listed as active and no longer recruiting, with an estimated primary completion of July 2028^[1].

CAPELLA (NCT07796646) is a Phase 2, open-label extension for people who finish 24 months in LUNA^[2]. People can continue ultevursen injections or join an observation-only group with no injections, and the main measure is side effects over 24 months^[2]. CAPELLA is listed as not yet recruiting, with no sites listed and an estimated primary completion of February 28, 2030^[2].

The earlier Stellar study (NCT03780257) was a Phase 1/2 trial of 20 people run by ProQR from March 2019 to October 2021^[3]. ProQR reported on March 24, 2021 that 14 people received a single dose at 1 of 3 levels and 6 had a sham procedure, and that across the 14 treated people, the treated eye did 6.0 letters better on the eye chart than the untreated eye at week 48^[10]. In the 6 people with advanced disease, ProQR reported a 9.3 letter difference^[10]. These figures come from ProQR's own release about a small study^[10].

Ultevursen has no FDA label, so its side effects are not set. Side effects in the eye and elsewhere in the body are a secondary measure in LUNA, counted up to month 24, and LUNA results have not been reported^[1]. In ProQR's earlier Stellar study, ProQR reported on March 24, 2021 that ultevursen was well tolerated at all doses, with no serious side effects and no inflammation^[10].

ProQR also reported that 1 person's existing cataracts worsened in both eyes, judged not related to treatment, and that 1 person's existing cystoid macular edema, a swelling at the center of the retina, got worse and was managed with standard care^[10]. Stellar treated 14 people^[10].

ProQR Therapeutics developed ultevursen under the code QR-421a, and ProQR and Radboud University researchers published its lab results in Molecular Therapy in 2021^[13]. After the Stellar results in March 2021, ProQR said the FDA had granted orphan drug, fast track and rare pediatric disease designations, the EU had granted orphan designation, and it would start 2 Phase 2/3 trials, Sirius for advanced disease and Celeste for early to moderate disease^[10].

Sirius (NCT05158296) and Celeste (NCT05176717) started in December 2021^[4][5]. On August 11, 2022 ProQR said it would focus on its Axiomer RNA editing platform, seek a partner for its eye programs, and wind down the Sirius trial and the Helia extension study while offering continued access to people already receiving ultevursen^[11]. ProQR's release did not name a safety problem as a reason^[11].

ClinicalTrials.gov lists Sirius, with 7 people enrolled, and Celeste, with 5, as terminated for a business decision, and Helia (NCT05085964), with 21, as terminated early by the sponsor^[4][5][6]. Laboratoires Théa bought ultevursen and sepofarsen from ProQR in a deal that closed on December 7, 2023^[12], and Théa's Sepul Bio unit dosed the first LUNA participant in December 2024^[8]. CAPELLA, the LUNA extension, was first posted on ClinicalTrials.gov on September 1, 2026^[2].