A Phase I/II Study to Assess the Safety and Tolerability of a Single Subretinal Administration of SPVN06 Gene Therapy in Subjects with Rod-Cone Dystrophy (RCD) Due to a Mutation in the RHO, PDE6A, or PDE6B Gene
This is a two-step, multicenter, Phase I/II study including an open-label dose-escalation phase (Step 1) and a three-arm, controlled, double-masked, randomized extension phase (Step 2), in subjects with advanced RCD due to a mutation in the RHO, PDE6A, or PDE6B gene.
‣ Subjects will be eligible to participate in this study only if all the following criteria apply:
• Able to give signed informed consent and comply with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
• Age ≥18 years at the time of ICF signature.
• Subjects of either gender previously diagnosed with advanced RCD due to biallelic mutations in the rod cGMP phosphodiesterase 6 beta (PDE6B) or rod cGMP phosphodiesterase alpha (PDE6A) genes, or due to a monoallelic dominant mutation in the rhodopsin (RHO) gene. The genotyping results must be documented before the initiation of the Screening Visit. Subjects should be retested by the investigator if their genotyping tests were not performed within the 7 previous years, or if they were not performed by an accredited laboratory. In this case, the screening period can be prolonged for 2 additional weeks to allow time to generate genotyping results.
• Advanced stage is defined as a stage of the natural history of the disease where both distance visual acuity and visual field are affected in both eyes. Substages within the advanced stage are defined as follows (monocular measurements, horizontal axis of isopter III4e for the visual field):
‣ Severe stage is defined by both a BCVA below or equal to 20/200 and above or equal to 20/800, and a visual field below or equal to 20 degrees (subjects of Cohorts 1 to 3)
⁃ Intermediate stage is defined by both a BCVA below or equal to 20/40 and above 20/200, and a visual field below or equal to 20 degrees (subjects of Cohorts 4 to 6)
• For subjects with severe advanced RCD enrolled in Step 1 only, the difference in visual acuity between the two eyes of a given subject should be equal to or below 0.3 logarithm of the minimal angle (LogMAR) (≤3 ETDRS lines), with a tolerance margin of 3 ETDRS letters.
• Clinical diagnosis of RCD based on past medical and family history, mid-peripheral visual field dysfunction, photopsia, night blindness (nyctalopia), and fundoscopic appearance (including but not restricted to bone spicule pigmentation, attenuation of the retinal vessels, and waxy pallor of the optic nerve).
• Diagnosis of RCD is confirmed on prior full-field ERG (any previously performed ERG is acceptable).
• Documented preservation of cone inner and outer segments considered good enough by the investigator for the subject to be included in the study.
• Negative serum pregnancy test for women of childbearing potential (please refer to Schedule of Assessments for details).
⁃ Women of childbearing potential (WOCBP) and men and/or their partner(s) of childbearing potential must agree to use a highly effective contraceptive method. This applies to the time period between ICF signature and 12 months after SPVN06 subretinal injection SRI (i.e., no longer applicable to subjects of Cohort 4 after randomization). The definition of highly effective contraceptive methods follows CTFG recommendations. Highly effective contraceptive methods are limited to:
∙ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
⁃ Oral
• Intravaginal
• Transdermal
‣ Progestogen-only hormonal contraception associated with inhibition of ovulation:
⁃ Oral
• Injectable
• Implantable
‣ Intrauterine device (IUD)
‣ Intrauterine hormone-releasing system (IUS)
‣ Bilateral tubal occlusion
‣ Vasectomized partner
‣ Sexual abstinence
⁃ Subjects must be affiliated to a health security system, if they are included in a clinical site based in France (per law).
⁃ No out-of-range values for clinical laboratory tests, however, if outside, must be considered as non-clinically relevant by the investigator using a multidisciplinary approach and compatible with a participation in the clinical study.
⁃ 12-lead electrocardiogram within normal limits, however, when outside, must be documented by the investigator using a multidisciplinary approach as not clinically relevant and compatible with a participation in the clinical study. Nota bene: This criterion of eligibility is only applicable to subjects assigned to a treatment cohort (Cohorts 1, 2, 3, 5, or 6), and is not required to authorize randomization in Step 2.
⁃ Physical examination without any clinical findings of clinical relevance (per medical/anesthesia staffs judgment) that could compromise participation in the clinical study or could affect the collection and/or evaluation of the study parameters. The findings of clinical relevance considered as contraindications to SPVN06 treatment include, but are not limited to, pulmonary pathology such as COPD, asthma, cardiac conditions such as congestive heart failure or valve disease, renal issues such as renal insufficiency and endocrine issues such as diabetes.