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Sparing gene therapy for Inherited ROd COne dystrophies

Periodic Reporting for period 2 - SIROCO (Sparing gene therapy for Inherited ROd COne dystrophies)

Reporting period: 2020-08-01 to 2021-07-31

Retinitis pigmentosa (RP) is a rare, genetic disorder characterized by progressive vision loss. The disease involves breakdown and loss of photoreceptors in the retina (see image attached). Symptoms typically appear in young adults, but sometime during childhood. RP is progressive as patients first lose night vision and can experience photophobia (over sensibility to light) due to rod degeneration. With the disease progression and the beginning of cone degeneration, the visual field starts to be restricted to a “tunnel vision”. The latest stage can lead to blindness in people approximatively 50 years-old. Many believe that corrective ophthalmology gene therapy is the future for rare diseases such as RP but with this kind of therapy only treating 1 out of 65 mutations of the pathology, only a small group of patients would be eligible for this therapy.
RP is a complex disease caused by mutation in one of at least 64 identified, distinct genes. The main factor leading to blindness is loss of a recently discovered protein called rod-derived cone viability factor (RdCVF). RdCVF stimulates cone's aerobic glycolysis which is essential for external cone's renewal. Another protein factor called RdCVFL is also secreted in both rods and cones and protects cones against oxidative stress.
The EU-funded SIROCO project aims to develop an innovative treatment for RP based on introduction of RdCVF and RdCVFL to protect cones from degeneration. SparingVision’s product, SPVN06, introduces DNAs coding for RdCVF (Rod-derived Cone-Viability Factor) and RdCVFL (Rod-derived Cone-Viability Factor Long) factors that can protect cones from degeneration. With a single injection under the retina, SparingVisions product can treat all the genetic forms of RP, potentially treat patients with dry AMD, and provide patients with long lasting efficacy.
The ambition of SparingVision is to be one of the first companies to bring to market a disease-modifier treatment addressing RP patients regardless of their mutations.
So, how does it work?
RdCVF is a factor secreted by the rods that serves as neuroprotector and anti-oxidative and is necessary to maintain day vision. SparingVision’s product provides protection to the cones by stimulating the glucose metabolism and repairing the oxidative damages. In SparingVisions proof of concept the product was injected to mice models and provided almost immediate protection and repair to the cones and the progression to blindness was stopped.
RP stands 20th for clinical trial investigation within the ophthalmology therapy area. The launch of the first FDA-approved corrective gene therapy for one single mutation in this disease will very partially fulfil the huge unmet need for a curative pharmacotherapy in RP. Approval of additional novel and stem cell therapy therapies for blind patients will provide more options for patients and stimulate competition. Providing a unique breakthrough product treating all the RP forms and stop the progression of the disease is a huge opportunity for the patients and a challenge for SparingVision.
The objectives for SparingVision in the context of the SIROCO project were defined in the structure of work packages. These were designed to ensure a successful path to phase III clinical trial and, further down the road, to the commercialization of the drug.
Objectives of work package 1 (WP 1): To produce two pilot batches to secure the production of the clinical batch, and then produce the clinical batch of SPVN06 to evaluate the safety and the efficacy of the gene therapy in the Phase I/II clinical trial

Objectives of work package 2 (WP 2): To further secure the clinical development of the gene therapy, SparingVision will extend the retrospective clinical study of the RP natural history by conducting a prospective study on 80 patients included in the retrospective study.
The objectives of these studies are:
• to further describe the natural history of retinal degeneration in patients with retinitis pigmentosa;
• to assess the best inclusion and efficacy evaluation criteria in particular a mobility test for the future Phase I/II trial;
• to identify patients to be included in the future Phase I/II trial
Objectives of work package 3 (WP 3): The objective of the Phase I/II trial is to assess safety, tolerability and efficacy of SPVN06 in adult patients with RP. The Phase I/II study will be multi centric with one site in France that will include the majority of the 36 patients planned to be included, and one site in the US to complete the French cohort.
Objectives of work package 4 (WP 4): To fulfil regulatory requirements of SPVN06 clinical development (Phase I/II and Phase III clinical trials) and secure every clinical step with agency consultations to ensure patient safety. The regulatory work package aims to secure the obtention of the market authorisations within the best timelines, by providing data required by regulators.
Objectives of work package 5 (WP 5): To prepare SPVN06 market access and communicate the project results to the opinion leaders and the general public, SparingVision plans to increase media coverage and dissemination results in congresses, publications and interviews in specialized magazines.
Work performed from August 2019 to July 2020:
Done/ Main results achieved
• Successful production of the cGMP Master Cell Bank & plasmids which are the key raw materials to produce the clinical batch that will be used for the Phase ½ clinical trial (cGMP stands for “in conditions of Good Manufacturing Practices required for products to be used in humans”) (WP 1)
• Analytical tests to perform the quality control of the GMP clinical batch have been qualified (except for one which has been delayed to Oct 2020) (WP 1)
• Successful production of 1 confirmation run and 2 pilot batches which confirmed the suitability of the manufacturing process developed for production of the clinical batch (WP 1)
• Stage Gate Review of the pilot batches data with GO decision for the GMP batch production (WP 1)
• Completion of the retrospective clinical study of RP natural history (110 patients) (WP 2)
• Finalization of Target Product Profile document (TPP) (WP 4)
• Based on TPP, questionnaires for KOL & payers and patients have been completed (WP 4)
• Completion of Forecast model for Market access study (WP 4)

Work performed from August 2020 to date:
Done/ Main results achieved
• cGMP HEH293 cell bank release (WP 1)
• Pilot batches certificates of analysis (WP 1)
• A DPO has been appointed (WP 6)
• Web site update (WP 5)
• Protocol Assistance to EMA and Pre IND to FDA have been performed to seek advice on product development plan (WP 4)
• SIROCO Grant agreement amendment
• The cGMP Master Cell Bank 18-month stability control has been passed (WP 1)
• Analytical tests to perform the quality control of the GMP clinical batch have been qualified (WP 1)
• GMP clinical batch has been produced, and released (WP 1)
• Patients’ enrollment in the retrospective clinical study of RP natural history (WP 2)
• Novel clinical development plan upon Regulatory authorities’ feedback (WP 4/ WP 3)
Progression of retinitis pigmentosa