OpRegen® is currently being tested in a Phase I/IIa clinical trial for the treatment of dry AMD with GA. OpRegen® is a cell-based product composed of retinal pigment epithelial (RPE) cells, derived from human embryonic stem cells (hESC) and administered as a cell suspension in ophthalmic Balanced Salt Solution Plus (BSS Plus).

Phase I/IIa Clinical Trial Highlights

December 2019 Clinical Update

The first Cohort 4 patient treated using both a new subretinal delivery system and Lineage’s new thaw-and-inject (TAI) formulation of OpRegen continued to demonstrate notable improvements in vision, having gained 25 readable letters (or 5 lines) 6 months following administration of OpRegen RPE cells, as assessed by the Early Treatment Diabetic Retinopathy Scale (ETDRS). This represents an improvement in visual acuity from a baseline of 20/250 to 20/100 in the treated eye. A second Cohort 4 patient had been similarly dosed, and though early, the patient had shown a small improvement in visual acuity in the treated eye at just 14 days following treatment. Both patients had rapid healing at the surgical site with no unexpected complications or any serious adverse events.

• The ETDRS eye chart consists of a set of letters of diminishing size on each line. The more letters a patient can read, the better their vision.
• Cohort 4 patients have better baseline vision and less advanced disease and to date, improvements have become most evident approximately three to six months after treatment.

Lineage is also collecting data on rate of geographic atrophy (GA) growth, best corrected visual acuity (BCVA), low-light visual acuity, reading speed, quality of life questionnaires, microperimetry, and assessing structural changes using optical coherence tomography (OCT), fundus autofluorescence (FAF), and color fundus photography.

2019 American Academy of Ophthalmology Annual Meeting Update

Data from the study presented at AAO 2019 demonstrated that treatment with OpRegen continued to be well tolerated and, at the furthest time point collected, all four Cohort 4 patients treated to date had better visual acuity on an ETDRS in the treated eye (range +8 to +19 letters) than in the untreated eye (range -2 to +7 letters). The largest increase recorded at any single timepoint in a Cohort 4 patient was +22 letters. Cohort 4 patients have better baseline vision and less advanced disease than Cohorts 1-3 patients, who were legally blind at baseline. Of note, the first patient successfully dosed using the Orbit Subretinal Delivery System (Orbit SDS) as well as a new Thaw-and-Inject (TAI) formulation of OpRegen is also demonstrating signs of improved visual acuity having gained 13 letters in the 3 months following administration as assessed by ETDRS.

Previously reported structural improvements in the retina and decreases in drusen density observed in some patients have been maintained and there is evidence of the continued presence of transplanted OpRegen cells in patients treated in the first 3 cohorts, some over 3 years following administration.

Overall, OpRegen appears well tolerated with preliminary evidence of improved structural changes and potential improvement in visual acuity following treatment in some patients.

• OpRegen, as well as both surgical procedures used to deliver OpRegen to the subretinal space via (i) pars plana vitrectomy (PPV) with retinotomy and (ii) the Orbit SDS, have been well tolerated.
• Notably, asymmetrical, reduced directional growth of the area of geographic atrophy (GA) in the treated area receiving OpRegen was observed in 3 patients.
• Imaging of several Cohort 1-3 patients, and of particular interest, those from the better vision Cohort 4, continue to demonstrate structural improvement within the retina and evidence of the continued presence of the transplanted OpRegen cells.
• Within the area of the OpRegen cell transplant, signs of a reduction and change in drusen material as well as improvements or possible restorations of the ellipsoid zone and retinal pigment epithelium (RPE) layers have persisted.
• The photoreceptor layer and ellipsoid zone assumed a more regular structural appearance in areas of the transition zone where OpRegen was administered, suggesting potential structural restoration of the retina in areas receiving the RPE cells. This is of particular importance because in dry AMD the structure of the retina can be impacted by the formation of excess drusen and ultimately death of RPE cells and photoreceptors, which are critical to sight.
• Other changes observed following OpRegen treatment persisted through the last time point examined (>3 years in some patients), included subretinal pigmentation and hyper-reflective areas seen on optical coherence tomography (OCT).

The Best Corrected Visual Acuity (BCVA) in eyes receiving OpRegen have not deteriorated more rapidly than expected and areas of GA have not progressed faster than historical averages. Taken together, there are early positive trends for both when compared with the untreated fellow eye. Importantly, the visual acuity of the first 4 Cohort 4 patients have all seen improvements from baseline levels and will be followed for longer periods of time. The next 5 Cohort 4 patients with less severe disease (i.e. smaller areas of GA and visual acuity of between 20/64 and 20/250), which is actively recruiting, will receive OpRegen via the Orbit SDS.

There have been no unexpected adverse events (AEs) or treatment-related systemic serious AEs reported in the first sixteen patients enrolled into this Phase I/IIa safety and tolerability study. The most common and expected ocular AEs were the formation or exacerbation of mild to moderate epiretinal membranes (ERMs) and a single report of a retinal detachment, all occurring in patients receiving OpRegen via the PPV route of administration. The Orbit SDS is an alternative to the PPV route and is designed to avoid ERM formation. The next 5 patients treated are expected to receive OpRegen via the Orbit SDS rather than the PPV route of administration.

About the Phase I/IIa Clinical Study

This is a Phase I/IIa open-label, dose escalation safety and efficacy study of a single injection of human retinal pigment epithelium cells derived from an established pluripotent cell line and transplanted subretinally in patients with advanced dry AMD with geographic atrophy. The study will enroll approximately 24 patients, divided into 4 cohorts. The first 3 cohorts consisted solely of legally blind patients, with best corrected visual acuity (BCVA) of 20/200 or worse. The fourth cohort will include approximately 12 patients with vision ranging from 20/250 to as high as 20/64. Cohort 4 also includes patients treated with one of two formulations of OpRegen; the first 3 patients were treated with a formulation which required plating and preparation of cells one day prior to use. The remaining patients on Cohort 4 will be treated with an “off-the-shelf” or “thaw-and-inject” formulation of OpRegen which can be shipped directly to sites and used immediately upon thawing, which removes the complications and logistics of having to use a dose preparation facility. Staggered intervals within and between cohorts are applied to ensure patient safety and welfare. The primary objective of the Phase I/IIa study is to evaluate the safety and tolerability of OpRegen as assessed by the incidence and frequency of treatment emergent adverse events. Secondary objectives are to evaluate the preliminary efficacy of OpRegen treatment by assessing the changes in ophthalmological parameters measured by various methods of primary clinical relevance. Additionally, for the patients in Cohort 4 that receive subretinal delivery of OpRegen utilizing Gyroscope Therapeutics’ Orbit Subretinal Delivery System (Orbit SDS), objectives will include the evaluation of the safety of delivery of OpRegen using the Orbit SDS.

In January 2019, Lineage entered into an exclusive partnership with Gyroscope Therapeutics (formerly Orbit Biomedical, Ltd.) to assess their approved Subretinal Delivery System, a vitrectomy-free delivery device for administration of OpRegen® within the ongoing Phase I/IIa clinical trial.

Many of the adverse effects that are observed in subretinal procedures are related to the delivery technique utilized during the surgery. The Gyroscope Subretinal Delivery System allows for access to the subretinal space via a suprachroidal approach without creating a hole in the retina and compromising its structural integrity. We believe that the use of this device could dramatically decrease the number of adverse effects as well as significantly improve dose control of cells in our clinical trials.

Lineage dosed its first patient with the Gyroscope Subretinal Delivery System in July 2019.

OpRegen is comprised of specialized retina cells which were derived from a cell line that is listed on the National Institutes of Health (NIH) Registry and are eligible for use in NIH funded research.