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Cell Replacement Therapy – A Promising Treatment for Age-Related Macular Degeneration

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Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel, “off the shelf” cell therapies for unmet medical needs. Lineage’s programs are based on its proprietary cell therapy platform and in-house development and manufacturing capabilities. Their lead program features the manufacture and transplant of retinal pigment epithelium cells for the treatment of dry age-related macular degeneration, one of the leading causes of blindness. The therapy recently completed enrolment in a Phase 1/2a clinical trial.

Here we share a Q&A with CEO Brian Culley. In this interview, Brian discusses age-related macular degeneration and retinal pigment epithelium transplant therapy.

Q: What is age-related macular degeneration and what is the current treatment landscape?

Age-related macular degeneration (AMD) is a leading cause of blindness in adults over the age of 50. Progression of the disease occurs as a result of the death of specialized retina cells in the area of the macula, which gradually leads to a decrease or complete loss of vision, particularly affecting the central vision, which is needed to use a cell phone, recognize faces, drive a car, etc. The causes of AMD are multifactorial and include age, genetics, smoking, and environmental influences. There are two forms of AMD. Dry AMD is the more common of the two types, accounting for approximately 85-90% of cases, while wet AMD is the less common, accounting for approximately 10-15% of cases.

Wet AMD, or neovascular macular degeneration, occurs due to an abnormal growth of blood vessels beneath the macula, resulting in spots in the visual field or straight lines appearing wavy to the patient. Unlike dry AMD, which develops slowly, wet AMD can rapidly progress and cause a loss of central vision. There are a number of effective U.S. Food and Drug Administration (FDA) approved treatment options available for wet AMD. These treatments are designed to stop the development or growth of blood vessels and are known as “antiangiogenic” or "anti-vascular endothelial growth factor (VEGF)” therapies. Anti-VEGF therapies can slow the progression of wet AMD and in some cases improve the patient’s vision.

In the early to intermediate stages of dry AMD development, retinal cells have died off and as a result, yellow deposits of metabolic waste products known as drusen begin to accumulate in the back of the eye. Drusen can vary in size and number and are considered a natural part of the eye’s aging process. However, in dry AMD, the retinal pigment epithelium (RPE) cells are dysfunctional or dying and unable to clear the metabolic waste. Over time, the disease will inevitably progress, sometimes into advanced dry AMD with geographic atrophy (GA), meaning total and irreversible loss of cells in an area. There are currently no FDA or European Medicines Agency approved treatment options for dry AMD. This is likely because dead cells cannot be restored. Humans lack the ability to regenerate retinal tissue and replace lost retina cells – which has led to a presumption that progression of GA may someday be slowed or halted but cannot be reversed.

Q: Could you tell us about the allogeneic RPE cell replacement therapy Lineage is developing for the treatment of dry AMD with GA?

One of the most promising potential therapies for advanced dry AMD with GA is cell replacement therapy, because cell therapy means transplanting cells which cannot be generated any other way. Most traditional approaches seek to slow or halt a disease process, but cannot reverse it. Cellular therapies are often aimed at regenerating or replacing absent cells and/or improving bodily functions. Therefore, cellular therapies may be shown to have broader or more suitable applicability than pharmaceuticals in the treatment of advanced dry AMD and other serious diseases. The benefits to the patient include drusen reduction, photoreceptor recovery and preserved or improved sight. At Lineage Cell Therapeutics we are exploring these potential benefits through the clinical development of an RPE cell replacement therapy called OpRegen.  

OpRegen is a formulation of allogeneic RPE cells, designed to ultimately be used as an “off-the-shelf” or “thaw-and-inject” treatment for advanced dry AMD with GA. That means we’re generating the cells outside of the body from established cell lines. The hypothesis of this therapy is that newly transplanted, healthy RPE cells may replace the patient’s dead RPE and support dysfunctional or dying RPE that would otherwise continue to progress to death. This is similar to a bone marrow transplant, except it is happening in the eye. The objective of OpRegen therapy is to slow, halt or even reverse the progression of dry AMD with GA. OpRegen is currently in a Phase 1/2a dose escalation safety and efficacy clinical study of a single injection of transplanted cells in patients with advanced dry AMD with GA. The primary objective of the study is to evaluate the safety and tolerability of OpRegen, while secondary objectives are to evaluate the preliminary efficacy of OpRegen treatment by assessing the changes in ophthalmological parameters, such as visual acuity and reading speed.

We recently reported evidence
 from a patient with atrophic end-stage disease, who received a transplant of allogeneic RPE cells and showed substantial restoration of retinal tissue within the area of GA. Specifically, the area of GA assessed at 9 months was approximately 25% smaller than the patient’s pre-treatment baseline and it grew approximately 50% slower than its historical rate during the subsequent six months. This patient’s area of GA remained below baseline for 23 months and counting. Lineage is not aware of any other company or academic lab which has shown such a dramatic reversal of the disease in a human. These unprecedented findings were initially observed by an independent external advisor using multiple imaging technologies and were subsequently confirmed by the reading center and additional experts in the field of retinal imaging.

To our knowledge, this is the first time any experimental treatment for dry AMD has demonstrated a reduction, rather than expansion, of an area of atrophy over a clinically meaningful time period. This finding supports the view that dry AMD is not an irreversible, degenerative condition and that some portion of diseased retinal tissue may be recoverable in atrophic end-stage disease patients.

Q: What are the manufacturing capabilities at Lineage, and could you touch on the purity of the RPE cells?

As we aim to pioneer a new branch of medicine, based on transplanting specific cell types into the body, relying on our competitive advantage of differentiating an unlimited supply of pluripotent stem cells into specialized cell types like retinal cells. Lineage has extensive experience directing the lineage of pluripotent cells into terminally differentiated, specialized cell types and scaling them up in preparation for commercialization. OpRegen cells are greater than 99% pure RPE cells manufactured from a pluripotent cell line that is NIH approved and established 20 plus years ago. The cells have undergone extensive characterization and karyotyping, and there are no genetic modifications made to the RPE cells. Commercial scale-up has already been achieved, with a current production scale of around 5 billion cells per 3-liter bioreactor, or the equivalent of greater than 2,500 clinical doses per batch. Further scale-up can be performed in larger or additional (i.e. parallel) reactors.