Age-related macular degeneration (AMD) is one of the world’s leading causes of blindness in people over the age of 50. There are two types of the disease – wet AMD and dry AMD.
The less common wet AMD is well understood as being caused by leaky blood vessels and has numerous effective treatments available. Dry AMD causes layers of the macula (including the photoreceptors and the retinal pigment epithelium) to get progressively thinner and function less and less well. This is called atrophy.
Advanced cases of dry AMD are known as geographic atrophy (GA) because large sections of the retina stop functioning.
There are around two million people in the US suffering with this severe form of the condition, and there are currently no treatments available, representing a huge unmet need. Historically, dry AMD has been viewed as an inevitably progressive disease.
California-headquartered Lineage Cell Therapeutics is taking a very different approach to the disease compared to traditional pharmaceutical approaches, which often involve targeting inflammation with small molecules and antibodies and treating patients either orally or locally in the eye.
With its lead candidate OpRegen, which is in an ongoing Phase I/IIa open-label clinical study, Lineage is manufacturing brand new retina cells and taking a transplant approach to the condition.
“It’s been very exciting what we have seen in the clinic so far,” the company’s CEO Brian Culley tells Clinical Trials Arena.
The one-time therapy consists of allogeneic retinal pigment epithelium (RPE) cells and is administered subretinally in patients with dry AMD and GA. The patient is locally anaesthetised and the procedure only takes about 30 minutes.
The firm uses pluripotent stem cells as a starting material to manufacture the therapy. “Just as flour can become bread or a cookie, [pluripotent] stem cells have within them the capability or the capacity to become any of the 200 cell types in your body,” says Culley.
“We instruct the cells to become a specific and exclusive type of cell and then we transplant those into the body. In the case of dry AMD we manufacture enormous numbers of retina cells and only retina cells, and then we transplant those cells to treat disease of the eye.”
The manufacture of cells requires “exquisite control over your process” as you are manufacturing a dynamic living entity at scale, Culley says. “If you cannot manufacture at large scale, you will never have an economically affordable solution.
The allogeneic rather than autologous nature of Lineage’s manufactured retinal cells provides advantages in scale, he argues.
“There are approaches that people take even in dry AMD where they take cells from a person’s eye, and they manipulate them and then they replace them, but here you’re talking about personalised medicine, which sounds great until you consider the cost.
“We’ve invested significantly in our manufacturing skills and created a huge number of patents from our manufacturing techniques. We are already at the point where, in a three-litre bioreactor, we can manufacture the equivalent of 2500 clinical courses so many thousands of treatments can come from basically a milk jug and scaling up is straightforward because we grow the cells on little microcarriers. We grow the cells in three-dimensional space and that allows us to increase the volume because the cell doesn’t really know the difference between growing in a tiny thimble or growing in a swimming pool.”
Cell therapy brings with it the complexity of dealing with a whole cell rather than just a single molecule, but that complexity is also the key to this approach.
“By the time retina cells are dying off, there are so many things going wrong in the eye that we don’t think that a single molecule is going to have enough horsepower to be able to drive a clinical outcome,” Culley says. “So we think you have to replace the entire cell.”
Trialling retinal cell replacement
The ongoing Phase I/IIa clinical trial evaluating OpRegen enrolled 24 people. Twelve of the participants treated with the therapy had very advanced AMD and were legally blind.
Culley says this cohort was used to assess the treatment’s safety and not much was seen in terms of efficacy but some encouraging anatomical changes were observed.
In the eye, the vision cycle’s metabolic activity leads to a waste material called drusen, which is cleared by healthy retina cells. In some of these patients, a reduction in drusen was observed.
The next group of 12 patients’ disease was far less advanced and they had far better baseline vision than the first; some even still had their driver’s licenses. At their earlier stage of disease, they had more retinal tissue with potential to be rescuable. When the trial moved into the group of patients with better starting vision, Culley and his team started to see very exciting effects in terms of visual acuity and anatomical changes.
“We were really happy to see that in that group of individuals, we’ve had better results,” Culley says. “We have seen an increase in vision, so people are seeing more letters on an eye chart, compared to their untreated eye. The majority of untreated eyes have gotten worse, which is what you would expect over time. In the treated eye it is reversed; we’ve actually seen people gain vision.”
No patients in the trial, which started treating patients with OpRegen five years ago, have rejected the cells, meaning all have stably integrated them. Most exciting of all are three cases of retinal restoration, which Culley says is “really unprecedented stuff” due to the progressive nature of the disease.
Unprecedented retinal restoration
“This is a new phenomenon,” says Culley. “Human beings cannot regenerate retinal tissue; when you lose retina cells, they’re gone forever. And that’s what this disease is all about – losing retina cells.”
Over a year ago, while looking at images of a patient’s eyes after OpRegen treatment, doctors noticed retina cells growing back around the spot of GA.
“We were absolutely blown away,” Culley says. “We actually sat on this initial finding for quite some time, because even though it was incredible, and exciting and maybe even predictable in some ways – you’re transplanting cells and if they’re taken up, survive and are functional why wouldn’t this happen – but nobody thought it was possible.”
The question the firm focused on while analysing the data and sending it out to third-party independent retinal imaging experts was simple – why did this patient experience retinal tissue regeneration while no one else did?
“We think the answer was that patient got a very complete delivery of our cells all across that atrophic area,” explains Culley.
Lineage repeated the procedure and got similarly extensive coverage across another two patients, and they also exhibited retinal restoration. “So we now have three cases that have exhibited retinal restoration. Now it’s not a one-time thing – we have some understanding, we could reproduce it, it’s quite clear.”
One of the trial participant’s atrophy originally got smaller but now has grown back to the size it was three years ago – meaning that essentially her AMD had been halted.
“In the three years since I had the operation, the eye that was operated on has not deteriorated which I reckon is almost miraculous,” said the patient, Sonia Cohen. “It’s really amazing. I can’t imagine what my life would have been like if I had continued to deteriorate.”
Culley says that with OpRegen’s clinical research thus far, his team has learned that being more aggressive with where they place the cells leads to better outcomes.
“Now we know that so we can repeat that. I think over time, it will get better and better, and I’d be really delighted if we get up to the point where it becomes like LASIK surgery, which is close to 100% success rate.”
Next steps: the vision for next-gen cell therapy
Later this year, Lineage is planning to discuss the design of its next trial with the US Food and Drug Administration. For now, the three cases of retinal restoration or reversal of AMD have provided a vital proof of concept.
“We want to go as quickly as possible into the next study, and having the backing of this reversal is very exciting because, from a statistical perspective, we probably don’t need 2,000 patients – we’re talking about hundreds of patients.”
On the future of cell therapy, Culley says it is a field that is quickly maturing. “It used to be like the wild west but now companies like ours are doing these rigorous clinical trials to find out ways to control it and dry AMD is a really cool place to start,” he says. “But, there are 199 other cell types that we could investigate so there is a long-term medical story here that is really about ushering in a new branch of medicine – manufacturing cells, transplanting them – that I’m really excited to be part of.”
Dry AMD is not the firm’s only focus; it has also embarked on clinical trials for VAC2, an allogeneic dendritic cell therapy currently enrolling a Phase I trial for the treatment of non-small cell lung cancer and has treated 25 people with spinal cord injuries with its candidate OPC1 in a Phase I/II trial, which Culley says has been very emotional.
“I know if I live long enough my retina cells are going to die off; if I smoke four packs of cigarettes [a day] I will get lung cancer, but nobody expects to get a spinal cord injury. All of these young people who fall off mountain bikes or get in car crashes and their lives are turned upside down. Their ability to just get some hand control to be able to move their wheelchair – that’s mobility and independence so if we can help regain mobility, that’s freedom – so I think the spinal cord program is really powerful.”