How difficult is it to make a cell type? How many of that cell type do you need? What’s the addressable market?
These are the first questions that Brian Culley—CEO at Lineage Cell Therapeutics, a clinical-stage biotechnology company developing cell therapies—and his team ask when they prepare to develop and manufacture a particular cell type.
Subsequent questions become more specific. Culley offers this example: Do you need 300 million natural killer (NK) cells or 30,000 auditory neurons? He adds, “When these characteristics get organized into a chart or heat map, the best opportunities can jump out at you.”
Cell therapies vs. transplants
Since Culley joined Lineage in 2018, the company has been focused on making differentiated cells into medicines via transplants. In a November 14, 2022 interview with GEN, Culley emphasized the term “differentiated” because, in his view, many cell therapy initiatives have relied on undifferentiated stem cells, with mixed results at best. Culley also emphasized the term “transplants.” He thinks that “cell therapy” encompasses many things, including the clinic down the street that spins down fat and injects it in the elbow or knee.
Along these lines, Culley said that he likes to think of Lineage as a cell transplant company. To take the company down this path, he’s looked at cells already used for allogeneic cell transplants. Take bone marrow transplants, for example, which have worked for decades.
Culley maintained, “If you replace the actual cell that’s missing because of some disease or condition where the problem is that a specific cell type is not functional or not present, manufacturing that cell and replacing it—as long as it’s stable, integrated, behaves, and has the function—ought to give you that activity back.”
Creating a cell therapy company
To take the company down the path of creating transplant-based-medicines that have a higher chance of success, Culley shut down or sold off certain programs after joining the company and focused on three clinical-stage cell transplant programs:
• OpRegen, a retinal pigment epithelial cell therapy in Phase IIa development for the treatment of geographic atrophy secondary to age-related macular degeneration (AMD). (Lineage is currently developing OpRegen in collaboration with Roche and Genentech.)
• OPC1, an oligodendrocyte progenitor cell therapy in Phase I/IIa development for the treatment of acute spinal cord injuries.
• VAC2, a dendritic cell therapy for immuno-oncology and infectious disease. (The therapy is currently in Phase I development for the treatment of non-small cell lung cancer.)
The retina program was already in-house when Culley joined the company. One of the first things Culley did after joining was to acquire oncology and spinal cord programs from Asteria Biotherapeutics. (Asteria is named after a starfish that can regrow limbs.)
Culley noted that Lineage plans to move away from fixing broken programs to building programs from scratch. So far, Lineage has launched two programs: ANP1, an auditory neuronal progenitor cell therapy for the treatment of auditory neuropathy, and PNC1, a photoreceptor neural cell therapy for treatment of vision loss due to photoreceptor dysfunction or damage.
The recipe for cell therapy products
Lineage has the in-house manufacturing capability to go from frozen master cell banks to clinical trial production. All of that is done at one facility with multiple GMP suites, enabling the company to run programs in parallel. Culley said that it is critical that Lineage does its own process development, which has to be optimized on a platform that can scale and be controlled.
“There are all sorts of things that can lead to a batch failing, and you have to create these methods that can be deployed by many different hands,” Culley explained. “The RPE program will ultimately be transferred to Roche, and they will have to do [manufacturing] themselves. That’s why we’ve recently expanded our manufacturing capabilities, because it is so important to have that part of it dialed in. If you don’t have the manufacturing process locked, you do not have a product.”
Although many cell therapy companies perform two-dimensional growth on large plastic plates, Lineage works in a three-dimensional environment using a bioreactor. “We can already generate 2,500 clinical courses of our RPE product in just a 3-L bioreactor—the size of a milk jug,” Culley asserted. “And we can scale higher to meet commercial demand. For the companies dosing 100, 300 million, or a billion cells of different types, commercial-scale manufacturing poses some daunting challenges.”
Royalties from Roche
In December 2021, Lineage announced that it had entered into an exclusive worldwide collaboration with Roche and Genentech for the development and commercialization of OpRegen for the treatment of ocular disorders, including advanced dry AMD with geographic atrophy. The transaction is worth up to $670 million plus double-digit royalties.
“If you’re transplanting replacement cells in the same location where they belong, and administering cells that are healthy and functional, you can regain that lost function,” Culley stressed. “That was one of the surprising and amazing findings from the eye program: We got people to increase their visual acuity. That never happens in this disease.”
Dry AMD is a progressive disease, but Culley said that Lineage reversed the condition in patients. “It’s also looking like it’s a one-and-done treatment—all the positives of gene therapy without the editing of someone’s genome,” he pointed out. “We’re getting pure populations of cells and sticking them in the body, and we’ve never had a single case of rejection. That’s pretty good. We also don’t have people on lifetime immunosuppression. They’re on for 90 days—and it’s not clear that amount is even necessary.”
Partnering with Roche in ophthalmology—specifically in dry AMD—is almost a no-brainer, Culley remarked. There are millions of patients in the United States alone. “We’re too small today to be an effective commercial competitor,” he admited. But he added that partnering with Roche has brought Lineage capital, capabilities, and “the credibility of a pharma partnership.”
In January 2022, Lineage received a $50-million upfront payment from Genentech. That should last a long time because Lineage’s predicted annual outlay is less than $30 million. It also allows Lineage to do some new things. “From the time we said let’s [launch the auditory neuron program] to the time we initiate preclinical animal testing will be less than one year and less than $1 million of our R&D budget,” Culley declared. He added that he would like to launch more programs. It’s all just a matter of growing at the right rate in this environment.