“How difficult is it to make a cell type? How many of that cell type do you need? What’s the addressable market?”
That’s the first line of questions that Brian Culley—CEO at Lineage Cell Therapeutics, a clinical-stage biotechnology company developing cell therapies with headquarters in San Diego, California—and his team asked when going after the development and manufacturing of a particular cell type.
“Do you need 300 million natural killer (NK) cells or 30,000 auditory neurons?” Culley told GEN Edge. “When these characteristics get organized into a chart or heat map, the best opportunities can jump out at you.”
Cell Therapies vs. transplants
Mr. Culley has more than 25 years of business and scientific experience in the life sciences industry. Prior to joining Lineage, Mr. Culley served from August 2017 to September 2018 as interim Chief Executive Officer at Artemis Therapeutics, Inc. (ATMS). He previously served as Chief Executive Officer of Mast Therapeutics, Inc. (MSTX), from 2010, and was also a member of its board of directors from 2011, until Mast’s merger with Savara, Inc. (SVRA) in April 2017.
Since Culley joined Lineage Cell Therapeutics in 2018, the company has been focused on making differentiated cells into medicines via transplants. Culley emphasizes the term “differentiated” because he thinks that cell therapy has had many initiatives where people use undifferentiated stem cells. But the results of most cell therapies, he says, have been mixed at best.
“I might be being complimentary by saying ‘mixed’,” he said. “It largely hasn’t worked. I’ve seen a lot of failures in that space. It just hasn’t really led to products yet.”
Culley also emphasizes the term “transplants.” That’s because he thinks “cell therapy” encompasses many things, including the clinic down the street that spins down fat and injects it in the elbow or knee.
“If I’m losing my vision because this one particular cell type is dying off, I’m replacing that cell and putting it in the body. It doesn’t get injected into my arm, float around, and secrete magical factors. A tumor might shrink spontaneously. Sometimes somebody goes down to South America and licks a frog, the tumor shrinks, and they say it was the frog. That does happen, but nobody’s area of atrophy in their eye ever gets better. It only gets worse.”
Along these lines, Culley thinks of Lineage Cell Therapeutics as a cell transplant company. To take the company down this path, he’s looked at cells already used for allogenic cell transplants. Take bone marrow transplants, for example, which have worked for decades.
“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, it ought to give you that activity back,” said Culley.
“When we transplant cells, and that area gets better—that’s extraordinary. That’s where I really see a difference between cell therapy, which sometimes includes the chiropractor down the road injecting stuff in the body to treat covid or whatever, and cell transplantation, which is our little corner of the medicinal universe.”
Creating a cell therapy company
To drive the company towards creating transplant based-medicines with 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 that they still have today:
- OpRegen, a retinal pigment epithelial cell therapy in Phase IIa development for the treatment of geographic atrophy secondary to age-related macular degeneration (AMD), is being developed under a worldwide collaboration with Roche and Genentech (a member of the Roche Group);
- OPC1, an oligodendrocyte progenitor cell therapy in Phase I/IIa development for the treatment of acute spinal cord injuries; and
- VAC2, a dendritic cell therapy produced from Lineage’s VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical 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 buy in the oncology and spinal cord programs.
“I bought those through the acquisition of a company called Asterias Biotherapeutics, which was named for a starfish because starfish can regrow their limbs,” said Culley. “But Asterias had some great challenges with manufacturing. Sometimes in this industry, a company will generate some evocative clinical data, but if you don’t have a clear line of sight to a product—if you can’t manufacture at scale, reproducibly, and have a stable cell line that’s been well-characterized—you may have a headline, but you don’t have a viable product.”
With the manufacturing capabilities at Lineage Cell Therapeutics, Culley identified two programs that he thought could be fixed.
“There were some non-target identity markers in the spinal cord material that, in some cases, were above 20%—that’s pretty dirty,” said Culley. “We’ve been able to get that number below 2%. So now we have these very highly pure populations of cells, an improvement in control and reproducibility which we think represents a maturation of the field.”
Going forward, Culley said he will move away from fixing broken programs to building programs from scratch.
“That’s where I think we have an opportunity to get it right, right from the gate,” said Culley. “Some programs in cell therapy are painfully slow and have a lot of deficiencies—there’s a lot of ‘we’ll figure that out later’ kinds of problems. Many of those programs are now falling by the wayside. Companies like Lineage can move much faster than we could have 10 years ago. I just got lucky that I happened to be showing up when the curve is really taking off.”
So far, Lineage Cell Therapeutics has launched two programs: ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy; and PNC1, a photoreceptor neural cell therapy for the potential treatment of vision loss due to photoreceptor dysfunction or damage.
The recipe for cell therapy products
Lineage Cell Therapeutics has the in-house manufacturing capability to go from the 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.
Critically, Culley said that Lineage Cell Therapeutics does its own process development, which has to be optimized on a platform that can scale and be controlled.
“You can’t put different cell blends into people each time,” said Culley. “This is fundamental to science, using the same material to see if there’s a benefit. All of that manufacturing is controlled in-house, and we have the same skilled team that can apply their techniques across multiple programs and train each other. All of this starts with a pluripotent, undifferentiated cell line and then learning how to take that cell and give it the instructions it needs to become only the cell type you want. We have complete control over that process.
“That’s really important, because some companies have tried just throwing their manufacturing over the wall to a CRO or CDMO. There are two things I think they’re missing there: they’re adding risk and missing out on potential intellectual property, because the intellectual property is often in the exploratory methods. How did you make that cookie? It’s the best cookie I’ve ever had in my life. How did you do that? Sorry, that’s a secret. So that’s one thing that you miss out on by outsourcing.”
Also, manufacturing cells is far more complex than manufacturing small molecules or antibodies. Cells behave differently based on how crowded they are and where they are on the plastic plate. Culley says that they have even identified variability stemming from how people pipette.
“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 and even by your partners’ employees,” said Culley. “The RPE program will ultimately be transferred to Roche, and they will have to do it [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.”
While many cell therapy companies do two-dimensional growth on big plastic plates, Lineage Cell Therapeutics works in a three-dimensional environment using a bioreactor. “We can already generate 2,500 clinical courses of our RPE product in just a three-liter bioreactor—the size of a milk jug,” said Culley. “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 poses some daunting challenges.”
Royalties from Roche
On December 20, 2021, Lineage announced that it had entered into an exclusive worldwide collaboration and license agreement with Roche and Genentech for the development and commercialization of OpRegen for the treatment of ocular disorders, including advanced dry AMD with geographic atrophy (GA). The transaction is worth up to $670 million in addition to double-digit royalties.
“If you transplant replacement cells in the same location that they belong and you’re administering cells that are healthy and functional, you can regain that lost function,” said Culley. “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; you only get worse. But we reversed the condition in these 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. We don’t do any editing ourselves. We’re just taking these cells, giving them developmental instructions, nature then does what it’s supposed to do, and we’re getting pure populations of cells, sticking them in the body, and 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.”
Culley explained the motivation behind the deal with Roche and Genentech, saying, “Partnering with Roche in ophthalmology, specifically in dry AMD, is almost a no-brainer. Dry AMD is too common and too big of an indication for us. Millions of people have it in this country. We’re too small today to be an effective commercial competitor. So, partnering with Roche obviously brought not just the capital, but also their capabilities and then the credibility of a pharma partnership.”
In January 2022, Lineage received a $50-million upfront payment from Genentech. That should last a long time, Culley says, “because our normalized net operating spend this year is going to be below $30 million and was even lower in years past,” said Culley. It also allows lineage to do some new things. “To give you a sense of how far that money can go, from the time we said let’s [launch the auditory neuron program] to initiating preclinical animal testing, will be less than one year and less than $1 million of our R&D budget.”
Culley said that he would like to launch more programs. It’s all just a management of the right growth rate in this environment.
(The interview between Brian Culley and Jonathan Grinstein took place on November 14, 2022).