How Elixirgen Manufactures Hematopoietic Stem Cells At The Bedside
A conversation with Aki Ko, CEO, Elixirgen Therapeutics
An FDA rare pediatric disease designation recently pushed extra wind into the sails of Elixirgen Therapeutics, an RNA cell therapy company.
With a Phase 1/2 trial to treat dyskeratosis congenita (DC) and other telomere biology disorders underway at Cincinnati Children’s Hospital, the Baltimore-based company aspires to rewrite some of the most patient-taxing parts of stem cell therapy — including extended manufacturing windows and unpleasant patient preconditioning, which is typical of cell therapy.
DC affects an estimated one in 1 million people, though the extent of incidence is unclear. The disease is characterized by stunted telomeres, which are the protective, stabilizing ends of chromosomes. DC presents in different ways all over the body and often leads to bone marrow failure.
Elixirgen’s candidate, EXG-34217, for the treatment of DC and telomere biology disorders received the FDA’s rare pediatric disease program designation last month. The label means Elixirgen is eligible for a transferrable priority review voucher, which kicks in if EXG-34217 gets approved. The acknowledgment affirms what they’re doing and the critical unmet need and gives investors confidence, too, says company CEO and cofounder Aki Ko.
Coincidentally, Elixirgen could be among the last companies to receive the designation. FDA began sunsetting the voucher program on September 30, per the Food, Drug, and Cosmetic Act. The National Organization for Rare Diseases (NORD) is advocating for reauthorization. Between the program’s 2012 creation and April 2024, FDA awarded 53 priority review vouchers, according to NORD.
We asked Ko to talk to us about the company’s clinical manufacturing strategy. His answers are edited for clarity and length.
What does your manufacturing process look like? Are you processing on-site or running cells back and forth from Baltimore?
Ko: We had considered the design of the cell therapy from the top down and bottom up, reexamining every factor that can be changed or improved.
This is an autologous therapy, it’s not allogeneic. What we do in our case is a locally delivered, locally manufactured autologous cell therapy. This would be on-site at clinics and hospitals that can carry out cell processing or even just have bedside space.
We can do that in part because we’re using a machine from Miltenyi Biotec called the CliniMACS Prodigy, which is an automated cell therapy system. Everything is in a sterile closed loop, and the entire process takes place on-site. There’s a custom program to deliver our vector and the ZSCAN4 gene, which is the therapeutic gene that extends the telomeres for the hematopoietic stem cells.
The process itself or actual inpatient time is only about 28 hours, so multi-day culture is not happening.
We measure the telomeres going back into the patients for those cells and have already seen that the telomeres are extended. It’s quite different from some of the autologous cell therapies I’ve seen so far.
The point of doing this is to reduce the logistics that are involved in shipping and centralizing. We’re avoiding freeze/thaw steps and things like that. Potentially, with a more decentralized strategy, there will be improved patient access, which is what we’re seeking to do.
So, your scale-up strategy is more of a scale-out strategy. You just add manufacturing units and people who can operate them.
Ko: In our case, there’s no need for a giant, centralized cell processing center. That’s in part because our process is fully automated. There are a few companies right now that are more focused on the cell processing and automation part, whereas we are focusing on developing a therapy first and foremost.
Having this kind of completely automated process where the liquids are just flowing back and forth between the sterile bags reduces the risk of error. Then it’s transferred to a bag for infusion and taken to the patient.
For patients, this is a much lighter procedure compared to allogeneic hematopoietic stem cell transplant, which is, I think, the only potentially similar option for telomere biology disorders.
I’ll share some of the bullet points on our therapy versus hematopoietic stem cell transplant because I’d like to compare the approaches. To start, there’s a matched donor required. Bone marrow ablation is often required before the donor hematopoietic stem cells come in. That means chemo or radiotherapy. That, for patients with telomere biology disorders, is very tough. Their DNA is already fragile compared to others and it’s less protected.
Immunosuppression is required from here on out, with the potential for graft versus host disease and other complications down the road.
Compared to that, we’re doing a similar process but, instead, we do no pre-conditioning with no chemotherapy or radiation. Then, obviously, it’s autologous, so there’s no need for immunosuppression. In a way, I think the safety advantages of autologous match the safety needs of the population with telomere biology disorders.
EXG-34217 uses a Sendai virus vector for delivery. From a manufacturability standpoint, what advantages does the Sendai virus vector offer?
Ko: The modified Sendai virus vector has several characteristics that we found to be very positive for our program.
One of the ways that ZSCAN4 has been applied and how it exists in nature is that it expresses at these rare, critical times in human development and in stem cells. It’s a transient effect; it’s not something that’s constitutively on. We replicate that with the Sendai virus vector, which is actually modified to be temperature controllable.
At 37 degrees (Celsius) and over, the virus is inactivated. In the 30 to 35 degrees range, it is functioning. While it is in the Prodigy, in the cell processing stage, it’s at the permissible temperature and expressing, and before it goes back into the body, it is turned off.
That modification has the benefit of not needing to have something on when you don’t need it to be, which we believe is an important safety feature.
Of course, we also have washing steps to remove vector from what’s being infused back to the patient. The actual vector itself is RNA virus-based. It doesn’t have a DNA form and there’s no integration into the genome.
There could be potential for carcinogenesis with genomic integration, so removing that possibility, however small, is great. What we’re using is non-transmissible as well, so there’s no production of infectious virus particles.
All of those factors lead up to something that’s particularly compelling for this therapy and people living with dyskeratosis congenita and related telomere biology disorders.
About The Expert:
Aki Ko is CEO and board chair at Elixirgen Therapeutics. Previously, he was COO of parent company Elixirgen LLC and president of sister company Elixirgen Scientific. He earned a B.S. degree from the University of Virginia.