Sangamo Therapeutics saw global potential for TxCell’s lead candidate TX200 as the anchor of a pipeline of chimeric antigen receptor-modified regulatory T-cell (CAR-Treg) therapies for solid organ transplants when it acquired TxCell in 2018 for about $74 million.
But with limited resources, French-based TxCell had only planned to develop TX200 in Europe, which is why its Phase I/II STEADFAST trial (NCT04817774) is only recruiting patients in Belgium, the Netherlands, and the U.K. TxCell’s European focus explains why Sangamo recently received the European Commission (EC)’s Orphan Medicinal Product Designation (OMPD) for TX200, but has not yet pursued the FDA’s Orphan Drug Designation.
“Their plan was to do the clinical trials only in Europe, just because of their potential and their reach. So we are running this first study only in Europe. But all future Treg programs will extend to the U.S. as well,” Sangamo CEO Sandy Macrae, PhD, told GEN Edge.
STEADFAST is a first-in-human study designed to assess TX200, which is indicated for the prevention of immune-mediated rejection in human leukocyte antigen A2 (HLA-A2) mismatched kidney transplantation from a living donor.
Sangamo says STEADFAST’s first patient has remained free of adverse events since being dosed with TX200 in March. The company plans to dose the second patient later this quarter, and the third by year’s end, with interim data expected next year. Sangamo plans to dose nine patients—three cohorts of three patients each—in the trial’s Phase I portion.
TX200 is designed to prevent rejection in kidney transplant patients by reducing local inflammation and promoting immunological tolerance to the graft. (TX200 consists of autologous Treg cells engineered to express an HLA-A2 CAR. Upon binding to the HLA-A2 antigen, TX200 cells are expected to localize to the graft and activate.)
Sangamo has another clinical-phase cell therapy candidate—the zinc finger nuclease gene-edited BIVV003 (formerly SAR445136)—for sickle-cell disease, now wholly owned after Sanofi ended its collaboration with Sangamo, citing a change in its cell therapy strategy. BIVV003 is under study in the Phase I/II PRECIZN-1 trial (NCT03653247).
Sangamo’s pipeline also includes five preclinical cell therapy programs. Three are wholly owned Treg cell therapies targeting inflammatory bowel disease, renal transplant (allogeneic) and multiple sclerosis. The other two are cancer candidates (KITE-037 and an undisclosed candidate) being co-developed with Kite, A Gilead Company, through an up-to-$3.16 billion collaboration launched in 2018.
In recent years, Sangamo has pivoted toward cell therapy and away from gene therapy, where its hemophilia A candidate (SB-525 or PF-07055480) is now overseen by Pfizer, and its wholly-owned Fabry disease gene therapy candidate, whose Phase I/II STAAR trial (NCT04046224 ) will advance from dose escalation into the expansion phase at the recommendation of the study’s Safety Monitoring Committee.
Macrae recently discussed TX200 and Sangamo’s other cell and gene therapy candidates with GEN Edge. (This interview has been lightly edited for length and clarity.)
GEN Edge: Can you discuss the significance of the TX200 designation in Europe?
Sandy Macrae: The significance is that it says the Agency regards or recognizes it as being both innovative and for an important medical unmet medical need. What pleases me most is the professionalism of my team in Europe, putting together these applications and making sure that we explain a novel medicine well to the regulators. This is the first time anyone has ever dosed a CAR Treg, and so we do it very carefully and with a great sense of responsibility.
What’s important is that the patient has now had their CAR Treg for four months. The remarkable thing is that nothing remarkable has happened! The patient remains well. We have the second dose manufactured for the second patient, and have line of sight for the third one, that hopefully we’ll now have three patients dosed with this novel treatment this year.
The team have done a great job, not just with getting the orphan designation, but they’ve also presented their data and their package to four local agencies. Each one of them has approved the progression of our studies so we’ve done a very professional job.
The science is fascinating. But to get there, you need to have a deep understanding of how to create an IND. You need to have an editing capability for when we start to move into allogeneic forms, and you have control of your own GMP manufacturing. It isn’t just about a spinout from a university lab, but it’s the many professional bits that go to make an IND and go to make a medicine.
GEN Edge: The first patient was dosed in March. When will the second patient be dosed?
Macrae: We’ve manufactured their cells and they’re due for dosing later this quarter. Then, the third patient has already had their transplant, so we’re at the process of preparing the manufacturing and getting ready for giving them their cells back.
GEN Edge: How is the first patient doing? You only said there’s been nothing adverse.
Macrae: That’s all we can say at the moment. Our intention is to talk about the efficacy when we have data from three patients, and that will be in the first half of next year. This is the first time that a CAR Treg has been given, and one has to be grateful for the diligence of the investigators, and the courage of a patient that takes a first of anything. That nothing has happened is something that all of the Treg companies will be pleased about and allows us to advance the field.
GEN Edge: What has Sangamo learned about TX200 so far?
Macrae: It’s been in one patient and has been well tolerated. Coming from the pharma world where you did studies in hundreds if not thousands of patients. It has been a real learning, the importance one puts on individual patients in rare diseases or in cutting edge therapies. I’m always hesitant to say too much about the results from one patient.
GEN Edge: Given the challenge of not having a larger field of patients, what extra care is taken to make sure you have the right patients?
Macrae: That’s a good question. We are lucky to have a passionate group of investigators that want something new for transplant patients. They feel that it’s been a while since anything significant has been developed in that area. They saw encouraging results from polyclonal Treg studies, and we’re very excited to do the first ever CAR Treg study in renal transplant.
When one does a study like this, you spend a lot of time taking advice from experts. You depend on internal science. Megan Levings [PhD, of BC Children’s Hospital Research Institute] is a scientific advisor. She has done much of the research that that led to this study. There are interactions with the regulators, where we learn something every time we talk with them.
Then putting the patient at the center of the conversation, this is something that you have to build a culture in a company to make sure that one takes one’s time, one is prudent, and you choose the right patient focused on the patient, not on the clamor to get things moving quicker.
GEN Edge: Anything you can share at this point on the patient’s age or gender?
Macrae: The patient is male.
GEN Edge: How soon will Sangamo release data from the STEADFAST trial?
Macrae: We plan to provide further updates once we have a meaningful package of data to disclose from our first complete cohort. Of course, if anything untoward happens, we’ll let people know, but we will not announce patient-by-patient dosing. We will just update you at each of the quarterly calls.
GEN Edge: What makes Tregs an ideal target?
Macrae: For years, they’ve been talked of as potentially controlling autoimmune disease in humans. T effector cells have been engineered now for cancer, and the CD19 T effectors look great, and we made a decision to partner our oncology opportunity with Kite.
When we looked around for the next cell that we felt would be engineerable and eventually become a medicine, the Tregs seemed the next place to go. It has been fascinating: We did this at the end of 2018, and there are now 15 Treg companies, of which we count nine as doing things that are analogous with Tregs. They’ve attracted a lot of funding and great scientists. Some of the scientists working are real gods of immunology! I feel that we were ahead of our time, and we’re reassured that many others see the same excitement in Tregs that we do.
GEN Edge: Of these companies, which focus on renal transplants?
Macrae: None that I’m aware of. There’s one company called Quell [Therapeutics], which is doing something very similar to us, except they’re going for liver transplant.
GEN Edge: TX200 is part of Sangamo’s CAR Treg cell therapy platform. There are five preclinical cell therapy programs: The inflammatory bowel disease, multiple sclerosis and renal transplant programs are wholly owned. How are those progressing?
Macrae: They’re progressing well. We reviewed the science on them recently, and it’s all looking good. The CAR Tregs for each of the new programs are doing exactly what we expect them to do and it’s just a matter of creating an IND that will take time to do. We look forward to saying more about these in the future.
GEN Edge: Sangamo’s other cell therapy candidate, BIVV003, was previously co-developed with Sanofi through a collaboration that has ended. What has happened since then?
Macrae: The collaboration was ended in December. Then, there was a six-month transition phase where [Sanofi] supported it. When you talk with the people at Sanofi, the team themselves, are very disappointed that this has stopped, and very passionate about it. So, we’ve had a great deal of help from the team to transition. The transition was completed at the end of June, and we are looking forward to seeing patients with the new process that Sanofi helped create. We’ll talk more about this at the turn of the year.
GEN Edge: Sangamo has discussed dosing eight patients under the old method and four patients with the new process.
Macrae: It’s up to eight, and it will just depend on the timing and comparing those results in our plans for Phase III.
GEN Edge: When is the additional data expected?
Macrae: We will continue to show data from our currently dosed patients this year. As for the new patients, they’re more likely to be informative at the beginning of next year.
GEN Edge: Sangamo’s gene therapy candidates include a wholly owned Fabry disease candidate, and a hemophilia A candidate whose development is now overseen by Pfizer. What is the status of those programs?
Macrae: Pfizer is guiding that they will restart the Phase III AFFINE trial (NCT04370054), so they’re going through that process. We’re very pleased with what we see from Pfizer.
And our Fabry study is looking great. We have now dosed nine patients, and we will show the results of that at an upcoming medical meeting. The patients are doing well, and up to this point, we’ve told the world that we have two patients that have withdrawn from ERT [enzyme replacement therapy], and don’t have any requirement to go back on it.
What pleases us greatly about that trial is the patients are feeling better. At least half of them were already on ERT. Despite that, when they got the gene therapy, they felt better. They sweated. Their cardiac function stabilized suggesting that the chronic production of alpha-GAL from the gene therapy is giving them something that the intermittent bolus of ERT was unable to do.
So we’re very pleased with the study. We have got patients queuing up to be dosed and we expect to dose more, soon. We have line of sight for the expansion cohorts, including women, which will be the first time a female Fabry patient will have been dosed with a gene therapy.
GEN Edge: How many patients will you have for the Fabry disease trial?
Macrae: That’s an open number. We’re now in our fourth cohort, and the plan for each cohort is to dose two patients. But in each cohort, you’re allowed then to add an extra two if you want more information, including patients that have or have not got neutralizing antibodies to alpha-GAL. So, we’ve dosed three in cohort three, and two in cohort four. Then, there’s another two patients coming up that we’ll slot into the appropriate cohort.
After that we can dose, I believe it’s six in each expansion cohort. For example, females will be an expansion cohort. Cardiovascular patients, an expansion cohort. I think the third one is renal. We can find patients with a particular type of disease and get more information. Now, that has to be balanced to starting the Phase III, which is a very formal thing that you have to start that just takes time to get going.
We will be filling these expansion cohorts while we get the Phase III going, with the intention of switching all our efforts and patients into the Phase III as soon as possible— next year.
GEN Edge: Sangamo is also building a pipeline of neurology treatments based on its zinc finger genome engineering platform. How far along is that portfolio?
Macrae: We have four wholly owned programs that are advancing and looking good. In addition, we are doing a lot of work in capsid evolution, because that will be the secret to CNS. It’s having adeno-associated viruses (AAVs) that could either be given intrathecally or intravenously and address a range of neurological diseases that are just waiting for someone to crack delivery. We and others are almost there, and it will be great to have that opportunity to use our technology in the brain.
GEN Edge: There’s the challenge of size in getting cargo into an AAV. How much of a problem has that been?
Macrae: It isn’t a problem for us, because zinc fingers are much, much smaller than CRISPR. They’re one-eighth to one-tenth the size, depending on what CRISPR you compare it to. We can easily package the zinc finger repressors and enhancers into an AAV. The poster child for the size problem is hemophilia A, because even the sub-portion that is used is right at the limits of what the AAV can carry.
Now, there are newer CRISPRs appearing. We count 27 CRISPR companies. … I’m not sure that each of these companies have all that they need, whereas with the zinc fingers, we have the central core zinc finger technology, which is a bit that localizes you to any nucleotide in the genome. Added to that, we’ve got nucleases, repressors, enhancers, and base editors, and we can apply the right tool from our toolbox to the problem.
I would argue that there are some CRISPR companies with spanners [spanner wrenches] and there are some with screwdrivers and there’s some with hammers. And the ones with hammers are trying to find nails, whereas we have whatever tool we need in our toolbox to be able to address the problem.