Sangamo Therapeutics envisioned becoming a leader in chimeric antigen receptor-modified regulatory T-cell (CAR-Treg) therapies for solid organ transplants when it acquired TxCell in 2018 for €72 million ($78.5 million). Sangamo was particularly attracted by the lead candidate TX200, which showed potential to be the first CAR-Treg candidate to carry a solid organ transplant indication.
“We believe CAR-Treg therapies will prove to be as exciting for immunology as CAR-T has been for oncology,” Sangamo CEO Sandy Macrae, PhD, stated at the time.
This year, Sangamo begins to find out if that prediction will hold true, and thus whether the money it shelled out for TxCell was well spent.
The company has dosed the first patient in its Phase I/II STEADFAST trial (NCT04817774), a first-in-human study designed to assess its wholly-owned autologous CAR-Treg cell therapy TX200, a product candidate for the prevention of immune-mediated rejection in human leukocyte antigen A2 (HLA-A2) mismatched kidney transplantation from a living donor.
The trial’s primary endpoint is safety and tolerability of TX200 28 days after infusion. Key secondary endpoints include the effect of TX200 on acute graft-related outcomes and on long-term safety outcomes, as well as the pharmacodynamic and pharmacokinetic effects of TX200.
Macrae told GEN Edge that Sangamo plans to dose a total of nine patients—three cohorts of three patients each in the Phase I portion. The second patient is expected to be dosed by the middle of 2022.
Dosing of patients occurs several months after patient enrollment, as prior to dosing each patient needs to undergo leukapheresis to collect their white blood cells, after which their Treg cells are isolated, genetically engineered, then cryopreserved. The patient undergoes transplantation surgery to receive a kidney from a living donor. After recovery, the patient receives their personalized TX200.
Sangamo is not yet saying how soon it plans to release data from STEADFAST, though such guidance could come when the company releases first quarter results later this spring.
“We have line of sight on the next two patients for Cohort 1. Then we meet with an SMC [safety monitoring committee] to make sure that it’s safe,” Macrae told GEN Edge recently. “We would look to complete Cohort 1 this year and be moving into Cohort 2 around the turn of the year. But the most important thing is proving that this is safe.”
Through the entire open-label trial, Sangamo has said it plans to recruit 21 cell donors and 21 cell recipients. Of the recipients, 15 would receive TX200 and the other six, standard of care with no study drug administered. Sangamo is recruiting participants at multiple centers in Belgium, the Netherlands, and the United Kingdom.
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.
Hope, innovation, and challenge
“The hope is that CAR-Treg cell therapies reduce the need for lifelong immunosuppressive medications, which are known to have challenging side effects,” said Jan-Stephan Sanders, MD, PhD, of the University Medical Center Groningen in The Netherlands, investigator of the STEADFAST trial.
Those side effects include an increased risk of severe life-threatening infections, malignancies, cardiovascular disease, and drug-related toxicities such as nephrotoxicity.
Approximately 21-26% of transplanted kidneys are estimated to be HLA-A2 mismatched, according to studies cited by Sangamo published between 1985 and 2007. An estimated 46,000 renal transplants were carried out in the U.S. and European Union last year, according to data cited by the company from the International Registry in Organ Donation and Transplantation.
Investors appeared to share Sanders’ hope, at least initially. Sangamo’s shares jumped nearly 10% the day of the dosing announcement March 29, rising to $6.28 from $5.73 the previous trading day. The stock has since fallen to $5.40 at the close of trading Monday.
“The innovation here is that we would be restricting the immune regulation mediated by the Tregs exclusively to that transplant kidney, and the person’s immune system would be otherwise completely normal and be fully able to act to keep that person healthy by fighting whatever pathogens, they are exposed to,” Jason Fontenot, PhD, Sangamo senior vice president and chief scientific officer, told GEN Edge. “It’s a very fundamental change and a shift in the way things are treated.”
Macrae said the greatest challenge for the study “is the transplant, because you’ve got to have two operating theaters to remove and replace the kidney. We don’t want to interfere in that process, so it’s just the timing of the patient’s transplant that will give the cadence of the study.”
The first dosed patient in the STEADFAST trial received a low dose of TX200, with medium and high doses also planned for the study, Sangamo executives told Jefferies analyst Maury Raycroft, PhD, according to a research note he co-authored on April 4.
Two days later, the cell dosage range was disclosed in a commentary as between 104 and 109 cells/kg body weight. The maximum dose is much higher than other studies, with an average of only 0.5 -106 cells/kg having been tested previously.
“The STEADFAST trial is a first in nephrology and transplantation, testing the use of genetically modified cells as therapy. It’s an exciting era where we hope the revolution of treatment care will follow what happened in cancer,” Stanford University researchers Caroline Lamarche, MD, and Jonathan S. Maltzman, MD, PhD, commented April 6 in Kidney International Reports.
“Success of the STEADFAST study is pivotal for the future use of genetically engineered cells in nephrology and transplantation with several possible further.”
In February, Raycroft and colleagues wrote their belief that TX200 “is in the lead competitively” among CAR-Treg candidates under study for transplant indications.
At least one other company is working to apply CAR-Tregs toward transplantation: Quell Therapeutics, whose lead candidate QEL-001, an antigen-specific multi-modular CAR-Treg cell therapy designed to prevent organ rejection in liver transplant patients.
Like TX200, QEL-001 is designed to eliminate the need for lifelong immunosuppression by inducing durable immune tolerance through an HLA-A2 specific CAR. In November, Quell completed a $156 million oversubscribed Series B financing, whose proceeds are intended in part to fund the Phase I/II LIBERATE trial (NCT05234190), designed to assess the safety and tolerability of QEL-001 in preventing allograft rejection following immunosuppression withdrawal in liver transplantation.
The LIBERATE trial was recruiting patients as of February 22, the date of the most recent update on ClinicalTrials.gov.
Since last year, at least four early-stage Treg and CAR-T biotechs focused primarily outside of transplantation, have attracted more than $600 million in financing:
- Sonoma Biotherapeutics—$265 million oversubscribed Series B completed in August 2021, targeting severe autoimmune and inflammatory diseases—including refractory rheumatoid arthritis, the indication of one of its two lead programs, the CAR-Treg cell therapy SBT-77-7101.
- Gentibio—$157 million Series A also completed in August; autoimmune, alloimmune, autoinflammatory, and allergic diseases.
- Abata Therapeutics—launch in June 2021 with a $95 million Series A round; progressive multiple sclerosis and other severe autoimmune and inflammatory diseases.
- Kyverna Therapeutics–$85 million oversubscribed Series B completed in January. Kyverna plans to advance into the clinic later this year the autologous anti-CD19 CAR-T candidate KYV-101 for B cell-driven autoimmune diseases; and further develop its synReg T-cell platform, engineering a synthetic version of Tregs by reprogramming T cells into CAR Treg cells.
First in the pipeline
Macrae and Fontenot said Sangamo envisions TX200 as the first of several CAR-Treg cell therapies that the company eventually plans to develop. “The reason that we’re so excited about our regulatory T cell platform is because it has the potential to treat many different autoimmune and inflammatory diseases,” Fontenot told GEN Edge.
“If you look across the space and where Tregs have been shown to have some potential to work—either in animal models, or by looking at patients and looking for issues that Tregs should be able to influence—there are many other diseases: rheumatoid arthritis type 1 diabetes, lupus—lots of other opportunities to go into.”
While some of these diseases can be treated safely and effectively with drugs, others cannot—and most of those therapeutics present the risk of general immune suppression that leave the patients vulnerable to infections or other issues, Fontenot explained.
“What’s so exciting about our CAR-Treg program is that (1) we’re targeting the immune regulation to a very specific tissue where the problem is and leaving the rest of the immune system fully capable of dealing with infections or cancer,” Fontenot said. “And (2) we’re dealing with a living drug that can work in through multiple mechanisms and responds to the changing conditions in the patient in a way that we think will be a fundamentally different way of treating the disease and has the potential to put patients into permanent remission, and really be a long-term solution to some of these diseases.”
In addition to TX200, Sangamo has another clinical-phase cell therapy candidate, the zinc finger nuclease gene-edited SAR445136 for sickle cell disease, now being co-developed with Sanofi and under study in the Phase I/II PRECIZN-1 trial (NCT03653247).
Sanofi is ending its collaboration with Sangamo to develop SAR445136 as of June 28, citing a change in its cell therapy strategy to focus on allogeneic universal genomic medicine approaches rather than autologous personalized cell therapies. The cell therapy generated positive early results in three patients last year—data that persuaded a committee of the European Medicines Agency (EMA) to support an orphan designation for the drug candidate.
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 Sangamo preclinical cell therapy programs are cancer candidates being co-developed with Kite, A Gilead Company, through an up-to-$3.16 billion-plus collaboration launched by the companies in 2018. The first candidate developed by the companies is KITE-037, an allogeneic anti-CD19 CAR-T cell therapy. While Kite opted in May 2021 not to submit an investigational new drug application (IND) for KITE-037, “the development program for KITE-037 remains active,” Sangamo stated in its Form 10-K annual report for 2021, filed February 24.
The other Sangamo-Kite candidate is being developed for an undisclosed oncology indication.
“We have a relationship with Kite/Gilead to do oncology, and they’re driving ahead with those programs. But it’s the Tregs that we’re most excited about,” Macrae said. “We’re blessed with riches, and we’re blessed with a technology that we can apply to many things.”
Sangamo’s revenue from the Kite and Sanofi collaboration fell last year by a combined $5.4 million—one reason why Sangamo’s overall revenues slid 6% year-over-year, to $110.7 million from $118.2 million. A larger factor was $47.4 million milestone fees and recognition of upfront license fees related to Sangamo completing activities under collaboration agreements with Pfizer for two gene therapy candidates, the Sangamo-created hemophilia A candidate giroctocogene fitelparvovec (SB-525 or PF-07055480) and a gene therapy using zinc finger protein transcription factors (ZFP-TFs) to treat amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) linked to mutations of the C9ORF72 gene.
Sangamo finished last year with a consolidated net loss of $178.3 million, up from a $121.1 million net loss in 2020. As of December 31, 2021, Sangamo had $464.7 million in cash, cash equivalents, and marketable securities—down 33% from $692 million a year earlier.
“We currently believe that our available cash, cash equivalents, and marketable securities and expected revenues from collaborations, strategic partnerships and research grants, will be adequate to fund our currently planned operations through at least the next 12 months,” Sangamo stated in its Form 10-K.
But the company added: “We may elect to raise additional capital through additional collaborative agreements or the sale of additional equity to fund our future needs beyond the next 12 months.”
Retreat from gene therapy
Cell therapy is one of Sangamo’s three major treatment areas, along with genome engineering and gene therapy.
In recent years, Sangamo has focused on applying its zinc finger platform to create two types of genomic medicines. One is its ex vivo cell therapy application, namely its CAR-Tregs produced using ZF engineering to address immune-mediated diseases. The other is an in vivo genome engineering application consisting of its zinc fingers coupled with transcription factor domains to regulate gene expression in neurological diseases.
Sangamo continues to pivot away from gene therapy despite positive results reported in recent months for its programs in the space.
On February 7, Sangamo reported updated preliminary Phase I/II data for its wholly-owned Fabry disease gene therapy candidate isaralgagene civaparvovec. The data, from the Phase 1/2 STAAR trial (NCT04046224), showed that the four longest treated patients—two each in dose cohorts of 0.5e13 vg/kg and 1e13 vg/kg—continued to exhibit elevated alpha-galactosidase A (α-Gal A) activity that ranged from 3-fold to 15-fold above mean normal. Sangamo expects to report updated data in the second half of this year.
The other gene therapy in Sangamo’s pipeline is hemophilia A candidate giroctocogene fitelparvovec, whose development is now being led by Pfizer. In December 2021, Pfizer presented 104-week data at the 63rd American Society for Hematology annual meeting showing a mean factor VIII (FVIII) activity of 25.4% in the five patients in the highest dose cohort (3e13 vg/kg.
Their mean annualized bleeding rate (ABR) was 0.0 in the first year post-infusion and 1.4 throughout the total duration of follow-up as of the October 1, 2021 cutoff date. All bleeding events occurred after week 69 post-infusion. While two patients experienced bleeding events requiring treatment with exogenous Factor VIII, no participants in the highest dose cohort resumed prophylaxis.
“In the future, our focus will be on cell therapy, such as the CAR-Tregs and genomic engineering, such as the repressors that we are working on in CNS,” Macrae said. “So, gene therapy is a thing, for now, and for the past few years. And in the future it’s going to be editing. And that’s why, having an editing technology like we do gives us a unique advantage and drives us forward into the future.”