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RheumaGen’s CEO discusses the company’s work editing HLA alleles.
Richard Freed
CEO
RheumaGen
Pharmaceutical Executive recently spoke with RheumaGen CEO Richard Freed about his career and the work the biotech is doing to find cures for autoimmune diseases.
Pharmaceutical Executive: Can you discuss the inception of RheumaGen and where the company is headed?
Richard Freed: RheumaGen started engineering a cure for autoimmune diseases in 2018. Prior to that, I was with the DuPont Company for 10 years mostly working in its industrial biotech space to help scientists scale up their inventions. I was working on editing yeast cells before the days of CRISPR to create new types of biofuels and biomaterials.
We were very close to completing that project and then oil prices went to $20 a barrel. I love biotech and helping scientists, so I moved into the DuPont VC group, which led me to a consulting group trying to open healthcare consulting. I moved to Denver for that and to reconnect with my uncle, Dr. Brian Freed. He is a professor of immunology at the University of Colorado, where he started ClinImmune: The Center for Clinical Immunology about 25 years ago.
The center is part of the University and essentially does the HLA testing for organ transplants that happen at hospitals across the country and developed the second cell therapy ever approved by FDA. They also ensure histocompatibility of hematopoietic-stem-cell transplants for cancer patients.
The researchers at the center used their knowledge of HLA, histocompatibility, and stem cells to discover that they could edit HLA to potentially create cures for autoimmune diseases. One thing led to another, and I decided to quit my job and go down this journey with them. That was in 2018, and then we got our seed funding by November 2019, which took us all the way through our Series A, which we announced early this year.
PE: Can you discuss the decisions that shaped your autoimmune disease pipeline?
Freed: Well, there are 10s of 1000s of HLA alleles out there. Each one of us has 10-14 alleles that express HLA molecules which sit on the surface of our immune cells, and they present foreign peptides to T cells. When you have an autoimmune disease, these HLA molecules and immune cells mistakenly present self-peptides. The researchers at the center investigated why some people are highly susceptible while other people are highly resistant to autoimmunity. Essentially, we developed a technology in which we make one nucleotide change to have your HLA mirror that resistant profile, while leaving a healthy immune system intact. It's resistant because it just can't physically bind to the autoantigens in question.
For each of our indications––rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), and others––it was going to be a somewhat similar but a technically different approach. However, in the last six-to-seven months, we have found a potential universal target. Just by editing this one position, which is common across nearly all humans, it turns off the alleles’ ability to present self-proteins, and it's the same target across our entire pipeline.
At present, we’re still conducting our IND-enabling studies for RG0401, our lead therapy designed to treat refractory RA. We plan to run our RG0401 Phase I safety trial, and then we would likely move to RG0401 Phase II, which will focus on testing efficacy. Because RG0401’s gene-editing target is shared across our entire pipeline, Phase I data will enable multiple Phase 2-ready assets.
PE: What's the presumed timeline for the IND enabling?
Freed: We expect to submit our IND to the FDA next year, with the goal of enrolling our first patient in early 2027.
We have a wholly owned subsidiary in Australia where we’ll be running the Phase I clinical trial. Australia has become a popular destination for first-in-human studies due to its generous R&D tax credit incentive, but we’re also excited that Australia has provided us with access to valuable KOLs whom we’ve successfully recruited. For example, one of our Australian directors is a former managing director and president of Janssen Pharmaceuticals for Australia and Japan, respectively.
PE: Has the preclinical proof of concept work been completed on RheumaGen’s secondary indications of multiple sclerosis and type 1 diabetes?
Freed: In those areas, we've done peptide-binding research, so the next piece is testing in animal models. The mouse models for MS and T1D are robust and well accepted. We will replicate the human HLA in the mice, and then we will test whether HLA gene editing will alter their disease state. We will also test whether tolerance is transferable among the mice. No system is perfect, but this is the gold standard for preclinical data.
PE: How did you land on the IP around this technology?
Freed: It’s been well known for years that certain HLA alleles are highly susceptible to certain autoimmune diseases, while other alleles are highly protective––but nobody understood why.So, Dr. Freed and his team set out to understand the underlying differences between those alleles and what made them act that way. To do so, they needed to develop a new way to isolate and test individual HLA alleles one at a time, compared to the standard method of testing all a patient’s alleles at once. In addition to their molecular engineering, the team also developed a bioinformatics program to help identify key amino acid differences to change someone from a highly susceptible profile to a resistant one. In the years since our initial discoveries, we have further developed the technology to find a single HLA gene-editing target that is shared across all our indications.
That said, the big leap of faith originally was believing that it might even be possible to edit a patient’s HLA gene to engineer a cure for their autoimmune disease. It's long been assumed that what we're doing is impossible. Here we are, over 10 years after the advent of CRISPR, and no one else has tried to edit HLA. That’s because, if there's any difference in your HLA, it's going to be rejected in a way similar to what would happen if you tried to transplant a mismatched kidney.
However, if you look at the crystalline models of an HLA molecule, it looks like a taco or a pita pocket, with a deep groove in the middle where peptides bind. If we were to change one of the amino acids protruding on the surface, that would be noticed by T cells and rejected. However, we hypothesized that if we made a single change deep inside the peptide-binding groove, well hidden from any interactions with T cells, it could go unnoticed by T cells and not be rejected by the body.
Then came one of our bet-the-company experiments in which we conducted skin grafts on RG0401 mice to test whether our HLA gene-editing target, with a single amino acid change, would be rejected. Thankfully, it worked perfectly, and we saw neither acute nor chronic rejection of these grafts in the mice. This opened a door to tremendous possibilities for HLA gene editing.
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