The field of human genetics is discovering disease-causing mutations at a rapid pace. These mutations drive thousands of rare, debilitating and fatal disorders. While some treatments are available to address symptoms, or slow the progression of genetic diseases, treatments that directly address the causative genes are needed to develop cures for patients.
Precise genomic correction of pathogenic mutations is of course an attractive therapeutic strategy. The emergence of CRISPR and newer forms of genome editing such as base editing are showing considerable promise in preclinical models and in early clinical trials. The ultimate goal of genetic medicine is to precisely and efficiently edit the human genome to correct somatic mutations or insert therapeutic sequences at targeted chromosomal locations.
Homology Medicines (Nasdaq: FIXX) is a clinical-stage genetic medicines company dedicated to helping patients suffering from rare genetic diseases with significant unmet medical needs by curing the underlying cause of the disease. Homology’s proprietary platform, which does not involve CRISPR, is designed to precisely and efficiently deliver genetic medicines in patients, either through a gene therapy or nuclease-free gene editing approach.
Homology’s gene editing construct enables the specific alignment to the desired genomic location and then, through the natural process of homologous recombination, correction of the diseased gene in the genome by replacement with a whole functional copy. The firm’s gene therapy construct includes a functional copy of the target gene and a promotor sequence that is designed to enable the gene to be turned on in the cell and ultimately transcribed to express a therapeutic protein without integrating into the genome.
This technology platform is based on the pioneering research of one of Homology Medicine’s founders, Saswati Chatterjee, PhD, professor of virology at the Beckman Research Institute at the City of Hope in California. Chatterjee and her team led the first adeno-associated virus (AAV) vector-mediated gene transfer studies into human hematopoietic stem cells (HSCs) and subsequently identified and isolated a series of naturally-occurring AAV vectors from human CD34+ cells (AAVHSCs).
GEN Edge sat down with Arthur Tzianabos, PhD, president and CEO, to discuss Homology Medicines’ approach to building a successful business around genetic medicines for a wide range of rare diseases.
GEN Edge: What were the company’s founding vision and mission?
Arthur Tzianabos, PhD: About five years ago, myself and our chief scientific officer, Albert Seymour, spent a lot of time together at Shire at the human genetic therapies division prior to the acquisition by Takeda. We had a hand in developing a number of programs that were enzyme replacement therapy chronic treatments to help patients suffering from rare genetic disorders. We had a lot of success in getting products launched that are still helping patients today. We’re both scientists by training.
But my passion and Albert’s passion has always been trying to get to a place where we can translate cutting-edge science into very important, meaningful, and transformational treatments for patients. With Homology Medicines, we can extend that to cures. The big vision for us is to have the ability to use a technology platform to cure genetic diseases that we’re targeting.
The company has a very strong sense of mission and culture. These folks are very talented, and we really like working with each other, which is one of the few times I’ve been able to say that in my career. The last five years have been awesome. The platform is just so powerful with vectors that already have been shown to be safe and effective.
GEN Edge: What is the rationale behind the diseases you have chosen to target?
Tzianabos: We chose diseases where there’s a huge unmet medical need. If you look at our pipeline, all those diseases need something. These patients are still largely untreated with any therapy at all. We also look to make sure that the approach that we’re bringing could potentially cure these patients as well as well.
If I take a disease like phenylketonuria (PKU), which has been recognized for almost 60 years on the newborn screening panel, that disease has a couple of drugs out there, but they really don’t address the underlying cause of the disease. Being able to put back the gene that these patients are missing, to be able to restore that biochemical pathway and prevent the IQ loss, executive function disorder, and the neurotoxicity that happens in that disease, those are really the multiple reasons why we selected PKU.
Our pipeline is pretty robust and covers different therapeutic areas. We’re always looking at new ways to apply this platform and family of vectors that we have access to, which is turning out to be very safe in people and very effective at delivering genes. While we still have a lot to do on the existing programs, we’re always bringing new discovery ideas forward, assessing them, and then figuring out whether they’re going to be able to make it to the clinic or not.
We’re one of the few companies are really addressing PKU from the actual cause of the disease. We’re actually replacing the enzyme and the gene for that enzyme back into the liver.
GEN Edge: How has a patient advocacy division helped the company, and has the therapy modality been an obstacle your patients, investors, or the FDA?
Tzianabos: It’s actually really helpful. We all have learned over the last 20 years working in this space that you absolutely need patient advocacy groups to be aligned with what you’re doing. For PKU, there’s the National PKU Association. They are extremely helpful, and we go to them quite often for advice, particularly when we’re talking about our protocol for our gene therapy trial. The patients and families are very excited about the prospect of a one-and-done potential cure.
The same goes for Hunter syndrome. We know there are multiple patients’ advocacy groups that we know well. We have a long-standing relationship with the Hunter community, the parents and their children. They’re very excited about what we’re doing. The idea of trying to get beyond a treatment that really doesn’t change the trajectory of a patient’s survival is really exciting to them.
The FDA goes up and down in terms of how flexible they are. Our interactions with FDA have been terrific. They’re very supportive of gene therapy. Everybody’s pulling on the same rope right now—the patients, the families, and the FDA.
GEN Edge: How is Homology Medicine’s pipeline structured?
Tzianabos: We are a fully integrated company. We have a great R&D team headed up by Albert, but we also have an outstanding internal manufacturing team. We made that investment almost three years ago. We wanted to make sure we had full control of that because manufacturing is so critical in making biologics. If you’re having to depend on CDMOs to make your material, you lose a lot of control over timing. Timelines are everything in this business as well as quality. That’s something that we will never take a shortcut on. We already have a commercial organization here, even though we’re still a clinical stage company. We plan on developing and commercializing our treatments here going forward.
GEN Edge: Why did Homology Medicines become a publicly traded company, and how has that affected the company?
Tzianabos: In order to compete and build everything that we built, you need access to capital. It is hard as a private company to get that access and stay private. We made that move as a preclinical company in 2018. That’s proven to be a good decision on our part. It occupies a lot of my time, communicating with investors and with analysts. But that’s part of the necessary things you need to do to keep the company moving forward.
GEN Edge: What are the major obstacles for the company?
Tzianabos: This is a hard business. We’ve experienced a lot of wins, but we’ve also had some losses. Manufacturing is typically a challenge for gene and cell therapy. I’m on the executive committee of the Alliance for Regenerative Medicine, a consortium of over 100 companies, and you always hear that manufacturing is the major hurdle. Thankfully, we’ve already addressed that.
It’s such a competitive space right now that people are probably the hardest thing to come by—making sure your talent stays with you because there are so many companies that are starting off, particularly in the Cambridge, MA area.
That can be a real drag on your company trajectory if you don’t stay ahead of it. I’m a big believer in people come first, our employees come first. We treat our folks very well. We want to develop their careers here. We’ve had an excellent retention rate, and we’ve been able to attract a lot of talent in the meantime. I see and hear in the industry that this is going to be one of the biggest challenges going forward over the next 5–10 years. There are not enough scientifically trained people coming out of academia with the experience to fill what is a burgeoning industry. That’s something that we’ve definitely prioritized and are moving forward on.
GEN Edge: How does Homology view collaborations with academia?
Tzianabos: I view collaboration as extremely important for us to continue to build and develop the company as well as these treatments on a number of levels. Having spent 15 years in academia and now 15 years in industry, I’ve got a pretty good sense of how to leverage the academic side. We have some key collaborations where they’re working on new ideas using our platform. We also have industry collaborations. We’ve had a relationship with Novartis as well as Pfizer. We’re working on underserved programs with them as well.
One of the coolest things is that there’s probably a call every couple of weeks from a parent who discovered their child has a rare genetic disorder. They’re asking if I’m working on this specific rare genetic disease. Typically, these are diseases where there’s probably 20 patients in the world that have been diagnosed.
One example is we’ve been guiding a particular family from Canada in the Ottawa with a very rare disorder. We told them that they need to start an advocacy group and get attention and draw families in with the same experience. Then they’ll be able to find an academic researcher or author who will develop an animal model with that specific mutation. Then we have to test whether or not putting that gene back in is going to work in the animal model. Somebody developed a model for this family in Canada in Ottawa, and we are shipping our vectors up to them with the gene in it. They’re doing those tests right now.
We’ve got several of those going on as well. It’s just an amazing field because everybody knows everybody else in the rare disease business. I will put them in touch with multiple people in my network to make sure that these families have some sort of hope. Unfortunately, a lot of these parents come to realize that a treatment isn’t going to happen in their child’s lifetime, but it’s enough for them to know that what they’re doing could help save future patients that get diagnosed with this disease. It makes it feel like we’re doing something. We relay this to the company all the time that we have this power. It’s almost like a superpower that we have, this technology and this capability. Let’s use it and help everybody we can.
GEN Edge: How profitable is it to go after rare diseases?
Tzianabos: The business reality is that you’re not ever going to be able to commercialize all these drugs for rare disorders. However, we have enough resources and enough contacts in the industry where you can cobble together a research plan where you can get some answers as to whether or not something’s going to work. It doesn’t take a lot of resources for us to make a vector with a gene in it and send it to an academic who’s working on behalf of a small patient advocacy group with a small group of families. That’s our way of giving back.
There’s a lot of cultural benefit that comes along with a company like ours, where people feel very vested and in that kind of mission. One of the reasons our folks stay here is because they know that we really have a lot of compassion and passion for what we’re doing. I often say to the company, you should consider this as the most noble thing you’re doing in your life. It’s a privilege to have the ability, resources, and capability to take these kinds of things on. I think people really resonate around that message.