Autoimmune Innovation Merits a “Greater Sense of Urgency”
Shawn Rose is a rheumatologist and immunologist who has spent his entire professional life as a physician-scientist studying new approaches to treat autoimmune diseases and bring biomedical breakthroughs to patients.
This summer, he took on a new career challenge as Chief Medical Officer and Head of R&D for Nkarta, drawn to the historic opportunity to pioneer natural killer (NK) cell therapy as a potentially transformative new treatment option for severe autoimmune conditions.
Dr. Rose sat down for a Q&A to talk about why cell therapy excites him and why it’s critical that innovators and advocates work with federal regulators to create a sense of urgency to speed new breakthroughs to patients running out of options and out of time.
You bring a wealth of experience to your new role, having spent your entire professional life as a rheumatologist and an immunology drug developer. As the field of cell therapy pivots into autoimmunity, how do you see the unmet needs facing these patients?
Dr Rose: While many of the autoimmune diseases we treat are potentially rare, if you add them all together, there’s not a person in this country who doesn’t know somebody that’s been affected by autoimmune disease. It’s often a family member or a close friend. When you bucket all the rare autoimmune conditions together, they’re quite common. Here at Nkarta, we’re in some spaces like lupus where there is a higher frequency in the overall population, especially when you consider the skin form, cutaneous lupus erythematosus (CLE). There are almost as many patients with CLE as there are with systemic disease. We’re currently studying our therapy in patients with seven autoimmune conditions, including systemic lupus erythematosus and lupus nephritis. We’re also enrolling patients with myasthenia gravis, one of the most common autoimmune diseases. Then, of course, there are a great many rare autoimmune diseases where the standard of care is woefully inadequate like systemic sclerosis and vasculitis.
How does this impact society? The answer is quite a bit. Many of the patients we’re enrolling in our trials at Nkarta are quite ill and have failed many therapies already. If they don’t get an effective intervention, they will live difficult, shortened lives. If you have lupus, you could have heart attacks and strokes in your 20s and 30s or even younger than that if you have a pediatric form of the condition. If you have lupus nephritis and kidney disease, are on dialysis and unable to get a transplant, it is a disease with high morbidity and mortality. The same goes for some of the forms of primary membranous nephropathy, idiopathic inflammatory myopathy, and systemic sclerosis that we’re enrolling in our trials. I’ve cared for these patients. Sometimes, the diagnosis comes when they are in the ICU, when their life is literally slipping away. I’ve lost patients with these conditions as a rheumatologist; there was literally nothing we could do for them. That’s the kind of patient we’re working so hard to help. But even for those with milder forms of autoimmune disease, it’s not an easy road. The symptoms are very difficult and have a tremendous impact on their life, their families, and their communities. Autoimmune disease is also incredibly costly to care for and resource-intensive for the healthcare system.
How can we speed up the process of getting life-changing and live-saving treatments to patients living with advanced autoimmune disease?
There’s still a lot of patient advocacy work that must be done when it comes to cell therapies and other advanced new modalities. We can’t continue to treat these patients with a lack of respect. What do I mean by that? Many autoimmune patients are just as sick as people living with certain terminal cancers. Yet when you do clinical trials to treat terminal cancers, the regulatory process is super-fast and super-aggressive – and appropriately so. However, now that we’re studying cell therapy and other next-generation treatments for advanced autoimmune patients, there seems to be much less urgency by regulators. We need to help them understand that these are very sick people, and we have an opportunity to give them a better life. We’re trying to prevent death, organ damage and severe disability. We need to find a way to create a regulatory sense of urgency commensurate with the gravity of diseases we’re studying for which there are few, if any, viable long-term treatment options. Patients are waiting!
I’m incredibly appreciative of our colleagues in oncology and have developed drugs a few times in that arena, which is really gratifying. In rheumatology, we beg, borrow and steal from their innovative modalities. They’re the pioneers, and I’m forever grateful for this. But for those of us in other fields that see severe, serious patients, we’re always wondering, “Where’s our Moonshot?” When you get an autoimmune disease, it’s happening in your teens, 20s, 30s and 40s generally. So, these are young, productive people. It has a huge impact on society and on patients at a critical, formative period in their lives.
The European healthcare system seems to be ahead of the United States in prioritizing autoimmune patients for advance treatments such as cell therapies. Why is this?
Our healthcare system has certain limitations when it comes to delivering advanced therapies. I’ve seen this, and it’s heart wrenching. I’ve partnered with multiple gene therapy companies. We’d go and talk to providers at U.S. healthcare institutions who’ve got these pediatric and young adult patients with a short time to live. They want to treat them with a new gene therapy on the market or in a clinical trial, but they can’t. Part of it is cost, but the bigger part is that the institutions that deliver this advanced care are laser focused on oncology, and they don’t have as much focus on genetic and immune-mediated diseases. That’s a business decision and I understand it. However, it takes us as healers away from the mission of wanting to do more to treat the entire population of patients who have a desperate need. The answer is not to reduce the focus on oncology patients. It doesn’t have to be an either/or situation. We must find a way to do both in what are resource-constrained times for many hospitals and medical practices.
One of the advantages of the approach we’re taking at Nkarta with cell therapy is accessibility. If we can continue to demonstrate the safety of this platform, we have the advantage of potentially administering our treatment on an outpatient basis. That would be a big turning point. The FDA just made a huge announcement that they are lifting enhanced risk evaluation and mitigation strategies (REMS) on CAR-T therapies. This can open new doors for cell therapy at healthcare institutions throughout the country. This is a big deal, and we need to leverage that.
You have experience as a rheumatologist and immunologist treating and/or studying all seven of the autoimmune indications Nkarta is exploring as possible drug candidates for its NK cell therapy. Is there a story that can help people understand what it’s like having one of these advanced conditions?
If you’ve ever taken blood from a systemic sclerosis patient – and I have many times – it’s tough. There’s just so much scar tissue you’re trying to get through to get to a vein. God forbid you have to put in an arterial line. You got your ultrasound probe, but the vessel is a fraction of the size it should be, because it’s compressed by so much scar tissue. If Nkarta can prove safety and efficacy in this population, we could potentially offer a much gentler approach for systemic sclerosis patients. I think they would really appreciate it compared to sitting for hours in a leukapheresis chair, which is used to collect large volumes of blood cells for generating autologous CAR therapies. I’ve donated cells using this procedure before when I was a student. I wanted to know what it was like and wanted to give back to the medical and patient community. It was brutal! I sat in the chair for four long hours with these large-bore needles that hurt like hell, hooked up to this noisy, clanking machine watching the blood flowing through. It was a harrowing experience. We will have to wait to see what the data reveal about safety and efficacy of our drug candidate, but I think it’s a competitive advantage for Nkarta that our off-the-shelf allogeneic cell therapy doesn’t require leukapheresis and is a more patient-friendly approach.
Cell therapy developers have used the word “transformative” when talking about the potential impact this next-generation modality can have on the treatment of autoimmune disease. Can you elaborate on that?
What cell therapy developers, including Nkarta, are really aiming to do is “reset” the immune system, and I don’t use that word lightly. You’re actually eliminating the pathogenic cells. The hope would be that even people with some underlying predisposition toward developing these autoimmune diseases could benefit from a lifetime cure or a prolonged remission before a relapse. We haven’t clinically demonstrated we can do this yet at Nkarta in patients with severe autoimmune diseases, but that’s where we hope to be. I’ve seen this with stem cell transplants. I treated a number of patients who received stem cell transplantation back when I was a practicing rheumatologist at Northwestern University. We were the first center in the U.S. doing this in various autoimmune disease populations. It was really encouraging, because we saw some patients with no recurring disease for the entire length of time that we followed them – basically, durable remission. There were others where the disease came back, but it wasn’t nearly as bad as it was before the stem-cell treatment. They could at least live a more normal life with their condition in a manageable state. Either way, that’s transformative for those patients. They would have died within a few years without that intervention. To me, that’s what “transformative” looks like.
One last question: There’s been a discernible uptick in the number of people diagnosed with autoimmune conditions. Do we know what’s driving this scientifically?
It’s a bit of an unanswerable question, but I can speculate. Some of it is increased recognition. We’re just a lot better at diagnosing things. But I think another factor has to do with our globalized world and being exposed to new infectious agents that are triggers. When you come back to it: Why does the immune system exist? It’s not just about defending the body against infection or preventing cancer. It’s about counteracting anything foreign that enters the body. The immune system says, “Whoa, you shouldn’t be here.” So new pathogens are inviting an opportunity to trigger an immune response. We also have a lot of new triggers out there since our environment has changed so much; so many chemicals and new materials have been created. And there’s probably also an impact from dietary habits. We know that obesity makes autoimmunity worse. I used to study psoriatic disease quite a bit, and there’s a large body of evidence that suggests it’s both a metabolic and an inflammatory autoimmune disease. I’d see adolescent patients who would come in, and would often say, “Before I got my psoriasis or psoriatic arthritis, I actually started gaining a ton of weight.” This is very common in that population. So, there’s a clear intersection with certain immune-mediated diseases and metabolic dysfunction. I used to study that at NIH. So, all these terrible foods that are highly processed tend to be quite cheap, yet we make the healthier food super expensive. It begs the question: What are we doing?