Why Autoimmune CAR T Needs a New Patient-Centered Playbook with Dr. Panteli Theocharous

Erin, thank you for the time and thank you for the opportunity to kind of build on, you know, our very informative and productive conversation last time round and hopefully we can kind of build on some of those themes and domains from last time round. But again, really thank you for the opportunity to be here again.

Yeah, I think, you know, again, you know, Erin, as you'd mentioned, kind of just building on some of those themes. I think, you know, as I kind of draw on, you know, some of my, you know, very practical experiences, you know, in the field over the last, you know, 30 years or so. I think one of the central errors in my mind and in my experience is extrapolating the risk tolerance calculus almost from a relapsed refractory oncology directly onto autoimmune indications, I think, without almost kind of re-examining the underlying assumptions. And that's really, that's really critical because I think that as we understand this is a fast-moving landscape and as we get close to the first CAR-T approval, it's in an ALS indication, a severely disabling neuromuscular condition in which a registrational trial demonstrates or, you know, potentially demonstrating roughly 23% of mobility aid-dependent patients regaining unassisted mobility. Now that result, I think, really earns its place in kind of the history of the development of this type of modality, but I think at the same time it doesn't really establish the same benefit-risk threshold that applies once we move into lupus nephritis or generalized myasthenia gravis or in seropositive rheumatoid arthritis. I think these patients are frequently ambulatory, they're employed, they're maintained on a biologic or a B-cell depleting monoclonal, a calcineurin inhibitor or an oral immunosuppressant. So that's imperfect, but it preserves function and I think that's key. So I think the informed consent framework for that patient population cannot simply mirror the oncology framework in structure and in emphasis, and I think the comparator disease trajectory is fundamentally different. So that's where I think we need to do a good job in ensuring that our patient-facing materials have been recalculated to reflect that. And I think again that's just a reflection of the kind of the ongoing and the changing paradigm. I think second to that, and certainly again in my experience, is the conditioning regimen itself is, I would say, under genuine scientific pressure to change and programs are still anchored to fludarabine or cyclophosphamide as a lymphodepletion and there's a fixed assumption behind where biology is moving. So that's very meaningful in terms of early signal in lupus that adequate B-cell aplasia sufficient to permit a very durable clinical response may be achievable even without full myeloablative or lymphodepleting chemotherapy or conditioning. So if that holds across larger cohorts, it directly addresses, I think, what patients are consistently identifying as their principal concern. So it's not the CAR construct itself, but it's more to do with the toxicity and the hospitalization burden of the conditioning regimen preceding it. And I think that again is an area that we continuously need to focus on and evolve. And then I think lastly I would say that patients, as we also focused on the last podcast, they want an accurate account of what is established, what remains uncertain, and what could still change with the longer follow-up, not reassurance in place of specificity. So regulatory approval changes the evidentiary record, that's agreed, but it doesn't change the clinical obligation to communicate individualized risk honestly to the patient, and again, a central theme of our last conversation.

I think, you know, and again, it's, you know, it's a really another really, you know, relevant and important question. And I think that the comparator arm is determining variability. And in oncology, for example, the comparator is frequently progressive, ultimately a fatal disease. I think in autoimmune indications the comparator is a chronic but often adequately controlled standard of care, which means that our endpoint selection must really substantiate a materially higher bar in some ways. So what we're now seeing is meaningful proportions of treated lupus patients achieving DORIS-defined remission or complete renal response and discontinuing immunosuppressive therapy entirely, I think some tapering of corticosteroids in that process. So that's categorically different in value in terms of the proposition than a reduction in SLEDAI-2K score or an autoantibody titer alone. It's a patient exiting a decade-long, I would say, relationship with maintenance immunosuppression and it's the only class of evidence that actually justifies that clinical exit, so to speak. So trial design, I think, still underweights the comparator selection and functional and in patient-reported endpoints relative, I think, to serologic normalization. So what I'm trying to say is that from a biological perspective, you know, there is a little bit of a paradigm shift in that regard, and I say that from inside the process. So as I lead clinical strategy across a very broad portfolio of worldwide clinical trials, I think sponsors somewhat default to a, you know, to the biomarker because it's faster and it's less costly to collect, but it rarely, I think, constitutes the evidence that we're looking for and that I think persuades the audience whose judgment matters most, and that's the patient, the treating rheumatologist or neurologist, the payer, for example, that is going to be evaluating the health technology assessment submission. So again, it goes back to the fundamental where we have an obligation to power the trials and select the endpoints for that audience, not the ones that are operationally convenient to measure. So again, it's about raising that bar. I would, the other point I would certainly say to this particular question is on support infrastructure, and again, this kind of builds on that theme. So in oncology, for example, the nurse navigator model doesn't transfer intact, and what again, what I mean by that is we're looking for degrees of confidence and continuity. So in autoimmune, this population is disproportionately, I would say, in active employment or managing dependent care in ways an acutely ill oncology population frequently is not. So commercially, whichever program, I think, secures the first labeled autoimmune indication establishes the reference case against which every subsequent HTA submission and payer negotiation will be benchmarked. So I would say lastly that, you know, get that drug-free remission argument right in that first submission and then you set the evidentiary standard for the entire modality that follows. So again, we're looking at continuity, setting a bar that's very high, but reflecting the patient population of interest.

Yeah, you know, again, I think that, you know, as we sort of discussed, you know, last time round in terms of, you know, the patient journey, the patient experience, I think referral and screening remain in my mind the most underappreciated bottleneck. So rheumatology, neurology, nephrology have not built two decades of referral infrastructure with certified cell therapy centers that oncology has. So I think closing that gap is a shared obligation across sponsors, CROs such as Worldwide Clinical Trials, and referring physicians, and it requires deliberate investment in clinical education, not passive diffusion of awareness. I would say from a development perspective, the development I direct listeners to because I think it's the one most likely to sort of almost kind of restructure this entire bottleneck is in vivo CAR-T generation. So, and even more specifically, the shift toward things like circular RNA as the delivery payload. So just to kind of give, you know, I think the audience a little bit of a little bit of insight, and this is certainly very exciting from my perspective, but circular RNA lacks the free 5' and 3' ends that expose linear mRNA to exonuclease-mediated degradation. So that extends the functional scope or expression from a matter of hours to a matter of days within the target cell. And I think again, very exciting, you know, recent preclinical work has, I think, demonstrated substantially higher in vivo T-cell reprogramming efficiency with circ constructs compared with linear mRNA encoding a very identical CAR. So differences on the order of, I would say, tens of percent versus under 1% of the circulating T-cell compartment if you look at it in its entirety in that regard. So that's not an incremental improvement in transfection efficiency. I think it reflects a materially different PK and translational profile. So let's pair that payload with the delivery vehicle engineered for T-cell tropism, I would say. So a targeted lipid nanoparticle that's conjugated to a T-cell-directed antibody fragment, for instance, or an engineered lentiviral pseudotype, and you have a mechanism, I would say, that's then capable of eliminating leukapheresis and ex vivo manufacturing from the pathway altogether. And again, that's a paradigm shift. I think we need to be very cautious, methodical, thoughtful around some of the early non-human primate data, which has shown to some extent almost near-complete B-cell aplasia within a framework, a time window of around 24 hours of a single dose without chemotherapy preconditioning. So let's take a step back now. So if that translates faithfully into first-in-human and later-phase data, in my mind it collapses referral, apheresis, and bridging as bottlenecks almost simultaneously, because now there's no manufacturing slot to await and potentially no conditioning regimen to bridge at all. So I think again we're talking about paradigm shifts here in terms of technology and platform, but ultimately what this will mean for the, from a patient's perspective, and I want to be precise here in terms of the evidentiary maturity, because this is preclinical, it's very early, almost kind of investigator-driven clinical data, not an established treatment pathway. And in some ways, the transient, non-integrating nature of circRNA expression, whilst advantageous for safety, also raises some open questions about durability of response and redosing strategy that the field somewhat hasn't answered yet. But I think we're certainly moving in that direction. But it is, I think, in my opinion, the single development in this space that I would tell any biotech leadership team to be tracking most closely because it doesn't simply optimize the existing operational model. I think it helps to interrogate whether autologous ex vivo manufacturing remains the correct model at all for a subset of indications. And I think for the autologous programs advancing toward approval today, bridging remains, I think, genuinely difficult mechanistically, but maintaining background immunosuppression through the collection window, I think, risks compromising apheresis product quality, CD3-positive T-cell collection yield, whilst at the same time tapering risks a disease flare before the patient reaches manufacturing. So I think, you know, again, it's finding that very exquisite balance from a clinical, biological, practicality perspective. And I think lastly, I think long-term monitoring is where I remain most cautious. I think, you know, again, as we think about, you know, my experience in stem cell and bone marrow transplantation, as we were building long-term survivorship programs, I think multi-year follow-up is a standing regulatory expectation for gene-modified cell products, and the durability argument underpins the commercial case for this entire modality that depends on patients who are asymptomatic remaining engaged in almost kind of structured monitoring years after they've ceased to identify as patients. So I think we've got the ability to leverage technology and innovation as part of that longitudinal patient experience and journey, and I think we'll certainly see those types of solutions being integrated and adopted as part of that patient journey moving forward.