Good morning, everyone. For today's our first session, we have Spero Therapeutics, and on the stage with me is Esther Rajavelu, the CEO of Spero. Thanks for coming, Esther.
Thank you for having us.
Absolutely. We have about 15 minutes or so. Let's just jump right into it. Maybe you can start with an introduction, overview of Spero today. You've made some changes, right? Repositioned the company around SP001, the immunology story. Just walk us through what happened, and how did you go about this, and what are your next 12 months going to look like?
Sure. Thank you. Before I answer that question, I'll just refer you to our forward-looking statements, which you can find in our corporate deck. But really, Spero today, we are a development stage company, and we've always been a development stage company. Our lead asset, as you say, is SP001, which is an anti-CD40 ligand targeting antibody. It's a third-gen antibody, and we can get into why that's relevant. We're planning a phase II trial in immunoglobulin G4-related disease, planning to initiate that trial in the second quarter of 2027. Having gotten our first drug approved and out-licensed to GSK for commercialization. Also, we've also fundraised about $105 million in a non-dilutive, non-recourse partial monetization off those commercial milestones. We feel we're in a very good position to bring this new asset in and continue developing.
Perfect. Why lead with IgG4-RD, right? Because you have Sjögren's data. How did you pick IgG4-RD? Sjögren's is a bigger market size than IgG4-RD, so walk us through that rationale.
Sure. We find IgG4-RD to be a very compelling development opportunity. It is an indication that's fairly early in its life cycle. We think that the unmet need and the potential for a differentiated mechanism would be highly relevant to this treatment paradigm. Because, as you know, this indication, the first drug was approved just last year, and there are the other agents, the couple of other agents that are in development all focus on B cells, and we're moving upstream of that, targeting the CD40 ligand, and we think that potentially has the ability to cover aspects of the disease that are not appropriately being addressed by B cell targeting agents. Sjögren's is also highly attractive to us. Obviously, there is no approved therapy, especially in the West, for that indication.
Our partner, Innovent, is guided to initiating a phase II trial in Sjögren's by early 2027. The evidence for SP001 in Sjögren's will continue to evolve as we make progress in IgG4-RD.
Perfect. You mentioned Innovent, so you got the asset from Innovent. What did your diligence focus on? What was convincing before you got on board?
Sure. Being a clinical stage company, our sort of search parameters were focused on validated targets or targets that at least had partial validation in the clinic. We were looking for molecules that had the potential to differentiate relative to other agents that are in development. The third aspect was really being able to differentiate with that target in evolving markets across different therapeutic areas. We were able to hit all of those with the CD40 ligand antibody that we in-licensed. As is typical in any BD process, we checked all the boxes. We looked at non-clinical and clinical data, IP, the regulatory interactions that Innovent had had, CMC quality. Very typical of a process like this.
Okay, perfect. The first-gen CD40 antibodies had problems with thrombosis, mainly driven by Fc binding to Fc gamma RIIa on platelets. How is your silencing going to address that, and how confident are you? What evidence did you see that that would be addressed?
Yeah. The history of the target was something that we spent a lot of time thinking about. The first-gen molecules, the first-gen antibodies had an active Fc region, which led to the thrombotic events that we saw in the first trials that were ran, I believe, in lupus. SP001 has a fully silent Fc region, and the antibody has been tested in two healthy volunteer trials in phase I, as well as a phase Ib Sjögren's trial. In approximately 100 plus human subjects that have been tested, we haven't seen any evidence of thrombotic events. Obviously, safety is something that we will continue to monitor very closely and will be a focus for our trials going forward.
Okay, perfect. CD40L is upstream of both T and B cells, right? The goal is to address fibrosis and not just flares. What evidence supports that? How are you going to measure that in the clinic?
Yeah. The phase II that we are planning to run in IgG4-RD will generate the evidence based on some of the data points that we are planning to collect in that trial. Really the onus is on us to provide the evidence on the role of T cells in IgG4-RD. There are some publications that discuss it, but for this particular antibody, our phase II would be very relevant. There is evidence that T cells play a role in the pathophysiology of IgG4-RD, and CD40 ligand sits upstream, and it is an upstream mediator of both the innate and the adaptive immune responses. We think both aspects of those immune responses play a role in the steady state of four IgG4-RD patients.
Our objective is to gather data points in the phase II trial that would really help us characterize the benefits of targeting CD40 ligand for this population, and that could include impact on fibrosis.
Wonderful. Okay, let us talk a little bit about the actual data itself. Maybe start with the mouse model. Your 1 mg/kg suppressed anti-KLH response more than rituximab, right? How is that preclinical potency going to translate to human dosing? What studies have you done to check for translation? Then maybe you can put the phase Ib data into context as well. Is the cross-trial comparison relevant, small n sizes, that sort of thing, on ESSDAI and the placebo-adjusted changes, et cetera?
Yeah. I would not really look for translation directly from the mouse model dosing into human clinical trials. What the in vivo mouse model data really demonstrates the antibody's biological activity, and we would have to rely on the full database of human trials and the data that Innovent has generated to really think through dosing for IgG4-RD. With regards to the phase Ib Sjögren's trial that was done, and I think you are referring to one of the slides in our deck-
that does a cross-trial comparison. I would view that data set as contextualizing versus really making a head-to-head comparison with those trials. Obviously, these were different trials run in different patient demographics across different geographies. But what really excited us was even though the phase Ib was a very small trial with three doses across three cohorts, with eight active and two placebo patients, so a very small data set. Even within a small treatment duration of four months versus six months with the other agents,
Right.
we saw evidence of activity across all the doses. That supports continued investment in that antibody.
Yeah. Not much weight on the cross-trial comparison, but what does that tell us about dose response? How are you picking doses, et cetera?
Yeah. The data set that we have includes the two phase I healthy volunteer trials where both PK/PD were assessed, and then the phase Ib Sjögren's. We would have to look at that entire totality of the data, look at PK/PD as well as the safety and tolerability data across all those trials to really determine a dose to move forward. The phase II trial that we are planning to initiate will have two doses for IgG4-RD, and those data will also continue to inform us about the appropriate dose in a registrational trial.
Okay, perfect. Put the safety data in context, especially the upper respiratory infections. Is this something you are watching for, and what should the FDA see before you start dosing in the IgG4-RD indication?
Sure. As with any immunomodulatory agent, monitoring for risk of infections, and tolerability, and safety is going to be fundamental, and our phase II trial will include the appropriate metrics to continue to inform us on the tolerability and the safety profile of the drug. I think your second part of the question was what would the FDA need to see?
Correct.
We believe the data package that we have from Innovent positions us well to initiate those conversations with the FDA, and the phase II trial design that we are contemplating is reflective of the other two phase II trials that were conducted in this indication.
Perfect. In the last five minutes or so, let's talk a little bit about differentiation and competition.
with what's out there, then wrap it up with the catalyst and cash runway. We have Uplizna, you have obexelimab, and rilzabrutinib all potentially could enter. Where do you fit in the treatment paradigm? Is it going to be after the B-cell therapy fails or more in terms of long-term maintenance? Frame that for us.
Yeah. It's a little early for us to really hone in on where in the treatment paradigm this asset would fit. What we're trying to do is really contribute to the understanding of this disease. As I said before, it's very early in its life cycle, and there is still a lot of information gathering that is happening. Our objective is to really differentiate with a new mechanism that focuses on the T- cells, B- cells, and the antigen-presenting cells, all of which play a role in the pathophysiology of IgG4-RD. Some of the other agents you mentioned focus primarily on B-cell targeting.
That, from the data that has been generated to date, provide compelling evidence on flare control. But we do think that IgG4-RD has other features, especially continuing tissue damage and fibrosis and prevention or preservation of organ damage. All of those things are important aspects of managing a patient that we think a differentiated mechanism could potentially address better than just controlling flares.
Got it. But on flares, specifically, are you trying to beat, for example, the 56% reduction that obexelimab showed and about, I think 87 or so that Uplizna showed? Is that the goal?
The B-cell targeting agents have done a fantastic job with managing flares, either controlling them. Our objective with the CD40 ligand as a target is to address broader aspects of the disease that are not appropriately addressed with just controlling flares. Some of the data that we are going to gather in our phase II trial should provide evidence to support that.
Okay. Perfect. Then in terms of the IV and the self-injection subcutaneous oral, how much of a hurdle do you think it is that you do not necessarily have subcutaneous because it is an IV drug, correct?
Yeah. The drug is currently formulated to be a once monthly IV dosing. IgG4-RD is a serious chronic condition, and paramount is safety and tolerability and the efficacy signals. So we are planning to initiate our phase II with the IV dosing to establish proof of concept. While there are advantages with coverage within IV therapy, we do think patient convenience is important and could potentially explore other delivery modalities as well.
Okay, awesome. In the last two minutes or so, maybe just walk us through your next catalyst that we should watch out for and what the cash position is and the runway would support.
Sure. When we announced the in-licensing in July, concurrent with that, we also announced $105 million non-dilutive, non-recourse financing through a partial monetization of the royalties from our commercial partner, GSK, for the first drug that was approved, Utebzi. That positions us to deliver data on the phase II for IgG4-RD. Our runway is into the second half of 2029, so we do have a comfortable cushion for that readout. Our next catalyst is really the launch of this phase II trial, which we have guided to in the second quarter of 2027.
Okay, awesome. I think we have time for that much, and we will leave it at that.
Great.
Thank you so much for coming.
Thank you so much. Thanks for having us.