Laura Chico: And then just beyond that, I guess, is to spreading just the primary criteria you’re going to be evaluating for advancement or kind of the threshold. And is there a specific degree or magnitude of effect that you’re kind of hoping to see? Thanks very much.
Dr. Al Sandrock: Well, we saw 70% — approximately 70% reduction in spreading from one hippocampus to the other side to the other hippocampus in our in our animal models. So we have that as sort of an animal experiment. But in terms of the human experiment, I mean I think right now, I’d be happy to see a statistically significant decrease in tau spreading as the first stage in a relatively small study. And then hopefully, by then, we will know the clinical significance of that. Somebody will likely have drawn the — figured out the relationship between tau spreading or tau reduction in a certain brain region and the clinical consequence of that. And so, in this way, actually, not being first can be helpful sometimes because we will learn from the people who have entered the clinic first.
Operator: Our next question coming from the line of Yanan Zhu with Wells Fargo.
Yanan Zhu: A couple questions on tau. And I too wanted to ask about the CTAD presentation for tau ASL. Al, I was wondering if you can share your assessment about the magnitude of the signal of benefit on cognitive function and also on the time point at which these signals were — was achieved or observed and whether these signals of benefit in your mind is consistent with more of a reduction of the tau in existing neurons that have these neurofibrillary tangles or could it be also consistent with the spreading during this time frame. I just want to understand a little better the contribution of those two separate compartments to this potential clinical benefit that was observed.
Dr. Al Sandrock: So, in terms of the magnitude, I think it’d be kind of premature to really understand. I don’t think we can fully understand the magnitude when you have 16 to 20 patients per group, right? It’s a very small sample size. So I think it’d be hard. Also, it’s a group that’s chosen. It’s the first foray into the choice of patients. So I think — so I would say that. And then there’s the matter of multiple different endpoints. The nice thing is that it was seen across several endpoints. So, there seems to be a high degree of consistency regardless of the endpoint. So, rather than focus on the magnitude, have been focusing more on the consistency of effect across multiple endpoints. With respect to the time point, it’s not uncommon that you would see an effect on tau — on PET imaging and then to have a sort of a delayed effect on the clinical outcomes.
I think this is something that we’ve seen kind of more than once in neurodegenerative disease that you get an effect on target engagement. We see an effect on target engagement and even pharmacodynamic effects, biological effects and then the clinical effects takes a little longer to see. And so, the fact that they had to wait, I believe, as much as two years to see some of the effect does not surprise me. In fact, that’s what you see with amyloid drugs too, that you can see an effect on amyloid PET imaging within 6 months. But it takes longer to see the clinical effect. And I would say you see something similar in ALS as well. In terms of your question, I think you hit on something that’s pretty darn interesting, which is that you see an actual reduction in the tau PET signal in neurons or at least in the regions.
And that’s a bit surprising to me because I always used to think of neurofibrillary tangles as pretty highly aggregated and the fact that you can actually reduce the tau PET signal, and the ligands are specific for aggregated misfolded forms of tau. So maybe that — maybe there’s more — maybe these neurofibrillary tangles are not quite as sort of end stage, if you will, and that there can be this reversible aggregation or it can be removed. It’s an intracellular tangle. So I don’t think it’s phagocytosis. It must be that these aggregates are more dynamic and perhaps reversible than we once thought. Then in terms of what causes the efficacy that you see, whether it’s the reduction in tau and cells, or is it a block of spreading, while both are being seen with BIIB080, so it’s hard for you to discern which it is — whether it’s the block of — interference with spreading or the actual reduction in cells, it could — it’s hard to discern which, based on the data, at least as far as I’m concerned, Todd, I don’t know whether you have any other thoughts on that.
Dr. Todd Carter: I think you’ve covered it. I think it’s — overall, it’s early data. I think it’s extremely exciting. We still have a lot to learn.
Yanan Zhu: Got it. Very helpful. And then, I was wondering, obviously, the SOD1 program will be the first gene therapy program, your internal program to enter the clinic, hopefully, in 2025. But I was also wondering for the tau silencing gene therapy program, how much of the component would need to be different. Obviously, the trigger sequence obviously is different. But I was wondering is there also differences in the capsid, for example, depending — due to the different cell type to be targeted. So, I’m just wondering how much can the tau gene silencing program leverage the first in clinic gene therapy SOD1 program.
Dr. Al Sandrock: So I’m not sure I fully understood your question, Yanan. But Todd, did you understand it because if you did, why don’t you go ahead.
Dr. Todd Carter: Yes. So I think the fundamental question is, can we take learnings from SOD1 to move forward quickly with the tau knockdown program. And I think the answer is it’s fundamentally yes, but there are different components. So there’s the capsid and then there’s the payload. We’re learning a lot about our novel capsids through our current programs. We’ll continue to learn about them as we move along. We may or may not select the same capsid for tau knockdown, say, as we do for the SOD1, but we might select the same capsid. It depends upon the particular characteristics. For something like SOD1, we know we want to get to the spinal cord, motorneurons and probably astrocytes in the spinal cord. And we want to get to motorneurons and the brainstem and perhaps the cortex as well.
For tau, we want to get a broader delivery across cortex. The spinal cord is much less important for tau. But we are looking for different things from our capsids in that context. Just as an example, in terms of the payload, they are both vectorized siRNA payloads. We have a lot of experience with siRNA, vectorizing siRNA here at Voyager, and we’re certainly deleveraging that for tau knockdown as we are for the SOD1 program. Obviously, the sequences will be different because we’re targeting different genes. But in terms of off-target, et cetera, there are synergies and our knowledge base there. We can — we have the opportunity, just different kinds of promoters in terms of the different cell types you want to target. So the answer is, I think we will learn.
