Dyne Therapeutics, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

The state of affairs are very good. It's a great time for Dyne. Really an exciting time, actually. Over the last probably year and a half, 2 years, we've spent time kind of building out a management team, leadership team, to prepare the company for the transition we're going through, which is to be prepared to launch two major drugs in two areas where there's very serious unmet need. Our first one is right around the corner with DMD. It is a phenomenal opportunity, with a drug called z-rostudirsen, and we have a PDUFA date in January. We're transitioning to a commercial company. We're executing well. Clinical execution has been very, very good. Regulatory execution, strong. We've got the team now to kind of commercialize a couple of products, and for a young company, it doesn't get any better than that.

I think it all kind of builds off of the platform that we have as a company, and you know about the platform, Eric, and that platform is very much based upon a delivery technology we call FORCE that gives us the ability to deliver oligonucleotides broadly and deeply to tissue, and I think in a way that exceeds what anybody has seen before, including to the CNS. That same platform is what we've used with two different types of oligonucleotides treating two different diseases. We're in a really unique position now, overcoming that kind of technical hurdle in the field, and I think it just hearkens to a bright future for nucleic acid medicines, and we're kind of in a leadership position there.

Well, I think we were surprised by that, just like most. I think that they had used a particular endpoint that they didn't meet as a phase III primary endpoint called VHOT, or video hand opening time for myotonia, and that's a very easy endpoint to move in that field. So we had expected them to meet that endpoint. We are using, as you know, VHOT as an intermediate clinical endpoint for an accelerated approval, very different kind of pathway, and only at 6 months. We can talk about some of the differences in approach with that. I don't have insights into what happened statistically for them.

I would come back to, and I think it's important to come back to, there are very significant differences between our molecule and the molecule you referenced, and it gets down to the fundamental science, and people are now starting to go back to that as you know. Our payload is a very different payload from the Avidity or Novartis molecule. They used an siRNA. We are using an ASO, and we intentionally used an ASO, an antisense oligonucleotide, to get to the nucleus, and this disease is ultimately a nuclear spliceopathy. So it very much is about getting sufficient drug to the target.

When we did our early work on our MAD study to pick the right dose to get to the nucleus and affect the disease broadly, including VHOT, we did a dose escalation study, and we saw that we had VHOT improvement at a very low dose. In other words, you need very little splicing correction to get there. We continued to evaluate splicing correction as we dose escalated and went all the way up to 6.8 mg, so a much higher dose than what we've seen with the competition, because we can. The Fab allows us to do that within a reasonable safety profile. One of the questions has been, in their early study in MARINA, at 2 mg/kg, they did not see much with VHOT. They went to 4 mg/kg, but dosing every 6 weeks. They saw VHOT improvement. I think now people are asking, well, when they went to the phase III HARBOR study, they extended the dosing frequency to Q8.

I think we do wonder whether or not they had enough payload really to get to the target, or were they on the edge? We don't believe we're anywhere near the edge when it comes to VHOT. We are far beyond where we need to be for VHOT, and in fact, we're at a dose that ultimately is allowing us to see potential CNS effect and other much more clinically meaningful measures associated with this disease.

The fundamental premise that this company was built on was that there are companies who are using monoclonal antibodies to target the transferrin receptor. Virtually everyone, including the Avidity molecule, would run into an issue where with monoclonal antibodies, you'd block that receptor for a month or more just based on the half-life of an antibody. We used an antibody fragment, just hit a particular epitope, and have a half-life of maybe 3 hours, so that the transferrin receptor could transport iron as normal. In other words, so we would not be limited in dose by anemia. That was the case, and we have continued. In fact, we weren't even limited at the 6.8. At the 1.8 mg per kg when we first started dosing in the mAb, we had some splicing correction, a little noisy, lower.

As we moved up to 5.4, we were getting in the 20% splicing correction range. Our belief was if you got to that kind of splicing correction, and without getting into too much of the molecular aspects, it would free up what was known as the MBNL protein that is bound up in the nucleus because of the disease, and that would allow for normal transcription, and you might start seeing all kinds of positive effects. The effects that we saw early on, even at 1.8, was VHOT improvement. That was easy. You need very little splicing correction to get that improvement. But we said, "That's not enough. We want to see improvement in five-times sit to stand, quantitative muscle testing.