Evaluating Kylo-11 for Long-Acting Lipoprotein(a) Suppression

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Dr. Steven Nissen:

I'm Dr. Steve Nissen, and I'm here with Dr. Ashish Sarraju. We're going to talk about a drug known as Kylo-11, which is a long-acting, very durable drug for lowering lipoprotein(a). Dr. Sarraju, tell us a little more about Kylo-11. It's not your usual siRNA, is it?

Dr. Ashish Sarraju:

No, no, it's not. Thank you for the nice introduction. Kylo-11 is an siRNA, or a small interfering RNA. As we all know, siRNAs, the way they work is essentially by suppressing the synthesis of whatever protein you're trying to target at the RNA level. When siRNAs are developed, you want to think of two things. You want to think of how effective they are and how long they're going to last to exert their effect. One way that stability can be achieved is by trying to make the structure itself more targeted to the liver, for example, where lipoprotein(a) is made, and more resistant to degradation. With that said, the way Kylo-11 differs from a lot of the other siRNAs is that it has four GalNAc particles, which are these particles that are attached to the siRNA to make it more selective for hepatocyte targeting and perhaps more resistant to degradation.

Dr. Steven Nissen:

Tell us a little more about GalNAc and how does it work? Why is GalNAc now being used in almost all these hepatically targeted siRNAs?

Dr. Ashish Sarraju:

Yeah, it's a great question. It's this essentially molecular structure that is selective for a specific receptor called the ASPGR receptor that sits on hepatocytes. The idea is that it's selectively targeted to the hepatocytes and that it makes the siRNAs more resistant to metabolizing and degradation within the hepatocyte.

Dr. Steven Nissen:

Yeah. Now the study that you are reporting on is a first in human study.

Dr. Ashish Sarraju:

That's right.

Dr. Steven Nissen:

How is it designed? And let's talk a little bit about what you found.

Dr. Ashish Sarraju:

This was a phase 1 study, placebo-controlled, double-blind, randomized study. Participants received a wide range of doses of Kylo-11, ranging from nine milligrams to 600 milligrams, or matching placebo. A total of around 70 participants were in the study at the end receiving either Kylo-11 or placebo. The randomization was an eight-to-two ratio. More people received Kylo-11 than placebo.

Dr. Steven Nissen:

But then you pooled the placebo groups together, so you'd have a pretty good size placebo group.

Dr. Ashish Sarraju:

That's exactly right, yeah. We pool the placebo groups together and then we look at safety and efficacy of the different Kylo-11 dosing groups, again, from nine milligrams all the way up to 600 milligrams.

Dr. Steven Nissen:

How effective was this drug at lowering lipoprotein(a)?

Dr. Ashish Sarraju:

What we observed was, in terms of percentage lowering over the course of the study, which went on for 48 weeks, so essentially one year, the lipoprotein(a) was reduced by around 50% in the smallest dose, all the way up to 97% in the 600 milligram doses. The lowering exceeded 94% in all doses that were 225 milligrams or higher.

Dr. Steven Nissen:

And what about the durability question? What happened? How long did Lp(a) stay down?

Dr. Ashish Sarraju:

In this study, as it turns out, all participants only got one injection right at the beginning of the study. This 97%, for example, that I mentioned for the 600 milligrams dose, that was at the end of one year after a single injection. We saw this extended durability at these higher doses of 225 milligrams or higher up to one year.

Dr. Steven Nissen:

So, even the submaximal dose of 225 milligrams had an effect exceeding 95% out to a full year.

Dr. Ashish Sarraju:

Out to a full year.

Dr. Steven Nissen:

Is this the longest duration effect that we've seen with a therapy like this for lipoprotein(a)?

Dr. Ashish Sarraju:

Yeah, this is the longest duration effect, especially for this level of lipoprotein(a) reduction that we've seen for a therapy like this.

Dr. Steven Nissen:

Now, what about safety?

Dr. Ashish Sarraju:

One of the main reasons we do a phase 1 study is for safety, to ensure that the phase 2 and phase 3 studies are feasible. What we observed was that, of course, there were adverse effects as you would expect, but there were no injection site reactions observed. That's a very important adverse effect, as you know, for these sorts of therapies, which are injectables. There were no serious adverse effects. There were no deaths. Grade three or higher adverse effects, which are really significant and meaningful, there were three of them. None of them were judged as being related to Kylo-11. Overall, the safety and tolerability data support the continued study and development of this therapy.

Dr. Steven Nissen:

What's the next step for this very interesting drug?

Dr. Ashish Sarraju:

We're going to move on to phase 2 trials, one of which is already ongoing. We're going to continue the development process here. What we're going to want to see, as is the case as we go from phase 1 to phase 2 to phase 3, is that we broaden the groups that are included. We get a wider range of people, we get a broader group of people with underlying heart disease and we try to assess safety and efficacy in larger and larger populations.

Dr. Steven Nissen:

This is a promising therapy for lipoprotein(a). If it's successful, really it's kind of vaccine-like in its efficacy, isn't it?

Dr. Ashish Sarraju:

It is, yeah. If lipoprotein(a) lowering is validated as a strategy to lower events, and of course, you're leading multiple trials asking and answering that question, if it's validated, then you can imagine that once-a-year injection could be a very practical, pragmatic way of trying to achieve that goal.

Dr. Steven Nissen:

Well, fantastic work. This area of lipoprotein(a) reduction, we seem to get better and better therapies as more and more research is being done. You seem to have now been able to finish a trial with the most efficacious drug we've seen yet.

Dr. Ashish Sarraju:

Yeah. Onwards to the next one.

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