I'm Dr Stephen Greene from the Duke Clinical Research Institute, and I'll be talking about the results of the VELOCITY study which studied initiation of a 5 milligram dose of vericiguat for patients with heart failure.

What is the rationale behind starting patients directly at 5mg vericiguat rather than the typical titration approach?

So as background with our other GDMTs, we know that many of our patients with heart failure with reduced EF never get to target doses of GDMT, and they come back clinic visit after clinic visit. We don't make medication changes. And we see this even when patients have robust blood pressures, normal kidney function, even when we're talking about inexpensive medications. Totality of data suggests there's a strong sense of clinical inertia towards medication changes.

So therefore, in VELOCITY we wanted to say, hey, can we take the normal vericiguat dose titration schedule which usually starts at a 2.5 milligram dose, increase to 5 milligrams two weeks later, increase to 10 milligrams two weeks after that? Could we take that two-step approach and safely simplify it to a one-step dose titration pathway? And this was really our first experience starting direct initiation of a 5 milligram starting dose.

What is the patient population and study design?

So VELOCITY was a prospective, multinational, two-week, single-arm study. So the patients that were enrolled were those with heart failure with an EF less than 45%. We included patients with or without a recent worsening heart failure event. And all patients though did require to have a systolic blood pressure at baseline of at least 100 millimeters of mercury and no history of symptomatic hypotension in the four weeks prior to screening. We then enrolled 106 patients and they were initiated on 5mg of vericiguat and we followed them for two weeks.

That was a study period. And over that two weeks the primary safety and tolerability endpoint was completion of that two-week period with no more than one day of study drug interruption and without moderate to severe hypotension. Secondary endpoints were related to adverse events, related to vericiguat and continuous intake of vericiguat over the two-week period.

What are the key findings?

So the key findings in VELOCITY was that when we looked at the patients initiated on a 5 milligram starting dose of vericiguat, we saw 93% of them successfully met the safety and tolerability endpoint and also about 90% or higher met all of the secondary endpoints.

And just to put that in context, you know, first of all, that's of course 9 out of 10 patients safely tolerating the study drug at a 5 milligram starting dose. But just to put that in context, we also looked back to the prior VICTORIA trial with vericiguat, that was the registration trial for the drug, and there we looked at the patients that were initiated on the 2.5 milligrams—that's the traditional starting dose.

And we saw the patients initiated on a 2.5 milligram dose had about a 97% rate of completing this tolerability endpoint. So we had 93%. Again, roughly similar in the sense that whether you're starting 2.5 or 5 milligrams, more than a 9 out of 10 chance that your patient's going to successfully tolerate initiation of a study drug.

So another thing that we presented in the results is the effect on systolic blood pressure of a starting dose of 2.5mg versus 5mg. So when we looked back at the prior VICTORIA trial, the patients initiated on 2.5 milligrams, we saw that they had a decrease in their blood pressure of 3.2 points mean over the first two weeks after starting the study drug.

Then we did VELOCITY starting at 5 milligrams. We saw over the two weeks after 5 milligram initiation the same mean reduction in blood pressure: 3.2 millimeters of mercury. So again, no difference in terms of the blood pressure effect of a 2.5 versus 5 milligram based on the data that we have.

And then when you also consider in VICTORIA, even the placebo arm had a decrease in blood pressure and, you know, VELOCITY was not placebo-controlled, but had it been placebo-corrected, we expect, you know, that 3.2 millimeter mercury difference would likely have been further attenuated. So again, it kind of goes what we already know about vericiguat being minimal to no effect on systolic blood pressure.

What potential healthcare benefits might result from eliminating the titration period?

So right now our clinical guidance is a two-step titration and, again, just puts our patients when they start this drug far away from getting the 10 milligram target dose. So to me, simplifying is one of the most strongest tools we have for implementation. So if we can start at 5mg and have confidence in the safety, that just makes implementation in terms of visits to the clinic to titrate medicines, ease of use, it just makes it that much easier and increases our chances of our patients getting to a 10 milligram target dose.

What follow-up studies would be needed, and what are the next steps?

So we'll have to see what regulators and clinical guidance thinks of VELOCITY studying whether we change clinical guidance to start at a 5 milligram starting dose. We're also waiting with other studies coming down the pipe with vericiguat.

The VICTOR study has now fully enrolled and will be presented later this year from what it sounds like. And that will be a study of patients with vericiguat without a history of recent worsening heart failure. That will be starting at the 2.5 milligram dose—the traditional dosing scheme that was studied in VICTORIA.

But importantly, in VELOCITY, we did include patients with or without recent worsening heart failure. So that will include some of the patients that are going to be enrolled in VICTOR. And we'll see how that translates if we get regulatory and updated clinical guidance to again start at the 5 milligrams; it would apply across the spectrum of worsening heart failure or no worsening heart failure.