(Length of Presentation: 11 min)

Benjamin Brucker, MD presents his 2018 AUA presentation Extended First Uninterrupted Sleep Period in Elderly Patients Following Treatment with AV002, an Emulsified Low Dose Vasopressin Analog for Nocturia in a detailed video lecture. A brief review of the short-term and long-term negative consequences of nocturia highlights the relevance of this trial.  The objective of the study was to assess Noctiva (AV002), in older adults (≥65 years and ≥75 years) on first uninterrupted sleep period, the percentage of nights with < 1 nocturic voids, and safety.   They sought to evaluate if efficacy in this more difficult to treat population is consistent with the broader > 50 years population.


Biography:
Benjamin M. Brucker, MD

Read the full video transcript

Dr. Benjamin Brucker: Thanks for joining me in this webcast today. I'm going to be presenting some data to you about the extended first uninterrupted sleep period in elderly patients following treatment with NOCTIVA AV002, an emulsified low dose vasopressin analog for nocturia.

Nocturia has many negative consequences for patients. We know that there are a lot of associations with really significant impacts for patients. There is a reduction in quality of life that we see when patients have nocturia. Patients have worse overall health, reduced work productivity, poorer mental health, frailty, even studies showing associations with frailty and mortality. The short-term consequences of the condition of nocturia include daytime sleepiness, fatigue, reduction in psychomotor functions, decreased concentration and even poor mood. There's data that shows that patients in nursing homes are actually more combative when they have nocturia. Long-term consequences of the condition are really far-reaching but depression, which is a condition we all know affects many people, is something that is a consequence of patients that are not sleeping at night. There is a susceptibility to somatic diseases, things like diabetes, cardiovascular disease and even the risk of car accidents.

When we talk about nocturia, we need to consider two different measures. First is the idea of the uninterrupted sleep period and this is defined as the time from the time you go to bed to the time you first wake to void, or awake if no void occurs. The first three to four hours of sleep are crucially important. This is where we get our deep, restorative, slow wave sleep which correlates with productivity the next day. The other measure that we look at in studies of nocturia are nocturic voids and we know that there is a correlation, as we mentioned before, with a reduction in quality of life and health-related outcomes that gets worse as patients are voiding more. When we define nocturia in most studies, we are talking about two or greater nocturic episodes. So if we have someone that can only get up one time or zero time, we could consider that normal and that might be an appropriate goal of therapy.

There are many benefits and impacts of AV002 technologies. Really what I like to call to your attention is the immediate effect of the medication, the four to six-hour duration and the low risk of hyponatremia. The advanced technology focuses around three different aspects. It's an engineered formulation that's meant to permeate the nasal mucosa quickly and efficiently. It's a microdose of desmopressin, that's this vasopressin analog, and this microdose is probably 200 times less than some formulations in some cases. It's also a geometry of the spray that's actually quite unique. So there's torus plume that comes out of the actuator for the drug, distributes this emulsified formulation to the nasal turbinates to have a very predictable surface area where this medication can be absorbed. The benefits are we can use a very low, effective dose of medication, it's highly consistent when it's dosed and there's a high bioavailability.  Again, orders of magnitude greater than other formulations that need to pass through the digestive tract and liver. There's no depot effect and again, as I mentioned, the formulation increases absorption. This results in an immediate effect. So if we're using a medication for nocturia, we want the effect to be immediate, we want the duration to be defined and this allows us to mitigate the risk of hyponatremia from the drug lasting longer than we'd like.

So to introduce this concept that this study is looking at, we're looking at older adults. Here, we define them as 65 and older, and 75 and older. Patients in this age range tend to have more adverse events and risk of hyponatremia with older formulations of desmopressin. The other concern is with lots of medications, elderly patients may not respond the same as our younger patients and so we wanted to look at efficacy of the drug due to the complicating comorbidities that are sometimes associated with older age. So the objective here is to assess AV002 in older adults, those over the age of 65 and over the age on 75 on those two measures I mentioned. The first uninterrupted sleep period as well as the percentage of nights where they're getting up one or fewer times to void. We also want to look at safety data to see if age was something we need to consider when treating older patients and this will allow us to understand how the drug performs in the older population and compare it to those patients who are older the age of 50, which is part of a larger cohort. 

The over 50 cohort involves over 1,000 patients that were studied. All of these patients had a history of nocturic voids two or greater for at least six months. There were patients that were 65 and older, about 700 patients, and there were about 300 patients that were over the age of 75, and they were included in the secondary analysis of a larger dataset to give us some information on efficacy and safety. There were two phase three pivotal trials that this data came from and they included initial screening, a double-blinded placebo lead-in and treatment with AV002 at two microdoses or placebo. And you can see this study design here. Again, randomized the day 15 and exit the study at day 99. It's interesting to note that there was no diet or fluid modification that was suggested for the study, and patients had overactive bladder and BPH and they were not excluded in the study.

So this is the patient demographics and the intent-to-treat population. You can see that it's well-balanced across treatment arms. We have a lot of patients that are in this over 65 age category, not shying away from that population. About 30% of patients fall into that over 65 and about 20% of patients in the over 75. We can see that it's not necessarily a picked population of only very healthy patients. BMI is sort of in the normal range of what we'd see in our clinic and there's a nice spread between men and women across treatment arms. We also see that race is evenly distributed and looks very similar to other drugs that have been studied in lower urinary tract symptoms in terms of those demographics.

So AV002 consistently extended the first uninterrupted sleep period across all age groups. And the top bar graph here shows that in the overall cohort, those over 65, patients were getting interrupted at baseline about 2.4 hours and that's, again, before we get to that critical three or four-hour mark of deeper, restorative sleep. If we look at the higher of the two microdoses, we can see they're above four hours. And if we look at the lower of the two microdoses, we can see we're right at that four-hour mark. So now the analysis that we're looking at is what if we only investigate those patients that are over the age of 65? And it turns out that, once again, not only do we see statistically significant separation from placebo in this harder to treat group, but we see we're getting to this clinically meaningful three and a half to four-hour mark. If we look at the patients over the age of 75, so again now this is a really significantly older population, once again we see that the medication does work better than placebo and also it does get us into that clinically significant range. So looks very consistent across all the age groups in terms of the low dose versus the high dose. A higher dose is showing a little bit more efficacy but again, even the lower dose having nice efficacy compared to placebo.

So patients experience nearly 50% of nights with one or fewer voids and this is something that is actually quite impactful for patients. The chronic deprivation of sleep has the impact and if we can get some nights where there is actually normal sleep, it's like taking a night off. And you can see here in the over 50 cohort again, we have in the higher of the two microdoses of 47% that were experiencing, 50% had one or fewer voids and about 40% in the lower of the two doses. And again, in the 65 and 75 categories, very consistent even as we're using patients that may have more comorbidities. So again, you can see sort of the numbers across. This is sort of the percentage of nights, the mean increase compared to baseline and I think you can see that not only does it have an impact on the first uninterrupted sleep but it's getting patients into this more "normal" category.

The rate of hyponatremia, the safety data, was actually excellent across the board. We can see that in the 0.83 mcg dose, there were no patients that experienced hyponatremia that was considered significantly or severe, which was a serum sodium of less than 125 milliequivalents. If we look at those patients in the 1.66 dose, we can see that 1% of patients had hyponatremia that was considered severe. Looking specifically at those patients, we can see that all five of those patients actually were in the older cohorts, so those are the patients over the age of 65. And based on the fact that these are the patients that were at risk, the suggested starting dose now of the medication would be to use the 0.83 mcg dose. But if we look more specifically at that older patient, those over the age of 65 on the higher dose that had severe hyponatremia, it turns out that four out of those five patients were on systemic or inhaled glucocorticosteroids. That's a drug that is now considered a contraindication to the medication. Again, there were two patients of that over 65 that were actually over the age of 75. The moderate hyponatremia patients thankfully were all also asymptomatic, so this is something that was noticed on just a blood test routinely and not something where patients experienced symptomatic problems from their hyponatremia, whether it was moderate or severe.

So in conclusion, we can see that both the 65 and older and 75 and older group treated with AV002 experienced a significant improvement in this first uninterrupted sleep period. And additionally, they had an improvement in the percentage of nights with one or fewer nocturic voids. None of the patients in the 0.83 mcg dose, now the recommended starting dose for those 65 or older, experienced severe hyponatremia. These results suggest that AV002 is effective therapy and has a favorable safety profile in older adults with nocturia. I think that addressing nocturia in older adults may have a big impact on improving sleep quality but more importantly, some of the other issues that are associated like the health-related, quality of life, overall health and increased productivity. Thanks so much for taking the time to listen to this webcast.