The following article is part of conference coverage from the 2018 American Urological Association meeting in San Francisco. Renal and Urology News’ staff will be reporting live on medical studies conducted by urologists and other specialists who are tops in their field in kidney stones, prostate cancer, kidney cancer, bladder cancer, enlarged prostate, and more. Check back for the latest news from AUA 2018.
SAN FRANCISCO—In separate phase 3 trials, elderly patients with nocturia treated with Noctiva (AV002), a microdose desmopressin nasal spray, experienced a significant improvement in first uninterrupted sleep period (FUSP) compared with placebo, investigators reported at the American Urological Association 2018 annual meeting.
Noctiva is the first and only medication that is FDA approved to treat nocturia due to nocturnal polyuria in adults.
The trials compared Noctiva, which is made by Avadel Pharmaceuticals, with placebo among patients in 2 age groups: 65 years and older and 75 years and older. Investigators randomly assigned patients to receive Noctiva 1.66 mcg or 0.83 mcg or placebo.
Among patients in both age groups, the mean time to FUSP was significantly longer in the 1.66 mcg and 0.83 mcg AV002 groups than in the placebo arms, said presenting author Benjamin M. Brucker, MD, of New York University Langone Medical Center. Investigators defined FUSP as time from time from bedtime to first nocturic episode (NOEP) or awakening if no void occurred.
The mean increase in time to first NOEP was 102 minutes in both younger and older 1.66 mcg groups and 90 and 78 minutes in the younger and older 0.83 mcg groups, respectively. By comparison, the mean time to first NOEP in the placebo group was 66 and 54 minutes in the younger and older age groups, respectively.
Noctiva also was associated with a significant increase in the percentage of patients with 1 or fewer NEOP on a per-patient basis compared with placebo. Among the 1.66 mcg recipients, the mean percentage increase was 43% in the younger age group and 39% in the older age group. In the 0.83 mcg group, the mean percentage increase was 37% and 32%, respectively. In the placebo arm, the mean percentage increase was 31% and 28%, respectively.
Severe hyponatremia, defined as a serum sodium level of 125 mmol/L or less, occurred in none of the patients in the lower-dose Noctiva group and 5 (1.1%) in the higher-dose group. Of these 5, 4 were taking systemic corticosteroids, which may have an effect on salt balance and hyponatremia. Systemic corticosteroid use is now a contradiction for Noctiva. In a 126-week extension study, no patient experienced severe hyponatremia.
“These results suggest that AV002 is an effective therapy with a favorable safety profile in older adults with nocturia,” Dr Brucker told attendees. “Addressing nocturia in older adults may result in better quality of sleep, increased productivity during the daytime, and improvement in overall health, and importantly, an improvement in health-related quality of life.”
In an interview with Renal & Urology News, Dr Brucker emphasized that Noctiva is extremely safe. The doses of Noctiva are 20 to 200 times lower than the traditional desmopressin formulations that have been used. In addition, Noctiva has a unique delivery system that enables precise control of blood levels. As a result, the rates of hyponatremia—a common complication of desmopressin therapy—are exceedingly low. With the 1.66 mcg dose, only 1.1% of patients experienced severe hyponatremia. “This drug is so well understood pharmacokinetically, that you can really manipulate not only the effectiveness of the drug, but also the safety profile,” Dr Brucker said.
He noted that the studies enrolled “all-comers,” and included patients with such comorbidities as benign prostatic hyperplasia and overactive bladder. In addition, patients were not asked to change their behaviors with respect to fluid intake at bedtime. Thus, the cohorts reflect real-world patients for whom physicians will be prescribing Noctiva.
Dr Brucker stressed the importance of the first uninterrupted sleep period. He explained that the critical restorative sleep occurs in the early part of the sleep cycle. Any disturbance of sleep, especially the early stages, has a profound impact on health and quality of life. Nocturic patients usually get up to void 2 or 2½ hours after going to sleep, thus disturbing the period of restorative sleep. “You never really get that back, even if you fall back to sleep,” he said. AV002 enables patients to get through the important early sleep stages, he said.
The current studies, for the first time, show consistency in safety and efficacy across age groups. “Whether you’re 50 to 75, the medication works.”
Seymour Fein, MD, who led the team that developed Noctiva, said the studies demonstrated a clinical benefit using the first quality of life (QOL) questionnaire designed specifically for nocturia, the Impact of Nighttime Urination instrument, which was developed in collaboration with the FDA. Patient responses to this questionnaire showed that decreasing the number of nighttime voids and thereby improving the first duration of uninterrupted sleep actually translated into a better QOL. “Patients felt better the next day and they functioned better the next day, as documented by this validated instrument,” Dr Fein said.
With respect to hyponatremia, the most important potential adverse effect of desmopressin therapy, he noted that other companies have attempted to develop desmopressin formulations that ameliorate the risk of this complication, but have not succeeded.
He and his team reasoned that by dramatically decreasing the dose and engineering a formulation that would produce highly consistent pharmacokinetics and blood levels from dose to dose and patient to patient, they would largely solve the safety problem with hyponatremia.
“No other formulation of desmopressin is both low dose and highly consistent pharmacokinetically or provides the efficacy and safety, and clinical benefit for nocturia than Noctiva does,” Dr Fein said.
With the drug’s pharmacokinetic consistency, greater bioavailability, and more rapid and complete absorption, peak blood levels can be achieved at about 20 or 25 minutes, which is even more rapid than a subcutaneous bolus injection of desmopressin, Dr Fein explained. “If you accomplish all of that, then you can predict the peak blood level accurately,” he said. “And if you control that peak blood level to a narrow low range, you can control the duration of the antidiuretic effect. In doing so, you limit it to just 4 to 6 hours a night, when the patient’s sleeping and not ingesting fluids. It’s gone by the next morning when they wake up and start drinking.”
Brucker BM, Francis L, Yang, Rovner ES. Extended first uninterrupted sleep period in elderly patients following treatment with AV002, an emulsified low dose vasopressin analog for nocturia. Data presented at the American Urological Association 2018 annual meeting, San Francisco, May 18–21. LBA12.