A Tale Of Two Desmopressins: Trial Design Gave Noctiva Advantage Over Nocdurna, US FDA Says

Secondary endpoints in Serenity Pharmaceuticals LLC's pivotal trials of Noctiva helped to demonstrate the clinical meaningfulness of the desmopressin nasal spray for nocturia, FDA said in its denial of a potential Noctiva competitor's citizen petition.

FDA approved Noctiva, a nasal spray formulation of the vasopressin analog desmopressin, on March 3 for treatment of nocturia due to nocturnal polyuria, or excess production of urine at night, in adults who awaken at least two times a night to void. (Also see "Keeping Track: Xermelo, Odactra, Noctiva Approved; Second Submissions For Avelumab And Deutetrabenazine" - Pink Sheet, 4 Mar, 2017.)

The approval makes Noctiva the first drug approved for nocturia in adults, although other formulations and doses of desmopressin are widely used for diabetes insipidus, primary nocturnal enuresis in children, and other indications.

Serenity's regulatory progress had drawn opposition from Ferring Pharmaceuticals AS, which has been trying to get FDA approval for its orally disintegrating tablet version of desmopressin for nocturia, Nocdurna, since 2009. Nocdurna has received three complete response letters, and FDA denied Ferring's bid to overturn the non-approval actions through the formal dispute resolution process (see regulatory history chart below).

Ferring then turned to the citizen petition process, asking the agency to withhold approval for Serenity's product until "consistent interpretation" of standards for safety and efficacy in nocturia treatment were established. (Also see "Desmopressin Battle: Ferring Asks FDA To Reject Serenity's Nocturia Drug" - Pink Sheet, 1 Dec, 2016.)

FDA agreed with Ferring that "both applications raised questions as to whether the observed treatment effects are clinically meaningful," Center for Drug Evaluation and Research (CDER) Director Janet Woodcock stated in the March 3 denial of the citizen petition. The difference in regulatory outcome reflected differences in the data submitted, especially in trial design, she explained.

"Critical to approval of SER120 were several endpoints in Serenity's development program that were absent from Nocdurna's program," Woodcock said. The SER120 trials used secondary endpoints in particular that illustrated the clinical meaningfulness of results on the primary endpoints.

Both the Nocdurna and the Noctiva clinical programs used similar co-primary endpoints, one evaluating the change from baseline in mean number of nocturic voids per night during three months of treatment and the other looking at the percentage of patients meeting a definition of response. The responder endpoint was defined differently, however, with Noctiva trials looking for patients experiencing a 50% or greater reduction from baseline in mean number of nocturic voids and Nocdurna studies looking at the odds of achieving a 33% decrease.

Both Nocdurna and Noctiva found small reductions of "unclear clinical benefit" the in mean number of voids per night, according to FDA. The small effect size, in light of the known risk of hyponatremia with desmopressin use, was a main topic at the advisory committee reviews of both drugs, which went negatively for Nocdurna but positively for Noctiva.

For Noctiva, however, "the findings on the 50% responder co-primary endpoint combined with the two secondary endpoints of the percentage of nights with no nocturic voids and the percentage of nights with one or fewer nocturic voids provided convincing evidence of a clinically meaningful benefit," Woodcock said.

"The percentage of nights with no nocturic episodes reflects, for those nights, a complete resolution of the symptom being treated," she said. "Having one or fewer nocturic episodes per night reflects, for those nights, a reduction in nocturia below the threshold for which the drug is indicated."

The secondary endpoints in the Nocdurna dataset, in contrast, "did not support a conclusion that there was a clinically meaningful treatment effect for the drug," Woodcock stated. Secondary endpoints measuring change from baseline in mean number of nocturnal voids at three months and the proportion of 33% responders at three months "essentially showed the same results as the two co-primary efficacy endpoints and therefore were not informative about the clinical significance of the treatment effects," she observed.

Ferring's response to the agency's concerns in the CRLs about clinical meaningfulness emphasized findings about the time to first void, another secondary endpoint. A longer time to first void is associated with better sleep quality, according to the company. FDA, however, was unpersuaded in the clinical meaningfulness of the metric. "Ferring did not provide data in its trials to show that the change in time from bedetime to first nocturnal void affected how patients feel or function."

All PRO Instruments Are Not Equal

While FDA's first CRL for Nocdurna urged the company to develop a patient-reported outcome (PRO) measure that could help interpret clinical benefit for the patient, the agency's denial of the Ferring petition suggests that the PRO issue ultimately did not play a large role in FDA's decision. "PRO data were not ultimately determinative in FDA's assessment of whether SER120 met the statutory approval standard," Woodcock said.

Nonetheless, she points out differences in the PRO measures used by the two sponsors. Serenity pre-specified the Impact of Nighttime Urination (INTU) instrument as a secondary efficacy endpoint, and submitted evidence to support the measure's "validity, reliability, and ability to detect change" that was consistent with FDA's PRO guidance.

Ferring, on the other hand, used the NQoL instrument as an exploratory measure and "did not submit sufficient qualitative evidence to support its content validity and use in the expected patient population," Woodcock said. "Without first establishing content validity, FDA could not review other measurement properties such as reliability, ability to detect change, and construct validity."

Reflecting The Real World In Clinical Trials

A major difference between the Nocdurna and Noctiva development strategy was the choice of patient population in clinical trials. The risk of the most serious adverse event associated with desmopressin, hyponatremia, "increases with advancing age," Woodcock noted. Since nocturia is more prevalent in older people, risk management was an important factor in FDA's decision making.

The Nocdurna trials, however, allowed patients as young as 18 years old to enroll. The Noctiva trials were limited to patients 50 years and older, which "more closely resembled the expected patient population" on the market.

The Noctiva trials also provided "more assurance that the treatment results are closer to what could be expected with 'real world' use of the drug," Woodcock added. Ferring's Nocdurna trials included restrictions on fluid, alcohol and caffeine intake to reduce the risk of developing hyponatremia, while the Noctiva trials did not. Fluid restrictions like those in the Nocdurna trials "may be difficult to maintain with real-world use of the drug," she commented. "Therefore, the SER120 trials included additional systemic stressors that were absent from the Nocdurna trials."

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