Desmopressin (DDAVP^®; Ferring Pharmaceuticals Inc) was approved in the US in 1978. DDAVP is currently approved to treat central diabetes insipidus, hemophilia A, type 1 von Willebrand’s disease, nocturnal enuresis (bedwetting) in children, and as a diagnostic test to measure renal concentrating abilities.

Desmopressin is approved for the treatment of nocturia in more than 80 countries, and was recently approved in Europe via a Decentralized Procedure in May 2016. Desmopressin is used off-label to treat nocturia within the US. So when Ferring sought to have desmopressin approved for nocturia in the US, it may not have been expecting the process would involve 3 complete responses letters, an appeal, an advisory committee meeting, and possibly getting beaten to the finish line by another company.

Nocturia

Nocturia is commonly referred to as waking 2 or more times to void, or urinate, with each episode followed by sleep. The prevalence of nocturia increases with age and is highly prevalent in individuals over 60 years of age. Nocturia is associated with sleep disturbance, depression, decreased quality of life, and in older patients, falls and fracture. Nocturia is a heterogeneous condition with multiple known and unknown causes.

Desmopressin is a synthetic analog of the naturally occurring antidiuretic hormone, arginine vasopressin. Desmopressin reduces urinary volume through reabsorption of free water. Compared to arginine vasopressin, desmospressin has a longer duration of action, greater anti-diuretic properties and lower blood pressure raising effects.

Approval of a new indication for an approved drug usually occurs via the 505(b)(2) regulatory pathway as the application relies on information in the literature and product labeling. As regular readers of Premier Consulting’s blog will know, the 505(b)(2) pathway reduces the size or scope of studies required for approval compared with full 505(b)(1) applications for new drugs. Desmopressin fits this scenario as there is a long history of clinical use for nocturia. Add to this the safety concern associated with the off-label use of approved desmopressin products as the approved dose for other indications is higher than the dose used to treat nocturia. Sounds like a welcome prospect for approval, right?

Regulatory Background

August 2009: Ferring submitted an NDA for an orally-disintegrating tablet formulation of desmopressin (Nocdurna^®). The initial indication proposed was the treatment of nocturia due to nocturnal polyuria in all adult patients who awaken at least twice per night to void.

April 2010: Complete Response Letter. The 100-mcg dose used was associated with unacceptable toxicity (hyponatremia). If Ferring was to pursue a lower dose, new data would be required. Development of a tool for assessing Patient-Reported Outcomes (PROs) was recommended.

November 2010: Special Protocol Assessment (SPA)s for 2 new trials were agreed upon.

August 2012: NDA amendment-Complete Response containing 2 new confirmatory trials submitted by Ferring.

January 2013: 2^nd Complete Response Letter. The FDA required evidence of clinical benefit.

July 2013: NDA amendment-Complete Response containing a Statistical Robustness report and a Sleep White Paper was submitted by Ferring.

August 2014: FDA sent an acknowledgement of Incomplete Response Letter as no additional trial was conducted.

December 2014: Sponsor filed Request for Formal Dispute Resolution (FDRR).

January 2014: Appeal for approval was denied by the FDA. The FDA suggested an Advisory Committee Meeting

January 2015:The Advisory Committee voted 10-5 against approval of Nocdurna.

(Source: FDA and Ferring Advisory Committee Briefing Documents for Nocdurna)

So What Went Wrong?

Ferring consulted with the FDA at an end-of-Phase 2 meeting regarding the design of the Phase 3 study, and at a pre-NDA meeting to discuss the adequacy of the data. Special Protocol Assessments were agreed upon by FDA for a further 2 confirmatory studies that were conducted. All studies met their endpoints with significant differences to placebo. However, the FDA could not agree that the benefit-risk profile for Ferring’s product was reasonable. Issues included the dose, indication, demonstration of meaningful clinical benefit, safety, and use of PRO instruments.

The dose and indication were clear problems in the first Complete Response. Statistical significance was seen only at the highest dose of 100 mcg for both co-primary endpoints, but this dose could not be approved because of the risk of hyponatremia. Relative to placebo, the observed changes were much smaller than the changes seen with respect to baseline and therefore of unclear clinical benefit.

In the second review cycle, Ferring submitted 2 new studies testing lower doses in women and men. Again, the differences between groups were significant but small. The FDA found that the PRO had several problems, including a lack of validation, reliance on a long patient memory recall, and that the analysis was post-hoc. The FDA asked for another study using a PRO co-developed with sponsor and FDA input. (see the FDA’s PRO Guidance)

For the first 2 review cycles, the proposed indication was for the treatment of adults with nocturia regardless of age or cause. This broad indication was a problem as many patients susceptible to hyponatremia were excluded by study design. In the 3rd review cycle, the proposed indication was the treatment of nocturia due to nocturnal polyuria in all adult patients who awaken at least twice per night to void. This indication still does not match the study population.

The issue of meaningful clinical benefit was raised by the FDA from the start. The FDA noted as early as the End-Of-Phase 2 meeting that the Phase 3 study design would provide no guarantee that a substantial percentage of patients would have a large enough reduction in voids to be clinically relevant (is a reduction of 1.7 voids per week clinically relevant?). Any potential benefits must be weighed against the known safety risks, such as hyponatremia. Further, the FDA recommended that Ferring develop a tool for assessing PROs to assist in understanding the clinically meaningful benefit. At all times, the FDA consistently expressed concerns about the lack of a meaningful clinical benefit with such small differences between groups. In the Advisory Committee Meeting Minutes, it was noted that support for clinical meaningfulness data may come from an appropriate PRO, sleep disturbance or wakefulness-related parameters, or actual rates of falls. Despite conducting at least 16 studies in patients with nocturia, including two with primary endpoints and 9 with secondary endpoints to address clinical meaningfulness, Ferring evidently could not overcome this problem. This appears to be at least partly due to their inconsistent use and choice of PRO instruments.

Enter Serenity

Serenity Pharmaceuticals, LLC, founded in 2006, and with financial backing from Allergan PLC is also developing desmopressin for nocturia. Their nasally administered SER120 product is seeking a similar indication and has conducted similar studies with similar results. But an advisory committee convened in October of 2016 voted in favor of approving SER120.

Does Serenity’s SER120 Product Have the Same Problems?

The indication proposed for SER120 is broad and does not match the population in the Phase 3 study. Serenity has similar problems of safety at higher doses and a lack of efficacy at lower doses that were tested. The FDA had similar issues in finding clinically meaningful clinical benefit due to the small improvement in nocturia and the large placebo effect. For both SER120 and Nocdurna, the FDA asked the respective advisory committees to consider very similar draft points.

However, it appears that Serenity’s PRO included greater feedback from the FDA than that of Ferring. For example, in Ferring’s first Phase 3 study, it used the Nocturia Quality of Life instrument, which the FDA noted had several problems and did not fit with the 2009 guidelines for PROs. Although the FDA advised Ferring to develop a validated tool, Ferring used the Nocturia Quality of Life instrument in the subsequent studies. Ferring did develop a new PRO instrument with the FDA, but only applied this to one subsequent study. Unfortunately, this new tool only showed improvement in the treatment group in a post hoc analysis and could not be used to support a clinical benefit.

Serenity’s PRO was also only used in one study, however, the benefit reported by patients treated with SER120 was significantly better, yet once again, small. The FDA was unclear whether the small magnitude of difference was clinically meaningful to patients. Apparently, the Advisory Committee did find the difference to be meaningful as it voted 14-4 in favor of the benefit-risk profile for SER120.

Will Serenity’s Product Get Approved?

The FDA is not bound by the findings of Advisory Committees. However, the positive findings of the SER120 Advisory Committee are more likely to lead to a favorable approval decision than those of the Nocdurna Advisory Committee. And Serenity has managed to show a significant difference via a validated PRO instrument. But the FDA’s consistent cautious interpretation of meaningful clinical benefit is noted and may be a sign of things to come for Serenity. If the importance of meaningful clinical benefit was ever in doubt, Ferring’s Citizen Petition requesting that the FDA refrain from approving SER120 until consistent standards are established will serve as a reminder. The PDUFA goal date for SER120 is estimated to be later this month*.

To learn more about drug development strategy, the importance of the Pre-IND meeting to align with the FDA, successful clinical study design, and getting a new indication approved via the 505(b)(2) pathway, contact us.

*In the unlikely event that FDA determines, as a result of Ferring’s petition, that approval of SER120 negatively affects the public health, a potential approval can be delayed.

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Author:

Angela Drew, PhD
Product Ideation Consultant