Zealand Pharma US, Inc.: glepaglutide

In situations such as this, we recognize the need to incorporate regulatory flexibility, while still ensuring that substantial evidence of effectiveness is demonstrated.

Based upon our review of your submitted data, we are unable to conclude that there is substantial evidence of effectiveness (SEE), nor that the benefits outweigh the known and anticipated risks.

We have completed our review of NDA 218828 and have determined that the data submitted in the NDA are inadequate to support demonstration of efficacy and safety of glepaglutide for the treatment of adult patients with short bowel syndrome.

B. Incomplete or missing documentations of urinary output in the 48 hours prior to study visits were observed in up to 12% of subjects in EASE-1 and 68% of subjects in EASE-2. Additionally, up to 20% of subjects in EASE-2 had no documentation for urinary volume at 25 visits.

Although results of sensitivity analyses conducted by FDA with and without the "notes-to-file" data appeared to be consistent with the primary analysis, uncertainty remains regarding the accuracy and reliability of the PS volume data, especially when viewed together with other trial conduct issues described in this letter.

E. The quantitative analyses conducted were inadequate to determine clinically meaningful within-patient change in PS volume.

As the goal of treatment is to reduce reliance upon PS to maintain nutritional status, significant weight loss raises concerns regarding whether the reduction in PS was appropriate and consistent with clinically meaningful benefit.

However, the descriptive efficacy results of a subset of patients in EASE-2 who received active treatment for the first time in EASE-2 showed no clear dose response after 24 weeks of treatment (a similar duration as EASE-1).

TW) were not evaluated in your phase 2 studies wherein you evaluated 0.1 mg, 1 mg, and 10 mg daily regimen for 3 weeks, using different endpoints than those evaluated in EASE-1. Although an apparent dose-response relationship was observed in EASE-1, exposure response analyses suggested a lack of relationship between observed glepaglutide exposure and the primary efficacy endpoint.

The results from the two metabolic studies ZP1848-15073 and EASE-4 did not provide adequate mechanistic or confirmatory evidence to support EASE-1 results for the following reasons:

The results showed inconsistent dose response between the three evaluated doses (0.1 mg, 1 mg, 10 mg daily) and their effects on wet weight ostomy output/diarrhea and urinary output (reported as urine weight).

We acknowledge that your 120-day safety update report included additional safety information available for the TBM dosage, providing a total of |{i}) subjects who received the TBM dosage for at least 1 year in your safety database.

However, we generally recommend a safety database that includes at least ~100 subjects treated with the TBM dosage for at least 1 year, to inform the safety profile of a new drug intended for chronic use.

Multiple safety concerns, including potential drug-induced liver injury, cancers (gastric neuroendocrine carcinoma, basal cell carcinoma of skin and basosquamous carcinoma of skin), and gastric polyps were identified within this limited safety database.

Given that this site enrolled a relatively large representation of the study population (approximately 9%), as well as the types and frequency of the adverse events observed but were omitted from this site's safety data, these inspection findings raise significant concerns regarding the reliability of the data to inform the benefit-risk assessment of glepaglutide.

We recommend that you leverage the existing data to inform the design of the new study to confirm the efficacy of the TBM dosage of glepaglutide and generate additional controlled safety data to support chronic administration.

We recommend that you conduct a double-blinded, placebo-controlled trial including a treatment period of at least 52 weeks.

EASE-1 and EASE-2 study results, we recommend that you extend the controlled period to at least 52 weeks to better characterize the safety profile of glepaglutide and assess the durability of response in the intended population.

To aid in the interpretation of PS volume related endpoint results, a range of withinpatient score change thresholds that patients consider clinically meaningful should be established through anchor-based methods using appropriate anchor measures, supplemented with empirical cumulative distribution function (eCDF) curves using data pooled across treatment arms.

Office of Surveillance and Epidemiology are unable to determine whether a risk evaluation and mitigation strategy (REMS) will be necessary to ensure the benefits of the drug outweigh the risks, and if necessary, what the required elements will be.

The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA 483 prior to your complete response.

FDA may need to conduct a pre-approval inspection/pre-licensing inspection (PAI/PLI) of the facility.

NDA 217724 provides for the use of dasiglucagon injection for the following indications which, for administrative purposes, we have designated as follows:

All future submissions to NDA 217724/Original 1 and NDA 217724/Original 2 should specify the NDA number and the Original number to which each submission pertains.

We have completed our review of NDA 217724/Original 1 and have determined that we cannot approve this application in its present form.

The facility's satisfactory responses are dependent on FDA's determination hat the facility has come into compliance with CGMP and may require re-inspection of he facility.

The deficiencies identified during the inspection may not be specific to your pending application, therefore, you should coordinate with the facility for timely resolution.

FDA may need to conduct a pre-approval inspection (PAI) of the facility.

As the Applicant, we do not expect a response to this acility related deficiency when responding to any other deficiencies cited in this or other letters, instead, please work with the facility, as applicable, in resolving the related deficiencies.

The marked-up copy should include annotations that support any proposed changes.

However, we request you submit your responses with your complete response to this letter.

Furthermore, we note that the simulated 95% confidence interval (Cl) upper limit of dasiglucagon exposures (based on 70 microgram/hour dose) for body weight < 4.1 kg is anticipated to exceed the peak plasma exposure of 3.78 nmol/L at the no observed adverse effect level (NOAEL) for the transient freezing absences in rats.

2001 Mar;107(3):595-7; Charsha DS, et al. Pediatrics.