Regulatory Focus™ > News Articles > 2021 > 9 > FDA proposes to refuse Intarcia’s exenatide combo product NDA —again

FDA proposes to refuse Intarcia’s exenatide combo product NDA —again

Posted 01 September 2021 | By Jeff Craven 

FDA proposes to refuse Intarcia’s exenatide combo product NDA —again

The US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has told Intarcia Therapeutics it is proposing to refuse a new drug application for their type 2 diabetes drug-device combination product ITCA 650.
 
In a notice posted in the Federal Register, the agency said Intarcia can request a hearing from FDA on the proposal, but if the hearing is waived or it is determined the reason for the hearing isn’t sufficient, FDA will move forward and refuse the new drug application (NDA).
 
This is not the first time Intarcia has had this NDA for ITCA 650 rejected. In November 2016, Intarcia initially submitted the NDA for ITCA 650, an implantable DUROS device that delivers the glucagon-like peptide-1 receptor (GLP-1) agonist exenatide subcutaneously to patients with type 2 diabetes for glycemic control as an adjunct to diet and exercise. CDER’s former Division of Metabolism and Endocrinology Products (DMEP) wrote back to Intarcia in September of 2017, issuing a complete response letter highlighting deficiencies in the NDA. Intarcia resubmitted the NDA in September 2019, and CDER’s former DEMP wrote back with another complete response letter in March 2020 with deficiencies in the NDA to be remedied.
 
The problems highlighted by DEMP include clinical trial data submitted that showed a higher-than-normal risk of acute kidney injury (AKI) among patients who received ITCA 650 (0.6%) compared with other GLP-1 agonist therapies. In addition, some of the AKI events like vomiting, diarrhea, and dehydration, are “known adverse reactions associated with exenatide therapy,” the agency said. “This AKI risk for ITCA 650, compared to other members of the GLP-1 RA class, is particularly concerning because it was identified from these adequate and well-controlled clinical trials, which constitute stronger evidence for assessing a drug’s safety than spontaneous postmarketing adverse event reports,” FDA wrote.
 
The risk mitigation measures Intarcia proposed to FDA were not adequate for several reasons, including that serious AKI events were seen in individuals who were not at risk of developing AKI or who were taking the initial/reduced dose or nominal maintenance dose of the medication.
 
ITCA 650 also appears to carry a risk of major adverse cardiovascular events (MACE), defined as myocardial infarction, nonfatal stroke, and cardiovascular death, and were seen more often in individuals 65 years and older. In the notice, FDA said Intarcia “failed to provide sufficient assurance that ITCA 650 is not associated with excess cardiovascular (CV) risk.”
 
“This CV risk resulting from ITCA 650 use is particularly concerning when compared to the beneficial effect of other drugs in this class on CV outcomes,” the agency said.  
 
FDA also raised manufacturing issues about ITCA 650 in the notice, questioning the device’s sterility and reliability for performance and drug delivery. Additionally, an FDA visit to Intarcia’s manufacturing facility turned up “deficiencies with the manufacturing practices” that weren’t addressed by the company, including a lack of safeguards to ensure the company wouldn’t ship empty devices in the final product.
 
Both complete response letters asked Intarcia to address these issues as well as “provide additional clinical data that adequately address the clinical risks and establish that ITCA 650 is safe and effective for the intended use.” Intarcia filed a formal dispute resolution request (FDRR) in June 2020 in response to the March 2020 complete response letter, which was denied in July; the company filed another FDRR in August 2020 that was denied in October, and a third FDRR in November 2020 that was denied in February 2021.
 
FDA warned Intarcia in the notice that it won’t grant a request for a hearing on just any grounds and the company should come with a plan to address all the deficiencies outlined in the complete response letters. The “request for a hearing may not rest upon mere allegations or denials, but must present specific facts showing that there is a genuine and substantial issue of fact that requires a hearing to resolve,” they wrote.
 
Intarcia has not responded to the current notice from the FDA, but stated in March 2020 the company was “extremely disappointed” at the time to receive a complete response letter from the agency. “We remain steadfast in our belief that ITCA 650 holds important potential as a new treatment option for people managing type 2 diabetes,” Intarcia said in the statement.
 
Federal Register notice
 

 

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