Third Time's a Charm for GLP-1 Diabetes Device? FDA Staff Suggest Otherwise.

As an investigational diabetes drug implant that promises better adherence faces FDA review for a third time, safety concerns ranging from adverse heart and kidney events are expected to be points of contention at an advisory committee meeting slated for Thursday.

The drug-device in question is Intarcia Therapeutics' ITCA 650, featuring the GLP-1 receptor agonist exenatide (Byetta, Bydureon) in a DUROS device, with a proposed indication of improving glycemic control in adults with type 2 diabetes along with diet and exercise. The small, subcutaneously implanted device has an osmotic mini-pump that drives a consistent daily dose of exenatide into the patient; after an initial 3-month dosing period, the device would be swapped out every 6 months for maintenance dosing.

But the device has a checkered regulatory history after it was initially rejected by the FDA in 2017 due to manufacturing and safety concerns -- mainly acute kidney injury (AKI) and major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal MI, and non-fatal stroke. Intarcia tried again, resubmitting the device for approval in 2019, but it was rejected yet again a few months later because of similar issues. At Thursday's meeting, the Endocrinologic and Metabolic Drugs Advisory Committee will weigh in on the agency's lingering concerns.

Briefing documents released ahead of the meeting suggest a difficult path to approval, with FDA staff noting that ITCA 650's application "is not approvable in its current form because the benefit-risk assessment for the product is unfavorable based on the available data."

The FDA's Center for Drug Evaluation and Research (CDER) "has repeatedly communicated this assessment" to Intarcia and even recommended a complete redesign of the product paired with new clinical trial testing in the March 2020 complete response letter, so that the product could provide "reliable and clinically appropriate exenatide release rates over the life of the product," reviewers wrote.

However, briefing documents provided by Intarcia claimed there were "substantial factual inaccuracies in the issues stated by CDER."

Exenatide is currently approved as a twice-daily injectable (Byetta) and once-weekly injectable (Bydureon); other approved GLP-1 receptor agonists include injectable and oral forms as well.

According to FDA staff, Intarcia has stated that ITCA 650 can improve patient adherence over weekly injectable GLP-1 receptor agonists. "In benefit-risk considerations, however, the potential for improved adherence among individuals who might prefer biannual medical procedures versus once weekly self-administered injections needs to be balanced against any additional risks associated with the drug," the agency reviewers wrote.

Concerning Safety Data

In the phase III clinical program, there were more AKI events in those who received the active device versus placebo. This included all AKI events (1.8% vs 1.0%) and serious events (0.56% vs 0.16%). But after reviewing the death narratives for two participants in the active treatment arm, CDER considered the "actual imbalance" of serious AKI events to be greater than previously suspected, at 0.64% vs 0.16%.

As for MACE concerns, clinical trial data suggested that the device was noninferior compared with placebo. According to 2008 FDA guidance, the upper bound of the 95% confidence interval for cardiovascular events needs to be below 1.8. While MACE risk here technically fell within that range (HR 1.12, 95% CI 0.83-1.51), this was still higher than the GLP-1 receptor agonist class average. "Our current understanding is that an HR of 0.8 to 0.9 would be anticipated (i.e., favorable effect on CV [cardiovascular] outcomes)," FDA staff noted, adding that "concerning trends may warrant collection of additional premarket CV safety data to evaluate CV risk of a product."

In the cardiovascular-focused phase III trial in the program, there was also an imbalance in all-cause mortality leaning towards those on ITCA 650 (49 vs 40 deaths). Both the trends towards higher all-cause mortality and MACE are contradictory to what has been reported with other GLP-1 receptor agonists, which have been shown to significantly reduce these two outcomes.

The placebo-controlled clinical trial tested ITCA 650 at a 20 mcg/day dose of exenatide for 13 weeks -- considered the "initiation dose" -- followed by removal and replacement of the device to deliver a 40 or 60 mcg/day dose for 26 weeks. Of those on ITCA 650, 12.4% discontinued treatment early due to adverse events compared with 5% on placebo.

At week 39, those on 60 mcg/day of ITCA 650 experienced a 1.1% (97.5% CI -1.4 to -0.8%) drop in HbA1c compared with placebo, according to the applicant's analysis; CDER placed the benefit as a clinically meaningful 0.7% (97.5% CI -1.0 to -0.4) reduction in HbA1c.

As far as device complications, of the more than 5,000 patients who received at least one implant, 1.6% experienced an infection related to the device placement, 1.7% experienced application site hemorrhage, and bruising was reported in 1.4%. Of the more than 15,000 total device removals during, 1.1% required help from a surgeon or interventional radiologist.

"The Applicant posits that an implantable device will lead to increased treatment adherence because once implanted, the product does not require patients to take any action," wrote FDA staff. "[Type 2 diabetes mellitus], however, is a chronic condition that requires lifelong treatment. The ITCA 650 device needs to be exchanged every 6 months and the removal/replacement procedure is nontrivial, as it requires a clinic visit and medical procedure by a healthcare professional with specific training."

While the FDA is not required to follow the recommendations of its advisory committees, it typically does.

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