In 2015, Intarcia Therapeutics was flying high.
The biotech unicorn’s value was estimated at some $5 billion as it seemed poised to enter into a market estimated at more than $20 billion with an extended-release diabetes drug implant, ITCA 650. Intarcia touted the implant as an easier and more convenient way for patients with Type 2 diabetes taking GLP-1 agonists to control their blood sugar.
But Intarcia’s outlook became considerably less sanguine when the FDA rejected its NDA for ITCA 650 in 2017 due in part to potential safety issues, setting off a multi-year effort to earn approval that continues to this day.
As Intarcia struggled to push through, Vivani Medical, a clinical-stage biopharma company focused on developing miniature subdermal implants is now entering phase 2 with its own extended-release diabetes drug implant, NPM-119. The NanoPortal technology uses the same drug, exenatide, as Intarcia to manage blood sugar levels. But CEO Adam Mendelsohn believes the smaller device, which is less invasive for a healthcare provider to insert, may succeed where Intarcia seems to be falling short.
The question is: Will one, both, or neither Intarcia nor Vivani be able to bring this highly-anticipated technology across the finish line?
A boon for patients
There are two different exenatide products on the market already to treat Type 2 diabetes, both injectables from AstraZeneca. Bydureon BCise is a once-weekly injection, and Byetta, taken twice daily.
“There was a lot of hype around the possibility of an implant being able to provide Type 2 diabetes therapy with twice-yearly administration,” Mendelsohn said. “Intarcia never went public, but they raised almost $2 billion from top-tier investment groups.”
A common problem doctors face when working with diabetes patients is that only half of them take their medication as prescribed, Mendelsohn said. An implant like Vivani’s device, which is worn for six months at a time, delivers a steady dose to tackle that problem. The value of improving adherence is tremendously high, he said, but the appeal isn’t limited to those at risk of missing doses.
“Some people, I think, will just enjoy the convenience,” Mendelsohn said. “Even people that do regularly take their medicine may prefer to know that they don't have to be thinking about it. They can live relatively worry-free about the treatment burden.”
Patients also skip medication doses due to cost concerns, but manufacturing a twice-yearly device could offer a less expensive option than daily or weekly dose delivery systems.
Facing setbacks
Intarcia’s ITCA 650 seemed ready to deliver on the promise of this technology based on trial results of its twice-yearly implantable device, a small osmotic mini pump delivery system about the size of a matchstick that is inserted under the skin in the abdominal area. But despite solid efficacy data, FDA officials saw safety red flags.
Approved exenatide products and other drugs in this category do carry the risk of potentially serious side effects. In fact, Bydureon BCise includes a boxed warning that it’s linked to a higher risk of Thyroid C-cell tumors, as do other drugs in this class. Both it and Byetta are also linked to a range of other potential side effects including acute pancreatitis and serious kidney injuries, some of which were severe enough to require a transplant.
"One of the features of our technology is there are no moving parts. The release is very regular and controlled."
Adam Mendelsohn
CEO, Vivani Medical
And regulators said that based on Intarcia’s data, it appeared ITCA 650 could trigger a higher risk of acute kidney injuries — sometimes fatal or causing damage that led to a need for dialysis — than other approved exenatide products or drugs in the class. The FDA also expressed concern that ITCA 650 appeared to elevate cardiovascular risks, including a higher rate of adverse cardiovascular events, such as heart attacks, strokes and cardiovascular death. People with Type 2 diabetes already face an elevated risk in this area.
Intarcia has been going back and forth with the FDA for years, unsuccessfully trying to get the product back on track. Currently, company officials are awaiting a hearing to make a last-ditch case for approval.
“The chief scientist of the FDA granted them a hearing, so they are going to get a hearing by June 20,” Mendelsohn said. “This is rare. The FDA has not really been granting hearings, and the drug division, which is the reviewing agency, recommended against providing a hearing.”
Intarcia contends that the adverse effects flagged by the FDA are similar to other drugs in this category that have gotten approved, provided they included the risks on the warning label. In a letter to the FDA, the company stated: “Intarcia continues to believe that the facts in the NDA record allow for the approval of ITCA 650 with labeling consistent with this class of drugs, on the basis of Intarcia’s existing clinical data.”
But Mendelsohn said he isn’t convinced that the data Intarcia cites in its defense doesn’t show elevated risks.
“The FDA believes that the daily variability of release is responsible for that clinical safety issue,” Mendelsohn said. “In fact, in this letter from July of last year ... they say that the root cause of the critical safety issues can reasonably be concluded to be irregular and uncontrolled exenatide release.”
An opportunity
If the problem is, as the FDA contends, related to the device, and not the drug, then it’s potentially a best-case scenario for Vivani. While NPM-119 also uses exenatide, it has an entirely different device.
“One of the features of our technology is there are no moving parts,” he said. “The release is very regular and very controlled to the point where even on two-and-a-half hour time intervals we can't measure fluctuations being present.”
This may improve its safety profile, but also potentially reduce some of the more bothersome gastrointestinal side effects, which the company plans to study in its upcoming trials. If so, it could be another selling point for patients.
In the meantime, Vivani is watching to see how the Intarcia saga plays out. Intarcia could potentially get another denial, or the FDA could decide on an alternative path, such as approval with a label notifying patients of potential risks. Either way, Vivani sees a path forward for NPM-119 — one with or without competition.
“We began this effort, expecting that (Intarcia) would get approved and we’d come in with a better mousetrap that was smaller, that would be easier and preferable for patients and physicians,” Mendelsohn said.
But now, provided trials move forward as expected, they also see the potential to tout the benefits as a unique technology.
“That's probably our critical differentiator and why we think we will be able to ultimately obtain an approval, addressing the same massive market opportunity, but using a different drug delivery technology that overcomes challenges that that ITCA 650 has faced,” Mendelsohn said.
