A new pill taken once a day could be the first of its kind to treat type 1 diabetes (T1D).

Currently under development by North Carolina-based pharmaceutical company vTv Therapeutics, this future medication is called TTP399. That’s an investigational-stage moniker that will eventually be replaced with a snappier brand name.

If it makes it to market, vTv suggests that this daily pill, taken alongside insulin, could mean lower A1C levels, more glucose time in range (TIR) without risk of increased hypo or hyperglycemia (dangerously high or low blood sugars), decreased insulin needs, and no side effects that often accompany add-on medications promising better blood sugars.

To date, no oral treatments like this exist for T1D. There are only similar type 2 diabetes (T2D) medications, often used by people with T1D “off-label” (meaning unsanctioned by the Food and Drug Administration).

“This would be history-making,” said Dr. John Buse, director of the Diabetes Center and Translational and Clinical Sciences Institute at the University of North Carolina (UNC) at Chapel Hill School of Medicine.

“What’s most significant is that it’s the first that could be approved in the United States for type 1 diabetes, and it doesn’t have the sort of Achilles heel we’ve often seen with other treatments used alongside insulin,” he said.

This small molecule compound is a liver-selective glucokinase activator (GKA), meaning it targets the liver and essentially helps improve the body’s natural glucose-sensing and response.

Working within the liver, TTP399 allows for more efficient processing of glucose into energy so blood sugars don’t rise as dramatically as they would otherwise. (Blood glucose levels spike after eating, especially after eating carbohydrates.)

GKA compounds have been an area of interest in diabetes drug development since the 1990s, especially for T2D, but have often led to adverse effects in people, and thus haven’t been as successful for new treatments as once hoped.

This is the first to focus on T1D.

Clinical research firms up the promise TTP399 offers for T1D treatment.

In June 2019, vTv published results from the first part of its two-pronged phase II trial dubbed the Simplici-T1 trial.

This multicenter “learn and confirm” study included 20 participants on both insulin pumps and CGMs in the first leg, showing an overall A1C decline of 0.6 percent after 12 weeks on the drug, as well as decreased insulin usage, without any hypos or incidents of diabetic ketoacidosis (DKA).

A second leg followed with results released in early 2020, including 85 participants with T1D using CGMs with both insulin pumps and MDI (multiple daily injection) therapy to broaden the study participation.

Results showed A1C improvements much like the first leg, with a secondary analysis eliminating the possibility that extra insulin was responsible for the improved A1C. Overall, the A1C reduction was 0.21 percent for those taking TTP399.

Buse, who led the study, notes that it’s important in any clinical trial for an insulin therapy add-on medication that you closely account for any insulin changes made during the course of the trial. That happened here and yielded the same positive results, he says.

Dr. John Buse

Two-thirds of the study participants saw both a decrease in A1C as well as a decrease in the amount of insulin they needed, he says — including an 11 percent decrease in how much insulin was used for mealtime doses.

Also impressive was how TIR improved by approximately 2 hours each day for those using TTP399 during the trial period.

“This tells me that at least for some subset of patients, this drug is doing exactly what we want it do,” Buse said, adding that it’s unclear so far whether the fewer hypos were a result of the decrease in insulin doses.

“But again, we’re seeing that these results are not a fluke, as they continue to be happening in the trials,” he said.

To date, 12 clinical trials have examined this compound, including a 6-month study in which participants with T2D saw sustained, meaningful reductions in A1C as well as no hypoglycemia or DKA.

Buse says he believes one of the most game-changing aspects of TTP399 is that it presents no traditional adverse effects, such as higher cholesterol or nausea — common in past research on GKA molecules for T2D, and often seen with adjunctive medications used alongside insulin.

“I’m very enthusiastic about this as an adjunctive therapy for type 1 diabetes to use with insulin, and it can have a substantive impact,” especially for patients who struggle with precise insulin dosing, Buse said.

“A fly in the ointment, the only thing that gives me pause in this whole story, is that we’re still talking about a handful of patients right now,” he cautioned.

“We definitely need bigger trials with more people, and more sites beyond just UNC. Then we’ll know with more certainty what the benefits are,” he said.

Interestingly, the concept for TTP399 came about roughly 20 years ago — just after vTv was first founded in 2000 as TransTech Pharma, using proprietary technology to develop small molecule compounds.

At the time, pharma giant Novo Nordisk, one of the “big three” insulin-makers worldwide, was interested in a small molecule that targets GKA in the liver but not the pancreas.

Then-TransTech used its technology to discover this particular small molecule and worked with Novo for several years.

But a little more than a decade ago, Novo moved away from small molecules and abandoned this research; vTv got to keep the TTP399 compound it had discovered, and carry on the research itself.

“We’ve gone from an idea with this drug all the way to testing it in type 2 and now focusing on type 1,” said vTv CEO Steve Holcombe.

Dr. Carmen Valcarce

Leading the way on this TTP399 research is Dr. Carmen Valcarce, vTv’s executive vice president and chief scientific officer, who’s been involved with this medication since the start.

An inventor with her name attached to numerous patents through the years, Valcarce had worked at Novo Nordisk overseas as GKA project lead before leaving Spain in 2007 to join vTv in the United States and continue with her research on this particular compound.

“It’s been incredible to see her idea grow from the ground up, coming across the sea from Spain with her husband and son to become U.S. citizens and become part of our team in moving this forward,” Holcombe said. “She is now one of the experts here in the U.S. from the clinical and scientific point of view, and has such a passion on this.”

As a small company roughly an hour west of the prestigious North Carolina Research Triangle anchored by major research universities, vTv has about two dozen employees and is focusing on TTP399 as well as seven or eight other small molecules in early to middle clinical trial stages.

“This is our lead horse right now, and where most of our investors are interested,” Holcombe said. “We do think we’re in a unique position, and we’ll keep pushing it forward.”

Holcombe says they hope to get FDA approval by year-end 2020 to start the phase III trial with more participants and sites, and begin finalizing product labeling.

Some of that timeline may depend on COVID-19 delays in being able to conduct clinical research trials, particularly with blood draws and medication dosing happening in person.

With all of that in mind, it could be at least another year or two before late stage clinical trials take shape to begin moving toward commercialization.

Holcombe points out that vTv is a clinical-stage company, meaning they’d likely work to find a partner down the road interested in acquiring the medication or licensing it for sale. (This isn’t uncommon and happens regularly in pharma.)

That means once TTP399 moves through clinical research completion and FDA evaluation, it will likely be launched and sold by another pharma company — potentially even insulin-maker Novo, which was there in the beginning.

“We’ve talked with some larger pharma companies who’ve said that once we have more data to show, they may be interested. Those folks are interested because they’d like to be able to throw this into the medicine bag and offer it along with everything else they’re selling,” Holcombe said.

As people living with T1D for dozens of years ourselves, we would love to throw an easy and effective once-a-day pill into our medicine bags, too.