There is exactly one medication that is essential for the treatment of type 1 diabetes: insulin. One hundred years after insulin’s discovery, people with type 1 are still waiting for another important drug designed specifically for them.

Cadisegliatin, an investigative therapy currently entering phase 3 trials, could be the next important drug indicated for type 1. “Cadi,” as its backers have nicknamed it, works in concert with insulin by helping to improve the liver’s glucose regulation system.

Early results suggest that cadisegliatin can flexibly regulate blood glucose levels in response to need by instructing the liver to absorb glucose when there is too much of it in the bloodstream and helping it release stored glucose when there is too little. The result is reduced A1C and reduced risk of hypoglycemia, all at the same time.

Investors, including JDRF’s venture philanthropy fund, just made a big bet on cadisegliatin’s potential, committing $51 million to vTv Therapeutics, the biopharmaceutical company developing the drug. vTv’s Thomas Strack, MD, the business’ chief medical officer, spoke to Diabetes Daily about his company’s innovation.

Type 1 Diabetes and the Liver

For all the attention we pay to the pancreas, the liver, too, plays a pivotal role in glucose regulation. While the liver is not directly damaged by the autoimmune attack that causes type 1 diabetes, damage to the pancreas prevents the liver from doing its job properly.

While we tend to think that blood sugar comes directly from the foods that we eat, the truth is that much of it comes from the liver. The liver can store sugar, release sugar, and even create sugar, all of which it does around the clock to help keep the right amount of sugar in the bloodstream. Much of this activity is regulated by the pancreas, which continually secretes the hormones insulin and glucagon in response to the changing blood sugar concentrations.

Insulin, among its many other functions, instructs the liver to store more sugar and release less. Glucagon does the opposite. Glucagon rescue medication takes advantage of this latter effect — a large dose of synthetic glucagon forces the liver to dump large amounts of sugar into the bloodstream, a life-saving treatment for severe hypoglycemia.

In type 1 diabetes, however, both insulin and glucagon signaling are dysfunctional, and neither is fully corrected by the insulin we inject underneath the skin. The insulin administered by needles, pens, and pumps starts on the body’s periphery and then travels throughout the circulatory system; it cannot mimic the natural liver-signaling activity of insulin, which travels directly to the liver through the portal vein.

Meanwhile, people with type 1 diabetes still secrete glucagon, sometimes too much of it. Without a concentrated source of insulin to serve as a counterbalance, the liver doesn’t take up as much glucose as it should, increasing blood sugar levels and reducing the amount of stored sugar available for emergencies.

“The lack of insulin in the liver cannot be compensated with current insulin delivery technology,” says Dr. Strack.

“How can we help the liver regain its normal activity?”

Introducing Cadisegliatin

Cadisegliatin, which will come in the form of a daily or twice-daily pill, helps address these signaling deficiencies by activating a natural substance in the liver named glucokinase.

Glucokinase is an enzyme that is a kind of middleman between the pancreas and the liver. Throughout the day, but especially after meals, the pancreas secretes insulin and sends it to the liver through the portal vein, where it sparks the synthesis of glucokinase. Glucokinase, in turn, helps the liver remove sugar from the bloodstream and store it in the form of glycogen. This system is sugar-sensitive: The liver will store more glycogen when your blood sugar is high, and less when it is low.

Of course, with type 1 diabetes, none of this works the way it’s supposed to:

“In diabetes, unfortunately, insulin levels are low in the portal system,” says Strack. “When portal insulin levels drop, glucokinase levels drop too, and the ability of the liver to help sustain healthy blood sugar levels really goes down.”

Cadisegliatin is a glucokinase activator. It “binds to glucokinase and enhances its activity,” according to Strack. If we can’t get insulin into the portal vein to help synthesize glucokinase, maybe we can send this glucokinase activator to get the same result.

When glucokinase activity is increased by cadisegliatin, there should be two almost paradoxical benefits simultaneously:

  • Improvement in the liver’s ability to remove glucose from the bloodstream, leading to lower blood sugar levels (A1C)
  • Improvement in the liver’s ability to release glucose during hypoglycemic emergencies, leading to fewer severe hypos

“It can do both tricks,” says Strack.

The Results So Far

In its phase 2 trial, cadisegliatin (then referred to only as “TTP399”) was tested in 46 adults with type 1 diabetes. These volunteers had an average age of about 40 and an average A1C of about 7.5 percent. After 12 weeks of treatment with cadisegliatin, they enjoyed the following benefits:

  • An A1C reduction of 0.36 percentage points
  • A reduction in total insulin use
  • About half as many symptomatic hypoglycemic events in comparison with a control group

Though the glycemic improvements were modest in comparison to those of other novel drugs such as SGLT2 inhibitors and GLP-1 receptor agonists, the reduction in hypoglycemia was unique. SGLT2s are generally considered too dangerous for people with type 1, due to an enhanced risk of diabetic ketoacidosis, and GLP-1s introduce multiple risks that require careful management. In fact, cadisegliatin was not statistically associated with any side effects at all.

“Our compound is hepatoselective,” says Strack. “It only will mainly go into the liver cells, and no other cells in the body.”

The Future for Cadisegliatin

vTv Therapeutics is currently enrolling a phase 3 trial of cadisegliatin. This trial will be the new drug’s largest and most significant test yet, lasting an entire year. The experiment will test the drug in a larger and more diverse population while looking at different dosages and evaluating both safety and efficacy in people with different styles of diabetes management. More trials could follow over the next few years to refine our understanding of cadisegliatin’s potential — including pediatric trials to assess the drug’s potential in children.

“Our goal is to make this accessible for any patients with type 1 diabetes,” Strack says.

In theory, cadisegliatin should also work for people with type 2 diabetes, who likewise experience dysfunction in glucagon regulation, and vTv will soon begin a phase 2 trial to explore the drug’s effects in that population. But the need is less pressing there, because hypoglycemia is less common. People with type 1 diabetes are “the patient population where you can really maximize the benefits.”

There’s no telling how far away we are from the day that cadisegliatin could become available. “Phase 3 programs generally take a few years to complete,” says Strack. “From this juncture, development time ranges from three to five years up until potential [U.S. Food and Drug Administration] FDA approval.”

Bengtsen MB et al. Mini‐Review: Glucagon Responses in Type 1 Diabetes – A Matter of Complexity. Physiological Reports. August 2021.

Klein KR et al. The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes. Diabetes Care. April 2021.

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Read more about A1c, cadisegliatin, GLP-1, insulin, Intensive management, low blood sugar (hypoglycemia), SGLT-2, type 1 diabetes, type 1 diabetes study, U.S. Food & Drug Administration (FDA).

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