A small biotechnology company in Israel says it can dramatically restore insulin production in people with type 1 diabetes by combining two existing medications with a proprietary version of a common supplement.
Levicure’s triple-combo oral therapy is already considered very safe, because it involves two drugs approved by the U.S. Food and Drug Administration (FDA) and a well-known supplement.
Here’s a look at Levicure’s history, research, and upcoming clinical trial.
What Is Levicure’s Triple-Combo Oral Therapy?
Levicure’s therapy combines two drugs and one supplement, which together appear to restore some insulin production in people with type 1 diabetes — especially those who have been newly diagnosed with the condition.
The therapy is a combination of:
DPP4-inhibitors, a common type 2 diabetes medication
Proton pump inhibitors (PPIs), a drug for severe acid reflux
A proprietary version of gamma-aminobutyric acid (GABA), a supplement often used to treat anxiety
None of these medications can restore insulin production in a person with type 1 diabetes on their own. But when combined, Levicure says, the triple-combo therapy works to reverse the progression of type 1 diabetes and restore insulin production by targeting issues within both the immune system and the metabolic system.
Levicure says the combined effect can block beta cell destruction, suppress autoimmunity, and restore beta cell function.
DPP-4 Inhibitors
Normally prescribed to people with type 2 diabetes, DPP-4 inhibitors help protect the body’s production of GLP-1 hormones, the hormones mimicked by the blockbuster diabetes drugs semaglutide (Ozempic) and tirzepatide (Mounjaro). DPP-4 inhibitors prevent the breakdown of your natural GLP-1 hormones. GLP-1 hormones help regulate your appetite, metabolism, natural insulin production, sensitivity to insulin, how quickly you break down food, and how much glucose your liver produces.
DPP-4s have been studied in people with T1D, but the results weren’t good enough to warrant prescribing them regularly.
Proton Pump Inhibitors
Normally prescribed to people with chronic acid reflux, proton pump inhibitors (PPI) reduce the amount of acid your stomach produces.
PPIs also increase levels of gastrin — a hormone that plays a significant role in your stomach’s ability to digest and absorb nutrients from the food you eat. Gastrin can also stimulate insulin production. Decades ago, researchers tested ways to use gastrin to help treat type 1 diabetes but were unable to devise a stable and effective therapy.
GABA
GABA is a neurotransmitter, a chemical naturally produced in the body that carries information between nerve cells and other parts of the body. It is an inhibitory neurotransmitter, which means that it slows down or blocks those chemical connections. You can buy GABA supplements, which are often recommended to calm people with anxiety or stress, over the counter.
GABA does more than modulate brain and nerve activity, however. It also protects pancreatic cells, including the islet cells that produce beta cells that secrete insulin. In people without type 1 diabetes, the beta cells normally release GABA to encourage insulin production, and GABA helps manage how much sugar is released by the liver. GABA also affects the immune system, says Levicure, possibly even suppressing some aspects of the autoimmune attack that causes type 1 diabetes.
In people with type 1, GABA levels are severely depleted. But there is no evidence that over-the-counter GABA supplements alone can improve the problems caused by GABA depletion in people with T1D.
Levicure’s Triple Therapy: Early Results
So far, Levicure’s triple therapy has gone through only one retrospective chart review; it has not been put to the test in a randomized controlled trial, the gold standard for evaluating new drug treatments.
Nevertheless, Levicure is excited about the early results, which suggest that the therapy:
Stops the immune system from attacking beta cells
Creates new beta cells
Helps damaged beta cells regenerate
Preserves existing beta cells
Increases insulin production
Increases GLP-1 hormone production
Reduces how much glucose the liver produces
The results were published in 2023. A total of 19 participants were divided into two groups: those newly diagnosed with type 1 diabetes (within the past 12 months), and those with long-standing type 1 diabetes.
Group 1 Results: Newly Diagnosed
70 percent of participants achieved insulin independence.
Reduced insulin demands by 69 percent.
A1C levels reduced by 38 percent.
C-peptide levels increased by 147 percent.
C-peptide is a substance produced by the pancreas when it produces insulin. It is the simplest way to measure insulin production at varying stages of type 1 or type 2 diabetes.
Group 2 Results: Long-Standing T1D
Reduced insulin demands by 38 percent
Reduced fasting blood glucose by 19 percent
“While patients with long-term type 1 diabetes also experienced improvement in glycemic control and decrease in exogenous insulin demand, it was really the early diagnosed group that showed such an unexpected result,” says Daniil Koshelev, CEO and co-founder of Levicure.
The History of Levicure’s Triple-Drug Therapy
To appreciate Levicure’s progress today, you’ll need to know about a forgotten and underappreciated leader in type 1 diabetes research.
Alex Rabinovitch, MD, dedicated his entire career to the challenge of regenerating beta cells in people with T1D. He was the director of diabetes research at the University of Alberta in Canada and was honored with many awards throughout his career, including the Excellence in Clinical Research from Breakthrough T1D (formerly JDRF).
Beginning in the 1970s, Dr. Rabinovitch identified and explained the key role of the hormone gastrin in the body’s ability to produce insulin. He became a leader in the science of beta cell regeneration and discovered that the combination of PPIs and DPP-4 inhibitors could restore the function of beta cells in the pancreas.
By the 2000s, his experiments had produced remarkable results on mice with type 1 diabetes — the combination of DPP4 inhibitors and PPIs skyrocketed their insulin production. But he couldn’t reproduce the same results in humans.
Despite the failure, the founders of Levicure believed that Rabinovitch was onto something.
“Dr. Rabinovitch was ahead of his time,” says Koshelev. He and his co-founder, Shmuel Levit, MD, PhD, the head of the Endocrinology and Diabetology Institute at Assuta Medical Center in Tel Aviv, Israel, were determined to follow the path that Rabinovitch had started down.
Koshelev says that Rabinovitch was close to a significant breakthrough, but he was missing the key ingredient: GABA.
Could Levicure Help People With Long-Standing T1D?
Though Levicure’s trial had promising results in a small sample of people with long-standing type 1 diabetes, significantly reducing insulin requirements, the company is currently developing its therapy only for people who are newly diagnosed.
Koshelev says that Levicure can’t pursue a larger trial of its therapy in people who have had T1D for years, because so far they have been unable to produce the benefits that the FDA requires for the therapy.
“We have to demonstrate a significant reduction in A1C levels,” says Koshelev. Even if study participants with long-standing T1D see a significant reduction in their daily insulin needs, what matters more to the FDA is a significant reduction in A1C levels.
“For these reasons, we have to focus our trial on a treatment that protects and regenerates beta cells in people newly diagnosed with T1D,” says Koshelev.
For now, we don’t know how long the revitalized beta cells will continue to produce enough insulin. In the longer term, the business hopes to partner with another lab to maximize their lifespan.
“Our goal is to provide a therapy that regenerates beta cells,” explains Koshelev, “and then work with an immunomodulatory company that can help protect those new cells long term from the type 1 immune system.”
Levicure’s Next Clinical Trial
Next, Levicure is preparing for phase 2 of its clinical trial. This next phase will further evaluate the efficacy of the triple-medication therapy.
Here are the key details for the trial, which will include a total of 50 participants and should begin during the summer of 2025:
Study Volunteers Must:
Have been diagnosed with type 1 diabetes within the past six months
Test positive for at least one autoantibody
Have c-peptide levels above 100 pmol/L
Be between 16 and 45 years old
Follow 24 weeks of treatment
Levicure executives anticipate that their therapy will be able to breeze through the approval process:
Green light on safety: All three components of the therapy are already considered extremely safe, which speeds up their developmental and clinical trial process significantly.
Potential accelerated approval: Based on the phase 2 results, Levicure expects an accelerated approval process due to the known safety of the triple-therapy combo. This also means Levicure expects to get the eventual product on the market sooner rather than later.
While it may sound ambitious, Levicure hopes to bring this medication to the market by 2029 — just a few years away!