Drug development for type 1 diabetes is witnessing the beginnings of a possible shift. After decades of focusing almost exclusively on developing new insulins, some biotechs are now running clinical trials for therapies that could slow or even delay type 1 diabetes progression.

In November 2022, a major breakthrough occurred when Provention’s Tzield (teplizumab), an anti-CD3 monoclonal antibody, became the first and only drug approved for delaying the onset of type 1 diabetes. In 2023, four more trials will shed light on Tzield and three experimental therapies for the chronic autoimmune disease: Diamyd Medical’s gamma-aminobutyric acid (GABA), Imcyse’s IMCY-0098, and ProKidney’s renal autologous cell therapy (REACT).

While more sponsors look to test therapies that can slow or delay type 1 diabetes, enrolling patients can pose a major challenge, explains Dr. Kevan Herold, endocrinologist at Yale Medical School, New Haven, Connecticut. Trials that recruit children pose additional regulatory hurdles, and trials that require recently diagnosed patients can have trouble recruiting qualified patients, he notes.

Despite the clinical trial challenges, the unmet need for new therapies in type 1 diabetes looms large. Currently, a diagnosis of type 1 diabetes results in a lifetime of insulin dosing and management, Herold says. “The impact of successful trials for delay or prevention of type 1 diabetes is enormous,” he adds.

Provention targets new population with Tzield

After the breakthrough approval of Tzield for delaying onset of type 1 diabetes, Provention is now studying the treatment in children and adolescents diagnosed with type 1 diabetes within the past six weeks.

The 300-patient Phase III PROTECT trial (NCT03875729) in recent-onset diabetes has topline results expected in H2 2023. As a primary endpoint, the study evaluates a pharmacokinetic measure of C-peptide levels, which signal whether the body is producing insulin. Secondary endpoints include insulin use, hemoglobin A1C (HbA1c) levels, and hypoglycemic episodes.

When designing trials for recent-onset type 1 diabetes, the biggest challenge is selecting the right clinical endpoints, Herold explains. Delaying type 1 diabetes is relatively straightforward as it involves measuring the incidence of disease diagnosis, he says. However, endocrinologists and the FDA often disagree on the optimal endpoints for preserving beta cell function, with regulators often preferring immediate clinical endpoints like glucose control or insulin use, he says.

Diamyd and Imcyse investigate adults with Type 1 diabetes

Diamyd’s remygen and Imcyse’s IMCY-0098 are in clinical trials for adults with type 1 diabetes, but each targets a different stage of disease progression.

The investigator-sponsored, 35-patient Phase I/II REGENERATE-I trial (NCT03635437) of Diamyd’s remygen has results expected by the end of Q1. The study looks at whether patients can regain endogenous insulin secretion and improve quality of life in adults diagnosed with type 1 diabetes for at least five years.

The trial’s primary endpoint is safety, with secondary endpoints including measures of C-peptide and glucagon levels, as well as patient assessments of symptoms. Remygen is an agonist of the GABA receptor, which can lower T-cell autoimmunity to control disease progression.

Meanwhile, the 108-patient Phase II IMPACT study (NCT04524949) of Imcyse’s IMCY-0098 has topline results expected H2. Although the study also targets adults, it requires them to have been diagnosed with type 1 diabetes within the past nine weeks.

Like Tzield’s PROTECT trial, IMPACT has a primary endpoint assessing pharmacokinetic measure of C-peptide levels. IMCY-0098 is a modified peptide that activates cytolytic CD4+ T-cells that destroy the immune cells damaging the pancreas. In an interim analysis of 17 patients, IMCY-0098 increased CD4+ T cell levels in blood samples.

ProKidney aims to regenerate renal cells

ProKidney is assessing whether two injections of autologous renal cells can restore kidney function in patients with type 1 diabetes, type 2 diabetes, or chronic kidney disease.

The 50-patient REGEN-007 trial (NCT05018416) has interim Phase II results expected in H2. As co-primary endpoints, the trial assesses adverse events and estimated glomerular filtration rate (eGFR)—a validated measure of kidney function.

While ProKidney is investigating a cell-based approach to restoring organ function, other companies in the diabetes space are pursuing artificial organs, including the pancreas, to improve glucose management in patients with diabetes. If ProKidney’s REACT injections prove to be effective, they may also answer the high unmet need for therapies in chronic kidney disease.

Bringing industry on board

As the pharma space awaits results from these four important studies in type 1 diabetes, Herold hopes that more investment will start trickling into the field. “As a trial investigator, one of the big challenges is bringing companies to the table,” he explains.

Among active trials testing non-insulin therapies for type 1 diabetes, institutions are the most common sponsors, according to GlobalData’s Clinical Trials Database. Although industry sponsors represent slightly more than half of Phase I and Phase III trials, they only account for 28% of Phase II studies. GlobalData is the parent company of Clinical Trials Arena.

As new therapies like Tzield enter the market, questions remain about the access to and reach of these therapies for the people who need them most. The forthcoming four trial results represent an important step in the long journey of developing and delivering disease-modifying therapies for patients.

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