LOS ANGELES – Injections may be the most common way for patients with diabetes to take insulin, but other modes of delivery are coming of age.
George Grunberger, MD, chairman of the Grunberger Diabetes Institute in Bloomfield Township, Mich., said that at least seven different agents that are being studied for the oral delivery of biologics for diabetes.
He outlined several at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
ORMD-0801 from Oramed is an oral insulin capsule that prevents enzyme degradation and enhances intestinal absorption. Top-line, unpublished findings from a phase 2 study, which the company announced in November 2019, showed that ORMD-0801 significantly reduced hemoglobin A1c levels in patients with type 2 diabetes who were inadequately controlled on other standard-of-care drugs. ORMD-0801 dosed once daily reduced HbA1c by 0.60%, compared with 0.06% by placebo. “We’ll see when it’s going to wind up in the clinic,” Dr. Grunberger said. Oramed is also developing an oral glucagonlike peptide–1 analogue capsule, ORMD-0901, which has potential to be the first orally ingestible GLP-1 analogue.
Inhaled and absorbed insulin
Technosphere insulin (Affreza) is a novel inhalation powder for the treatment of diabetes that was developed by MannKind and approved by the Food and Drug Administration in 2014. Clinical studies have shown that Technosphere insulin delivers insulin with an ultrarapid pharmacokinetic profile that is different from all other insulin products, but similar to natural insulin release. “The idea was to develop a more patient-friendly device to deliver insulin directly into the lungs,” said Dr. Grunberger, who is also a clinical professor of internal medicine and molecular medicine and genetics at Wayne State University, Detroit. “When you inhale this into the lungs, there is one cell layer between the air sac and the circulation, so it works very quickly. The idea is to try to avoid injecting insulin to see if it helps. This is a prandial insulin – you inhale it before meals. The whole idea is that hopefully, you can reduce any fear of delayed postprandial hyperglycemia.”
In a randomized trial of 353 patients with inadequately controlled type 2 diabetes, those in the Technosphere insulin arm significantly reduced HbA1c by 0.8% from a baseline of 8.3%, compared with the placebo arm, which was reduced by 0.4% (P less than .0001; Diabetes Care. 2015;38:2274-81). A greater number of patients treated with Technosphere insulin achieved an HbA1c of 7.0% or less, compared with placebo (38% vs. 19%; P = .0005). Dr. Grunberger noted that, in clinical trials lasting up to 2 years, patients treated with Technosphere insulin had a 40-mL greater decline from baseline in forced expiratory volume in 1 second (FEV1 ), compared with patients treated with comparator antidiabetes treatments. “But once you stop using the drug, FEV1 reverts to normal,” he said. “So, there does not appear to be lasting damage to your lungs and respiratory ability.”
In another development, Oral-Lyn from Generex Biotechnology, which delivers insulin through the oral mucosa, is being evaluated as a potential treatment option. In 2015, Generex partnered with the University of Toronto’s Center for Molecular Design and Preformulations to increase the bioavailability of insulin in the product and to reduce the number of sprays required to achieve effective prandial glucose control. In 2019, the company formed the NuGenerex Diabetes Research Center, which intended to accelerate the development of the reformulated Oral-Lyn-2, for type 2 diabetes, and Altsulin, for the treatment of type 1 diabetes. The programs are expected to initiate in the first quarter of 2020.
In the meantime, studies of intranasally delivered insulin continue to advance. “It works. It lowers glucose, but there is a whole slew of knowledge now about how it can also improve neurocognitive function,” Dr. Grunberger said.