Ultrafast insulin in the pipeline thanks to CSIRO

CSIRO researchers have worked with Stanford University scientists to develop a new ultrafast insulin that potentially works four times as fast as current commercial fast-acting insulin formulations.

Scientists at CSIRO Manufacturing in Victoria are working on a monomeric insulin that has overcome stability problems usually associated with this molecular structure.

Monomeric insulin is usually too unstable for practical use, but the researchers used new materials science techniques to develop an excipient that allows the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable for 25  hours compared to five hours for commercial fast-acting insulin lispro formulations (Humalog).

Reporting their results in Science Translational Medicine, they say that in a porcine model of insulin-deficient diabetes, the UFAL formulation exhibited peak action at 9 ± 4 minutes, whereas commercial Humalog exhibited peak action at 25 ± 10 min.

“These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes,” they say.

In their paper, the researchers explain that current commercial formulations of insulin contain a mix of three forms: monomers, dimers and hexamers. Scientists have assumed monomers would be the most readily useful in the body but, within vials, the insulin molecules are drawn to the surface of the liquid where they aggregate and become inactive.

This is where the custom polymer that is attracted to the air/water interface is effective.

“We focused on polymers that would preferentially go to that interface and act as a barrier between any of the insulin molecules trying to gather there,” said Joseph Mann, a graduate student in the Stanford lab of Professor Eric Appel, and co-lead author of the paper. Crucially, the polymer can do this without interacting with the insulin molecules themselves, allowing the drug to take effect unimpeded.

Finding the right polymer with the desired properties was a long process that involved a trip to CSIRO in Melbourne, where a fast-moving robot created approximately 1500 preliminary candidates.

This was followed by processing and testing individually by hand at Stanford to identify polymers that successfully exhibited the desired barrier behaviour.

In commercial insulin – which typically remains stable for about 10 hours in accelerated ageing tests – the polymer drastically increased the duration of stability for upwards of a month. The next step was to see how the polymer affected monomeric insulin, which on its own aggregates in one to two hours.

It was another welcome victory when the researchers confirmed that their formulation could remain stable for over 24 hours under stress.

“In terms of stability, we took a big step backward by making the insulin monomeric. Then, by adding our polymer, we met more than double the stability of the current commercial standard,” says Caitlin Maikawa, a graduate student in the Appel lab and co-lead author of the paper.

The researchers were then able to validate their new monomeric insulin formulation in diabetic pigs – the most advanced non-human animal model – and found that their insulin reached 90% of its peak activity within five minutes after the insulin injection. For comparison, the commercial fast-acting insulin began showing significant activity only after 10 minutes.

Furthermore, the monomeric insulin activity peaked at about 10 minutes while the commercial insulin required 25 minutes. In humans, this difference could translate to a four-fold decrease in the time insulin takes to reach peak activity.

“It’s really unprecedented,” says Professor Appel, who is senior author of the paper. “This has been a major target for many big pharmaceutical companies for decades.”

The monomeric insulin also finished its action sooner. Both beginning and ending activity sooner makes it easier for people to use insulin in coordination with mealtime glucose levels to appropriately manage their blood sugar levels.

The researchers say they now plan to apply to the Food and Drug Administration for approval to test their insulin formulation in clinical trials with human participants.

And because their insulin formulation activates so quickly – and, therefore, more like insulin in a person without diabetes – the researchers are excited by the possibility that it could aid the development of an artificial pancreas device that functions without the need for patient intervention at mealtimes.

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