Tethering together typediabetes drugs increases efficacy of
combination therapy

Date:
August 26, 2020
Source:
Duke University
Summary:
Biomedical engineers have shown that the effectiveness of a
two-pronged type 2 diabetes treatment increases when the drugs
are linked by a heat- sensitive tether rather than concurrently
administered. The combination molecule forms a gel-like depot under
the skin that slowly releases the drug. These findings suggest
that this approach to combination drug design could be applied to
disease therapies beyond diabetes.



FULL STORY ========================================================================== Biomedical engineers at Duke University have shown that the efficacy
of a two- pronged type 2 diabetes treatment increases when the drugs
are linked by a heat-sensitive tether rather than simply concurrently administered. The combination molecule is formed by an elastin-like
polypeptide (ELP) linker that forms a gel-like depot when injected under
the skin, which slowly dissolves and releases the active drug over time.


==========================================================================
This novel approach features the commonly prescribed type 2 diabetes
drug glucagon-like peptide-1 (GLP-1) and the compelling drug candidate fibroblast growth factor 21 (FGF21) that together create tight glycemic
control and potent weight-reduction in diabetic mice. Coupled with the slow-release function of the ELP, the effects last longer than one week
with a single injection.

Because GLP-1, a short peptide, and FGF21, a large folded protein, are
such different compounds, these findings suggest that this approach to combination drug design could be applied to disease therapies beyond
diabetes.

The results appear online on August 26 in the journal Science Advances.

"In the burgeoning field of multi-functioning single-molecule diabetes
drug design, researchers primarily unite drugs that are similar in size, structure and function," said Caslin Gilroy, a postdoctoral scholar at the University of California, Berkeley, who led the project while completing
her PhD in biomedical engineering at Duke. "Being able to combine such structurally distinct drugs into a single molecule while maintaining the bioactivity and stability of each is a big technological achievement."
Type 2 diabetes is a progressive disease where body tissues become
resistant to the effects of insulin, which regulates the movement of
sugar from the bloodstream into cells. When this carefully tuned system
breaks down, blood sugar levels remain toxically elevated and a host of
serious complications can follow. While many treatment options exist,
a single drug is rarely able to treat an advanced case. Conventional medications lose their potency over time and frequently cause weight gain, which itself can promote insulin resistance and exacerbate the disease.



==========================================================================
A growing class of drugs is based on GLP-1, a naturally occurring
peptide released from the intestines after a meal. GLP-1 therapy
enhances the release of insulin from the pancreas while promoting
weight loss. However, the high doses of GLP-1 that are sometimes
necessary to maintain healthy blood sugar levels have been shown to
cause gastrointestinal distress. Researchers are exploring combination therapies that strategically pair GLP-1 with additional drugs to maximize glucose control, minimize side effects and augment weight loss.

While most drug combinations incorporate small peptides from the same
family as GLP-1, Gilroy and Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke, chose to work
with FGF21. A metabolic hormone, FGF21 regulates insulin sensitivity,
energy expenditure and fat metabolism within body tissues.

"FGF21 functions through a different mechanism than GLP-1, and we
hypothesized that the two drugs would complement each other nicely," said Gilroy. "GLP- 1 increases insulin secretion by the pancreas, while FGF21 enhances the body's response to the insulin. GLP-1 reduces food intake,
while FGF21 helps burn more calories." But rather than simply injecting diabetic mice with both drugs at the same time, the researchers decided
to link GLP-1 and FGF21 together into a single molecule. This approach
to combination therapy has several advantages. A single molecule is more predictable in how it will disperse through the body, act on its target
tissues and eventually be cleared. A single drug is also beneficial
for the prescribing physician and patient, as it reduces the medication
burden and simplifies the treatment regimen. And the FDA approval process
for a single drug is more straightforward than for a drug mixture.

GLP-1 and FGF21, however, are both peptide-based drugs, heavily reliant
on shape and surface features to function. Tethering the two without interfering with either is easier said than done.



==========================================================================
To form one drug out of two, the researchers turned to the ELP -- a
specialty of the Chilkoti research group. ELPs are chains of repetitive
peptide sequences that are highly disordered in nature. This disorder
provides flexibility, enabling drugs fused at each end of the ELP the room
to do their respective jobs. The modularity of ELPs also make them highly tunable, allowing for the design of the best delivery system possible.

Peptide-based drugs suffer from two notable disadvantages; they have a
short half-life, due to rapid clearance from the body, and they must
be administered by needle. An ELP-based delivery platform, however,
addresses both of these issues.

"Linking the drugs to an ELP allows us to design a compound that is
liquid at room temperature but forms a gel-like depot upon injection,"
said Gilroy. "The depot dissolves over the course of at least a week,
slowly and regularly releasing drug to the system over time." Chilkoti
already has two Phase II clinical trials underway using ELPs as slow-
release delivery systems. One trial aims to treat pulmonary arterial hypertension, while the second involves a potential therapy for COVID-19.

In the study, after verifying that GLP-1 and FGF21 retain their respective functions and potencies when linked together by an ELP, Gilroy and
Chilkoti tested their multi-functioning, slow-release molecule in a
mouse model of diabetes.

The results show that levels of drug circulating in the system remained
steady while blood sugar levels were brought down to a healthy level
and maintained for up to 10 days following a single dosing. Mice treated
with the GLP-1/FGF21 combination drug were better able to recover from a glucose challenge compared to either drug alone, and were the only test
group to lose weight during the trial.

The drug combination also worked better when GLP-1 and FGF21 were
tethered together rather than being delivered as a mixture of individual
drugs. The researchers think that linking them guarantees that GLP-1 and
FGF21 are always acting in concert at the same point in time, allowing
their mechanisms of action to synergize and work together.

"We had speculated that we may see synergy when we combined GLP-1 and
FGF-21 because they have different modes of action," said Chilkoti. "That
was really just a hope at the outset of this project, and we were more
than pleasantly surprised when Caslin showed that combining these drugs
into a single molecule clearly showed a synergistic therapeutic effect
compared to a mixture of the two drugs. The data is so compelling
that we believe it's ready for a company to pursue this strategy
commercially. Duke's Office of Licensing and Ventures is currently
looking to license it." This work was supported by Duke MEDx, a Duke University program that supports engineering innovation in medicine.


========================================================================== Story Source: Materials provided by Duke_University. Original written
by Ken Kingery. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. C.A. Gilroy, M.E. Capozzi, A.K. Varanko, J.Tong, D.A. D'Alessio,
J.E.

Campbell, A. Chilkoti. Sustained Release of a GLP-1 and FGF21 Dual
Agonist from an Injectable 2 Depot Protects Mice from Obesity and
Hyperglycemia. Science Advances, 2020 DOI: 10.1126/sciadv.aaz9890 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200826151300.htm

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