Health

Single-Molecule Combinatorial Therapeutics for Treating Obesity and Diabetes

It will soon be 100 years since Frederick G. Banting, Charles Best, James Collip, and John J.R. Macleod in 1921 demonstrated that extracts of the pancreas had breathtaking beneficial effects to restore the health of patients with diabetes. While their breakthrough revolutionized the medical management of diabetes, the disease continues today to spread worldwide along with a global increase in obesity. Novel unimolecular gut hormone polyagonists have shown unique potential to reverse obesity and diabetes in animal models and are currently being assessed in multiple clinical trials for their efficacy and safety.

INSULIN IS NOT THE CURE

Insulin replacement therapy currently remains a central pillar of diabetes management while additional anti diabetes medicines enhance production, secretion, and action of insulin to improve disease management and enhance patient care. Enormous progress has been made in the precise and continuous quantification of blood glucose, which, together with next-generation insulin pumps, has enabled closed-loop delivery systems, a sizable step forward in the direction of automatized insulin therapy.

The cure still remains elusive, and prevalence of the disease continues to rise across the globe, frighteningly so at an accelerated pace in some of the most populous countries. How can it be that a century after the discovery of insulin, the occurrence of disease is increasing with no cure to stem the epidemic in sight? The vast majority of diabetes worldwide is constituted of what was traditionally characterized as adult-onset, type 2 diabetes (T2D).

This form of diabetes is clearly driven by another pandemic-that of obesity-and to an increasing extent is no longer an adult-onset disease. While the specific molecular mechanisms by which obesity is promoting the diabetes epidemic remain unclear, there is no controversy that in the absence of obesity, the magnitude of the diabetes problem would be far less significant and more manageable.

A RAPIDLY CLOSING WINDOW?

Has the fight against obesity been lost and with it our chances to reverse the T2D pandemic? Considerable worldwide public health efforts promoting healthier lifestyles via education and public policies have not stemmed the increase in diabetes prevalence. While this certainly should not lessen our resolve to identify alternatives to pharmaceutical intervention, it does underscore the increased importance and urgency to identify therapeutics with curative potential.

At this point it appears possible that such a discovery remains the only way to save coming generations from an unimaginable health crisis. The urgency of the situation is magnified by recent insights in epigenetics research. A growing body of data supports a model where daily environmental and behavioral factors can significantly alter stable heritable traits to change protein expression, which cannot be explained by changes in DNA sequence. Changes in histone code or DNA methylation patterns are frequently considered to be the basis of such epigenetic modifications.

Such molecular alterations may promote diabetes susceptibility in subsequent generations, rendering them less likely to respond to novel prevention medicines with otherwise curative potential discovered using current models of the disease. Therefore, there is unprecedented urgency in the scientific community to sufficiently address the pandemic until more creative public policy and effective education might deliver a significant epidemiological impact.

INDIRECT BRAIN TARGETING WITH MULTIPLE SIGNALS

Almost a quarter of a century ago, significant hope and enthusiasm were triggered by Friedman’s discovery of the adipocyte-derived hormone leptin. It suggested the existence of a hormone with sufficient pharmacological effect to manage severe body weight disorders in a fashion analogous to insulin treatment of severe diabetes. Unfortunately, only a very small number of obese patients directly benefit from leptin therapy; the majority of the obese population did not improve in response to treatment.

Still, this unique hormone, which physiologically regulates appetite and energy metabolism, taught us several important points. Most importantly, the seminal role of the central nervous system as the key organ in the regulation of food intake, body weight, energy balance, and system-wide cellular metabolism was embellished. Similar insights were gained from identification of the gastric-derived peptide ghrelin as an endogenous hunger hormone, which along with leptin serves to control body weight.

Today, when accounting for the entirety of data available through genome-wide association studies, it appears quite clear that obesity as the epidemiological driver of the T2D pandemic is predominantly a brain disease. Most of the single nucleotide polymorphisms identified through obesity genetics studies and confirmed in ever larger human populations pertain to proteins expressed or exerting their most important functions in the brain. Therefore, it seems inevitable that the discovery of obesity therapeutics would need to target brain pathways.

HARNESSING GUT–BRAIN COMMUNICATION WITHUNIMOLECULAR POLYAGONISTS

Beginning in 2003, with the goal of engineering novel agents with a superior potency and safety profile, we envisioned molecules modulating several gut-derived signals and thereby indirectly adjusting the control of appetite and metabolism in the brain and other metabolic control organs. Glucagon-like peptide 1 (GLP-1) receptor agonists target hypothalamic control circuits, offer proven metabolic benefits as well as pancreatic incretin action, and induce a small to modest loss of body fat in most patients.

Our key approach was to significantly enhance the efficacy and action profile of incretin-like agents by engineering peptides to also include glucagon action. At the time, this strategy seemed counterintuitive to academic and pharmaceutical communities, as all glucagon-based research was focused on hyperglycemia, not obesity, and directed exclusively to antagonism at the glucagon receptor. How could it be a winning strategy for a new antiobesity drug to include actions of a hormone most widely known for its ability to increase hepatic glucose output? Intriguingly, the action profile of glucagon includes modulation of many metabolic processes beyond glycogenolysis and gluconeogenesis.

Among those, lipolysis in adipose tissue, appetite suppression in the central nervous system, and promotion of energy expenditure recruited our interest to integrate glucagon action into unimolecular polyagonist peptides. We hoped that these desired metabolic actions would synergize with the classic benefits offered by incretin biology and that, simultaneously, GLP-1 agonism would counterbalance the diabetogenic liability of glucagon to provide a therapeutic of superior efficacy in its metabolic profile. The first encouraging studies showed that comparably adding the nine–amino acid COOH-terminal tail that differentiates exendin from GLP-1 to glucagon provided a soluble, stable and selective glucagon agonist that exemplified glucagon’s weight loss–inducing efficacy

TOWARD PERSONALIZED PRECISION MEDICINESFOR DIABETES AND OBESITY

Sufficiently powered clinical studies will demonstrate whether gut hormone polyagonists can reverse the obesity and diabetes pandemic. In parallel, more and more evidence suggests that obesity and diabetes are heterogeneous disease entities consisting of several populations of differing disease subtypes. While the conditions of some patients seem to be clearly driven by morbid obesity, others are affected by pancreatic failure, fatty liver disease, or less well-established pathophysiological conditions such as hypothalamic inflammation.

A new generation of precision medicines may need to target each disease subtype in an appropriately personalized manner. With these needs in mind, we pioneered another series of novel metabolic disease drug candidates. Here we chemically fused steroid hormones such as estrogen or thyroid hormone onto gut hormone peptides. With this novel strategy, we pursued two goals. On one hand, this approach offered more possible hormonal combinations to be assessed for hidden synergistic profiles. On the other hand, the gut peptides would serve as “trojan horse” shuttles and deliver powerful nuclear hormones selectively to metabolically relevant cells while keeping them away from cells where they might have toxic effects.

Several of these drug candidates have been discovered and show additional potential in the treatment of obesity and diabetes. Among them, GLP-1–based estrogen delivery improves hypothalamic neuropeptide balance and decreases body fat mass, and glucagon-based targeting of thyroid hormones improves liver lipid metabolism and atherosclerosis while minimizing adverse effects such as inappropriate increase in body temperature.

We find ourselves at a precarious point where our direction has been enlightened by the advances in modern-age biology but challenged by the global pandemic of disease and the uncertain consequence it represents for future generations. The importance of novel therapeutics with the potential to cure obesity and diabetes cannot be overstated, and the certainty of these being discovered removed from the urgency has never been greater.

What we have witnessed is that through the coordinated action of multiple hormones, often in a targeted fashion, much enhanced efficacy can be achieved and is often devoid of classic toxicity. Within the complexity of polyagonism resides the performance that we most need to address the epidemic of disease. Whether polyagonist-based therapies provide clinical benefits approaching what has been observed in multiple preclinical species will be determined, and we remain optimistic.

Author:Matthias Tschöp and Richard DiMarchi

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