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PEPTIDE TRENDS OCTOBER 2019

MEET US AT IN-COSMETICS NORTH AMERICA

in-cosmetics North America is the region’s most interactive show for personal care ingredients.

This interactive exhibition brings together personal care ingredients suppliers with finished product manufacturers and indie brands, each looking to immerse themselves in the latest trends, innovations, techniques and ingredients that are transforming new product development.

 

The 2019 edition will take place on October 23rd - 24th at the Jacob K. Javits Convention Center in New York City.

 

Due to the continued interest on peptides as ingredients in cosmetic products, most notably in anti-aging therapy, and our offer for cosmeceutical-related products, our excellent service for custom peptide synthesis, and our capabilities for small to industrial scale synthesis of peptides of any complexity we are confident to be the ideal partner in the development and production of cosmetic peptides.

 

We are excited to meet with our customers at this part of the world and discuss how Bachem can help with their cosmetic peptide needs. We invite you to visit us at our Booth C22: please contact us to schedule a meeting in advance.

 

We look forward to meeting you at in-cosmetics North America 2019!

GLUCAGON

Glucagon, named for its «glucose agonist» effect, is a linear peptide secreted by pancreatic α cells. This peptide hormone was first identified in 1923 when a component in pancreatic extracts was found to induce hyperglycemia. Glucagon plays a role in maintaining a normal concentration of glucose in the blood and it counteracts the effect of insulin in glucose metabolism regulation (Figure 1) (1). Glucagon prevents blood glucose from dropping to dangerous levels by stimulating the conversion of glycogen to glucose in the liver in a process called glycogenolysis. In addition, glucagon prevents the liver from consuming some glucose so that more glucose is able to enter the bloodstream. Finally, glucagon is involved in hepatic gluconeogenesis, the production of glucose from noncarbohydrate precursors such as the carbon skeleton of glucogenic amino acids.

 

 

 

Figure 1 Opposing Effects of Glucagon and Insulin

 

 

Source: Bachem Product Monograph – Diabetes Peptides, August 2019

 

 

Glucagon is a 29 amino acid peptide and its sequence is known to be highly conserved across mammalian species. Structurally, glucagon is related to the secretin family of peptide hormones. The glucagon sequence is synthesized as proglucagon and proteolytically processed into glucagon by prohormone convertase 2 (PC2) within the α cells of the pancreatic islets. Proglucagon is also expressed in the intestinal tract. In the intestinal enteroendocrine cells (L-cells), prohormone convertase 1/3 (PC1/3) is greater than PC2 action so the proglucagon sequence is cleaved to yield GLP-1, GLP-2, oxyntomodulin, glicentin and IP2 (Figure 2). There is evidence that PC1/3 is also expressed in the α cells of the pancreatic islets but at lower levels than PC2 suggesting that there is some pancreatic islet production of GLP-1 (2).

 

 

 

Figure 2 Processing of Proglucagon in the Pancreas and the Intestine

(GRPP: Glicentin-related Pancreatic Peptide, IP: Intervening Peptide; GLP: Glucagon-like Peptide)

 

 

 

Glucagon Receptor

The glucagon receptor (GCGR) sequence is also highly conserved across mammalian species. Binding of glucagon to GCGR activates adenylyl cyclase through G proteins of the Gs subtype which then generates cAMP and leads to activation of PKA. The largest amount of glucagon binding takes place in the liver and kidney. Consequently, the liver and kidney are involved in glucagon clearance from the circulation. Binding also occurs in the heart, adipose tissue, the CNS, adrenal gland and spleen (2).

 

Glucagon Therapy

Despite advances in the treatment of type 1 diabetes such as continuous subcutaneous insulin infusion, continuous glucose monitoring, fast-acting insulin analogs and other treatments, hypoglycemia is a common complication of insulin therapy in people with diabetes. Even common exercise poses particular challenges for people with type 1 diabetes due to increased risk of hypoglycemia. Hypoglycemia is a major concern because it is potentially life-threatening. Hypoglycemia may lead to sudden death, possibly due to cardiac arrhythmia, and if hypoglycemia is prolonged it can lead to cerebral death (1).

 

Injectable glucagon is the recommended treatment for severe hypoglycemia episodes because the patient is unable to consume carbohydrates. On the other hand, the intake of oral carbohydrates is recommended for non-severe hypoglycemia. The frequency of hypoglycemia in people with type 1 diabetes is estimated to be two events per week of non-severe hypoglycemia and one event per year of severe hypoglycemia (1).

 

Injectable glucagon is an approved treatment for severe hypoglycemia episodes. Glucagon is unstable in a liquid so it is available as a lyophilized powder that requires reconstitution by a caregiver before use. Marketed injectable glucagon products include Novo Nordisk's GlucaGen® Hypokit and Eli Lilly's Glucagon Emergency Kit (3).

 

Due to the challenges associated with injectable glucagon, nasally administered glucagon was developed as a ready-to-use and needle-free rescue device. In June 2019, Eli Lilly and Company announced that the U.S. Food and Drug Administration approved BAQSIMI (glucagon), the first nasally administered glucagon for the treatment of severe hypoglycemia in people with diabetes ages four years and above (4). The nasal route of administration makes it easier for non-trained caregivers to administer glucagon compared to parenteral administration. In addition, there is less of a chance of erroneous administration of insulin instead of glucagon due to the different route of administration (1).

 

For the management of mild or impending hypoglycemia, mini-dose glucagon is often used off-label and administered as a small subcutaneous injection. Mini-dose glucagon is used in the management of sick days in type 1 diabetes children when they are unable to eat such as during a gastrointestinal illness. Also, mini-dose glucagon has proven useful for diabetic children at camps. Camps are an example of situations where the level of physical exercise is increased and there is more frequent risk for hypoglycemia (5).

 

Researchers are also developing systems, called dual-hormone artificial pancreas systems for the automatic delivery of glucagon and insulin. These systems infuse intermittent mini-boluses of glucagon in response to glucose sensor data to treat or prevent hypoglycemic episodes. Potential benefits for type 1 diabetes patients from the artificial pancreas systems are that they will allow for better, safer and easier glucose control. Short-term studies have confirmed an additional reduction in hypoglycemic risks with the use of glucagon in an artificial pancreas system (6).

 

New formulations of glucagon are in development including stable preparations of glucagon for injection or continuous subcutaneous infusion in artificial pancreas systems. These new formulations and the recent approval of nasal glucagon could help ease the burden and risks for those living with diabetes. Bachem offers a selection of Glucagon and Glucagon-Like Peptides for research and Glucagon as a generic active pharmaceutical ingredient (API).

 

References

1) P.Beato-Vicora and F.Arroyo-Diez, New uses and formulations of glucagon for hypoglycaemia. Drugs in Context 2019, 8, 212599

2) D.A.Sandoval and D.A.D’Alessio, Physiology of proglucagon peptides: Role of glucagon and GLP-1 in health and disease. Physiological Review 2015, 95(2), 513-548

3) Global Data. 2019

4) BAQSIMI™ (glucagon) nasal powder 3 mg, the first and only nasally administered glucagon to treat severe hypoglycemia in adults and children with diabetes ages four years and older, Approved by FDA. Lilly 2019

5) S.T.Chung and M.W.Haymond, Minimizing morbidity or hypoglycemia in diabetes a review of mini-dose glucagon. Journal of Diabetes Science Technology 2015, 9(1), 44-51

6) N.Taleb et al., Glucagon in artificial pancreas systems: Potential benefits and safety profile of future chronic use. Diabetes, Obesity Metabolism 2017, 19(1), 13-23

GLUCAGON DRUG CANDIDATES IN CLINICAL DEVELOPMENT

Novel formulations of glucagon and glucagon analogs offer promise for people with diabetes, congenital hyperinsulinism and other related diseases. Glucagon is unstable in aqueous solution so most commercially available products contain lyophilized glucagon that requires reconstitution prior to injection. However, the recent U.S. Food and Drug Administration (FDA) approval of Eli Lilly’s BaqsimiTM (glucagon nasal powder), provides a more convenient needle-free option for treating severe hypoglycemia. Other innovate glucagon product candidates are in clinical development along with a glucagon analog as shown in Table 1.

Table 1 Glucagon Product Candidates in Phase I to Pre-registration

Product Name Pipeline Indication(s) Highest Development Stage Companies
Gvoke HypoPen Hypoglycemia; Hypoglycemia-associated autonomic failure; Hyperinsulinemia Pre-registration Xeris Pharmaceuticals
Dasiglucagon Hyperinsulinemia; Hypoglycemia; Type 1 Diabetes Phase III Zealand Pharma AS
Biochaperone Glucagon Hypoglycemia Phase I Adocia SAS

Clinical Drug Candidates

Xeris Pharmaceuticals is developing the GvokeTM HypoPen for the treatment of hypoglycemia, hypoglycemia-associated autonomic failure and hyperinsulinemia. Gvoke is a room-temperature stable non-aqueous glucagon solution. In 2018, Xeris Pharmaceuticals submitted a New Drug Application (NDA) to the FDA for their glucagon product candidate for the treatment of hypoglycemia in type 1 diabetes patients (1). In June 2019, the company announced that the FDA extended the Prescription Drug User Fee Act (PDUFA) goal date for its review of the Gvoke NDA to September 10, 2019 (2).

 

Dasiglucagon (ZP-4207) is under development by Zealand Pharma for the treatment of hypoglycemia, type 1 diabetes with an artificial pancreas system and congenital hyperinsulinemia. Zealand’s dasiglucagon is a glucagon analog that is stable in liquid formulation. Dasiglucagon is administered intravenously, intramuscularly and subcutaneously as a liquid formulation. The company is planning to file an NDA during the second half of 2019 for dasiglucagon in the treatment of severe hypoglycemia (1).

 

Adocia is developing a stable ready-to-use glucagon for the treatment of hypoglycemia. The company’s glucagon drug candidate utilizes the Biochaperone technology, a group of polysaccharides designed to form a reversible molecular complex in order to solubilize and stabilize protein therapeutics. The company is planning a Phase I/II study of BioChaperone Glucagon for initiation in 2019 (1).

 

Conclusion

Innovative and needle-free forms of glucagon are desired to overcome the limitations associated with parenteral glucagon and are potential game-changers in the treatment of severe hypoglycemia. For researchers and organizations working in this field, Bachem offers a selection of Glucagon research peptides, a comprehensive custom peptide synthesis service, a selection of Generic Active Pharmaceutical Ingredients including Glucagon and the production of New Chemical Entities.

 

References

(1) GlobalData 2019

(2) Xeris Pharmaceuticals receives notification of PDUFA date extension for Gvoke™. Xeris Pharmaceuticals 2019

MEET BACHEM: RINSON MANKUDIYIL, PART-TIME WORKING STUDENT IN GLOBAL MARKETING

PT: What is your official job title at Bachem?

Rinson: I am a part-time working student in the marketing team. Currently, I am also in the Business Development & Sales team equally as a part-time worker.

 

PT: How long have you been with Bachem? Where did you work before Bachem?

Rinson: I am here at Bachem since April 2019. Before that, I worked for a year in the finance department of the Canton of Basel-Stadt as Junior Project Management Officer.

 

PT: Briefly, what do you do at Bachem?

Rinson: In the Global Marketing Team, I am responsible for two internal team projects. At Business Development & Sales, I am temporary supporting a big project.

 

PT: What is your academic background/degrees or training?

Rinson: I am currently completing my Bachelor of Science in Business IT at the FHNW as a part-time student. Before that, I completed my apprenticeship as a computer scientist in systems engineering and then absolved my technical vocational Matura.

 

PT: What do you like to do outside of work?

Rinson: In my free time, I like to spend time with my friends and family. My hobbies are to play football and do some workouts at the gym.

 

PT: What makes a perfect day for you?

Rinson: If I can go to bed in the evening with the conscience that I have put meaningful work, help or activity on the day.

 

PT: Thank you very much Rinson.

PEPTIDE HIGHLIGHTS

Interesting news about peptides in basic research and pharmaceutical development:

Anti-cancer immune cells protect against MS in mice-FierceBiotech

New mechanism that could counteract obesity-Science Daily

Peptide hydrogels could help heal traumatic brain injuries-EurekAlert!

Lilly’s new diabetes treatment now available in USA-ThePharmaLetter

LITERATURE CITATIONS

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

N.Al-Zamel et al.

A dual GLP-1/GIP receptor agonist does not antagonize glucagon at its receptor but may act as a biased agonist at the GLP-1 receptor.

International Journal of Molecular Sciences 20, (2019)

 

I.M.Modvig et al.

Peptone-mediated glucagon-like peptide-1 secretion depends on intestinal absorption and activation of basolaterally located calcium-sensing receptors.

Physiological Reports 7, e14056 (2019)

 

T.Morais et al.

GLP-1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats.

Journal of Cellular Biochemistry 120, 14573-14584 (2019)

 

W.Yue et al.

The GLP-1 receptor agonist liraglutide protects against oxidized LDL-induced endothelial inflammation and dysfunction via KLF2.

IUBMB Life 71, 1347-1354 (2019)