Europe/India/Near East USA Asia
Bachem AG Bachem Americas, Inc. Bachem Japan K.K.
Hauptstrasse 144 3132 Kashiwa Street Ueno Bldg, 8F
4416 Bubendorf - Switzerland Torrance, CA 90505 - USA 1-9-10 Nihonbashi-Horidome cho, Chuo-ku
Tel +41 58 595 2021 Tel +1 888 422 2436 Tokyo 103-0012 - Japan
Fax +41 58 595 2040 Tel +1 888 4BACHEM Tel +81 3 6661 0774
Email sales.ch@bachem.com Fax +1 310 539 9428 Email sales.jp@bachem.com
  E-mail sales.us@bachem.com  

PEPTIDE TRENDS JULY 2019

MEET US AT IMAP 2019

The 9th International Meeting on Antimicrobial Peptides (IMAP 2019) will take place at the Utrecht University, Utrecht, The Netherlands on August 28-30, 2019. The meeting covers the antimicrobial activity of peptides and their role in regulation and modulation of the immune system.

 

Bachem supports its customers in the pursuit of groundbreaking discoveries that further scientific advances, particularly in the field of medicine. With a record of accomplishment in custom synthesis projects, the high quality of our peptides for research and development projects and our capacity to upscale the production of simple and modified peptides, we are the Pioneering Partner for Peptides. Bachem’s comprehensive catalog of biochemicals, our exclusive custom synthesis service for research labs and a full range of services to the pharma and biotech industries complete our service portfolio.

 

Bachem's offer for research of the immune defense system comprises a broad choice of AMPs and fragments deliverable ex-stock, including LL-37, Cecropins and Defensins.

 

Dr. Stefanie Dobitz, Group Leader Custom Synthesis at Bachem AG, is excited to meet with you, learn your needs for peptides and discuss how Bachem can assist to advance your research.

 

We invite you to drop by our booth or to contact us to schedule a meeting in advance.

 

We look forward to meeting you at the IMAP 2019!

BIOAVAILABILITY OF PEPTIDES

One of the major challenges for the use of peptides as therapeutics is their bioavailability. Bioavailability is defined as the percentage of a substance, which reaches the systemic circulation after the drug has been administered. The route of administration has a strong impact on this percentage.

 

Intravenous or subcutaneous administration allows for a less hindered uptake of a drug substance compared to oral or nasal administration and therefore a higher bioavailability of the drug. At the same time, these routes of administration are very invasive and in some cases health professionals are needed to administer the drug, making them unsuitable for a widespread application. While subcutaneous self-administration of drugs is possible, it faces problems in terms of patient compliance, due to the aforementioned invasiveness.

 

High patient compliance is one of the key arguments for nasal and oral application as non-invasive routes of administration. Unfortunately, peptides administered via these routes can exhibit low bioavailability, sometimes in the single digit range. However, there are tools available to increase oral or nasal bioavailability, which can be rationalized once the mechanisms of transport across epithelial layers has been understood.

 

Transport Mechanism Across Epithelial Cell Layers

As depicted in Figure 1, there are two main pathways a drug molecule can take to cross the epithelial cell layer

 

  • The paracellular pathway, in which a drug molecule passes through tight junctions between cells
  • The transcellular pathway, in which the molecule traverses the cell itself either passively or in a vesicle (transcytosis)

 

 

Figure 1 Schematic Representation of the Two Principal Pathways of Transport Across an Epithelium

 

Paracellular transport is especially important for hydrophilic drug molecules, since it allows them to pass into the circulation avoiding the hydrophobic section of the lipid membrane of the epithelial cells. The main drawback of paracellular drug delivery is that this mode of transport in inherently passive. This means, that only the concentration gradient between both sides of the epithelial layer influences the diffusion rate. This is especially disadvantageous in the case of lipophilic molecules, since their poor aqueous solubility leads to a low effective concentration and subsequently a shallow gradient, even if administered in high doses.

 

Intracellular passive transport is possible as well. The presence of transporters in the cell membrane does additionally allow for the possibility of active intracellular transport. In general, the intracellular pathway requires a molecule with at least a partially lipophilic character, since the lipid bilayer of the cell membrane is an environment with a much lower dielectric constant compared to the surrounding aqueous milieu. Intracellular transport is especially important for drugs targeting the brain, since the capillaries of the blood-brain barrier (BBB) allow only for transcellular transport. Since the cellular membrane also offers a higher surface area than the junction between cells, the intracellular uptake of peptide drugs is of great interest in drug development.

 

Enhancing Cell Permeability of Peptides

A major impediment to peptide absorption into a lipid bilayer is the energy, which is required to break the hydrogen bonds between the peptide and water molecules. The amine and amide groups of a peptide represent a potential source of hydrogen bonds. The interaction of these groups with water molecules can be easily inhibited by replacing a hydrogen atom with a methyl group. This increases the lipophilicity of the molecule and leads to an overall higher cell permeability. One of the first therapeutic peptides, which was identified to be orally bioavailable – Cyclosporin A – does indeed show a high degree of N-methylation (see Figure 2)

 

Figure 2 Structure of Cyclosporine A – Methylated Nitrogen Atoms Are Highlighted in Green.

 

 

Methylation of the amide backbone of a peptide leads to a cis-configuration of the peptide bond, which induces β-turn motives. These have been proposed to be beneficial for cell permeability. Bachem offers many different N-methylated building blocks and you can find more information in our brochure “N-Methylated Amino Acid Derivatives”.

 

Another option to increase the lipophilicity of peptide drugs is the introduction of fatty acid side chains, such as stearic acid or palmitic acid (Pam). This is a commonly used strategy in the synthesis of GLP-1 analogs, for which Bachem offers the commonly used building block Fmoc-Lys(palmitoyl-Glu-OtBu)-OH.

 

However, increasing the lipophilicity of a peptide drug does not guarantee an increase of bioavailability. Highly lipophilic peptides can exhibit unfavorable solubility in water, and at some point, will actually reside in the lipid bilayer of the cell membrane instead of crossing it. A balance between hydro- and lipophilicity is key for enhanced cell permeability.

 

Peptide Modifications to Increase Metabolic Stability

Slow cell penetration is especially problematic during nasal uptake. Nasally-applied drugs are cleared from the nose with a half-life of approximately 21 minutes due to the regeneration of the respiratory mucosa. Therefore, if the cell penetration rate were the only factor governing bioavailability, oral uptake would result in a higher bioavailability compared to the nasal route, due to the longer gastric residence time of the drug.

 

In reality, this is not the case since peptides are rapidly degraded by exopeptidases present in the nose, the gastrointestinal tract, as well as in the bloodstream. Therefore, a successful drug candidate needs to be somewhat metabolically stable in order to reach its therapeutic target before losing its bioactivity through degradation. Even after passing into the bloodstream, unmodified peptides do not circulate for more than a few minutes because of enzymatic degradation. In order to allow a drug molecule to reach its target before degradation, a variety of strategies are available.

 

  • Modification of the C- and N-terminus drastically improves the stability towards exopeptidases and is a feature also observed in hormones and neuropeptides, such as TRH and α-MSH (see Figure 3).

 

Figure 3 Structures of the Hormones TRH (left) and α-MSH (right). Stabilizing Modifications Are Highlighted at the N-Terminus (green) and C-terminus (magenta).

 

 

  • Cyclization can be considered a modification encompassing both termini of the peptide chain and has been shown to increase peptide stability. For more information about cyclic peptides please consult our Peptide Trends May 2019.

  • N-methylation of amide bonds is not only beneficial for membrane permeability, as outlined in the previous section, it can also protect the amide bond from degradation by endopeptidases.

  • Changing the chirality of one or more amino acids may increase the resistance to proteolytic degradation and renders the peptide sequence potentially less immunogenic. However, depending on the mechanism of action, a change in chirality in the active sequence could lead to a loss in activity.

  • Incorporation of other non-proteinogenic amino acids can be performed to increase the stability of the peptide. Especially sterically hindered amino acids such as 2-aminoisobutyric acid (Aib) or tert-leucine (Tle) confer a great degree of stability, but carry the risk of influencing the conformation of the peptide. Bachem offers a wide variety of alpha-methyl amino acids.

  • Side Chain modifications such as glycosylation or PEGylation exist as additional tools to increase metabolic stability.

 

In summary, both metabolic stability and cell permeability are important factors governing the bioavailability of peptides and there are numerous tools available to influence them. You can find the building blocks to do so in our online shop and should you require further assistance, our professional custom synthesis service is at your disposal.

 

References

A.Celine, S.Claudio, Converting a peptide into a drug: Strategies to improve stability and bioavailability. Current medicinal chemistry 2002, 9, 963-978

E.S.Khafagy, N.Kamei, M.Takeda-Morishita, Cell-penetrating peptide-biodrug strategy for oral and nasal delivery: Review of recent findings. Journal of Experimental & Clinical Medicine 2012, 4, 198-202

Y.Ozsoy, S.Gungor, E.Cevher, Nasal delivery of high molecular weight drugs. Molecules 2009, 14, 3754-3779

A.F.B.Räder, F.Reichart, M.Weinmüller, H.Kessler, Improving oral bioavailability of cyclic peptides by N-methylation. Bioorganic & Medicinal Chemistry 2018, 26, 2766-2773

C.K.Wang, D.J.Craik, Cyclic peptide oral bioavailability: Lessons from the past. Peptide Science 2016, 106, 901-909

DELIVERY ROUTES FOR BIOAVAILABILITY OF PEPTIDES

Advancements in drug delivery technologies have sought to overcome the challenges associated with peptides, such as poor bioavailability that results from their low permeability of biological membranes and rapid degradation in the body. Peptides are frequently administered by subcutaneous injection but only a few subcutaneous systems offer sustained peptide release. As a result, uncomfortable injections can be necessary, often several times daily (1). To provide convenience and patient adherence, oral administration of peptides as well as other non-invasive routes such as nasal and inhalational have been a main focus of formulation research for the delivery of peptide therapeutics. Currently, there are approximately 70 peptide drug candidates in various phases of clinical development that are delivered via oral, nasal and inhalational routes. A selection of these peptides in Phase III or the Pre-Registration stage of development are shown in Table 1.

Table 1 Peptides in Phase III or Pre-Registration Phase of Development with Oral, Nasal or Inhalational Delivery

Product Name Generic Name Route of Administration Indication Highest Phase Companies
LY-900018 Glucagon Nasal Hypoglycemia Pre-Registration Eli Lilly and Co
Tbria Calcitonin Oral Post-menopausal Osteoporosis Pre-Registration Tarsa Therapeutics Inc
NN-9924 Semaglutide Oral Type 2 Diabetes; Cardiovascular Risk Factors Pre-Registration Novo Nordisk AS
Libicore -- Nasal Female Hypoactive Sexual Desire Disorder Phase III Ivix Ltd
Aviptadil Aviptadil Inhalational Sarcoidosis Phase III Relief Therapeutics Holding AG
Mycapssa Octreotide acetate Oral Acromegaly Phase III Chiasma Inc

Advancements in drug delivery technologies have sought to overcome the challenges associated with peptides, such as poor bioavailability that results from their low permeability of biological membranes and rapid degradation in the body. Peptides are frequently administered by subcutaneous injection but only a few subcutaneous systems offer sustained peptide release. As a result, uncomfortable injections can be necessary, often several times daily (1). To provide convenience and patient adherence, oral administration of peptides as well as other non-invasive routes such as nasal and inhalational have been a main focus of formulation research for the delivery of peptide therapeutics. Currently, there are approximately 70 peptide drug candidates in various phases of clinical development that are delivered via oral, nasal and inhalational routes. A selection of these peptides in Phase III or the Pre-Registration stage of development are shown in Table 1.

 

Oral Delivery Candidates

TbriaTM, a once-daily oral formulation of recombinant calcitonin, was under development by Tarsa Therapeutics for the treatment of post-menopausal osteoporosis (2). In 2019, R-Pharm JSC acquired the rights to Tbria and R-Pharm JSC will assume responsibility for its clinical development. This oral formulation of calcitonin utilizes a patented oral delivery technology that is licensed from Enteris Biopharma (3).

 

Novo Nordisk is developing NN-9924, a once-daily oral formulation of semaglutide that is produced as a tablet. The oral formulation is based on Eligen® technology developed by Emisphere Technologies and utilizes SNAC (N-(8-(2-hydroxybenzoyl) amino) caprylic acid), an absorption-enhancing excipient. In March 2019, the company filed for marketing approval in the United States and Canada for the treatment of type 2 diabetes and cardiovascular (CV) risk reduction indication in adults with type 2 diabetes. In April 2019, Novo Nordisk filed for marketing authorization with the European Medicines Agency. Assuming that oral semaglutide is approved, it will become the first glucagon-like peptide-1 (GLP-1) receptor agonist available in a tablet form (2).

 

Mycapssa®, an oral octreotide capsule, is under development by Chiasma for the treatment of acromegaly, a disorder that can develop when a benign tumor of the pituitary gland releases excess growth hormone. The capsules utilize Chiasma’s Transient Permeability Enhancer (TPE) technology that facilitates gastrointestinal absorption of the drug. The company is conducting a Phase III trial of Mycapssa, named Chiasma Optimal, for the maintenance therapy of acromegaly. Assuming positive data from the Phase III trial, Chiasma expects to file a New Drug Application with the U.S. Food and Administration by the end of 2019. If Mycapssa is approved, it will become the first oral somatostatin analog treatment of acromegaly (2).

 

Nasal and Inhalational Candidates

LY-900018, a nasal glucagon mist, is being developed by Eli Lilly for the treatment of hypoglycemia in type 1 and type 2 diabetes patients. Eli Lilly has filed for market approval of nasal glucagon in the United States, the European Union and Japan for severe hypoglycemia and for pediatric hypoglycemia in the United States (2). The nasal glucagon is administered in a ready-to-use device which is inserted into a person’s nostril and allows a caregiver to release the glucagon which then passes through the nasal cavity lining (4).

 

Ivix, a subsidiary of Ovoca Bio, is developing Libicore, a peptide that targets the limbic-hypothalamic pituitary axis, for the treatment of female hypoactive sexual desire disorder. Libicore is administered as a nasal spray. In 2019, Ovoca Bio announced positive top-line results from a Phase III clinical trial of Libicore (2).

 

Relief Therapeutics Holding is developing aviptadil, an analog of vasoactive intestinal polypeptide for the treatment of sarcoidosis. The route of administration for the company’s aviptadil candidate is inhalation. Relief Therapeutics is expected to begin enrollment for a Phase III study to evaluate the efficacy of aviptadil in the treatment of patients with pulmonary sarcoidosis (2).

 

Conclusion

The development of formulations for the oral delivery of peptides and other non-invasive routes of administration is a promising area of research. To support organizations developing peptides, Bachem offers a comprehensive custom peptide synthesis service, the production of New Chemical Entities, and Generic Active Pharmaceutical Ingredients.

 

References

(1) M.Kovalainen, Novel delivery systems for improving the clinical use of peptides. Pharmacol. Rev. 67(3), 541-561 (2015)

(2) GlobalData (2019)

(3) R-Pharm JSC acquires rights to Tarsa’s TBRIA™, novel oral treatment for post-menopausal osteoporosis. Tarsa Therapeutics (2019)

(4) Eli Lilly launches nasal glucagon drug applications in Europe and US. Diabetes.co.uk (2018)

MEET BACHEM: RAMONA GANTENBEIN, CONTRACT MANAGER

PT: What is your official job title at Bachem?

Ramona: I am a contract manager.

 

PT: Briefly, what do you do at Bachem?

Ramona: My job includes preparing and reviewing commercial and quality agreements, negotiating contract terms in cooperation with internal stakeholders as well as managing record keeping for the contracts.

 

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

Ramona: I have been with Bachem for 1 ½ years now. Previously, I was doing traineeships in a pharmaceutical company and at the department of finance in Basel.

 

PT: What is your academic background?

Ramona: I have a master’s degree in law from the University of Zurich.

 

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

Ramona: I like spending time with family and friends, reading, swimming and cooking.

 

PT: What do you like most about your job?

Ramona: When reviewing a contract, I do not only have to take legal considerations into account but also technical and commercial ones. I find this combination very interesting and it allows me to learn more about various business-relevant topics. Furthermore, I appreciate the exchange with the other departments when working on a contract as well as the direct communication with our customers.

 

PT: Thank you very much Ramona.

PEPTIDE HIGHLIGHTS

LITERATURE CITATIONS

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

 

Y.Mao et al.

Chylomicron-pretended nano-bio self-assembling vehicle to promote lymphatic transport and GALTs target of oral drugs.

Biomaterials 188, 173-186 (2019)

 

S.Bonengel et al.

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs.

Journal of Controlled Release 273, 21-29 (2018)

 

M.Rezvani et al.

Development and characterization of nanostructured pharmacosomal mesophases: an innovative delivery system for bioactive peptides.

Advanced Pharmaceutical Bulletin 8, 609-615 (2018)

 

T.Vorherr et al.

Modulation of oral bioavailability and metabolism for closely related cyclic hexapeptides.

International Journal of Peptide Research and Therapeutics 24, 35-48 (2018)