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PEPTIDE TRENDS JULY 2018

MEET US AT THE 35TH EUROPEAN PEPTIDE SYMPOSIUM, 35EPS

The European Peptide Symposium is a well-established biennial peptide conference organized by the European Peptide Society, a nonprofit scientific and educational organization dedicated to advancing and promoting knowledge of the chemistry, biochemistry, biology and pharmacology of peptides. The upcoming 35th European Peptide Symposium, 35EPS, will be held on August 26 - 31, 2018 at the Dublin City University in Dublin, Ireland.

 

The symposium is a unique opportunity to learn about the ever-growing impact of peptide research in a multitude of scientific areas. It has been well attended by Nobel Laureates, world-class scientists, leading scientific investigators, world-renowned commercial partners, publishers and leading companies in the area of peptide research and its applications. The symposium provides therefore a forum to learn and share the latest results and to build productive professional ties with like-minded scientists on a global scale.

 

Bachem supports its customers in the pursuit of groundbreaking discoveries that further scientific advances, particularly in the field of medicine. A comprehensive catalog of biochemicals deliverable ex-stock, an exclusive custom syntheses service for research labs and a full range of services to the pharma and biotech industries complete our service portfolio. Dr. Stefanie Dobitz, Research Chemicals Department at Bachem AG, is excited to meet with our partners, learn their needs for peptides and discuss how Bachem can assist to advance their research.

 

We invite you to visit us at our Booth #2: please contact us to schedule a meeting in advance.

 

We look forward to meeting you at 35EPS!

LHRH AGONISTS AND ANTAGONISTS

LHRH (luteinizing hormone-releasing hormone) is a decapeptide hormone which is synthesized in neurosecretory cells within the hypothalamus and released in a pulsatile fashion into the pituitary portal circulation. Since it controls the secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) from the anterior pituitary gland, it is also designated as GnRH (gonadotropin-releasing hormone). Pulsatile secretion is essential for reproductive functions, sexual development and differentiation. Prolonged non-pulsatile administration of LHRH results in a down-regulation of LH and FSH secretion from the anterior pituitary gland, followed by a suppression of gonadal steroid synthesis. This effect, which is shared by longer-acting GnRH agonists, is used for the treatment of hormone-dependent breast and prostate cancers but also for the treatment of endometriosis and precocious puberty. In reproductive medicine, continuous administration of LHRH agonists serves to prevent a premature LH surge prior to stimulation of ovulation.

 

Back in the 1930s it was already known that the central nervous system in mammals was able to control the release of LH and FSH from the pituitary gland. Electrophysiological studies hinted at the hypothalamus as a link between the central nervous system and the pituitary gland. The mechanism of this hypothalamic control, however, was not elucidated at that time. The discovery of the hypothalamo-hypophyseal portal system, a blood vessel system linking the hypothalamus to the anterior pituitary, led to the hypothesis that neurosecretory cells of the hypothalamus synthesize hormones which are released into the portal system and thereby stimulate the secretion of hypophyseal hormones.

 

This concept of the hypothalamic control of the adenohypophysis was strongly supported by the findings by J.D. Green and G.W. Harris. They discovered that interruption of the blood vessels between the hypothalamus and the anterior pituitary, by sectioning the pituitary stalk, prevented ovulation in their experimental animals. In 1960, S.M. McCann and coworkers demonstrated that an extract from rat hypothalami contained an activity which could cause the release of LH from the pituitary. After a tremendous effort to isolate and determine the structure of this LHRH activity, A.V. Schally et al. were able to present the structure of porcine LHRH at the congress of the Endocrine Society in San Francisco in 1971. Porcine LHRH was shown to be a decapeptide with the following structure:

 

Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (pEHWSYGLRPG amide)

 

Since LHRH also stimulates the release of FSH from the pituitary gland, it was also designated as GnRH (gonadotropin-releasing hormone, gonadorelin).

 

In the following years, LHRHs from other species were isolated and sequenced. It turned out that most vertebrates produce two, and fishes even three LHRH isoforms, LHRH, LHRH II, and LHRH III. The LHRH isoform I from all mammalian species examined had the same amino acid sequence as the porcine peptide. The sequence of GnRH II, pEHWSHGWYPG amide, which was first isolated from chicken brains in 1984, is conserved even stronger. It could be detected in all jawed vertebrates examined. In contrast to the other vertebrate classes, the sequences of the piscine GnRH isoforms show a considerable diversity. One of them, lamprey GnRH III (peforelin), has found use in veterinary medicine.

 

After the primary structure of gonadorelin had been elucidated, an enormous research interest focused on the determination of the structure-activity relationship. Since GnRH has a very short half-life of several minutes only, the fundamental aim behind this effort was to find more potent and longer-acting agonists for clinical applications. Until now, several thousand LHRH analogs have been synthesized. It became clear that the amino acids at the positions 1 and 4-10 were essential for binding to the receptors and for exerting conformational effects.

 

The elucidation of the primary structure of LHRH and the availability of synthetic GnRH and GnRH analogs have contributed to the understanding of the physiological role and mode of action of the hormone. LHRH secretion occurs in a pulsatile fashion which is due to oscillations in the electrical activity of the LHRH pulse generator in the medial basal hypothalamus. The pulsatile secretion pattern, which is different in males and females, changes during sexual maturation. Regulation of the secretion pattern is essential for proper development and maintenance of reproductive functions. The diverse effects of LHRH and its agonists, dependent on the way of administration either as a single injection, multiple injections, or continuous infusion, have found their use in reproductive medicine and in the treatment of various disorders.

 

Application of LHRH Agonists and Antagonists

Continuous administration first results in an increase in the release of LH and FSH, followed by a down-regulation due to pituitary desensitization. As a consequence, gonadal steroid plasma concentrations are lowered to castrate levels. The inhibiting effect of GnRH agonists on gonadal steroids is used in the treatment of hormone-dependent prostate and breast cancer. Continuous administration of LHRH agonists is also indicated for the treatment of endometriosis since reduction of the estrogen levels results in a shrinking of the uterine and ectopic endometrial tissue. Besides these indications, LHRH-induced suppression of gonadal hormone levels also allows the treatment of central precocious puberty, which is manifested by the premature development of sexual characteristics. Most children with this disorder grow fast at first, but also finish growing before reaching their full potential height. Normal puberty is resumed after discontinuation of GnRH agonist administration. In assisted reproduction, LHRH agonists are used to prevent a premature LH surge and consequent ovulation prior to ovarian stimulation with gonadotropins. GnRH and its agonists have found broad use in veterinary medicine and animal husbandry. Generally, variation of the dosage regimen of these drugs allows to induce either reproduction or infertility in animals. The most important application of gonadorelin itself is the synchronization of ovulation in dairy cattle. Other LHRH agonists are used in the reproduction management of companion animals and horses. For example, administration of deslorelin triggers ovulation in estrous mares and a single dose of buserelin induces ovulation in bitches in heat.

 

GnRH agonists can be conveniently applied in humans and animals as slow-release depot formulation. Diffusion-controlled drug delivery systems for subcutaneous implantation allow continuous administration of the drugs during months or even years. For example, once-yearly histrelin-releasing implants for the treatment of prostate cancer in men or deslorelin-releasing reservoirs implanted for the prolonged reversible castration of male dogs and the suppression of the oestrus of bitches. The elevation of LH with the dysregulation of the hypothalamic-pituitary-gonadal axis at menopause and andropause could play a role in modulating the susceptibility to, and progression of, Alzheimer’s disease (AD). This hypothesis has raised substantial interest in GnRH agonists as potential drugs for the therapeutic intervention in AD patients. A beneficial effect could be observed in mild-to-moderate cases when administering leuprolide to female AD patients.

 

Apart from LHRH agonists, LHRH antagonists have also found their way into assisted reproduction. The severe side-effects of the active compounds developed initially, which were caused by concomitant histamine release, could be vastly reduced in the safe and effective «third-generation» (e.g. abarelix, acyline, antide (iturelix), cetrorelix, ganirelix) and «fourth-generation» (e.g. degarelix, ozarelix) GnRH antagonists. Cetrorelix and ganirelix have gained approval for the inhibition of premature LH surges in women undergoing controlled ovarian (hyper)stimulation. A major disadvantage of LHRH agonists in the treatment of hormone-dependent cancer has been attributed to their potential stimulatory effects on the hormone-dependent cancer cells due to initial stimulation of LH and FSH and the concomitant increase in gonadal steroid levels. Antagonists have therefore been suggested to offer a safer treatment option. Abarelix and degarelix have been approved by the FDA for the treatment of advanced prostate cancer in patients who can’t be treated by other options.

 

Since the isolation and characterization of LHRH about 50 years ago, we have enormously improved our understanding about its function in physiological and developmental processes. The search for potential GnRH analogs has provided us with information about a multitude of agonists and antagonists. Research in this field is still active, and there is a persistent interest in finding more sophisticated drug regimens, especially as long-lasting depot formulations, and in gaining approval for additional therapeutic applications.

 

Explore our wide selection of LHRH Agonists and Antagonistsin our online shop.

 

References

Product Monograph LHRH Agonists and Antagonists

LHRH AGONISTS AND ANTAGONISTS IN CLINICAL DEVELOPMENT

Luteinizing Hormone-Releasing Hormone (LHRH), also known as Gonadotropin-releasing hormone (GnRH), and its analogs are widely used as therapeutics in clinical medicine. LHRH analogs have proved useful in a variety of indications including precocious puberty, delayed puberty, endometriosis, uterine fibroids, hirsutism, dysfunctional uterine bleeding, assisted reproduction, premenstrual syndrome and hormone-dependent tumors. The discovery of the amino acid sequence of LHRH led to the development of analogs with agonistic or antagonistic properties in order to increase potency and duration compared to native LHRH (1). Today, there are several peptide-based LHRH analogs in clinical development as shown in Table 1.

Table 1 Peptide-based LHRH analogs in Phase I to Phase III Clinical Development (2)

Product Name Active Ingredient Condition Treated Highest Phase Companies
FP-001 leuprolide mesylate Prostate Cancer Phase III Foresee Pharmaceuticals Co Ltd
CAM-2032 leuprolide acetate Metastatic Prostate Cancer Phase II Camurus AB
Ovarest® leuprolide Endometriosis Phase II Enteris BioPharma Inc
ISR-48 triptorelin acetate Human Immunodeficiency Virus (HIV) Infections (AIDS); Genital Herpes Phase II ISR Immune System Regulation Holding AB
LY01005 goserelin Breast Cancer, Prostate Cancer; Endometriosis Phase I Luye Pharma Group Ltd
Triptorelin triptorelin Prostate Cancer Phase I GP Pharm SA
LY01007 triptorelin acetate Breast Cancer; Prostate Cancer; Uterine Leiomyoma (Uterine Fibroids); Endometriosis; Women Infertility; Precocious Puberty Phase I Luye Pharma Group Ltd

Phase III Candidate

FP-001 is under development by Forsee Pharmaceuticals for the treatment of prostate cancer. This product candidate is a 6-month depot of leuprolide mesylate that utilizes a controlled-release delivery system developed by Foresee. In 2017, Forsee announced positive top-line results from a Phase III registration study in advanced prostate cancer in which the primary efficacy end-point was achieved in 97% of subjects. The company plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency in 2019 (2).

 

Phase II Candidates

Camurus AB is developing, CAM-2032, a long-acting leuprolide acetate product candidate for the treatment of metastatic prostate cancer. CAM-2032 uses Camurus’ proprietary FluidCrystal® injection depot technology. In 2016, Camurus announced positive results from a Phase II trial of two different doses of CAM-2032 and Eligard® (2).

 

Another leuprolide candidate, Ovarest®, is under development by Enteris BioPharma for the treatment of endometriosis. Enteris’ candidate uses Unigene’s patented oral technology and offers a daily oral option for women suffering from endometriosis (3). In 2018, Enteris announced positive results from a Phase IIa clinical trial of Ovarest® for the treatment of endometriosis. Enteris is planning a Phase IIb trial for later in 2018. The company also plans to begin development for additional indications such as uterine fibroid tumors and prostate cancer (4).

 

ISR-48 is under development by Immune System Regulation Holding AB for the treatment of Human Immunodeficiency Virus (HIV) infections. The product candidate is triptorelin acetate formulated as a depot for injection. The company is planning a Phase IIa trial of ISR048 to evaluate efficacy and safety for HIV-1 reservoir reduction in ART treated HIV-1 infected patients. In addition, the company is planning a Phase IIb trial of ISR48 in untreated HIV patients (2).

 

Phase I Candidates

Luye Pharma Group is developing LY01005, an extended release form of goserelin, for the treatment of breast cancer, prostate cancer and endometriosis. This product candidate makes use of a microsphere injection technology. In 2018, the company registered a Phase I study with the U.S. National Institutes of Health to assess the pharmacokinetics, pharmacodynamics and safety of LY01005 versus Zoladex® in patients with prostate cancer (2).

 

GP Pharm SA is developing a triptorelin depot candidate for the treatment of prostate cancer. GP Pharm’s triptorelin candidate utilizes a microsphere drug delivery system. The company has completed a Phase I clinical study to evaluate triptorelin depot administered as one dose per month (2).

 

In addition to extended release goserelin, Luye Pharma Group is developing an extended release formulation of triptorelin acetate, LY01007, for the treatment of breast cancer, prostate cancer, uterine fibroids, endometriosis, infertility and precocious puberty. Like Luye Pharma’s LY01005, this candidate is based on microsphere technology. LY01007 is in a Phase I study to compare the pharmacokinetics, pharmacodynamics and safety of triptorelin acetate sustained-release microspheres and Diphereline (2).

 

Conclusion

There are several LHRH analogs in development, many of which make use of specialized delivery systems. To support companies and organizations working in this area, Bachem offers generic peptide APIs such as leuprolide acetate, goserelin acetate and triptorelin acetate. In addition, Bachem offers over ninety LHRH analogs, agonists and antagonists for research, a comprehensive custom peptide synthesis service and the production of New Chemical Entities.

 

References

(1) P. Kumar and A. Sharma, Gonadotropin-releasing hormone analogs: Understanding advantages and limitations, Journal of Human Reproductive Sciences. 7(3), 170-174 (2014)

(2) GlobalData (2018)

(3) Ovarest, Enteris BioPharma (2018)

(4) Positive results in Ovarest® clinical trial for endometriosis treatment, Enteris BioPharma, January 3 (2018)

MEET BACHEM: ADAM HIBBERT, FACILITIES MANAGER

PT: What is your official job title at Bachem?

Adam: Facilities Manager

 

PT: How long have you been with Bachem?

Adam: I have been with Bachem for 1 year and 1 month.

 

PT: Briefly, what do you do at Bachem?

Adam: I manage the facilities team which controls the maintenance of the facility including all utilities and production equipment/machinery ensuring minimal downtime and quick responses to breakdowns or operating issues.

 

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

Adam: My background is engineering within GMP pharmaceutical companies. I came up through the apprentice route and completed qualifications and training in mechanical, electrical and instrumentation to HNC/HND level whilst working on site for a vaccine manufacturer. Throughout all my roles I have focused on continuous improvement in processes, people and equipment. This has made my career progression possible from Maintenance Engineer to Site Engineer and now Facilities and Maintenance Manager.

 

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

Adam: My hobbies are mainly focused around health and keeping fit. I am an ex-competing Thai boxer and still like to keep healthy with weight lifting, hiking and climbing. Last year I took part in the Welsh 3000s which is a challenge of climbing a total of 15 peaks all over 3000 feet in under 24 hours.

 

PT: What makes a perfect day for you?

Adam: My perfect day is a productive day, for me I need to accomplish something positive everyday no matter how small. That way you are always moving forward.

 

PT: What is your business motto?

Adam: I like to focus on continuous improvement and always moving forward no matter how small the steps may be. Looking at this from an engineering perspective, if you have to fix something, can it be improved in the process and not just replace like-for-like?

 

PT: What do you like most about your job?

Adam: The aspect I enjoy most in my job is the autonomy and trust. Knowing that my co-workers have the confidence in me to know I can make the correct decisions and be relied on.

 

PT: Have you had any particular expectation when you came to Bachem and have these been fulfilled?

Adam: As I have a background in large Pharmaceutical GMP sites, I was keen to see how Bachem UK would compare to this. I came to Bachem UK at a time of expansion and also working towards ISO 13485 standard. I was impressed with how the site and people embraced change and took it as an opportunity to improve themselves, as well as their processes. I am excited to see how our site develops in the coming years with further expansions and developments.

 

PT: What do you do for fun?

Adam: I am a very family driven man; there is nothing I enjoy more than spending time with family and friends. I also like to get involved in charity work. «Alzheimer’s society» is one that is close to my heart and I like to do what I can to fund raise for this cause.

PT: Thank you very much Adam.

PEPTIDE HIGHLIGHTS

Interesting news about peptides in basic research and pharmaceutical development:

Opening up a drug delivery route: Discovery of a new vehicle peptide-Science Daily

Synthetic peptides enhance antibiotic attack of skin infections in mice-EurekAlert!

HIV Vaccine Elicits Antibodies in Animals that Neutralize Dozens of HIV Strains-National Institute of Allergy and Infectious Diseases

Simulations show how beta-amyloid may kill neural cells-Purdue University

LITERATURE CITATIONS

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

 

M.Y. Chen et al.

Transdermal delivery of luteinizing hormone-releasing hormone with chitosan microneedles: a promising tool for androgen deprivation therapy.

Anticancer Research 37, 6791-6797 (2017)

 

M. Chmielewska et al.

The programmed DNA elimination and formation of micronuclei in germ line cells of the natural hybridogenetic water frog Pelophylax esculentus..

Scientific Reports 8, 7870 (2018)

 

J. Hu et al.

Enhanced cellular uptake of LHRH-conjugated PEG-coated magnetite nanoparticles for specific targeting of triple negative breast cancer cells.

Materials Science and Engineering: C 88, 32-45 (2018)

 

D.O. Larco et al.

GNRH-(1-5) inhibitsTGF-beta signaling to regulate the migration of immortalized gonadotropin-releasing hormone neurons.

Frontiers in Endocrinology 9, 45 (2018)