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PEPTIDE TRENDS AUGUST 2019

MEET US AT BASEL LIFE 2019, IN BASEL, SWITZERLAND

Basel Life 2019 will take place at the Congress Centre Basel in September 9-12, 2019. Bachem supports Basel Life by sponsoring the Peptide Therapeutics Forum at the Innovation Forums, September 10-11. The presentations will give an outlook to the latest news on drug discovery and successful development of therapeutic peptides. The first day is focused on topics to be addressed earlier during peptide optimization, while the second day is more focused on issues related to later-stage development.

 

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 portfolio.

 

Christophe Chambard, Business Development Manager 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 at the Peptide Therapeutics Forum or to contact us to schedule a meeting in advance.

 

We look forward to meeting you at Basel Life 2019!

PARKINSON’S DISEASE

Parkinson’s disease (PD) affects about ten million people worldwide (1). PD is a progressive neurodegenerative disorder that involves dopaminergic neurons in the area of the brain known as the substantia nigra. Symptoms often progress slowly over time and vary from person to person. Common PD symptoms and signs include tremor, bradykinesia, rigidity and imbalance. Individuals may also experience non-motor symptoms including depression, olfactory dysfunction, REM sleep behavior disorder, constipation and cognitive impairment. While the specific cause of PD is unknown, researchers believe that multiple factors such as aging, genetics and environmental factors play a role (2). James Parkinson, a London-based general practice physician, first described the disease in 1817 and reported on many clinical features of the disease in his publication on “the shaking palsy”. It was not known until the 1960s that researchers discovered that the loss of dopamine producing cells that help direct muscle activity is a primary hallmark of PD. This discovery ignited new research and development efforts for PD treatments (3). The symptoms and signs of PD are known as Parkinsonism. The most common form of Parkinsonism is Idiopathic Parkinson’s or primary Parkinsonism but approximately 15% of people with symptoms have what is called an atypical parkinsonism disorder that can be harder to treat. Types of Parkinsonism include the following (4):

 

  • Idiopathic Parkinson’s

  • Atypical Parkinsonism

    • Multiple System Atrophy (MSA)

    • Progressive Supranuclear Palsy (PSP)

    • Corticobasal Syndrome (CBS)

    • Dementia with Lewy Bodies (DLB)

    • Drug-induced Parkinsonism or secondary parkinsonism

    • Vascular Parkinsonism (VP)

 

Pathophysiology

PD is characterized by diminished dopamine levels due to the degeneration or death of neurons in the substantia nigra. Dopamine is responsible for relaying messages between the substantia nigra and other parts of the brain to control movements of the body. Normal dopamine levels regulate the excitability of striatal neurons, which are involved in controlling the balance of body movement. Inadequate dopamine levels cause less inhibition of the activity of striatal neurons, which allows them to over fire leading to uncontrolled movements (5). Motor symptoms associated with PD appear when approximately 60 to 80% of dopamine-producing cells are damaged (3).

 

 

Source: Studio BKK/Shutterstock.com

 

Additionally, Lewy bodies, abnormal accumulations of the protein α-synuclein, are found in the substantia nigra neurons of PD patients. Researchers are still trying to understand the role of α-synuclein and how this protein may influence PD and Lewy body dementia (LBD). LBD encompasses the two related clinical diagnoses of PD dementia and dementia with Lewy bodies (6). Some research efforts have been focused on blocking the formation of α-synuclein to slow the progression of PD. α-Synuclein exists in several structural forms and researchers have identified that the β-sheet oligomer form of α-synuclein produces a significant loss of dopamine neurons in the substantia nigra. Reducing the formation and propagation of the β-sheet oligomers could be a new route for therapeutic intervention (7).

 

PD patients also have a loss of nerve endings that produce norepinephrine, an important chemical messenger that controls automatic body functions such as blood pressure. This loss results in some of the non-movement related symptoms of PD such as fatigue and irregular blood pressure (2).

 

Current drugs for PD improve symptoms but they do not slow or stop disease progression. By the time that patients start experiencing PD symptoms, substantia nigra neurons are already impaired or lost. Researchers are working towards developing new treatments for PD and identifying biomarkers of the disease that may provide opportunity for early diagnosis.

 

Peptides and Proteins in PD Research

Glial cell line-derived neurotrophic factor (GDNF) is a potential treatment for PD. In preclinical studies with an animal model of PD, a single injection of microencapsulated GDNF achieved sustained GDNF levels within the brain and provided improved motor function and dopaminergic function restoration (8).

 

Due to interactions between the neurotensin and dopamine systems, neurotensin, a 13 amino acid peptide, is of interest for PD research but clinical use of neurotensin has been limited due to its rapid degradation. Recently, neurotensin (8-13) analogs have been designed to limit degradation and researchers have investigated their possible neuroprotective effects on an experimental model of PD in rats induced with 6-hydroxydopamine (6-OHDA) treatment to produce striatal lesions. In the study, the neurotensin fragment analogs were found to penetrate the blood-brain barrier and treatment with the neurotensin analogs improved the memory of lesioned animals. Also, dopamine content in the brain of neurotensin analog treated rats increased (9).

 

There has been increasing interest in GLP-1 receptor agonists such as exenatide, liraglutide and lixisenatide as potential disease modifying agents in PD. GLP-1 receptors have been found throughout the brain. Systemic insulin resistance is thought to be associated with the onset of PD. Patients with PD usually have impaired glucose tolerance that can induce brain insulin resistance which is implicated in the neurodegenerative process. In preclinical models of PD, exenatide and other approved GLP-1 receptor agonists have demonstrated neuroprotective effects. Recently, a randomized, double-blind, placebo-controlled clinical study of exenatide in the treatment of PD, showed that patients using exenatide displayed better motor function compared to the placebo group (10). Additional clinical trials are underway to evaluate GLP-1 receptor agonists in patients with PD.

 

Orexins, neuropeptides produced by neurons in the lateral hypothalamus and perifornical area, are also suspected to be involved in PD. The orexin system plays a role in motor control as well as regulating other vital body functions such as feeding and sleep. Research has shown that PD patients have a loss of orexinergic neurons and the level of orexins in plasma and cerebrospinal fluids is decreased. In a study of orexin-A treatment on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD, orexin-A significantly protected the dopaminergic neurons in the substantia nigra and improved motor and cognitive impairments that were induced by MPTP (11).

 

Current PD Treatments

There are several types of drugs available to treat the symptoms of PD (Table 1).

Table 1 Type of Drug for Treatment of PD

Type of Treatment Generic Drug Names
Dopamine precursor levodopa (L-dopa)
Dopamine agonists apomorphine, rotigotine, pramipexole, ropinirole
MAO-B (monoamine oxidase B) inhibitors rasagiline, selegeline, safinamide
COMT (catechol-O-methyl transferase) inhibitors entacapone, tolcapone
Mixed mechanisms, including NMDA (N-methyl-D-aspartate) antagonism amantadine
Anticholinergic Trihexyphenidyl, benztropine

Levodopa is the primary treatment for PD and levodopa is often prescribed with carbidopa. Levodopa helps the nerve cells make dopamine. Carbidopa serves to prevent or reduce the undesirable side effects of levodopa such as nausea and vomiting (2). While levodopa attenuates the symptoms of PD, it does not halt the progressive degeneration of dopaminergic neurons.

 

In addition to prescription drugs, patients benefit from physical, occupational and speech therapy to help manage PD symptoms. In some cases, deep brain stimulation (DBS) is used to help stop movement-related symptoms of PD (2).

 

Conclusion

PD is a common neurodegenerative disease and there is a critical need for treatments to slow or stop the progression of PD. GLP-1 analogs and other peptides show promise as novel treatments for PD.

 

Explore our PD related products in our Online Shop. Learn more about Active Pharmaceutical Ingredients (APIs).

 

References

1) Statistics. Parkinson’s Foundation 2019.

2) Parkinson’s Disease. National Institute on Aging 2017.

3) P.Bansode, C.Vaishnavi ,A.P.Nikalje, A brief review on Parkinson’s disease. EC Pharmacology and Toxicology 2018, 6.7, 509-527.

4) Types of Parkinsonisms. Parkinson's Foundation 2019.

5) P.Maiti, J. Manna, G.L.Dunbar, Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments, Translational Neurodegeneration 2017, 6, 28.

6) What is LBD? Lewy Body Dementia Association 2019.

7) J.M.Froula et al, Defining α-synuclein species responsible for Parkinson disease phenotypes in mice, Journal of Biological Chemistry 2019.

8) E.Garbayo et al, Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys, Biomaterials 2016, 110, 11-23.

9) M.Lazarova, et al, Preventive effect of two new neurotensin analogues on Parkinson’s disease rat model, Journal of Molecular Neuroscience 2018, 66, 552-560.

10) D.Athuada et al, Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial, The Lancet 2017, 390, 1664-1675.

11) M.F. Liu et al, Orexin-A exerts neuroprotective effects via OX1R in Parkinson’s disease, Frontiers in Neuroscience 2019, 12, 835.

PEPTIDES FOR THE TREATMENT OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is a common neurologic disorder that affects approximately 1% of individuals older than 60 years. The disease is about 1.5 times more common in men than in women. While the cause of PD is unknown, a combination of genetic and environmental factors are suspected to play a role in the disease. Current treatments for PD focus on managing the dopamine levels in the brain and levodopa-based therapies such as the branded drugs Sinemet® (carbidopa/levodopa) and Madopar® (benserazide/levodopa) are the mainstay for motor symptoms in PD treatment (1). Despite the availability of many PD drug options, there are no disease-modifying therapies. Currently, there are several peptides in clinical development, shown in Table 2, that offer promise as disease-modifying therapies for the treatment of PD.

Table 2 Peptides in Clinical Development for the Treatment of PD

Product Name Generic Name Pipeline Indication(s) Phase for PD Indication Companies
Saxenda, Victoza liraglutide Parkinson's Disease; Smoking Cessation; Binge Eating Disorder II Novo Nordisk AS
Lixisenatide lixisenatide Parkinson's Disease; Type 1 Diabetes II Sanofi
GM-6 -- Alzheimer's Disease, Multiple Sclerosis, Parkinson's Disease, Acute Ischemic Stroke, Huntington Disease, Amyotrophic Lateral Sclerosis II Genervon Biopharmaceuticals LLC
PT-320 exenatide Parkinson's Disease, Drug-Induced Dyskinesia II Peptron Inc
NLY-001 -- Alzheimer's Disease; Parkinson's Disease I Neuraly Inc

Phase II Candidates

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is under development for PD. Liraglutide is approved by the U.S. Food and Drug Administration and other regulatory authorities to treat adults with type 2 diabetes and to treat obesity. In 2017, Cedars-Sinai Medical Center in collaboration with The Cure Parkinsons Trust and Novo Nordisk initiated a Phase II trial to evaluate the safety and efficacy of liraglutide in PD (1).

 

Lixisenatide, an approved drug for Type 2 diabetes, is under development at Sanofi for the treatment of PD. Lixisenatide is a GLP-1 receptor agonist. In 2018, University Hospital, Toulouse in collaboration with Cure Parkinson, Reseau NS-Park, EUCLID and Sanofi registered a Phase II study of lixisenatide in patients with early PD (1).

 

GM-6 is under development at Genervon Biopharmaceuticals for PD and several other indications including Alzheimer's disease, amyotrophic lateral sclerosis, acute middle cerebral artery ischemic stroke, Huntington's disease and multiple sclerosis. GM6 is an analog of motoneuronotrophic factor (MNTF). The drug candidate targets apoptosis regulator BAX, free radicals, insulin receptors IGF1, IGF2, Akt and phosphatidylinositol (3,4,5)-trisphosphate. In 2014, the company completed a Phase II study to compare the safety, tolerability and efficacy of GM-6 with placebo in subjects with early PD.

 

Peptron is developing PT-320 for the treatment of PD. The drug candidate was developed as part of a cooperative research and development agreement (CRADA) between Peptron and the National Institutes of Health (NIH). PT-320 is a sustained release microsphere injection of exenatide that utilizes SmartDepot™, Peptron’s ultrasonic spray drying technology (3). Peptron is recruiting for a Phase II clinical trial in PD in Korea (1).

 

 

Phase I Candidate

NLY-001, a pegylated, long-acting form of exenatide, is under development at Neuraly for the treatment of PD and Alzheimer's disease. Originally developed by researchers at Johns Hopkins University, the researchers found in preclinical studies that NLY-001 slows the progression of PD as well as its symptoms in mice. NLY-001 acts by targeting the GLP-1 receptor. In 2018, Neuraly registered a Phase I study to assess the safety, tolerability, and pharmacokinetics of NLY-01 in healthy subjects (1).

 

Conclusions

With the variety of ongoing clinical trials for PD including those involving peptides, we may see better treatment options in the future. To support researchers and organizations studying PD, Bachem offers a selection of PD research products. In addition, Bachem offers a comprehensive custom peptide synthesis service, a selection of Generic Active Pharmaceutical Ingredients, and the production of New Chemical Entities.

 

References

(1) BioPharm Insight (2019)

(2) GlobalData (2019)

(3) SmartDepot, Peptron (2019)

MEET BACHEM: MAREN SCHULZE, PROJECT MANAGER

PT: What is your official job title at Bachem?

Maren: I am a Project Manager.

 

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

Maren: I have been with Bachem for over 5 years now. I first worked in R&D as a Project Chemist and later as a Group Leader and joined the Project Management team just recently. Before my time at Bachem, I did my PhD in polymer & organic chemistry at the University of Fribourg.

 

PT: Briefly, what do you do at Bachem?

Maren: I lead and manage NCE projects in collaboration with an individual project team both at Bachem and on the customer’s side.

 

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

Maren: Being with friends and family. I like doing sports such as yoga, running and skiing. I also enjoy cooking very much, especially while listening to some good music and I love going to concerts.

 

PT: What makes a perfect day for you?

Maren: Trying or creating something new, meeting with people, having a good laugh, being outside, finding a few moments for myself.

 

PT: What do you like most about your job?

Maren: I like the complexity and versatility - not only in respect to the various tasks and projects, but also to the many different people I work with. Each day I learn something new, about team work, about peptides, about the pharmaceutical industry and in the end also about myself.

 

PT: What do you do for fun?

Maren: Singing.

 

PT: Thank you very much Maren.

PEPTIDE HIGHLIGHTS

LITERATURE CITATIONS

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

 

S.Pain et al.

Inflammatory process in Parkinson disease: neuroprotection by neuropeptide Y.

Fundamental & Clinical Pharmacology (2019)

 

R.P.McGlinchey et al.

C-terminal alpha-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease.

Journal of Biolological Chemistry 294, 9973-9984 (2019)

 

A.A.Orr et al.

Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins.

Computers & Chemical Engineering 116, 322-332 (2018)

 

X.-z.Guo et al.

Osteocalcin ameliorates motor dysfunction in a 6-hydroxydopamine-induced Parkinson’s disease rat model through AKT/GSK3β signaling.

Frontiers in Molecular Neuroscience 11, (2018)