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PEPTIDE TRENDS SEPTEMBER 2016

MEET US CPHI WORLDWIDE

CPhI Worldwide, the world’s leading pharmaceutical platform, together with co-located events ICSE, InnoPack, P-MEC and FDF, hosts more than 36,000 visiting pharma professionals over three days.

 

It is our pleasure to inform you that we will be present at this year’s CPhI, October 4-6, 2016 in Barcelona. We would like to meet with you to discuss how Bachem can help you with your API custom manufacturing needs.

 

Bachem is your trusted supplier of peptide and small molecule generics. With over 80 DMF filings and more in the pipeline we support the success of our partners.

 

The Bachem Approach to Quality by Design (QBD) will be presented by Michael Postlethwaite, Ph.D., Business Development Manager, Bachem AG at the CPhI Exhibitor Showcase, Hall 2, booth #2C70 on October 4, 2016 at 1:30 PM.

 

The 2016 Global Generics & Biosimilars Innovation of the Year Award is sponsored by Bachem. The Award will recognize the industry for their achievements and emphasize the importance of innovation. For more information about the Award, entering or attending, please contact us.

 

We invite you to drop by our booth #7H14 in Hall 7. To schedule a personal meeting please contact us.

TAU PROTEIN AND ALZHEIMER’S DISEASE

Alzheimer’s disease is a neurodegenerative disease characterized by extracellular Amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles containing pathological tau protein aggregates (1).

Even though both, Aβ and tau, are related to Alzheimer’s disease, studies have shown that the degree of tau related pathology correlates better with the degree of dementia than the amyloid plaque burden (1).

Tau protein is primarily expressed in neuronal cell bodies and axons and, depending on its six isoforms, has a length of 352 to 441 amino acids (1). It is used in the cerebrospinal fluid as a sensitive and specific biomarker for Alzheimer’s disease, usually determined by ELISA. Recently an LCMS method has been developed, that measures seven tryptic tau peptides (2).

Indicators of Alzheimer’s disease are tangles made of hyperphosphorylated tau and plaques composed of amyloid precursor protein derived Aβ. Many kinases or phosphatases are deregulated in brains suffering from Alzheimer’s disease (3).

Due to the importance of the phosphorylation of tau, various approaches have been made to overcome a hyperphosphorylation: inhibition of kinases or activation of protein phosphatase to dephosphorylate tau, inhibition of aggregation, and increase of tau degradation (1).

A recent research publication has indicated that that the interactions of the two important fragments Aβ (25-35) and tau (273-284) affect the self-assembly process of both Aβ and tau (4).

Also trans/cis isomerization of the pThr231-Pro232 sequence in phosphorylated tau seems to play a role with Alzheimer’s disease. The cis isomer exclusively accumulates in degenerative neurons, cannot promote microtubule assembly and is more resistant to dephosphorylation. “Peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1” (Pin1) converts the cis to the trans isomer to prevent Alzheimer’s tau pathology. For that, isomer-specific antibodies might be an approach for diagnosis and treatment of Alzheimer’s disease. Antibodies have been used to selectively determine both isoforms in vivo. Five different phosphorylated peptides have been used to produce and purify these antibodies (3).

 

 

Figure 1: cis-trans TAU Pin1

 

In addition to our catalog portfolio of over 200 Alzheimer’s disease related research products, Bachem now offers these five phosphorylated peptides, the fragment tau (273-284) and other important once related to the tau research, as new catalog products at shop.bachem.com. To support Pin1 related studies, Bachem offers five different substrates for this enzyme.

 

References

(1)   A. Boutajangout and T. Wisniewski, Tau-based therapeutic approaches for Alzheimer's disease - a mini-review, Gerontology 60, 381-385 (2014)

(2)   P. Bros et al., Antibody-free quantification of seven tau peptides in human CSF using targeted mass spectrometry, Front. Neurosci. 9, 302 (2015)

(3)   K. Nakamura et al., Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease, Cell 149, 232-244 (2012)

(4)   T. Do et al., Interactions between Amyloidβ and Tau Fragments Promote Aberrant Aggregates: Implications for Amyloid Toxicity, J. Phys. Chem. B 118, 11220-11230 (2014)

 

TAU-BASED DRUGS IN CLINICAL DEVELOPMENT

In Alzheimer’s disease (AD) and in tauopathies, a class of related neurodegenerative diseases caused by misfolding of the tau protein, the protein tau is abnormally hyperphosporylated and aggregated, leading to neurofibrillary degeneration. Tauopathies include neurodegenerative diseases such as Guam Parkinsonism–dementia complex, dementia pugilistica, corticobasal degeneration, Pick disease, progressive supranuclear palsy and others (1). Many of the drugs under development for the treatment of AD, are focused on inhibiting β-Amyloid; however, there is increased interest in developing tau-based drugs for AD and tauopathies (2). A number of approaches have come into consideration for the development of new therapeutics including inhibiting tau phosphorylation, increasing microtubule stabilization, increasing tau clearance and inhibiting tau aggregation (3).

A selection of tau-centric candidates in various phases of clinical development is shown in Table 1.

 

Product Name

Active Ingredient

Condition Treated

Highest Phase

Companies

LMTX

methylene blue

Alzheimer's Disease(III), Frontotemporal Dementia(III), Progressive Supranuclear Palsy(II), Parkinson's Disease(I)

Phase III

TauRx Pharmaceuticals Ltd

AADvac1

--

Alzheimer's Disease(II)

Phase II

Axon Neuroscience SE

AL208

davunetide

Alzheimer's Disease(II), Mild Cognitive Impairment(II)

Phase II

Allon Therapeutics Inc

Posiphen

phenserine tartrate

Alzheimer's Disease(II), Parkinson's Disease(II), Down Syndrome(PC), Huntington's Disease(PC)Traumatic Brain Injury(PC)

Phase II

QR Pharma Inc, The Rockefeller University, Axonyx Inc, TorreyPines Therapeutics, Inc.

T3D959

--

Alzheimer's Disease(II)

Phase II

Bayer HealthCare AG, T3D Therapeutics, Midatech Pharma US Inc

TPI287

--

Glioblastoma Multiforme(II), Metastatic Breast Cancer(II), Metastatic Melanoma(II), Neuroblastoma(II), Alzheimer's Disease(I), Neurodegenerative Disorders(I), Oncology(I)

Phase II

Tapestry Pharmaceuticals Inc, Cortice Biosciences Inc

RG7345

--

Alzheimer's Disease(I)

Phase I

Roche

ABBV 8E12

--

Progressive Supranuclear Palsy(I)

Neurological Disorders(PC)

Phase I

AbbVie Inc
C2N Diagnostics

ACI35

--

Alzheimer's Disease(I)

Phase I

AC Immune SA, Janssen Pharmaceuticals Inc

AV1980D

tau peptide

Alzheimer's Disease(I)

Phase I

Capo Therapeutics Inc

AV1980R

tau peptide

Alzheimer's Disease(I)

Phase I

Capo Therapeutics Inc

BMS986168

microtubule-associated protein tau monoclonal antibody

Neurodegenerative Disorders(I), Progressive Supranuclear Palsy(I)

Phase I

iPierian Inc, Bristol-Myers Squibb Company

RG6100

--

Alzheimer's Disease(I)

Phase I

AC Immune SA, Genentech Inc, Roche

SGC1061

--

Alzheimer's Disease(I)

Phase I

Queen's University, sGC Pharma Inc, University of Illinois at Chicago

Taupro

--

Progressive Supranuclear Palsy(I)

Phase I

ProteoTech Inc

Table 1: Tau-Based Drugs and Vaccines in Phase I-III Clinical Development (4)

 

Phase III Candidate

The most advanced candidate is LMTX® (methylene blue) also known as TRX0237. LMTX is being developed by TauRx Therapeutics. It acts as a neuroprotectant and inhibits tau hyperphosphorylation, dissolves tau aggregates and prevents tau aggregation. In July 2016, TauRx reported results from a Phase III trial. The study failed to meet its co-primary endpoints; however, the drug did show a benefit in patients who were not taking other Alzheimer’s drugs (4).

 

Phase II Candidates

Axon Neuroscience SE is developing AADvac1, a vaccine containing a peptide fragment, amino acids 294 to 305 of the tau sequence, coupled to keyhole limpet haemocyanin (KLH) carrier. The vaccine is designed to stimulate patients’ immune systems to attack dysfunctional tau proteins and thereby stop the progression of AD. A Phase I clinical trial with AADvac1 was completed in 2015 and results from the study showed the vaccine to be safe and well tolerated in the assessed parameters. In addition, treatment with the vaccine induced a robust immune response and average cognition of patients remained stable (5).

 

Allon Therapeutics (a subsidiary of Paladin Labs, now Endo International) was developing AL208 (davunetide). This eight amino acid peptide acts by reducing tau hyperphosphorylation. No new development has been reported for AL208 after Phase II clinical trials for the treatment of mild cognitive impairment following coronary artery bypass graft surgery. In addition, no new development has been reported for AL208 after Phase II clinical trials for the treatment of AD (4).

 

Posiphen® (phenserine tartrate) is a small molecule being developed by QR Pharma. It acts by reducing tau hyperphosphorylation as well as inhibiting amyloid precursor protein synthesis, reducing β-amyloid peptide and inhibiting α-Synuclein. Posiphen is in Phase II clinical studies for the treatment of AD. In 2014, QR Pharma reported that Posiphen influences AD at an early stage to prevent the onset or diminish cognitive decline (4).

 

Therapeutics is developing another tau hyperphosphorylation inhibitor known as T3D959. T3D959 is currently in a phase IIa study and in July 2016, the company reported that enrollment and dosing was completed for this trial. In addition, the company received approval from the United States FDA for an open-label, 6-month extension study to the 2-week Phase IIa trial of T3D-959 (4).

 

Cortice Biosciences is developing TPI287, a novel taxoid derivative that acts by stabilizing neuronal microtubules and decreasing toxic tau aggregation. It is currently in a Phase I clinical trial for the treatment of AD (4).

 

Phase I Candidates

There are several candidates earlier in the pipeline in Phase I development. One of these candidates is an immunotherapy known as ACI-35 that targets tau. ACI-35 is a liposomal vaccine containing a phosphorylated human tau protein fragment (4). In 2015, AC Immune partnered with Janssen Pharmaceuticals to develop ACI-35 and the product is currently in a Phase 1b clinical study in patients with mild to moderate AD (6). Also, AC Immune is collaborating with Genentech to develop an anti-tau monoclonal antibody, known as RG6100, for the treatment of AD (4). Additional candidates are also in Phase I development at other companies including AbbVie, Roche, Capo Therapeutics, iPerian, sGC Pharma and Proteotech.

 

Conclusion

Tau-based therapies have been the subject of increased interest in recent years. To support companies and organizations studying tau protein and its role in AD and related tauopathies, Bachem offers a selection of tau research peptides, custom peptide synthesis and the production of peptide-based new chemical entities.

 

References

(1)   K. Iqbal et al., Mechanisms of tau-induced neurodegeneration, Acta Neuropathol. 118, 53-69 (2009)

(2)   K. Iqbal and I. Grundke-Iqbal, Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention, J. Cell. Mol. Med. 12, 38-55 (2008)

(3)   F. Panza et al., Tau-centric targets and drugs in clinical development for the treatment of Alzheimer's disease, Biomed. Res. Int. 3245935 (2016)

(4)   Medtrack (2016)

(5)   Encouraging results of Axon's tau vaccine advance Alzheimer's therapy, Axon Neuroscience (2015)

(6)  AD treatment and prevention, AC Immune (2015)

MEET BACHEM: MARCO PEGURRI, GROUP LEADER GENERICS

PT: What is your official job title at Bachem?

Marco: My official job title is Group Leader Generics

 

PT: How long have you been with Bachem? Where did you work before Bachem?
Marco: I started in January 2014 as a Sales Manager in Bachem and before that I worked at Novartis in the pharmaceutical research.

 

PT: Briefly, what do you do at Bachem?

Marco: From September 1st I am heading the Generic Sales team in Bachem. Our group is taking care of the customers interested in our Generic API portfolio. Further we analyze new market potentials for our current APIs and evaluate also new possible Generic API candidates.

 

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

Marco: My training began as a lab technician in cellular and molecular biology and later I studied Life science with focus on medical engineering.

 

PT: What do you like to do outside of work (interests, hobbies)?

Marco: I spent most of my free time outdoor doing any kind of sports. Also I enjoy inviting friends for dinner and travelling around the world.

 

PT: How is the Marketing & Sales team partnering with their customers?

Marco: Our main goal is to understand the needs of our customers and to provide them with the appropriate support. This can only be ensured by constantly connecting with our customers during face to face meetings, calls or regular email exchange.

 

PT: What do you like most about your job?

Marco: I love the variety of tasks and the interaction with our partners. Finding creative solutions to help our customers to be successful on the generic market is one of my key drivers.

 

PT: What do you do for fun?

Marco: Travelling around with my camper in Europe.

 

PT:Thank you very much Marco.

PEPTIDE HIGHLIGHTS

LITERATURE CITATIONS

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

 

A. Szabó, C. Pilsak, M. Bence, H. Witt, and M. Sahin-Tóth

Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2

J. Biol. Chem., Aug 2016; 291: 17706 - 17716.

http://www.ncbi.nlm.nih.gov/pubmed/27358403

 

H. Zheng, T. Miyakawa, Y. Sawano, A. Asano, A. Okumura, S. Yamagoe, and M. Tanokura

Crystal Structure of Human Leukocyte Cell-derived Chemotaxin 2 (LECT2) Reveals a Mechanistic Basis of Functional Evolution in a Mammalian Protein with an M23 Metalloendopeptidase Fold

J. Biol. Chem., Aug 2016; 291: 17133 - 17142.

http://www.jbc.org/content/early/2016/06/22/jbc.M116.720375.abstract

 

G. D. Manocha, A. M. Floden, K. Rausch, J. A. Kulas, B. A. McGregor, L. Rojanathammanee, K. R. Puig, K. L. Puig, S. Karki, M. R. Nichols, D. C. Darland, J. E. Porter, and C. K. Combs

APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

J. Neurosci., Aug 2016; 36: 8471 - 8486.

http://www.jneurosci.org/content/36/32/8471.short

 

A.-L. Wenger Combremont, L. Bayer, A. Dupré, M. Mühlethaler, and M. Serafin

Effects of Hypocretin/Orexin and Major Transmitters of Arousal on Fast Spiking Neurons in Mouse Cortical Layer 6B

Cereb. Cortex, Aug 2016; 26: 3553 - 3562.

http://cercor.oxfordjournals.org/content/early/2016/05/27/cercor.bhw158.full

 

S. N. Rylova, B. Waser, L. Del Pozzo, R. Tönnesmann, R. Mansi, P. T. Meyer, J. C. Reubi, and H. R. Maecke

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

J. Nucl. Med., Aug 2016; 57: 1282 – 1288

http://www.ncbi.nlm.nih.gov/pubmed/27127218