Expert Intelligence for Better Decisions Macrocycles:

Transcription

1 Expert Intelligence for Better Decisions Macrocycles: Discovery, Development & Technologies

2 Using This Document Insight Pharma Reports are interactive electronic documents which offer many of the features of Web sites, including navigation, search, bookmarks, download options, and additional layered content. A navigation bar containing links to the Table of, a feature, Previous/Next page arrows, and a Return button is anchored at the bottom of each page. Hyperlinks throughout the document are designated by blue, underlined text. Hyperlinks on the Index page are also rendered as blue text, and will navigate you to a company s Web site. Table of listings are hyperlinked and will navigate you directly to that specific content, Table or Figure. Reports are also available in printed format References can be accessed by clicking directly on the Reference number. There is also a References page at the end of the document. To order copies of this report, customized for your organization, contact: Rose LaRaia P E rlaraia@healthtech.com Next Page Return This button will return you to a previously visited, non-sequential page Access the Table of the Report Insight Pharma Reports Web site Visit our site to research additional Report titles Previous Page i

3 Insight Pharma Reports Single User License This License permits only the Licensee with individual access to the report. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Multi-User License This License permits up to 5 Licensees with access to the report. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Single Site License This License permits the Licensee to share or distribute the contents of the report with all company or organization employees at the same site or physical location. This License also permits the Licensee to share or distribute the contents of the report with all employees of a company or organization subsidiary at the same site or physical location. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Multi-Site License This License permits the Licensee to share or distribute the contents of the report with all company or organization employees worldwide. This License also permits the Licensee to share or distribute the contents of the report with all employees of a company or organization subsidiary. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. ii

4 Macrocycles: Discovery, Development & Technologies Published in September 2013 by Cambridge Healthtech Institute iii

5 Insight Pharma Reports is a division of Cambridge Healthtech Institute, a world leader in life science information and analysis through conferences, research reports, and targeted publications. Insight Pharma Reports focus on pharmaceutical R&D the technologies, the companies, the markets, and the strategic business impacts. They regularly feature interviews with key opinion leaders; surveys of the activities, views, and plans of individuals in industry and nonprofit research; and substantive assessments of technologies and markets. Managers at the top 50 pharma companies, the top 100 biopharma companies, and the top 50 vendors of tools and services rely on Insight Pharma Reports as a trusted source of balanced and timely information. Managing Director: Design Director: Production Director: Customer Service: Corporate Subscriptions: Lisa Scimemi , lscimemi@healthtech.com Thomas Norton , tnorton@healthtech.com Ann Marie Handy , ahandy@healthtech.com Rose LaRaia , rlaraia@healthtech.com David Cunningham , cunningham@healthtech.com Insight Pharma Reports, 250 First Avenue, Suite 300, Needham, MA n iv

6 Macrocycles: Discovery, Development & Technologies For more information about published Insight Pharma Reports, visit or call Rose LaRaia at A Cambridge Healthtech Institute publication 2013 by Cambridge Healthtech Institute (CHI). This report cannot be duplicated without prior written permission from CHI. Every effort is made to ensure the accuracy of the information presented in Insight Pharma Reports. Much of this information comes from public sources or directly from company representatives. We do not assume any liability for the accuracy or completeness of this information or for the opinions presented. Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA Phone: n Fax: n v

7 Executive Summary Executive Summary This report covers several areas of macrocycles, including current use in pharmaceutical companies, rising technologies, and strategies used in biotechnology companies. The first two chapters cover background material, what macrocycles are, and the pharmacokinetic properties (absorption, distribution, metabolism, and excretion) they experience. Additionally, challenges including proper plasma concentrations, drug-drug interactions, drug dose administrations, cell permeability, oral bioavailability, and drug absorption design are also mentioned. Chapters 3-11 detail various companies and their technologies and strategies for studying macrocycles as drug candidates. In addition to researching companies, Insight Pharma Reports has also received the participation of Bicycle Therapeutics, Encycle Therapeutics, Ensemble Therapeutics, Lanthio Pharma, Oncodesign Biotechnology, Pepscan Therapeutics, PeptiDream Inc., Ra Pharmaceuticals, and Tranzyme Pharmaceuticals. Each section includes detailed descriptions of company overviews, technology platforms, benefits, challenges, and competitive advantages. Also exclusive to this report are interviews with these companies, which provide even more insight into their strategies and goals. To wrap up the report, Chapter 12 covers the benefits of macrocycles, why they are creating such a footprint in the R&D space, areas to improve in, and how they compare to conventional small molecules. Chapter 12 also concludes with a survey done by Insight Pharma Reports which includes over 90 participants. Questions included familiarity with macrocycles, use in research, and challenges encountered. According to the results, macrocycles are actively being studied by a number in industries in a variety of ways; while some people are looking into protein-protein interactions, others are studying binding mode properties and drug-drug interactions. With the diversity this class offers, macrocycles have the potential to be applied to many therapeutic areas. vi

8 Table of Table of Executive Summary vi Chapter 1 What are Macrocycles? 1 Chapter 2 How Important are Pharmacokinetic Properties? 3 Absorption 3 Distribution 4 Metabolism 4 Excretion 5 Challenges in reaching pharmacokinetic requirements 5 Plasma concentrations 5 Drug-drug interactions 5 Drug dose administration 6 Drug absorption design 6 Cell permeability 6 Oral bioavailability 7 Chapter 3 Bicycle Therapeutics 8 Company background 8 Cyclization chemistry platform 8 Benefits to the cyclization chemistry platform 9 Challenges and areas of improvement 10 Interview with Rolf Guenther and Christophe Bonny 10 Company background 10 vii

9 Table of Cyclization chemistry platform 11 Macrocyclic properties 12 Partnerships and future aspirations 12 Chapter 4 Encycle Therapeutics 13 Company background 13 Chemical technology platform 13 Partnerships, competitive advantage, and future outlook 14 Interview with Jeffrey Coull 15 Company background 15 Chemical technology platform 15 Tracking and properties of macrocycles 15 Partnerships and future aspirations 16 Chapter 5 Ensemble Therapeutics 17 Company background 17 DNA-programmed chemistry platform 17 Benefits to DNA-programmed chemistry platform 18 Challenges to DNA-programmed chemistry platform 19 Competitive advantage 19 Partnerships and future aspirations 19 Interview with Nick Terrett 20 Company background 20 Macrocycle background and goals 20 Macrocyclic creations and properties 21 DNA-programmed chemistry platform 22 Macrocyclic structures and expected interactions 24 Challenges and properties in macrocyclic development 26 viii

10 Table of Partnerships and future outlook 27 Chapter 6 Lanthio Pharma 28 Company background 28 Lactococcus lactis platform 28 Benefits to Lactococcus lactis platform 31 Challenges encountered 31 Competitive advantage 31 Partnerships and future growth 32 Interview with Gert Moll 33 Company background 33 Lactococcus lactis platform 34 Macrocyclic properties 34 Challenges encountered 36 Competitive advantage 37 Partnerships and future aspirations 37 Chapter 7 Oncodesign Biotechnology 39 Company background 39 Platforms developed 39 Nanocyclix platform 39 Benefits of Nanocyclix platform 40 Challenges encountered 41 Competitive advantage 42 Partnerships and future growth 43 Interview with Jan Hoflack 44 Company background 44 Nanocyclix platform 45 ix

11 Table of Nanocyclix properties 46 Partnerships and future aspirations 49 Chapter 8 Pepscan Therapeutics 52 Company background 52 Chemical linkage of peptides onto scaffolds (CLIPS) platform 52 Benefits to the CLIPS platform 53 Challenges to the CLIPS platform 53 Competitive advantage 53 Partnerships and future aspirations 54 Interview with Peter Timmerman 54 Company background 54 CLIPS platform 55 Macrocyclic properties 55 Partnerships and future aspirations 56 Chapter 9 PeptiDream Inc. 57 Company background 57 Peptide discovery platform system (PDPS) 57 Challenges to PDPS and macrocyclic creations 58 Competitive advantage, partnerships, and future aspirations 58 Interview with Patrick Reid 59 Company background 59 PDPS platform 60 Macrocyclic properties 61 Challenges encountered 61 Competitive advantage 62 Partnerships and future aspirations 62 x

12 Table of Chapter 10 Ra Pharmaceuticals 63 Company background 63 Translation platform and macrocyclic creations 63 Challenges encountered 64 Competitive advantage, partnerships, and future aspirations 64 Interview with Doug Treco 65 Company background 65 In vitro translation platform 65 Macrocycle tracking, creations, and properties 65 Challenges encountered 67 Partnerships and future aspirations 67 Chapter 11 Tranzyme Pharma 68 Company background 68 Macrocyclic template chemistry (MATCH) platform 69 Benefits and competitive advantages of MATCH platform 69 Areas of improvement to the MATCH platform 70 Partnerships and future aspirations 70 Interview with Mark L. Peterson and Helmut Thomas 71 Company background 71 Macrocyclic properties 72 MATCH platform 77 Partnerships and future aspirations 78 Chapter 12 Aileron Therapeutics 80 Company background 80 xi

13 Table of Stapled Peptide platform 80 Competitive advantage 81 Areas of improvement 81 Partnerships and future aspirations 82 Interview with Vincent Guerlavais 82 Company background 82 Stapled Peptide platform 83 Macrocyclic creations and properties 83 Competitive advantage 84 Chapter 13 Why Macrocycles? 85 What improvements do macrocycles exhibit over conventional small molecules? 85 Structural modifications 85 Structural stability 85 Cell permeability, molecular activity, and half-life 86 Protein-protein interactions 86 Higher binding affinity 86 Improved binding modes 87 Therapeutic applications 87 Challenges encountered 87 Who s working with macrocycles? 88 References 91 About Cambridge Healthtech Institute 93 xii

14 Table of Figures Figure 1.1: Example of Macrocycles 2 Figure 3.1: Different Peptide Structures with the same Amino Acid Sequence 9 Figure 4.1: Multicomponent Ugi Reaction Yields a Pentapeptide Constrained in a Macrocycle 14 Figure 5.1: Hybridization of DNA Synthesizes Macrocycle Compounds 18 Figure 6.1: Methyl-Lanthionine-Containing Peptides 29 Figure 6.2: Lanthipeptide Library on Lactococcus lactis Cell Surface 30 Figure 8.1: Linear Peptide vs. CLIPS-Peptide 53 Figure 13.1: Organizations Surveyed 89 Figure 13.3: Time Spent Studying Macrocycles 89 Figure 13.3: Areas of Study 90 Figure 13.4: Problems Encountered 90 xiii

15 What are Macrocycles? Chapter 1 What are Macrocycles? Macrocycles (Figure 1.1) are a drug class consisting of small to medium sized natural, semi-natural, or artificial molecules where atoms are connected in such a way that they form a ring, providing rigidity and stability to the structure.1 Traditionally, macrocycles are cyclic compounds or peptides that vary in size, and are typically 500-2,000 Da. 2 With such a variety in size, the bigger the molecule the more flexibility in structural combinations, allowing scientists to fine-tune the molecules function and performance. 1 Macrocycles are unique compounds in that larger molecules still maintain structural organization and stability, whereas linear molecules can usually adopt several different combinations; the larger the molecule, the more combinations it can achieve.1 Equipped with such dynamic features, macrocycles provide the necessary structural foundation for scientists to work with and apply to various areas of drug development, creating a footprint for a wide line of therapeutics. Some of the common areas for improvement and understanding in drug development include pharmacokinetics, cell permeability, oral bioavailability and selective targeting. 2 By meeting these requirements, macrocycles can have the potential to provide more flexibility for applications in drug development in addition to efficacy. The downside is that macrocycles are very difficult compounds to make, particularly the ones that occur naturally; to replicate their process would take years or even decades. Researchers pursued other means of creating macrocyclic therapeutics by adhering to Lipinski s rule-of-5 guidelines. Researchers now have the ability to screen libraries of compounds for potential drug candidates that contain the desirable pharmacokinetic properties, tailoring them as they see fit. 5 1

16 What are Macrocycles? Figure 1.1: Example of Macrocycles Figure 1.1 depicts the stereochemistry of a macrocycle. Its structure provides rigidity and stability to be applied and morphed in different therapeutic ways. syn-1 anti-1 syn-1 (enantiomer) Source: Haynes, Source: Haynes,

17 How Important are Pharmacokinetic Properties? Chapter 2 How Important are Pharmacokinetic Properties? Pharmacokinetics is the study of drug interactions within biologic patients over a period of time. 4,6 It is a specific focus on the drug disposition throughout the body (often described as what the body does to a drug vs. what a drug does to the body ) including absorption, distribution, metabolism, and excretion (ADME). 6 By studying these interactions, scientists can determine the proper dose regimens for a resulting plasma concentration, followed by a concentration at the site of action. 7 Determining the dose regimen allows the drug to have a therapeutic effect at the site of action, avoiding both ineffective low concentrations and potentially toxic high concentrations. Absorption Absorption is the first process in pharmacokinetic properties. Post administration, absorption is the process in which a drug passes through the body into the blood stream, oftentimes through passive diffusion, but sometimes through other methods as well. 8,10 During passive diffusion, drugs diffuse across a cell membrane from a higher concentration to a lower concentration. 10 Generally dependent directly on the concentration, factors that contribute to the ease of diffusion include lipid solubility, size of the molecule, degree of ionization, and the area of absorptive surface. 8 For obvious reasons, smaller molecules diffuse more rapidly than larger ones, and due to the hydrophobic properties of cell membranes, lipid soluble non-ionized drugs are absorbed even faster. 8,10 Passive diffusion can also be facilitated. Molecules that have low lipid solubility, such as glucose, have the ability to penetrate cell membranes more rapidly than expected. 10 This is likely due to facilitated passive diffusion, or, the help of a carrier protein that binds reversibly to a specific molecular configuration outside the membrane and transports it inside the cell. 10 Due to the lack of carrier proteins, this process of diffusion tends to be limited. Diffusion also cannot occur against the concentration gradient, limiting its occurrences even more so. 10 Contrary to facilitated passive diffusion, there s active diffusion, where transportation of a drug occurs against a concentration gradient. 10 This type of transportation requires the use of energy, often occurs in the small intestine, and tends to be limited to drugs structurally similar to endogenous substances such as ions, vitamins, sugars, and amino acids. 10 3

18 How Important are Pharmacokinetic Properties? The last type of diffusion, which plays a small role in drug transport, is pinocytosis. 10 This type of diffusion also involves energy, and is the process of a substance being engulfed by a cell membrane, causing it to invaginate and enclose around the substance, which fuses to the inside of the cell and creates a vesicle. 10 The vesicle later detaches and makes its way further into the cell interior. 10 Drugs will absorb differently depending on the type of administration. Oral drugs tend to get absorbed in the stomach and small intestine, while injectable drugs are directly absorbed into the circulatory system through the small pores in the capillary walls. 8,10 Once they have reached the bloodstream, drugs are able to be carried through the body to their site of action. This process is known as distribution. Distribution During distribution, drugs are moving throughout the body via the circulatory system. 8 Once the drug enters the blood, it is transferred to the tissues, often unevenly due to differences in blood perfusion, tissue binding, regional ph, and cell membrane permeability. 9 Additionally, the rate at which the drug enters tissues varies on the rate of the blood flow to the tissues, the tissue mass, and the partition characteristics between the blood and tissues. 9 During this travel, the specific chemical makeup of the drug plays a role in the type of transportation to export the drug from the vasculature system to other areas of the body. 8 One such transportation method is through plasma protein and tissue binding. 8,9 While in the bloodstream, drugs are transported partly as unbound and partly reversibly bound to blood components including plasma proteins and blood cells. 9 Although many proteins can interact with drugs, the most significant interactions are with albumin, which binds more extensively to acidic drugs, and α-1 acid glycoprotein and lipoproteins, both of which bind more extensively to basic drugs. 9 The concentration of unbound drugs typically determines the drug concentration at the site of action because only unbound drugs are available for subsequent transportation to extravascular or other tissue sites. 9 The drug concentration in the cells is in equilibrium with the drug concentration in the plasma; as the drug is eliminated from the body, the drug moves from the cells to the plasma. 9 Another type of transportation that occurs is when drugs cross the blood-brain barrier. 8,9 Drugs reach the central nervous system through the brain capillaries and cerebral spinal fluid. The blood-brain barrier has a variety of different characteristics from the rest of the body. While lipid molecules readily pass through due to the chemistry of the bloodbrain barrier (specifically the endothelial cells of the brain capillaries, which appear more tightly joined to one another than those of most capillaries, slowing the rate of diffusion of water-soluble drugs; and the astrocytic sheath, which is made up of a layer of glial connective tissue cells (astrocytes), which are close to the basement membrane of the capillary endothelium), polar ones do not. 9 Penetrating into the cerebral spinal fluid is often determined by the extent of protein binding properties, degree of ionization, and lipid-water partition coefficient of the drug, while in the central nervous system, the drug penetration rate is determined by permeability due to the perfusion properties of the central nervous system. 9 Metabolism As drugs are distributed throughout the body to their proper sites of action, they are metabolized and prepared for excretion. 11 Often occurring in the liver, drugs can be metabolized through a number of methods including oxidation, reduction, hydrolysis, hydration, and 4

19 How Important are Pharmacokinetic Properties? conjugation. 11 This process generally occurs in two phases. 11 Phase I reactions are usually nonsynthetic and entail the formation of a new or modified functional group or cleavage through processes including oxidation, reduction, and hydrolysis. 11 Perhaps the most important system in phase I metabolism is cytochrome P-450 (CYP450). 11 Made up of a microsomal superfamily of isoenzymes, the CYP450 system is known for catalyzing the oxidation of many drugs. 11 This system can be inhibited or induced by many drugs and substances which can contribute to drug-drug interactions that ultimately lead to either toxicity or reduced therapeutic effect. 11 Phase II reactions, on the other hand, are usually synthetic, entailing conjugation with an endogenous substance such as glucuronic acid, sulfate, or glycine. 11 Glucuronidation is not only the most common phase II reaction, but also the only one that takes place in the liver microsomal enzyme system. 11 Conjugation simplifies the work needed to be done by the kidneys to excrete glucuronides. 11 As drugs are metabolized by the liver and other parts of the body, they are prepared for excretion. Excretion Excretion is the riddance of the drug from the body. It typically occurs through urine or feces, but can also occur through sweat, saliva, and breast milk. 8,12 After they are metabolized in the liver, water-soluble substances are filtered through the kidneys, where most excretion takes place. 12 Although unionized forms of drugs tend to be readily reabsorbed, the majority of unbound drugs are typically excreted while plasma protein bound drugs remain in circulation. 12 Other factors affecting drug reabsorption and excretion include the ph of urine, concentration, and competition between anions and cations. 12 Challenges in reaching pharmacokinetic requirements Some of the challenges in developing new drugs is accounting for drug-drug interactions, metabolic rate of the liver, drug dose administration, and serum half-life. 4 Drugs that meet specific properties allow for more flexibility and treatment options, whereas drugs that do not meet the requirements are likely to be ineffective as therapeutics. Macrocycles have an advantage over other drugs in development. Given their chemistry and structural makeup, they have been shown to exhibit many pharmacokinetic properties, making them fundamentally applicable to various areas of treatment. However, as with any new compound, there are quite a few hurdles researchers have had to overcome. Plasma concentrations One of the pharmacokinetic properties often studied is plasma concentrations. Oftentimes when drugs are administered to patients, the plasma concentration of the drug is too low and/or the half-life is too short. 4 It is also impossible to know whether or not adequate absorption has occurred, unless the drug was administered through clinical testing. 4 Low plasma concentrations and a shorter than normal half-life cause the drug to be ineffective as a treatment option as they can result in insufficient absorption and/or rapid metabolism within the liver. With macrocycles, researchers can develop drugs with viable plasma concentrations and half-life properties, allowing for a variety of uses as a therapeutic. Drug-drug interactions Another pharmacokinetic challenge most researchers encounter is drug-drug interactions. 4 When drugs interact with each other it can 5

20 How Important are Pharmacokinetic Properties? cause fluctuations in the plasma concentrations and even inhibit the drug metabolism in the liver. 4 Higher plasma concentrations have the potential to result in toxicity, and lower plasma concentrations are likely to result in reduced or no therapeutic efficacy. When developing drugs, researchers have to make sure they are structurally stable as to not interact with other compounds. Although this area still needs to be explored, macrocycles are sufficient candidates of study because of their structural stability and rigidity. Drug dose administration While plasma concentrations and drug-drug interactions are key players in pharmacokinetic properties, another player is drug dose administration and how doses vary per patient. Administering appropriate doses per patient has proven to be difficult. 4 Because all patients are unique individuals and some may have different reactions compared to others, drugs cannot be administered on a one-size-fits-all basis. Variances in drug absorption can occur between patients as well as differences in drug metabolism in the liver, which can greatly affect the efficacy of the drug, with higher variances potentially causing toxicity and lower variances proving to be nontherapeutic. Drug absorption design Additionally, studies have shown that there is a link between cell permeability, drug absorption, and oral bioavailablity. 17,19 When drugs are engineered, these are some other factors that researchers consider in order to create highly effective drugs: How easily is it going to permeate into cells and be absorbed throughout the body? How fast does this occur, what is the concentration of the drug at the point of action (especially taking into consideration the half life of the drug), and how does this affect specific targeting? Even more importantly, how can the structures of potential drug candidates be altered to enhance these properties to their desired potential? The rate at which a drug is absorbed through the cells is directly related to the therapeutic affect at the site of action. Likewise, the way in which a drug is administered (preferably orally) is also related to this affect. Cell permeability The cell membrane is made up of a lipid bilayer, which allows hydrophobic molecules to easily pass through. According to a rule of chemistry like dissolves like, molecules with similar chemical properties dissolve each other, while molecules with opposite, or nonsimilar, chemical properties do not. Such an example would be with oil and water. Oil creates small vesicles within water because of its hydrophobic properties. In order for drugs to absorb at a faster rate, they must be able to permeate the cell membrane in a favorable manner. Without this ability, it poses a problem for oral administration and specific targeting. The best way to improve permeability properties is by altering the structure of the drug. 18 Several modification strategies that have shown an increase in cell permeability include: making an ionizable compound into a non-ionizable compound, adding lipophilicity, isoteric 6

21 How Important are Pharmacokinetic Properties? replacement of polar groups, esterifying carboxylic acids, reducing hydrogen bonding and polarity, reducing the size of the structure, adding a nonpolar side chain, or using a prodrug. 18 By incorporating these methods, researchers can fine-tune the properties of potential drugs to increase efficacy and specific targeting. Oral bioavailability Cell permeability and oral bioavailability go hand-in-hand; if a drug has poor cell permeability and absorption properties, then administering it orally isn t the best option. This is often tricky when developing drugs to hit a specific target. If the drug needs to affect dopamine levels, the blood-brain barrier has different permeability chemistries from the stomach or esophagus. To make orally bioavailable drugs, the chemical make-up would have to be fine-tuned. As a result, some drugs are administered with a proactive coating, which is intended to prevent them from dissolving until they reach the small intestine. 17 Other means of controlling absorption are through capsules or gels; liquid contents tend to absorb faster than solid contents. 17 The rate of absorption affects the plasma concentration. Controlling this with gel capsules or tablets helps avoid toxic levels from the drug being absorbed too fast, or ineffectiveness and excretion from the drug not being absorbed fast enough, and ultimately providing the precise therapeutic concentration for the target areas. 17 7