Innovating CMC for Oligonucleotide and Peptide Therapeutics
In this first edition of the TIDES eBook Series, we explore ways in which chemistry, manufacturing and controls (CMC) can be optimized.
Innovating CMC for Oligonucleotide and Peptide Therapeutics
Welcome to the new TIDES eBook Series from Informa Connect Life Sciences. Each edition investigates one area of oligonucleotide and peptide therapeutics. In this first edition, we explore ways in which chemistry, manufacturing and controls (CMC) can be optimized.
The task of developing oligonucleotide- and peptide-based therapeutic products faces unique challenges, making it difficult to meet regulatory requirements and scale production for commercialization. Due to their size and molecular complexity, peptides and oligos require special considerations along the way. Without innovation, CMC processes are likely to suffer additional strain from the ever-increasing demand in the market.
In the next pages, we explore CMC challenges in depth and identify the opportunities for optimization which lie ahead in technology, partnering strategies and technical approaches adopted by leaders in the industry.
Jump to any article using the contents on the following page, or at any time using the Contents menu in the top left. There you can also download this eBook as a PDF.
The synthesis by Gyros Protein Technologies of the 24 SARS-CoV-2 peptides with therapeutic potential published by Grifoni and colleagues (7) represents a real-world example of synthetic challenges brought by a diverse range of sequences.
Peptides represent a unique class of pharmaceutical compounds, molecularly poised between small molecules and proteins, yet biochemically and therapeutically different from both.
This whitepaper looks at the challenges and opportunities facing the peptide and oligonucleotide therapeutics industry in partnering, business development and commercialization strategies, using a
number of case studies.
An interview with John Lopez, Process Development Chemist at Novartis, who explores how Artificial Intelligence can revolutionize chemistry to make it a data driven field.
The challenges to a CDMO partner is to cost-effectively, quickly and easily scale up your oligonucleotide from research to commercial quantities, as well as having the facilities in place to manage commercial scale quantities.
Case Study: Generating a SARS-CoV-2 Epitope Library
Gyros Protein Technologies
Optimizing Synthesis of SARS-CoV-2 Peptides for Epitope Analysis
Figure 1. The structure of SARS-CoV-2. Contributed by Rohan Bir Singh, MD; made with Biorender.com. Included under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), from reference 10.
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has triggered intense activity around the world and may well represent a paradigm shift in fighting infectious disease. For example, the SARS-CoV-2 genome was published on January 12, 2020, less than two weeks after the first cases were reported, and the first vaccine candidate entered human clinical testing just two months later – just one example of an enormous range of prototype therapeutics and vaccines being developed (1–3).
Peptide synthesis is one valuable component of the toolbox needed to quickly investigate the mechanism of infection, and peptides may also prove to have therapeutic properties or form the basis of a vaccine.
The power and promise of therapeutic peptides
Therapeutic peptides have many advantages, including high activity, great chemical and biological diversity, and low toxicity. These and the relative ease and low cost of peptide manufacture compared to protein-based biologicals has meant that therapeutic peptides are now being used to treat a range of conditions, including metabolic diseases, cancer, cardiovascular, and infectious diseases.
The speed and flexibility of peptide synthesis is a major advantage when handling rapidly evolving conditions, such as neoantigen peptide-based vaccines for the individualized immunotherapy of certain forms of cancer. The dynamics of neoantigen presentation by the tumor cells demands high peptide purity and yield, and also the ability to quickly synthesize many peptides in parallel for timely treatment <GPT Neoantigen whitepaper, March 2020>. Such performance will be invaluable in fighting COVID-19.
In the highly dynamic world of COVID-19, a snapshot reveals the value of peptides in fighting the disease.
SARS-CoV-2 infection, like SARS-CoV that caused the SARS outbreak in 2003, invades host cells by binding the human angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface through its viral spike protein (S; Figure 1), and it may be possible to develop peptide therapeutics that disrupt this protein-protein interaction (PPI).
For example, pre-incubation with two peptides reduced the infectivity of SARS-CoV in cell culture by over 10,000-fold, and infectivity was completely inhibited by combining three peptides (4). A similar method involves a 23-aa peptide fragment of the ACE2 peptidase domain α1 helix that binds to the S receptor binding domain of SARS-CoV-2 with low nanomolar affinity that could prevent the entry of virus into human cells (5, 6).
In another approach, bioinformatics has been used to search for targets of immune responses to SARS-CoV-2 (7). Multiple specific regions in SARS-CoV-2 have been identified that have high homology to the SARS-CoV virus and could be promising targets to guide peptide vaccine design.
The need for rapid and flexible peptide synthesis
The search and discovery of potential therapeutic peptides and epitopes for vaccine design puts a number of demands on the peptide sequence:
- The need for rapid synthesis of multiple sequences in parallel to provide material in large-scale screening
- The ability to optimize the synthesis of problematic sequences using flexible synthetic routes
- The need to address regulatory challenges with validated methods and software designed for regulated environments (GMP manufacture, 21 CFR Part 11).
To illustrate how peptide synthesis can meet these needs, 24 peptides from a study on epitopes for COVID-19 vaccine development (7) were synthesized in parallel, followed by optimization of the synthesis of specific sequences.
Case study: Generating a SARS-CoV-2 Epitope Library
The synthesis by Gyros Protein Technologies of the 24 SARS-CoV-2 peptides (Table 1) with therapeutic potential published by Grifoni and colleagues (7) represents a real-world example of synthetic challenges brought by a diverse range of sequences:
- The need for rapid, parallel synthesis of peptides, of which some represent clear sequence-related challenges, and
- optimization of the synthesis of specific peptides to improve purity.
The steps in this process included:
- Synthesis using HCTU/DIPEA and capping
- Synthesis using DIC/OxymaPure® chemistry
- Synthesis of problematic peptides using DIC/OxymaPure chemistry and high temperature
Table 1. Sequences of peptides synthesized
1st Optimization round: Rapid parallel synthesis using HCTU/DIPEA chemistry
The first step in parallel synthesis on Symphony® X used fast HCTU/DIPEA and capping chemistry at 25 °C that enabled short coupling times (5 min), with the longest peptide (48-mer) taking 33 hours to synthesize. This chemistry resulted in crude purities of, for example, six of the 24 peptides in the range 17.9–79.1% (Fig. 2; full data for all peptides is shown in Fig. 5).
Figure 2. Analysis by reverse phase HPLC revealed that the crude purity of six of the 24 peptides, RV1–RV6, synthesized using HCTU/DIPEA chemistry ranged from 17.9% up to 79.1%.
2nd Optimization round: Parallel synthesis using DIC/OxymaPure chemistry
The second round involved exploiting the capacity of Symphony X to screen different chemistries to find optimum conditions, and involved testing the efficiency of DIC/OxymaPure coupling chemistry for all 24 peptides at 25 °C.
The results were slightly better compared to the syntheses based on HCTU in the first round, but the reaction time for DIC/OxymaPure is longer, which resulted in a longer overall cycle time. Some peptides did not perform well with either chemistry at 25 °C, therefore the next step was to try raising the coupling temperature.
Figure 3. Changing to DIC/OxymaPure chemistry increased the crude yield for some sequences.
3rd Optimization round: Increasing crude yield by raising coupling temperature
In the third round of optimization, particularly challenging peptides were synthesized on PurePep® Chorus using DIC/OxymaPure chemistry at 90°C.
Raising the temperature from 25 °C to 90 °C, using PurePep Chorus, improved crude purity for a number of peptides (Fig. 4):
PV4 NNNAATVLQLPQGTTLPKGF: 31.6 → 47.0%
PV7 KSFTVEKGIYQTSNFRVQ: 29.6 → 70.3%
PV10 KPFERDISTEIYQ: 33.3 → 79.5%
RV4 RPQGLPNNTASWFTALTQHGK: 31.8 → 85.1%
Figure 4: Optimizing the synthesis of PV7, for example, involved testing the chemistry from (Round 1) HCTU/DIPEA at 25 °C on Symphony X (25.8 % crude purity) and (Round 2) DIC/OxymaPure (29.6%), and then (Round 3) increasing the reaction temperature to 90 °C (70.3 %), run on PurePep Chorus.
Figure 5. Summary of optimizing the synthesis of a diverse range of 24 peptides in an epitope library. The initial coupling reagent scan compared HCTU/DIPEA with DIC/OxymaPure chemistry at 25 °C using Symphony X. The crude purity of some problematic peptides was improved by synthesis at 90 °C with DIC/OxymaPure chemistry using PurePep® Chorus.
This Case Study represents a typical real-world example of the challenges that must be overcome when synthesizing a library of peptides with highly diverse sequences (Fig. 5).
- 24 epitope peptides could be synthesized in just over 1 day at room temperature using Symphony X.
- Screening of multiple chemistries on Symphony X helped optimize reaction conditions.
- The ability to synthesize difficult or complex peptides on PurePep® Chorus using heat gave significant increases in crude purity compared to room temperature syntheses for certain peptides.
- The Symphony X multiplex synthesizer supports the removal of a reaction vessel as soon as a synthesis is finished, even if others are still running, thus increasing the efficiency of the synthesis workflow.
In conclusion, the purity of synthetic peptides for vaccine development must be high to ensure correct targeting of immune responses for specific epitopes. Synthesizing peptides with high crude purities effectively simplifies downstream processing or further purification, especially in the case of more complex or difficult peptide sequences. To achieve this means choosing the right peptide synthesizer, which should also help in establishing an efficient synthesis workflow when generating epitope libraries for time-critical projects.
DIC - N,N' -Diisopropylcarbodiimide
DIPEA - N, N-Diisopropylethylamine
HCTU - 2-(6-Chloro-1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.
Researching virus infection and developing therapeutics and vaccines requires a lot from a peptide synthesizer.
Symphony® X peptide synthesizer with the proprietary PurePep® Pathway, has the ability to run 12 independent reaction vessels and 24 reaction vessels overall, which is often desirable when dealing with peptide libraries.
Speed – able to synthesize 24 ‘epitope-type’ peptides in 12 hours (15–20 mers).
Purity is ensured due to the focus on ‘right first time’ methodology, with no reagent or resin cross-contamination, and minimizes the risk of re-synthesis.
Unique in providing multi-channel synthesis under inert atmosphere and with no cross contamination.
Supports GMP manufacture, designed for 21 CFR part 11 compliance, together with IQ/OQ support and PQ guidance are available to support work in regulated environments.
The proprietary PurePep® Pathway comprises fluidics that minimize cross-contamination, dead volumes, and reagent carryover. This is especially crucial for the synthesis of long sequences, in which even small amounts of impurities, side products, and incomplete reactions over many cycles can drastically reduce the final purity and yield of desired peptides.
Aggregation, secondary structure, steric hindrance, and conformational effects can still pose challenges in synthesis, and PurePep® Chorus features enabling technologies that aid the synthesis of complex peptides and peptidomimetic sequences. Intellisynth™ real-time UV monitoring optimizes reaction times to ensure complete deprotection. By monitoring at 301 nm, the instrument measures the progress of the reaction – avoiding guesswork that can lead to incomplete deprotections, deletions, and side reactions. This feature is available on all reaction vessels, providing UV monitoring on up to six peptides in a single synthesis.
PurePep® Chorus meets many of the demands made in the synthesis of complex peptides.
Other features include:
A modular peptide synthesizer that is in-lab upgradeable, from 2 to 4 to 6 reaction vessels to meet productivity needs.
Independent induction heating, simultaneous and configurable to multiple vessels, and the ability to run multiple conditions in one run speeds up method development.
Icon-driven intuitive software platform with pre- programmed methods, ability to import sequences and reagent preparation calculators.
Designed for 21 CFR part 11 compliance, together with IQ/OQ support and PQ guidance are available to support work in regulated environments.
1. The COVID-19 vaccine development landscape. Thanh Le T et al, Nat Rev Drug Discov. 2020 Apr 9. doi: 10.1038/d41573-020-00073-5.
2. Screening 10,000 compounds identifies six potential COVID-19 therapeutics. https://www.drugtargetreview.com/news/60316/screening-10000-compounds-identifies-six-potential-covid-19-therapeutics/
3. Biopharma products in development for COVID-19. https://www.bioworld.com/COVID19products
4. Synthetic peptides outside the spike protein heptad repeat regions as potent inhibitors of SARS-associated coronavirus. Zheng B-J et al. Antiviral Therapy 10 393-403. 2005
5. The first-in-class peptide binder to the SARS-CoV-2 spike protein. Zhang G. et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.03.19.999318.
6. An experimental peptide could block Covid-19. http://news.mit.edu/2020/peptide-drug-block-covid-19-cells-0327
7. A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2. Grifoni, A. et al. Cell Host & Microbe 27, 671–680 April 8, 2020 https://doi.org/10.1016/j.chom.2020.03.002
CMC Approaches to Accelerate Peptide, Oligonucleotide and mRNA Therapeutic Development
by Catarina Carrao
CMC Approaches to Accelerate Peptide, Oligonucleotide and mRNA Therapeutic Development
By Catarina Carrao
This piece represents the views of the author and not necessarily the views of Informa Connect.
Peptides, a unique class of compounds
Peptides represent a unique class of pharmaceutical compounds, molecularly poised between small molecules and proteins, yet biochemically and therapeutically different from both. With a fundamental signaling action for many physiological functions, they present an opportunity for therapeutic intervention that closely mimics natural pathways1. There are a variety of challenges for the development of peptide therapeutics: (i) their intrinsic complexity for manufacturing, characterization and formulation, which increases their costs; (ii) the preparation of peptides for other than injection is still a challenge, and requires extensive development; (iii) expectations from the agencies for the control of the purity profile of peptidic Active Pharmaceutical Ingredients (API) are becoming increasingly complex and require a thorough understanding of the nature and the fate of impurities2.
To address the first concern, many peptides are developed for niche markets with smaller drug product demands; where the typical high potency of peptides, offsets the costs of the API2.
Secondly, efforts are underway to improve the oral availability of peptide therapeutics by increasing drug stability in the gastrointestinal tract; formulating peptides with permeability enhancers; and, improving the peptide Central Nervous System (CNS) availability through conjugation to carrier molecules, or delivery in nanoparticles1. Ensuring identity, purity, and reproducibility are equally essential during synthetic chemistry, drug discovery, and pharmaceutical peptide safety. Many peptidic APIs are large molecules that require considerable effort for integrity assurance3. For example, manufacturing of peptides on solid support does not rely on intermediates, which can be crystallized to remove impurities in the course of the synthesis; but rather, progress through the so-called telescope steps, with final purification only2. Therefore regulators expect a high level of process understanding and control; and, specify in the regulations that starting materials (e.g. for protected aminoacid derivatives) should address impurities based on the origin, fate and purge; and, use validated analytical methods2.
A recent study based on quantum mechanical 1H iterative Full Spin Analysis (HiFSA) establishes new nuclear magnetic resonance (NMR) peptide sequencing methodology, that overcomes key limitations of basic methods in identifying small structural changes or minor impurities that might affect efficiency and safety of therapeutic peptides3. HiFSA sequencing produces simultaneously definitive identity and purity information, allowing for API quality assurance and control (QA/QC); and achieving full peptide analysis via NMR building blocks, in a process that serves both research and commercial applications3. One can expect a significant increase in interest in peptide pharmaceuticals, primarily due to their low toxicity and wide range of possible molecular targets4. Improvements in peptide screening and computational biology will continue to support peptide drug discovery1.
Safety and delivery of oligonucleotides
Oligonucleotides (oligos) have been under clinical development for almost the past 30 years, beginning with antisense oligonucleotides (ASOs) and aptamers; and, followed about 15 years ago by silencing RNAs (siRNAs)5. Oligonucleotides, as peptides, resemble biologics in some ways, because of their molecular complexity, but are much smaller in size; leading to unique concerns in the design of control strategies for these types of molecules. A good starting point to designing therapeutics in this class, is the usage of natural peptides to improve physical and chemical properties such as stability and bioavailability; and, in relation to methods of manufacture, chemical synthesis, recombinant DNA technology, or extraction from natural sources, continue to be the preferred methodology currently in use6.
Despite considerable progress, two major obstacles stand in the way of widespread application of oligonucleotide therapeutics and regulatory approval: (i) drug safety, and (ii) delivery. The administration of oligonucleotides has been associated with the activation of innate immunity through interactions with toll-like receptors (TLRs); with some oligonucleotides binding to TLRs, and inducing immune responses similar to those induced by viral and bacterial RNA and DNA7. Different sequence motifs have been identified as agonists of TLR family members; as such, avoiding these sequence motifs and using chemical modifications can minimize these immune-stimulatory effects8.
The use of some siRNA therapeutics in clinical trials may be associated with another liability: inflammatory responses to the lipid nanoparticle formulations used to promote the uptake of siRNAs7. Lipid nanoparticles are known to induce a complex antiviral-like response of innate immunity9. To diminish the immune-stimulatory effects of the formulations, siRNAs in lipid nanoparticles have been administered in combination with antihistamines, non-steroidal anti-inflammatory drugs, and glucocorticoids7. A well-defined means of delivery is to directly conjugate a bioactive ligand to the RNA that will allow it to enter the cell of interest10; and, perhaps the most clinically advanced example of this technique, is the conjugation of N-acetylgalactosamine (GalNAc), which targets the asialoglycoprotein receptor on hepatocytes, to siRNA11. This receptor-mediated uptake allows for lower dosing, than that required for the therapeutic delivery of unconjugated oligonucleotides7, which is an essential feature for regulators approval and certification12. Delivery to other cell types, such as muscle cells, can be accomplished by targeting antibodies or antibody fragments against cell-surface proteins known to be involved in intracellular transport13.
Chemistry, Manufacturing, and Control (CMC): FDA and EMA guidelines
These new scientific developments have shown us the different ways we can target unhealthy cells; but, aside from safety and delivery related issues that occur in the clinic, the greatest problem for approval is often not clinical efficiency, but Chemistry, Manufacturing, and Control (CMC) of quality processes. Some of these challenges include determining critical quality attributes and critical process parameters, low transduction efficiency, assessment of potency, assurance of product sterility, process validation, stability, and production at multiple manufacturing sites.
For that reason, in 2018, the FDA issued the CMC Information for Human Gene Therapy Investigational New Drug Applications (INDs) guidance document, intended to serve as part of a modern, comprehensive framework for how to advance the field of gene therapy14. In order to deliver a safe and effective product, human gene therapies present many manufacturing challenges. Some of these challenges include the variability and complexity inherent in the components used to generate the final product; such as the source of cells (i.e., autologous or allogeneic); the potential for adventitious agent contamination; the need for aseptic processing; and, in the case of ex vivo genetically modified cell therapies, the inability to “sterilize” the final product because it contains living cells15. Distribution of these products can also be a challenge due to stability issues, and the frequently short dating period of many ex vivo genetically modified cell products, which may need release of the final product for administration to a patient, before certain test results are available14. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device; and, provides sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity, and strength/potency of investigational gene therapy products16. By providing CMC information in an IND, the sponsor commits to perform the manufacturing and testing of the investigational product as described in the submission; and, to review it during all phases of development to ensure product safety and manufacturing control14. As clinical development proceeds, and additional product knowledge and manufacturing experience accumulate, sponsors should submit information amendments to modify the CMC information already submitted in the IND; and do so, prior to any implementation16.
The US Food and Drug Administration (FDA) approved more than 40 marketing applications for novel therapeutics and mechanisms of action in 2017, reflecting an unexpected quick progress in the field6.
Europe and the US have very different legal and regulatory regimes for approving gene therapies, with the main difference being that the FDA oversees clinical trials, whereas the European Medicines Agency (EMA) does not17. To run a clinical trial in any of the 28 members of the European Union (EU), approval needs to be gained from a competent authority and from the ethics committee in the specific member state; and, there is also the requisite to get approval for using a genetically modified organism (GMO)12. In the EU, this rapidly growing area of therapeutics is denominated Advanced Therapy Medicinal Products (ATMPs), which are legalized under a specific valid regulation (i.e., No. 1394/2007, EC)12. They are based on new and highly innovative technologies, that specifically cover cell and gene therapy products and tissue-engineered goods18. The Committee for Advanced Therapies (CAT) at EMA was established to ensure that the relevant expertise is available in regulatory decision making to support and evaluate these products19; and, in order to optimize their development and assessment, several guidelines have been developed by the EMA in collaboration with relevant regulatory experts within the EU12. A significant proportion of the products are being developed in academic settings or by small/medium-sized enterprises (SMEs)20. There are many factors that contribute to the challenges in developing these products in order to achieve successful clinical use, with the major one being the successful translation of the non-clinical (NC) (also often referred as pre-clinical) evidence to achieve clinical relevance19. The NC investigation for ATMPs is recommended to start with a risk-based approach (RBA) in planning, which is a unique feature in the ATMP regulation21. RBA aims to enable planning for relevant experiments for establishment of safety and efficiency, including first-in-human trial, market authorization and post-authorization follow-up19. Risks and risk factors are specific for the product and intended clinical use; and, they should be carefully determined by an integrated approach between CMC/NC/Clinical experts6. The certification procedure involves the scientific evaluation of quality data and, when available, non-clinical data that SMEs have generated at any stage of the ATMP development process. The goal of the certification is to identify any potential issues early on, so that these can be addressed before the submission of a marketing-authorization application21. If the data are in line with the requirements as set out in Directive 2001/83/EC, a certificate will be issued stating compliance of data with requirements6. An expedited regulatory pathway, known as the PRIME (PRIority Medicines) scheme, was introduced by the EMA in 2016 to facilitate approval of medicines that target unmet medical needs12, and to speed up patient access to these critical therapies. As in the US, the sponsor needs to ensure that the significant CMC aspects can be delivered, in the appropriate timeframe, such that safety and quality are not compromised6.
mRNAs: towards the future of protein replacement therapy
Synthetic mRNAs have the potential to be the new pillar for protein replacement therapy; since they are engineered to replace mutated mRNAs and to be immunologically unobtrusive, highly stable, while maximizing protein expression. There is no specific guidance from the FDA or EMA for mRNA therapeutic products; but the increasing number of clinical trials conducted under EMA and FDA oversight, shows that regulators have accepted the approaches proposed by various organizations to demonstrate that products are safe and acceptable for testing in humans22. Interestingly, depending on whether RNA-based therapeutics are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively22. If targeting against infectious diseases, mRNA falls into the broad vaccine category of genetic immunogens, then many of the guiding principles that have been defined for DNA vaccines and gene therapy vectors can likely be applied to mRNA, with some adaptations to reflect the unique features of mRNA23. Approaches to deliver mRNA into the cellular cytoplasm safely and efficiently have been developed, so that two mRNA-based approaches replacing Vascular Endothelial Growth Factor (VEGF), and Cystic Fibrosis Trans-membrane conductance Regulator (CFTR) have now made it into clinical trials23. All enzymes and reaction components required for the Good Manufacturing Practice (GMP) production of mRNA can be obtained from commercial suppliers as synthesized chemicals or bacterially expressed, animal component-free reagents, thus avoiding safety concerns that surround the adventitious agents that plague the manufacture of cell-culture-based therapeutics24. For some mRNA platforms, removal of double-stranded RNA, and other contaminants is a critical step for the potency of the final product, due to stimulation of interferon-dependent translation inhibition10. The use of reverse-phase Fast Protein Liquid Chromatography (FPLC) has successfully resolved this issue at the laboratory scale25, and processes of scalable aqueous purification approaches are now being considered23.
It is still early days for gene therapies and mRNA therapeutics; but so far, developers generally give regulatory agencies high marks as partners. There are now so many mechanisms for interacting with sponsors, that regulators have been very supportive of innovation and gene therapy in general. Both researchers and regulators in the field, say the new challenges come from the novelty of the science, and not so much from the regulatory aspects17.
ABOUT THE AUTHOR
Catarina Carrão, biochemist by degree, worked as a biomedical researcher at Max F. Perutz Laboratories, Yale Cardiovascular Center at Yale University School of Medicine, and the Center Cardiovascular Research (CCR) at Charité Medical University. She now runs BioSciPons and Countlesssheep.com, a science communication agency and blog.
1. Lau JL and Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26:2700-2707.
2. de Maria GM, BH. The expansion of the therapeutic applications of peptides: drivers and challenges. Oligos & Peptides. 2015;33.
3. Choules MP, Bisson J, Gao W, Lankin DC, McAlpine JB, Niemitz M, Jaki BU, Franzblau SG and Pauli GF. Quality Control of Therapeutic Peptides by (1)H NMR HiFSA Sequencing. J Org Chem. 2019;84:3055-3073.
4. Slominsky PS, M. Peptide pharmaceuticals: opportunities, Prospects and Limitations. Molecular Genetics Microbiology and Virology. 2018;33:8-14.
5. Stein CA and Castanotto D. FDA-Approved Oligonucleotide Therapies in 2017. Mol Ther. 2017;25:1069-1075.
6. Cauchon NS, Oghamian S, Hassanpour S and Abernathy M. Innovation in Chemistry, Manufacturing, and Controls-A Regulatory Perspective From Industry. J Pharm Sci. 2019.
7. Levin AA. Treating Disease at the RNA Level with Oligonucleotides. N Engl J Med. 2019;380:57-70.
8. Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides. 2008;18:305-19.
9. Pepini T, Pulichino AM, Carsillo T, Carlson AL, Sari-Sarraf F, Ramsauer K, Debasitis JC, Maruggi G, Otten GR, Geall AJ, Yu D, Ulmer JB and Iavarone C. Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design. J Immunol. 2017;198:4012-4024.
10. Kaczmarek JC, Kowalski PS and Anderson DG. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med. 2017;9:60.
11. Nair JK, Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, Hoekstra M, Kandasamy P, Kel'in AV, Milstein S, Taneja N, O'Shea J, Shaikh S, Zhang L, van der Sluis RJ, Jung ME, Akinc A, Hutabarat R, Kuchimanchi S, Fitzgerald K, Zimmermann T, van Berkel TJ, Maier MA, Rajeev KG and Manoharan M. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958-61.
12. EMA. EMA Guidelines Relevant for Advanced Therapy Medicinal Products. 2019;2019.
13. Sugo T, Terada M, Oikawa T, Miyata K, Nishimura S, Kenjo E, Ogasawara-Shimizu M, Makita Y, Imaichi S, Murata S, Otake K, Kikuchi K, Teratani M, Masuda Y, Kamei T, Takagahara S, Ikeda S, Ohtaki T and Matsumoto H. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release. 2016;237:1-13.
14. FDA. Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). FDA publications. 2008.
15. Collins FS and Gottlieb S. The Next Phase of Human Gene-Therapy Oversight. N Engl J Med. 2018;379:1393-1395.
16. Cook KE, S. FDA's New Guidance On CMC For Gene Therapy INDs — What You Need To Know. 2018;2019.
17. Bender E. Regulating the gene-therapy revolution. Nature. 2018;564:S20-S22.
18. EC. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation (EC) No 726/2004. 2019.
19. Rousseau CF, Maciulaitis R, Sladowski D and Narayanan G. Cell and Gene Therapies: European View on Challenges in Translation and How to Address Them. Front Med (Lausanne). 2018;5:158.
20. Maciulaitis R, D'Apote L, Buchanan A, Pioppo L and Schneider CK. Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive. Mol Ther. 2012;20:479-82.
21. EMA. Draft Guideline on the Risk-Based Approach According to Annex I part IV of Directive 2001/83/EC Applied to Advanced Therapy Medicinal Products EMA/CAT/CPWP/686637/2011 of 19. EU publications. 2012.
22. Hinz T, Kallen K, Britten CM, Flamion B, Granzer U, Hoos A, Huber C, Khleif S, Kreiter S, Rammensee HG, Sahin U, Singh-Jasuja H, Tureci O and Kalinke U. The European Regulatory Environment of RNA-Based Vaccines. Methods Mol Biol. 2017;1499:203-222.
23. Trepotec Z, Lichtenegger E, Plank C, Aneja MK and Rudolph C. Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases. Mol Ther. 2019;27:794-802.
24. Pardi N, Hogan MJ, Porter FW and Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17:261-279.
25. Weissman D, Pardi N, Muramatsu H and Kariko K. HPLC purification of in vitro transcribed long RNA. Methods Mol Biol. 2013;969:43-54.
Partnering in the Oligonucleotide and Peptide Therapeutics Industry
By David Orchard-Webb, PhD, Freelance Consultant and Medical/Biotech writer
Partnering in the Oligonucleotide and Peptide Therapeutics Industry
By David Orchard-Webb, PhD, Freelance Consultant & Medical/Biotech writer
This piece represents the views of the author and not necessarily the views of Informa Connect.
This whitepaper looks at the challenges and opportunities facing the peptide and oligonucleotide therapeutics industry in partnering, business development and commercialization strategies, using a number of case studies. The drug space is enormous and the fields of peptide and oligo development dynamic, with both technologies converging upon intracellular targets, as well as traditional extracellular ones, making the possibilities for collaboration, licensing and investment, large.
Early on in drug discovery there are a whole range of concerns that need to be considered if a drug is to move forward to the next stage. Smaller companies with exceptional expertise in certain areas may require outside resources for some of the more generic and regulatory focused concerns. Companies in the oligonucleotide space often face a dilemma, they are experts in disease biology and how to make RNA that specifically targets disease processes, however during development they may have used a generic solution to deliver their construct into cells. They may not be experts in therapy delivery. Other issues include preclinical safety assessment and toxicology studies.
Under such circumstances, the company can either spend time developing or hiring expertise in delivery vectors such as lipid nanoparticles or they can out-license the encapsulation and manufacture of their RNA product to a contract manufacturing organization (CDMO), such as Avanti Polar Lipids. Companies such as Charles River can provide expertise in safety and toxicology models.
Assuming manufacturing is successful a second problem may occur in the transition to scale, the company may never have taken a product through phase III clinical trials and may lack the resources. At such a point the merits of licensing/partnering with big pharma should be considered.
Out-licensing of product manufacturing to Pharma
One such example is Reblozyl (ACE-536) a ligand trap that inhibits members of the TGF-beta superfamily involved in late stages of erythropoiesis. The U.S. Food and Drug Administration (FDA) granted approval for Reblozyl (ACE-536) in November 2019, for the
treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions. In 2011, Acceleron Pharma and Celgene Corporation, now part of Bristol-Myers Squibb, announced that the companies had entered into a joint development and commercialization agreement for ACE-536 in the treatment of anemia. Celgene and Acceleron jointly developed, manufactured and commercialized ACE-536. Celgene had an option for future Acceleron programs developed for anemia and made an upfront payment to Acceleron of USD $25 million. Thus, Acceleron gained both expertise in
manufacturing at scale and cash flow from the licensing partnership with big pharma. Another example is JNJ-3989, formerly ARO-HBV, is a
sub-cutaneous, ribonucleic acid interference (RNAi) therapy candidate designed to silence all HBV gene products and intervenes upstream of the reverse transcription process where current standard-of-care drugs act.
In 2018 Arrowhead Pharmaceuticals entered into a license and collaboration agreement with Janssen Pharmaceuticals, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, to develop and commercialize JNJ-3989, which Arrowhead had previously solely developed. In addition, Arrowhead entered into a research collaboration and option agreement with Janssen to potentially collaborate for up to three additional RNA interference (RNAi) therapeutics against new targets to be selected by Janssen. The transactions had a combined potential value of over $3.7 billion for Arrowhead.
As with the Acceleron deal Arrowhead gained the resources they needed to fund and operationally execute large later-stage clinical trials. They also built a pathway for the development of their very early stage therapeutics.
Investments in the oligo and peptide space are largely driven by market forces such as the emergence of fatty liver disease and the recent coronavirus outbreak. That said rare diseases provide an excellent opportunity to establish value with proof of concept, especially for
companies focused on RNA interference.
As a shareholder the potential for return in rare disease is large, for example when Roche acquired Spark Therapeutics for $4.3 billion. The CHOP Foundation collected about $430 million of that total from its Spark shares — a huge return for the hospital’s $33 million investment. Venture capitalists and investment funds that backed the company early also profited massively.
Trends in the investment landscape
Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disease in historically industrialized nations, and its more serious form non‐alcoholic steatohepatitis (NASH) are especially highly prevalent in
patients with metabolic disorders such as type 2 diabetes and obesity. A major cause of liver fibrosis and cirrhosis, NASH is an area of high unmet medical need with no approved treatments available.
AKR-001 is an Fc-FGF21 fusion protein engineered to mimic the biological activity profile of native FGF21, an endogenous hormone that regulates lipid and energy metabolism, and is secreted throughout the body to alleviate cellular stress. Observations from clinical trials of AKR-001 and other FGF analogs point to AKR-001's potential to reduce liver fat, cellular stress, inflammation and fibrosis in people with non-alcoholic steatohepatitis (NASH), as well as to improve risk factors of cardiovascular disease, the principal cause of death among NASH patients.
Akero Therapeutics has raised a total of $135M in funding over 2 rounds. Their latest funding was raised on Dec 12, 2018 from a Series B round. The company has a market cap of USD $621.7 million and expects a data release from a Phase 2a (MRI‐PDFF) on AKR-001 in March.
As mentioned above investing in rare disease has potentially lucrative returns. Peptide and oligo therapeutic companies are at the cutting edge of rare disease therapy and are prime candidates for investment.
The leading cause of combined deafness and blindness is Usher syndrome, a rare genetic disease. Patients with Usher syndrome type 2 (USH2), the most common type of Usher syndrome, have a moderate to severe hearing impairment from birth. They usually experience the first symptoms of night blindness in their 20s, which progresses to complete blindness by the time they are over 30.
ProQR Therapeutics is developing an investigational oligonucleotide drug called QR-421a to treat progressive blindness in patients that have USH2 due to a mutation in exon 13 of the USH2A gene. QR-421a is an oligo that causes exon skipping, thereby removing the mutation in exon 13.
A first-in-human clinical trial of QR-421a is ongoing in Europe and North America. The Phase 1/2 study, named STELLAR, will include approximately 18 patients that experience vision loss due to mutation in exon 13 of the USH2A gene. ProQR raised USD $97.5M at IPO and has a market cap of USD $352.7 million with interim results from STELLAR expected to be available in March.
A number of companies are scrambling to develop COVID-19 vaccines and therapeutics with Moderna, Inc. seen as the most advanced to develop a vaccine. The company will be initiating human clinical trials for its vaccine in April. Notably Sirnaomics, Inc have also responded but are at a much earlier stage.
Case study of investment partnership
Apellis Pharmaceuticals Inc., a clinical-stage biopharmaceutical company focused on the development of novel therapeutic compounds to treat disease through the inhibition of the complement system recently initiated a novel, risk-sharing collaboration to support the development of APL-2, a synthetic cyclic peptide conjugated to a polyethylene glycol (PEG), in hematologic indications with SFJ Pharmaceuticals, a global drug development company backed by Blackstone Life Sciences and Abingworth.
The collaboration is the first time that SFJ Pharmaceuticals has partnered with a pre-revenue biopharma company. Under the terms of the agreement, SFJ has agreed to pay Apellis USD $60 million in support of the paroxysmal nocturnal hemoglobinuria (PNH) clinical program, with up to an additional $60 million based on Apellis meeting specific, pre-defined clinical milestones. Subject to mutual agreement, SFJ may also pay Apellis an additional $50 million in funding for the PNH clinical program following a specified, pre-defined clinical milestone.
Under the terms of the PNH agreement, Apellis will pay SFJ regulatory approval milestone payments in annual increments at a pre-determined payment schedule over six years, with the majority of payments to SFJ due in years 3-6 following regulatory approval. No approval payments are owed to SFJ should regulatory approval not be achieved for PNH. Apellis has an option to buyout of all or part of the milestone payments at any time following regulatory approval at a discounted rate. Apellis retains exclusive worldwide commercial rights to APL-2 in all indications.
SFJ Pharmaceuticals has taken a calculated risk that could pay off massively, provided their assessment of Apellis’ ability to deliver an effective therapeutic was correct. They have limited their risk by having
conditional milestones. The incentives for Apellis are great and will provide the funding they need to deliver their therapy, provided it turns out to be effective.
Entrepreneurs in life sciences
Usually, a new life science startup originating from a University is created when a scientist, through initial government or foundation grants, discovers a pathway, mechanism in biology, or drug development tool that is particularly novel and judged to have a good chance of competing in the biotech marketplace. A disclosure is filed through the university office and discussions are initiated with the technology transfer or licensing officer at the university about commercializing the discovery. A small business innovation research grant (SBIR) may be submitted to fund startup activities, which may require matched funds from the applicant.
Patrick Y. Lu, Ph.D, started his biopharmaceutical industry career in 1993 as a lab head in Novartis and was the co-founder and Executive VP of Intradigm Corporation (2001-2006). Patrick has authored more than 50 scientific papers, review articles and book chapters, and is an inventor for more than 50 issued and pending patents. In his latest venture, Sirnaomics has raised more than US$70 million dollars and has developed a series of “first-in-class” siRNA therapeutic candidates at different phases of clinical studies, in both USA and China. The company’s therapeutic programs are focused on anticancer and antifibrotic indications. Sirnaomics is also currently investigating treatment targets for coronavirus COVID-19 (SARSCoV-2).
Dr. Monia is the chief executive officer and a founding member of Ionis Pharmaceuticals. His contributions at Ionis include research into the medicinal chemistry and mechanisms of action of RNA-targeting modalities to treat human diseases, most notably antisense-based therapeutic strategies. Dr. Monia has published more than 200 primary research manuscripts, reviews and book chapters, and is an inventor on more than 100 issued patents. Dr. Monia is also an adjunct professor of biology at San Diego State University where he lectures at the graduate level on pharmacology.
Several companies are developing cell penetrating or lytic peptides that activate the immune system. AMAL Therapeutics SA, which was recently acquired by Boehringer Ingelheim, is developing a self-adjuvanting (TRL activating) peptide platform, with a multiantigenic domain with room for four antigens, and a cell penetrating peptide domain for efficient antigen delivery to immune cells such as dendritic cells. GV1001 is a 16-amino acid fragment of the human telomerase reverse transcriptase catalytic subunit (hTERT) developed as a cancer vaccine by KAEL-GemVax and also found to be a cell penetrating peptide through interaction with heat shock proteins. Lytix Biopharma develops proprietary oncolytic peptides. Lytix's lead candidate, LTX-315, is developed for intratumoral treatment of solid tumors.
In addition to being a catalyst for acquisitions, this technology is of great interest to investors. For example, Lytix Biopharma has already raised a total of USD $10.4M in funding from 7 investors.
Changing technologies impacting the biotech investment landscape
Peptides have traditionally been viewed to act predominately extracellularly, whereas oligonucleotides usually act within the cell. This prescribes their potential applications, however with the advent of cell penetrating peptides and also the ability to couple them with technologies such as T-cell receptor (TCR), it is possible to target intracellular processes with peptides as well as oligonucleotides.
From an investment perspective this means that funds that traditionally looked for intracellular pathways and technologies such as oligonucleotides, should now also cast their eye on peptide possibilities and realize that a peptide can be adapted to target intracellular processes, practically this means that oligos and peptides can “knock-down” or “trap” intracellular targets, respectively, in equal measure.
On November 24, 2019 Novartis acquired The Medicines Company, which was developing Inclisiran, potentially the first and only cholesterol-lowering therapy in the siRNA (small-interfering RNA) class. Inclisiran is a twice-yearly therapy in Phase III clinical development to evaluate its ability to reduce lowdensity lipoprotein cholesterol (also known as LDL-C).
The transaction is expected to close in the first quarter of 2020. Until closing, Novartis and The Medicines Company will continue to operate as separate and independent companies.
Under the terms of the agreement, Novartis will, through a subsidiary, commence a tender offer to purchase all outstanding shares of The Medicines
Company for USD $85.00 per share in cash. The Medicines Company is intended to become an indirect wholly-owned subsidiary of Novartis. The transaction is subject to customary closing conditions, including antitrust clearance.
On February 4, 2020 the Federal Trade Commission (FTC) and the Food and Drug Administration (FDA) released joint guidance concerning competition for biologics, including biosimilars. The joint guidance was intended to enhance competition for biologics and reduce manufacturers’ use of false or misleading promotional communications concerning the efficacy or safety of biosimilars and other biologics. The primary goal of the guidance appears to be to reduce the cost of medications for consumers and increase the level of competition in the biologics space. A merger intended to shut down a competing product would fall on the wrong side of antitrust.
Entrepreneurship, partnering, licensing, investment, and mergers & acquisitions within the oligonucleotide and peptide therapeutics industry is extremely robust and only likely to grow in the coming years with the development and maturation of new technologies. All of these elements play a role and at least a few, such as strong investment, big pharma acquisition, or outstanding entrepreneurship, are essential for fast tracking the path of therapeutic products to commercialization.
How AI Could Revolutionize Chemistry
Interview with John Lopez, Process Development Chemist at Novartis
How AI Could Revolutionize Chemistry - An Interview with John Lopez, Process Development Chemist at Novartis
John Lopez, a Process Development Chemist at Novartis, sat down with TIDES TV to discuss how artificial intelligence can revolutionize chemistry to make it a data-driven field.
Q&A With Ajinomoto Biopharma Services: Oligonucleotide Therapeutics - Partnering with the Right CDMO
Q&A With Aji BioPharma Services:
Partnering with the Right CDMO
The oligonucleotide market is poised for high growth over the next few year driven by a few factors, including high application potential of oligonucleotides for a variety of medical conditions, a growing number of FDA approved oligonucleotide drugs, an increased focus on personalized medicine, and a continued emphasis on the development of therapeutics for rare diseases. As a result, contract development and manufacturing organizations (CDMOs) are seeing increasing requests for oligonucleotide production from small to commercial scale. The challenges to a CDMO partner is to cost-effectively, quickly and easily scale up your oligonucleotide from research to commercial quantities, as well as having the facilities in place to manage commercial scale quantities.
Noriyasu Kataoka, M.Sc., is the Quality Manager & President and Akihiro Oota is the General Manager of Oligonucleotide & GMP Manufacturing at the Osaka site of Ajinomoto Bio-Pharma Services (Aji Bio-Pharma), which recently constructed and opened a new Oligonucleotide API Manufacturing Center.
The Osaka site has been successfully synthesizing oligonucleotides for research use for over 20 years prior to developing GMP manufacturing for oligonucleotides. In this Q&A, they discuss the resources and capabilities needed for a CDMO to seamlessly scale oligonucleotides from research to commercial manufacturing.
What are oligonucleotide therapeutics?
Noriyasu Kataoka: Oligonucleotide synthesis involves making changes to nucleobases, the sugar backbone, or the phosphodiester bonds to create a specific DNA or RNA molecule, for example BNA (bridged nucleic acids) and LNA (locked nucleic acids). These chemical modifications have led to the development of new drugs for various diseases and therapies that previously were difficult to treat using conventional drug treatments. Additional nucleic acid technologies include the custom synthesis of antisense oligonucleotides (ASO), RNA interference (RNAi), small interfering RNA (siRNA) and microRNA (miRNAs), which are used to modulate gene and protein expression, as well as aptamer RNAs, which modulates protein functions.
Vaccines are of particular interest in the oligonucleotide field, especially for the rapid development of vaccines for emerging diseases, such as malaria or COVID-19.
What is the benefit of using oligonucleotides for therapeutics?
Noriyasu Kataoka: With the broad variety of platforms and modalities, oligonucleotides hold a strong promise and a growing portfolio for researchers and biopharma drug companies in developing effective, targeted, next-generation therapeutic drugs and vaccines. Since oligonucleotides can target errors in the genetic code, many diseases and conditions that were previously untreatable using traditional medicines, can now be managed and with better safety and efficacy. Vaccines are of particular interest in the oligonucleotide field, especially for the rapid development of vaccines for emerging diseases, such as malaria or COVID-19. Oligonucleotides can be used as vaccines adjuvants, which can enhance the effect of the innate immune response by targeting cells’ toll-like receptors (TLR).
Are oligonucleotides considered large or small molecules?
Noriyasu Kataoka: Oligonucleotides are sized between small and large molecules, but with a large range in the mode of action at the cellular level. Therefore, while oligonucleotides are manufactured in a manner similar to small molecule active pharmaceutical ingredients (API), once administered they act more like a large molecule drug product. This has made for unique regulatory challenges, especially in regards to Chemistry, Manufacturing and Control (CMC) standards and characterization of the final drug product, to ensure safety and quality. Regulatory agencies are working with CDMOs and biopharmaceutical companies to help define these aspects during investigational New Drug (IND) applications, which can then be updated as the drug substance manufacturing is scaled-up.
What are some of the challenges between manufacturing for research vs. commercial use?
Akihiro Oota: Custom oligonucleotide manufacturing is accomplished through traditional solid phase synthesis (chain elongation) using fully automated oligonucleotide synthesizers, which can manufacture to a specific quantity size batches. The customizable configurations of the synthesizers allow for flexibility and yield improvements of the oligonucleotide. Large scale production of oligonucleotides has been a challenge due to increasing manufacturing costs, due to cost-inefficiencies from reagents and materials using small quantity synthesizers. To address this, in 2019, Ajinomoto Bio-Pharma Services opened a large scale oligonucleotide API manufacturing facility, which houses a synthesizer with the capability to produce up to 20 kg quantities. This helps alleviate the cost-inefficiencies, while maintaining the flexibility both of the individual oligonucleotide and between different lots.
What was your area of focus when designing the new API Manufacturing Center?
Akihiro Oota: Our main focus was to build a development and manufacturing facility that can manufacture large scale, high quality oligonucleotide therapeutics to meet the needs of our clients. The 2,000 m2 manufacturing facility provides a Class 100,000 clean area for cGMP manufacturing of oligonucleotide APIs, with two fully-separated production lines including, a multipurpose room to custom synthesize heavily modified oligonucleotides, two tray lyophilizers and an OligoProcess synthesizer area for large scale solid phase oligonucleotide manufacturing. The facility also houses R&D labs for the development of novel oligonucleotide manufacturing technologies, a dedicated warehouse, sampling room, and QC lab. With this facility, we have built a robust oligonucleotide development and manufacturing center able to meet the needs of later clinical and commercial quantities.
What are the most important factors when considering a CDMO for oligonucleotide manufacturing?
Noriyasu Kataoka: There are a few factors to that a sponsor should consider when selecting a CDMO to work with. Quality systems are of upmost importance. A CDMO should have a QA group, preferably onsite that is able to detail their quality strategy and demonstrate that they are able to effectively handle any investigations and/or resolve any deviations that might occur. Additionally, an onsite process development or tech transfer team that can work with customers during the scale-up process and actively troubleshoot activities in a timely manner. Another advantage would be for the CDMO to be able to perform the majority of the analytical testing (for example: purity, sequence confirmation, molecular weight confirmation, impurity analysis, oligonucleotide content, endotoxin, counter ion testing) onsite. It is also important to know if analytical development is available onsite, in case these methods need to be developed or optimized. Lastly, it is important to consider the internal value chain of the CDMO. If the CDMO has an onsite or related site that can perform the next steps, such as fill finish and/or packaging and labeling, this allows for a smoother transition than transferring to another company directly.
The oligo market is rapidly adapting to produce these new therapeutics. Can you share any new technologies or innovations that customers might see on the horizon?
Noriyasu Kataoka: The future of oligonucleotide synthesis and the ability to successfully manufacture large scale quantities of oligonucleotides that can be used in drug therapies are dependent on a CDMO’s ability to effectively scale up at a lower cost, while maintaining a high yield and purity. A specific example of this is long chain RNA, in which the yield goes down as chain length increases. The Research Institute of Bioscience Products and Fine Chemicals, a R&D arm of Ajinomoto Co., Inc., is working on a novel RNA producing system based on microbial fermentation of Corynebacterium glutamicum. In this innovative approach, C. glutamicum provides a novel RNA producing system for the production of various types of long chain RNA (60 - >300 mer) with high scalability and yield at a low cost with high purity profiles. Another example is AJIPHASE®, which is a hybrid of solid and solution phase synthesis providing equivalent quality and yield to traditional solid phase synthesis. This advanced technology allows Ajinomoto Bio-Pharma Services to manufacture high quality, commercial quantities of various oligonucleotides, PMOs and peptides under GMP.
Overall, there is a considerable amount of work and expertise necessary to make sure oligonucleotides are manufactured to the highest quality and the right cost.
As the biopharmaceutical industry ventures further into the rapidly growing oligonucleotide market, it is important to consider the right CDMO partner for your project and to ensure they have the correct resources, equipment, process know-how and quality expertise in place. The lack thereof can have detrimental effects to the timeline, costs and overall success, and therefore the ability to seamlessly supply oligonucleotides as they transition from a research project to a commercial drug product on the market.