Analytical Controls in an Evolving Technology and Regulatory Landscape

 
IBC's 18th Annual TIDES is the industry's #1 forum for oligonucleotide and peptide leaders to build successful partnerships and accelerate products from early discovery through late-stage development and commercialization. The TIDES team recently talked to Rachel Orr, Senior Scientist, GlaxoSmithKline R&D, United Kingdom for an exclusive interview that delves into analytical controls in an evolving technology and regulatory landscape, the topic of her presentation at the upcoming Oligonucleotide and Peptide Therapeutics event in Long Beach, CA.


1. What key analytical challenges do oligonucleotide developers need to overcome in order to achieve regulatory approval?

Oligonucleotides are inherently difficult to analyze - they are neither traditional, small nor large molecules, and the techniques and well established methodologies for pharmaceutical analysis are all focused on these distinct classes. In addition, there is very limited regulatory guidance when it comes to oligonucleotides, so there are no set rules to follow. There are often discussions as to whether oligonucleotide analysis should follow small molecule rules and regulations or align with biopharmaceuticals; opinions are divided.

With limited experience across the industry in marketing applications it is difficult to assess what is needed in order to gain regulatory approval and this is one of the biggest challenges in CMC oligonucleotide development. There is no recent precedence of global oligonucleotide marketing applications and as such it is difficult to ascertain what may and may not be acceptable. Close engagement with the regulators is something which helps to form strategies and controls and hopefully this will increase the likelihood of success of regulatory approvals going forwards.


2. How have advancements in technology improved the analytical process? Can you provide examples?

Since the last successful oligonucleotide marketing application there have been considerable enhancements in technologies. UHPLC is now common throughout the industry and techniques such as high resolution NMR and mass spectrometry are much more affordable and quick. These advances in technology mean that the resolution and robustness of methodologies can be much improved, however has a downside that the regulators may well expect us to present them with these improvements by first intent.

Increased understanding of non "typical" molecules throughout the industry has enabled wider thinking and collaboration between different pharmaceutical companies, with more people working together on the problem progress will inevitably come quicker. As more people engage with the concept of oligos and as technology continues to evolve, I anticipate a large shift in the way we look to control oligonucleotides analytically in coming years.


3. What are the most common mistakes that oligonucleotide drug developers encounter during CMC submissions?

Again, due to there being so few oligonucleotides which have gone through the full CMC process I think it is difficult to make too many sweeping statements, however the key issues that I have come across all stem from attempting to fit oligonucleotides into a box. Whether it is the small molecule group or the biopharmaceutical groups who take on the challenge of oligonucleotides, it is generally only a few "experts" within that team who work on the molecules. It is impossible to fit existing small or large molecule platforms onto oligonucleotides and a lot of time, resources and money can be wasted trying to do so! Due to the small pool of people working on the oligo projects it can also be challenging when it comes to elements such as wider reviews of submissions as the reviewers are not always as well informed about the challenges associated with oligonucleotide analysis. Education of these reviewers and key stakeholders is an activity that cannot be underestimated in time or importance! This emphasizes the benefits of cross-pharmaceutical company collaborations.


Want to hear more from industry experts like Rachel? See our exclusive TIDES speaker Q&A series here.

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Key Industry Business & Market Trends; From a CMO Perspective

For a sneak peek at the high caliber of content presented at BPI West, we had industry expert Dr. Victor Vinci of Cook Pharmica join us for an exclusive interview.

In this interview, Victor Vinci, Ph.D., Chief Scientific Officer and Vice President of Process Development at Cook Pharmica discusses key trends as they relate to the business and market landscape from a CMO perspective, what the risks are and how as a CMO do you share or mitigate those risks - as well as what that process of sharing and mitigating looks like, and finally he discusses Cook Pharmica and their unique position relative to other CMO's and the strategic direction they are taking.

Access the interview

Interested in learning more? Join us at BPI West - March 14-17 in Oakland, CA. Register before 2/19 with the code BPIWEST16BL and save $300! Click here to activate your savings.

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Industry Expert Paul Parren, Ph.D. Provides Exclusive Insights on ThinkTank

ThinkTank, is a free knowledge community focused on the antibody engineering field. Ask questions. Share answers. And boost your reputation. IBC Life Sciences, producer of the Antibody Engineering & Therapeutics conference, hosts these conversations to enable efficient knowledge exchange amongst practitioners. Insight is within sight.

ThinkTank has been built for professionals in a mobile world, who need high-quality answers to difficult questions from people with experience and expertise.

One of the many industry experts who actively participate on ThinkTank is Paul Parren, Ph.D., Senior Vice President and Scientific Director, Genmab, The Netherlands – Below you will find snippets of his responses to a variety of questions that have been posed on the platform. To continue your learnings with the Antibody Engineering community, be sure to login to ThinkTank now.


Excerpts from Dr. Parren's insights via ThinkTank;

With all the different antibody modalities to choose from (bispecifics, antibody fragments, antibody mixtures, ADCs and other conjugations, fusions, antibody combinations), how does one decide which approach to use in a specific project? And what are some advantages and disadvantages of these various modalities?

Dr. Parren: Your approach would be guided by the target product profile, i.e. does your application require long/short half-life, antibody effector function yes/no etc. This should eliminate a number of the possibilities. Then the approach becomes empirical in which I would recommend to produce a model antibody in a number of the remaining formats and assess for maximal activity/safety in comparison to competitor drugs.

Which immunotherapeutic antibody mechanisms have shown the most promise in the clinic? And where is this field headed next?

Dr. Parren: Hard to say in general. Preferably a therapeutic antibody engages multiple mechanisms as a single specific mechanism may, for example, not work against all diseased cells or in all anatomical niches. The required mechanisms will in addition be strongly dependent on your intended application.

The development future of non-canonical therapeutic antibodies (such as nanobodies, antibody scaffolds)? 

Dr. Parren: This is a very broad question and therefore not easy to answer in general terms. In my opinion, antibody fragments such as nanobodies, will have their strongest appeal in areas not served by classical, full length, antibodies. That is in areas for which topical or local administration is most appropriate. One could think of ocular injection or inhalation. In addition, applications which require a short in vivo half-life are attractive, e.g. imaging or in which short, temporary, target inhibition is important.

Should patients be pre-screened (genetically or epigentically) in order to achieve the maximum efficiency/efficacy of antibody therapy?

Dr. Parren: Prescreening of patients to be treated with targeted therapies is important to achieve maximal effects and proper patient selection is the future. Choosing the right biomarker or companion diagnostic will be critical however. Genetic prescreening may only be suitable for some applications, i.e. when screening for target expression, an antibody-based diagnostics may be more appropriate. The impact of the microbiome on antibody therapy is a relatively new field, which needs substantial further investigation, but definitely an area to watch.

The current therapeutic antibodies are targeting membrane-bound or circulating proteins. Any efforts or prospects on targeting intracelluar proteins using antibody/derivatives?

Dr. Parren: The best progress on targeting intracellular proteins is in the targeting of MHC-peptide (e.g. WT1 and NY-ESO-1) complexes presented on the surface of tumor cells with antibodies or affinity-matured TCR antibody-like constructs. Several groups are trying to target antibodies to intracellular compartments, but none of these efforts is ready for prime time yet.

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