THE LARGEST MEETING TO ACCELERATE OLIGONUCLEOTIDE AND PEPTIDE PRODUCTS FROM EARLY DISCOVERY TO LATE-STAGE DEVELOPMENT & COMMERCIALIZATION
Below are pre-event interviews with a few of the TIDES 2018 speakers.
Dr. Robert Langer, MIT
Robert Langer is the David H. Koch Institute Professor at MIT (there are 13 Institute Professors at MIT; being an Institute Professor is the highest honor that can be awarded to a faculty member). He has written more than 1,400 articles and has over 1,260 issued and pending patents worldwide.
His many awards include the US National Medal of Science, the US National Medal of Technology and Innovation, the Charles Stark Draper Prize (considered the engineering Nobel Prize), Albany Medical Center Prize (largest US medical prize), the Wolf Prize for Chemistry, the 2014 Kyoto Prize and the Lemelson-MIT prize, for being “one of history’s most prolific inventors in medicine.”
Langer is one of the very few individuals ever elected to the National Academy of Medicine, the National Academy of Engineering and the National Academy of Sciences.
What characteristics of genetically engineered proteins, DNA and RNAi make them so effective as drug delivery vehicles?
RL: I would not necessarily say they make effective delivery systems, although albumin has been used effectively and research has been done on others. More importantly, these molecules often require effective delivery systems because of the need for targeting in some cases and to make them last long enough to be effective in other cases.
Where are the opportunities/challenges for industry and academia to collaborate to improve the delivery of oligonucleotides, peptides and other therapeutic modalities?
RL: There are many and I think the ones that make the most sense are high risk, long range Projects. We have or have had collaborations with industry in such areas as oral delivery of proteins, long term delivery to the back of the eye, and delivery of nucleic acids.
You’ve previously served on the US FDA’s SCIENCE Board. Can you comment on the regulatory challenges that today’s oligonucleotide and peptide drug developers may face when trying to solve the delivery challenges of macromolecular therapeutics?
RL: I think safety and efficacy are still the key, but depending on the particular molecule there may be more complex analytical or immunological issues.
Congratulations on being named #1 Master of the Bench, Medicine Maker “Power List.” With so much innovation and research happening in the field of drug delivery, what opportunities over the next 5 years do you see for oligonucleotide and peptide drug developers?
RL: They are enormous. The next 5 years will certainly see the 1st approvals for RNA therapeutics, Alnylam is on the cusp of this already for siRna and Moderna is in some 10 clinical trials for mRna. And the opportunities will increase as innovation will hopefully occur in targeting, non invasive delivery ,and smart delivery systems.
Our readers are well aware of your professional accolades, but may not know much about the man behind the lab coat. Outside of the lab and classroom, what hobbies do you enjoy in your free time?
RL: I exercise a lot (I try to do a few hrs a day) in part because I like to eat so much, particularly chocolate. I used to do magic shows for children and I still enjoy magic. And I love to spend time with my wife and children and attend sporting events and go to nice places.
Dr. Tom Barnes, Intellia Therapeutics
Tom Barnes has led platform-based research and drug discovery teams for over 20 years, and is responsible for extending the reach of Intellia’s CRISPR platform into new areas. A veteran entrepreneur who has helped launch several companies, he has turned creative scientific visions into successful businesses for both startups and established organizations. Tom has wide-ranging knowledge of biological systems through his work across diverse platforms, including genomics and gene discovery, small molecule drug repositioning, and protein engineering.
How can oligonucleotide and peptide drug developers benefit from advances in CRISPR/Cas9 technology?
The straightforward way that CRISPR can help traditional drug modalities is by providing the ability to turn any cell system into a genetic system – essentially permanent RNAi. This is useful in target validation as well as for engineering cell lines to doing screens in. Of course, CRISPR is itself a new drug modality, when combined with the right delivery system such as lipid nanoparticles or viral delivery.
What opportunities and challenges do you see for CRISPR/Cas9 technology over the next 5 years?
I’ll split this into two – editing ex vivo, and in vivo. For ex vivo, I see the greatest opportunity in doing much more sophisticated engineering of cell therapies than has been done to date, effectively optimizing the cell’s behavior for its intended purpose. One of those improvements, creating allogeneic cells, could be broadly enabling for the whole class of engineered cell therapies. For in vivo editing, the challenge will be firstly to show that we can safely and effectively edit human tissues; secondly, it will be to show that we can repair as well as knock out genes. The key opportunity also lies here, namely to bring forward therapies for patients suffering from genetic disease, who typically have had few therapeutic options.
You’ve helped launch several successful companies and are currently Senior VP at Intellia Therapeutics. What advice can you share with our readers working to get their early stage start ups off the ground?
The elements of a successful startup are: a high-quality idea; committed investors; and a great team to execute. The idea should be more than something that’s do-able; it should be compelling. It should be able to outcompete other ideas that the investor may be considering. You’ll need a business plan, not just a research plan, that also suggests how you think the investors will exit. Having said that, different investors are looking for different things, so one “no” is not a condemnation of your idea. But be willing to hear what people tell you – a “no” with a good reason can help you see a better way. You believe in yourself, which is good, but you’ll need a team. Don’t be put off by the suggestion that people will need to be brought in above you, if you have limited experience. Biotech is a team sport where experience matters a lot, and investors know that.
Dr. Sheron Branham, Biogen
Sheron Branham is the Associate Director of Process Engineering and Manufacturing at Biogen and is responsible for the operation of their new antisense oligonucleotide clinical and commercial manufacturing facility. She is inspired by the potential impact ASOs could have on unserved patient populations and was driven to help in the mission. She serves on the site leadership team for Biogen’s RTP facility and has been at Biogen for just over four years.
Why did Biogen decide to internalize a manufacturing platform for antisense oligonucleotides, as opposed to outsourcing?
Several factors were considered in Biogen’s Make vs. Buy decision for antisense oligonucleotides, but three major reasons drove the decision towards internalization. The first was the strength of our pipeline of ASOs out of the Ionis partnership. We were on the verge of launching our first ASO, Spinraza, and we had a number of additional molecules in development with several more expected throughout the lifetime of our partnership agreement with Ionis. The second was the worldwide capacity constraint for ASO manufacturing. Limited flexibility, long waiting periods, and high cost to outsource were considered in the decision. Finally, Biogen’s ASO manufacturing process enabled the use of existing biologics purification and vial filling facilities, limiting capital costs to the installation of upstream synthesis only. Overall, the strategic benefits and cost analysis indicated the best decision for Biogen was to make.
What challenges did Biogen face during the construction of its new $23M facility?
There are always challenges associated with any startup, but launching a new manufacturing platform like ASOs in a company that has been protein-centric for 40 years presented some unique opportunities. I will discuss several of them in my presentation, but one challenge in particular was overcoming the lack of internal resources with ASO expertise. We have ASO expertise in our process development team, which is located in Boston, Massachusetts, however the manufacturing facilities were all to be located in North Carolina. We leveraged external experts throughout the design and construction phase to ensure safety and manufacturability in the new space. However, the manufacturing team was assembled with internal resources from our large and small molecule teams, including myself. We were very fortunate to be able to learn from the expertise of our Ionis and internal development colleagues, who were all very generous with giving their time and knowledge. We were also able to build in practice time into the schedule on our pilot scale equipment and then on the commercial scale equipment after installation. Even after our first successful GMP batch, we are continuing to learn and build on this baseline of knowledge that we gained in our first year as a team.
Where do you see potential opportunities and challenges for the oligonucleotide therapeutics field over the next 5 years?
The number of ASOs in clinical development has grown by over 300% in the last five years. As we continue to commercialize more and more ASOs, particularly in larger non-orphan patient populations, the expectations of regulatory agencies and the strain on the supply chain will also increase. As an industry we have an opportunity to align and collaborate to find solutions for single-sourced raw materials, undesirable and unknown side mechanisms, on-line process analytics, and more accessible analytical methods.
Dr. Dehua Pei, Ohio State University
Dehua Pei is the Charles H. Kimberly Professor of Chemistry and Biochemistry at The Ohio State University. He received his B.S. degree in chemistry from Wuhan University, China and a PhD degree in organic chemistry from University of California, Berkeley. He was a Damon Runyon-Winchell Walter Cancer Fund postdoctoral fellow at Harvard Medical School before joining the faculty at The Ohio State University. His research group is currently developing new methodologies for combinatorial synthesis and screening of macrocyclic peptides/peptidomimetcis, cyclic cell-penetrating peptides for drug delivery, and macrocyclic inhibitors against previously undruggable targets, such as intracellular protein-protein interactions.
You are involved in research regarding delivery strategies for a variety of different molecules. What are the opportunities for people working on different modalities/molecules to learn from each other regarding these delivery challenges?
All current non-viral delivery methods face the problem of low cytosolic delivery efficiency, which is believed to be primarily caused by inefficient release from the endosome. Since this is a common problem, improvements with one modality may be applicable to others.
Why are so many developers of biological modalities experiencing endosomal entrapment during drug delivery?
Biological modalities are generally internalized by cells through various forms of endocytosis and initially ended up inside the early endosomes. The early endosomes then mature into late endosomes and finally fuse with the lysosome. Unless something is done to facilitate the drug molecules’ escape from these vesicles, they will be sent into the lysosome and degraded, just like the nutrient molecules. Some viruses and bacterial toxins have evolved mechanisms to efficiently escape the endosomal/lysosomal pathway, but the molecular details of these mechanisms are unknown. Without a mechanistic understanding of the escape process, most drug developers rely on empirical approaches, which have had limited success.
Why are cell penetrating peptides advantageous as a delivery vehicle for macromolecular therapeutics?
I am not sure that cell-penetrating peptides are necessarily better delivery vehicles than others. But after three decades of intense efforts, we are finally gaining a good understanding of how the CPPs work including their mechanism of endosomal escape. Armed with this knowledge, we can now design/test CPPs for improved endocytic uptake and endosomal escape efficiencies. The same knowledge may be used to improve the performance of other delivery vehicles.
How can academic research from your lab benefit commercial developers of peptide and oligonucleotide therapeutics?
We discovered a family of small cyclic peptides as exceptionally active and bioavailable CPPs. We have also elucidated their mechanism of action (i.e., endocytic uptake followed by highly efficient release from the early endosome). We have demonstrated that these cyclic CPPs can efficiently deliver small molecules, linear peptides, cyclic peptides, proteins, and nucleic acids into the cytosol of mammalian cells in vitro and in vivo. We have developed macrocyclic peptidyl inhibitors against a variety of previously undruggable targets including those involved in intracellular protein-protein interactions (e.g., Ras-effector interaction). Some of these agents have demonstrated favorable pharmacokinetics and in vivo efficacy in animal models.