Ann Nguyen:

Hello, my name is Ann Nguyen, Senior Associate Conference Producer at Cambridge Healthtech Institute. Today we have a special podcast for the inaugural Oligonucleotide Therapeutics & Delivery conference this April 4th through 5th in Cambridge, Massachusetts. We are very excited to have one of our program advisors and workshop instructor joining us, Dr. Dmitry Samarsky, Senior Vice President of Technology and Global Business Development at OliX Pharmaceuticals.

Dmitry, how are you doing today?

Dmitry Samarsky:

I'm doing fine. Thank you.

Ann Nguyen:

My first question revolves around the challenges within this field, as the concept of utilizing nucleic acids for the development of novel therapies has been around for quite a while now, yet has not impacted the drug development landscape as much as small molecules or biologics. Given their obvious benefit of being able to dramatically expand target space, what major challenges have been encountered?

Dmitry Samarsky:

First of all, I think we should keep in mind that small molecules and biologics have been around for a long while, small molecules probably for centuries and millennia, and biologics later. The concept for oligonucleotide drugs showed up, antisense, much later. I'd say the traditional, conventional antisense drugs in the late ‘70s, and RNAi was introduced in the late ‘90s. The principles, the way antisense oligonucleotides work is a little different conceptually. They do not attack pathogenic proteins or cells directly. They act indirectly. They attack the mRNAs which lead to the malicious proteins. The mechanism for these were not really clearly understood and introduced until late in the development of molecular biologic approaches and understanding the molecular biology of protein production.

The antisense oligonucleotides, they can attack the mRNA, and because of that, they need to get inside the cell. They're small, and they're relatively easy and biodistribute inside the body. Biologics don't usually need to get inside the organs and the tissues and inside the cells, so they act on the outside. With the oligonucleotides, you have the highest challenge. It's a big charge ... small molecules that need to get inside the cell, and that's a big challenge. The bottom line, if I want to summarize why that was a problem, it's the delivery, essentially delivery of the oligonucleotides inside the cell where they would produce the effect and find transcripts and activate them. That's a major challenge, and that's what kept this technology from being materialized for a while.

Ann Nguyen:

It seems as if there has been a resurgence of interest in the discovery and development of oligonucleotide therapies. Why do you think this is? Another way to ask that is what has changed over the past few years?

Dmitry Samarsky:

I don't think there is a single factor that would affect and change the situation, oligonucleotide drugs. It's rather multiple events. In one word, if I would like to say, that it's the technology has matured. If you overlook different technologies and different new discoveries, which eventually lead to new types of therapeutics or types of products, they usually go through a curve. There is an initial excitement about the new technology and discoveries, and then usually this initial excitements are not substantiated by the resulting products. There is a disappointment period, and then the technology gets to that it actually belongs. If this is a vital technology, then eventually it gets where it belongs. That's what believe happened to antisense oligonucleotide technology is that they went through ups and downs and finally they get to the stage where it's becoming a mature technology and starts producing good products.

With oligonucleotides it's a little bit more complicated because there are different types of oligonucleotides, the conventional antisense oligonucleotides, which were introduced in the ‘70s and were developed in the ‘80s, and then RNAi popped up in the late ‘90s and dissolved. These curves sort of overlapped on the top of each other, but the result, RNAi and antisense technology are working side by side now and that’s producing interesting results.

Ann Nguyen:

You're hosting a workshop during the upcoming Oligonucleotide Therapeutics & Delivery conference, providing an overview of oligonucleotide therapeutics from discovery to manufacturing. Can you tell us more about this workshop? Who should attend this? What can they expect to learn during the workshop?

Dmitry Samarsky:

The workshop is planned to be carried out before the main conference. We’re certainly planning to give a nice introduction to the subject of oligonucleotide delivery, the challenges, and sort of a one-on-one overview of these challenge. We're probably going to go beyond that. I'm planning to have four or five top experts in different directions of oligonucleotide therapeutic development. We will assemble a set of questions, which will again talk about different dimensions of the challenge, but also will review the current status and the future challenges for the oligonucleotide development. In this respect, I believe that the workshop would be useful and interesting to any person interested in oligonucleotide development from the early introductory level to the expert level.

Ann Nguyen:

We like to end our podcasts with an outlook. Oligonucleotide therapeutic development seems to be evolving rapidly, but in your opinion, where do you see the greatest opportunities within the space over the next few years?

Dmitry Samarsky:

That is a challenging question, of course. I could comment based on observations that I've been making for the last, I would say, 2-3 years. One interesting trend right now is that while initially a lot of delivery approaches were based on application of liposomes, different kind of nanoparticles, people seemed to deviate from this direction and rather focus on delivery approaches, which I use. The [inaudible 00:06:15] is built inside the molecule itself. The conjugate, the chemical modification, the particular configurations which allow molecules to get inside the cells and biodistribute in the body by themselves. What I would foresee is that most of the therapeutic programs in the coming years would be mostly using the so-called naked molecules, which would not be delivered using some particular delivery vehicle.

I can see that the GalNAc conjugation that Alnylam and [inaudible 00:06:48] is using and several other companies and groups ... seem that this is going to be a big hit in different indications originating from liver. That's where the GalNAc conjugates seem to biodistribute the best. This, I think, is going to be a big direction in all possible indication connected with liver probably will be addressed in the coming years.

I personally would like to see more of the use of delivery devices. That's something. There are so many different approaches to develop macromolecules inside the body, and I don't see much of the synergy between the technologies that develop devices for delivery of macromolecules in the oligonucleotide field. That would be interesting to see if that materializes at some point.

I do not see the easy solution and application of oligonucleotides for oncological application. That's something that many people would like to see, but it's really difficult to get inside the tumors and distribute inside the cells. The alternative possibility that could be for oncological indication is [inaudible 00:08:02] applications, essentially taking cells and treating them outside of the body and using them as immunovaccines. I think that's potentially an interesting and promising direction.

Ann Nguyen:

Dmitry, it was a pleasure speaking with you. Thank you so much for your time, and we look forward to your upcoming workshop at the Oligonucleotide Therapeutics & Delivery conference this April.

Dmitry Samarsky:

Absolutely. Thank you very much for having me.

Ann Nguyen:

For those listening, thank you for tuning in, and we look forward to seeing you at the conference. Goodbye!