What hurdles in delivering new modalities, like biologics, are you seeing?
Delivery is really the key. We know, if we conduct experiments in the laboratory on cells, we can get incredible results. We have all kinds of different ways of delivering these types of biologics to cells in the laboratory. But then when we place it into the body, the results are not so great.
The reason is because there are multiple barriers that those agents face en route to their target. Whether it’s the harsh environment of the stomach, whether it’s the ability to pass through the intestine, make it past being metabolized by the liver, and get into the bloodstream. Whether when it gets to its target, the ability to exit blood vessels and get into the tissue. And then once it’s in the tissue, the ability to then get to the right cell types and through the cell membrane of those cells and then into the right location within the cell.
In addition to those multiple delivery barriers, there’s also the barrier of whether or not your agent gets to the target in a stable form and if you have high enough concentration to have a biological effect.
In the delivery development process, how involved are you with the formulation of drugs?
Usually where we start is defining the problem; that’s one of the most difficult things to do. The problem isn’t just a biological problem or a clinical problem, or an intellectual property problem, a regulatory problem, a sales problem, a manufacturing problem, etc. The problem needs to be quite broadly defined. There is also a competitive landscape aspect to the problem. There is also the question of “Are there aspects of biology that we don’t know yet that are critical for this approach to work?”
That’s where we typically start and try to spend a lot of time. It’s a process of gaining insights that help direct us towards a solution. Those insights serve as the basis for thinking about what might be a good solution, or aspects of a solution. We do a lot of formulation. We try not to constrain the projects early on.
It could end up being an oral delivery format, or a combination product, for example. But that’s really defined by how we think about the problem.
How does working with a next-generation modality, like large-molecule or RNA, change the way you approach assessing and understanding the problem, as you said before?
We ask a simple question, “What is the best result that anyone has ever achieved in a particular model system and how much better do we need to do to set this up for success?” Where “success” is changing patients’ lives. That, to me, is the key question to ask. If we’re in the context of, for example, sRNA or mRNA or whatever we’re thinking of delivering, if that ends up being what we think will be best based on the problem’s definition, we really need to know what is the best result that anyone has ever achieved in a particular model for the delivery of that specific drug or a related drug. That sets the bar for us. It creates an intention and vision for the project, and a framework for defining success, which I think is essential. For example, there could be a drug that’s a biologic that only has 1% bioavailability. Clearly that’s a problem, because biologics are expensive. The question then is, “How much improvement in bioavailability do we need to move the needle on the treatment of patients?”
Can you speak to the types of collaboration you’re bringing together to solve delivery issues?
One of the strategies that I’ve been advancing is the idea of minimizing overlap of expertise for the people in the lab. That way, if you envision people sitting around a table, everyone has different experiences and different expertise, different access to toolsets and ways of thinking, then you minimize the competition around the table. Everyone can provide a unique perspective, and when they do that, they feel validated and they’re more likely to go all-in. Another big part of it is that by having people with different expertise around the table, you extend your reach to tools, approaches, assays, and ways of thinking that extend far beyond any single individual at the table. You increase your ability to think laterally and come up with novel approaches.
What are the considerations that you’re keeping in mind when developing a delivery system, perhaps like patient experience or manufacturing cost?
As someone deeply rooted in academia with relatively narrow expertise, the key for me is forming relationships with people who exist deep within drug development and formulation work who can help guide the process, and therefore consider what are the most essential aspects of the product. For example, what the target product profile we must strive for in order to really do better than what currently exists.
A big part of it is, “What’s the efficacy? How much better is it than the existing approaches?” There’s also the safety profile. A lot of groups that are developing new drugs or formulations don’t necessarily consider the patient comfort; but these can make or break the final formulations.
There was an example several years ago involving an ocular insert, that was targeting patients with glaucoma. It got through trials but it didn’t do well on the market, and it was thought that one of the reasons was that patients who were older had trouble putting the inserts into their eyes. You need to rigorously think about compliance and how it can be affected by the target population, as well as the mode of delivery.
That’s why instead of me trying to figure that out, I’ll interact with people in the community who have experience with other related or relevant products and can assess what the most important aspects of the target product profile are.
What can you share with us of what you are currently working on?
One of the companies I co-founded with Bob Langer, Alivio Therapeutics, has a completely new drug delivery platform that can modulate the immune system at the site of the disease. The system that we’ve developed to restore immune homeostasis at inflamed sites while having minimal impact on the rest of the body’s immune system is based on an inflammation-targeting and inflammation-responsive material that we designed in my laboratory.
We’ve been rapidly advancing that platform for all kinds of drugs. We have shown great efficacy with small molecules and now we are focusing on oral delivery of biologics and achieving some really nice results in terms of stability of formulations and high drug-loading. We’re currently exploring this biologics delivery platform in multiple preclinical models.
What are the potential implications by focusing on inflammation as a target?
Inflammation is associated with almost every disease you can think of. It provides an additional handle to control the release. In the context of inflammatory bowel disease, for example – there are many scenarios where you want to target the drug and have it be active locally at that site disease. If you have inflammation-targeting, that allows you to achieve better efficacy and safety.
And then if it’s inflammation-responsive and you have higher levels of inflammation in certain regions, the drug can be released quicker. Therefore, you can change the local release profile, and the drug is self-tittering and has beneficial effects on the platform’s efficacy.
This long sought-after approach has the potential to broadly enable new medicines to treat a range of chronic and acute inflammatory disorders, including enabling the use of drugs which were previously limited by issues of systemic toxicity or pharmacokinetics (PK).
It’s almost like a living system in that it’s dependent on the level of inflammation and therefore you have an extra layer of control that can make all the difference to maximize efficacy and safety.
Does it reside in the body between inflammatory flare ups?
It depends on the application. In the context of inflammatory bowel disease, you’re delivering this topically in an oral format.
There are ulcers in the GI tract and it will bind selectively to those ulcers and release in response to the level of inflammation that’s there.
In the context of arthritis, you can inject this into an inflamed joint, and if you have a lot of inflammation, you have an anti-inflammatory drug that’s released which will inhibit the inflammation and then there is a residual of your drug delivery system still present in the joint. When you have flares followed by periods of remission, you don’t want to release the drug in remission because then you deplete your store for the next flare. If you can have a system that remains there in the absence of inflammation, then you can treat the next flare without having to deliver another dose.
What do you see on the horizon for drug delivery?
There is innovation happening in all areas. We’re seeing a lot of new approaches in oral delivery as well – various devices that can latch onto the GI tract at select locations to deliver drugs locally or into the stomach. We’re seeing a surge in the innovation around microneedles and their ability to deliver drugs in practical ways that can benefit patients. There has been innovation there in large-scale manufacturing of microneedles. And microneedles for sensing as well – to sense local concentrations of drugs or antibodies by measuring interstitial fluid levels of biomolecules. There is a lot of innovation happening around implantable devices that can have controlled drug release and be controlled externally. Also, the ability to use wearables to control drug delivery systems is on the horizon. People have been talking about smart delivery systems for ages.
Often you require a lot of progress to happen not just on the development of the technology but on the scalability and the regulatory experience and open mindedness and all of these things need to converge in order for things to make it. I think we’re seeing a lot of convergence right now in the field.