Oxalys Pharmaceuticals

[MUSIC PLAYING]

KATHARINE SEPP: I'm Katharine Sepp, CEO and co-founder of Oxalys, spin-off company from the Picower Institute that is developing small molecule therapeutics for neurodegenerative disorders. Our lead therapeutic is for Huntington's disease. And we also have a program in Parkinson's disease. We have transgenic platform for drug discovery that can also be used for search for gene targets.

And this can be developed as a service, but primarily, we're developing our drugs for the clinical trials to commercialize as quickly as possible. We do have a product engine that was developed at MIT. This is a system that closely replicates the physiology of neurodegenerative disease.

But it's miniaturizable, so you can test compounds in 384 well plate format. And this is a very robust way to find compounds that suppress the toxicity of human disease genes. So genes that drive the pathophysiology of neurodegenerative disease. We take human disease genes, we express them in drosophila neurons. These are freshly cultured neurons that we grow in the plates.

And then we use robotics to apply collections of compounds and compound libraries onto these plates. And we're looking for compounds that can improve the neurite morphology, so that the health of the cells, overall of the cells. And then we also track the profile of protein distribution of these mutant disease proteins.

Usually what we find, is the compounds that improve the health of the neurons, also change the distribution of these disease proteins. So we're looking for compounds that will treat the underlying cause of the disease, not just late stage symptoms. And so we call these, disease modifiers. The ultimate goal is to find a drug that has the capacity to slow, halt or reverse the course of neurodegeneration, not just change the symptoms.

Right now, we're strongly focused on getting our lead therapeutic into clinical trials. And for this, we will need to raise significant funding that can either come from VC funding or a large pharmaceutical partner. Either one would work. It will be a Series A fund-raising that we'll need to do to achieve our first key milestone, which is the completion of a phase two proof of concept trial. So it's a clinical trial that will show that there is some efficacy of these drugs to do something meaningful for the Huntington's disease patients.

[MUSIC PLAYING]

KATHARINE SEPP: Within our platform, it's a base system of using a freshly cultured neuron that you can take any disease gene that is expressed in humans that drives the disease process. So you can replicate that within these neurons. And it's ideal if you have a dominant inherited gene, but also, recessive genes will work too.

So it would work for basically any human disease that has a genetic component. So you take that human disease gene, put it in the drosophila neurons, and as long as there's a robust effect in the neurite morphology, then you'd have a platform for screening drugs.

Very early in the technology, my co-founder Joost Shulte, who's now Chief Scientific Officer of the company, he came to Troy Littleton's lab at the Picower Institute of MIT to work on the Huntington's disease model. So Joost came out of EnVivo Pharmaceuticals to work in Troy's lab, because at that time, the Huntington's disease model that Troy was using was the best one that expressed the greatest portion of the human disease gene.

So a larger gene fragment than any other model system. This system was in vivo. So in whole drosophila animals. And so you couldn't really do drug discovery in whole animals. It takes too long, it's very expensive. We needed to miniaturize it. So the solution was to take this model expressing the human disease gene that has a causal role in this disease and create fresh neuronal cultures.

So if you create fresh neuronal cultures out of this model, you can see that the neurons are dystrophic, they look funny. They don't develop as normal cells do. So it's a very strong, robust assay. You can tell clear differences between the freshly prepared neurons expressing the human disease gene versus neurons that don't carry the human disease gene.

We want to find compounds that would reverse the physical properties of the neurons expressing the disease gene, make them look normal. And at the same time, we are also tracking the position of the human disease proteins. So the gene that encodes Huntington, where does that Huntington's protein localize?

To do large scale screening, what we did was, we made these large cell cultures like volumes of large cell cultures. We plated them onto three to four well plates. So a plastic tissue culture plate with 384 wells. And we then used screening facilities that had compound libraries that had thousands of compounds that could be applied with robotics onto these three to four well plates. So every well and three to four well plate would have a different test compound.

So with these robotic systems, we then collected all the images of the cell cultures. So we tracked the neuron morphology with a green fluorescent protein and the human mutant disease protein with a red fluorescent protein. And then we did automated image analysis to find or hit compounds. So through that, we found two structural classes of compounds that reverted the disease morphology to the wild-type healthy neuron. And we also found a novel gene target that suppressed the toxicity of the protein.

Also, we had optimized the platform at the Broad Institute as well, using their robotics. But the actual pilot screen that we ran was conducted at the ICCB-L across the street, across the river. Alzheimer's is more complex, because there's multiple disease genes involved in that.

But our ultimate goal is to take multiple disease genes, so do a screen, a drug screen in a Parkinson's model. Take that same compound library and test it on a Huntington model. Take the same compound library and test it on an Alzheimer's model. Then look across those data sets to find compounds that reverse the disease process in each of those diseases.

And those hit compounds, the ones that work in all of those models, are likely to be compounds that affect the aging process of the brain. So one thing about neurological or neurodegenerative disorders is, they happen with age. And over the course of human brain aging, there are a number of processes that decline.

So for example, protein quality control. That's something that is issue in all of these major neurodegenerative diseases. So if you can find ways to improve protein quality control, these are compounds that are likely to be broadly neuroprotective. So applicable to Alzheimer's, Parkinson's, Huntington's. So as we increase our capacity to do screening within our company, that's our ultimate goal.

[MUSIC PLAYING]

KATHARINE SEPP: Being here in the Boston hub was really important because there's a lot of collaboration, both between MIT, the Broad Institute, and Harvard Medical School with sharing of these facilities with a lot of the robotics that you need for drug discovery. So this is a way that many different academic labs who don't specialize in these-- system that's necessarily-- they could develop a biological assay that could detect suppressors of toxicity for any other disease gene. They can test in these facilities. And you just go in, do your experiments, and then come out. And it will analyze your data and move on.

It's very efficient. And also, there are centers of expertise that, when you're developing your assay-- for example, at the Broad, when Yost was, early on, trying to optimize it, he was given a lot of advice on how to make sure that your platform is as robust as possible so that when you go to do your screen, your dynamic range is as wide as possible.

Yeah, the entrepreneurial ecosystem here is incredibly active. And there is a very strong can-do spirit. So the pervasive attitude is that everything's a solvable problem. And as long as you put your effort and your passion into it, you will make it.

You need to be clever. You need to change where you need to change. But it's all doable.

The approach with the MIT Venture Mentoring Service was that we want to build entrepreneurs. And there is a strong belief that building entrepreneurs is really, really important. Their approach was that your first company can even fail the. It's just the rationale that you need to be an entrepreneur for life and have an approach where you're constantly making change, you're seeing opportunities, and translating that into things that humanity can use.

It's really important to be in this environment. It's very active. You see other companies that are much further ahead and you use that as a role model.

We've even seen, within the Picower Institute, some other postdocs move onto start companies ahead of us. And there they're still active today. It's amazing to see how they've grown. And we've seen how our activity in starting a spin-off has changed the thinking of the other postdocs around who we've been working with to consider there's something to entrepreneurship, and there are alternatives to having an academic career. It could make a lot of sense in certain situations.

So it's been incredible. It's so active here. And it brings a lot of energy to us.

[MUSIC PLAYING]

KATHARINE SEPP: Basically, our motivation, what keeps us working on this is that we know that there is a tremendous unmet medical need for Huntington's disease, especially. There is only one FDA approved drug for Huntington's disease. Huntington's disease is a complex neurological disorder that involves psychiatric changes, cognitive decline, and changes in motor coordination.

The FDA approved drug currently lessons motor symptoms, but it does nothing to improve the cognitive decline or the psychiatric changes. It also has a number of side effects that are undesirable. Patients really struggle. And it's very devastating, because Huntington's disease is a dominant genetic disorder.

It runs in families in every generation. So if one parent has it, then the child, their children will have a 50-50 chance of inheriting the disease gene. If you have the disease gene, then you will have a 100% chance in developing the disorder.

What we really need to do is achieve the proof of concept in a phase two clinical trial. That's like the big one, which is the major value inflection point for the company as well. So that's our ultimate goal that we're setting our sights on, a lot of our planning and strategizing and pounding the pavement, and talking to KOLs, and what do you want to see in our clinical trial design.

We talk to people with regulatory expertise. We talk to investors. We ask them, what do you want to see us derisk in our program to make it attractive to you? We ask the same questions to potential pharma partners.

We just need to find all the angles for all the stakeholders to make sure that our plans are addressing all the needs of those additional stakeholders. So our planning is in place for that. Our IP is going to come likely this fall. And then that will help set the stage for investment.

Timing for starting clinical trials would be in about one to two years. And the variance around that revolves around what we will see in the remaining preclinical work that needs to be done. We're looking for investors, but also smart money.

So because we're a small virtual company with a small number of employees that uses outsourcing to move the programs forward, we need a lot of expertise that comes along with the money. So when we're seeking investors, we're looking for investors that have teams that are experienced in pharma development, ideally in neurology and even more ideally in neurodegeneration, and even more ideally in the specific disease areas that we're working on-- so Huntington's and Parkinson's disease. But also, we would consider working on working through this with a pharma partnership.

Usually, pharma partnerships want to come in after phase two. They want to see your phase two data before they come in. But in some cases, they come in early.

So we do speak to interested pharma partners. And we let them know how things progress as we move along with our smaller milestones. So there's multiple ways to move forward with funding.

A slower way to move forward is just through orphan drug development programs that are essentially grant funds. So there are a number around the world. And IH offers orphan drug programs.

Also, the European Horizon 2020 Program is very good for that too. So we keep all of our options open. We will try every single opportunity we can that comes forward.