S5, E07: Mission Therapeutics: Inhibiting DUBs to Halt Diseases

Sarah Almond (00:03):
I think we are moving towards definitely an era of disease modification. So previously treatments have been quite focused on the symptoms, dopamine replacement. But now there's a few therapies moving forward that say either target the specific genetic links with Parkinson's disease, so LRRK2 inhibitors, GBA, or really focusing on protecting the neuron and dampening down inflammation in the brain. So we should be able to actually halt the progress of these neurodegenerative conditions. And the other area is actually clearing, similar to we're seeing in Alzheimer's disease with therapies being approved to actually clear amyloid. There's efforts on clearing the pathological protein synuclein that's also implicated in Lewy bodies in Parkinson's disease. So we'll see movement there towards actually clearing that pathology as well.

Chris Garcia (01:11):
Neurodegenerative diseases such as Parkinson's disease and Alzheimer's affect millions worldwide and have historically posed significant challenges to drug developers. These conditions are characterized by the progressive degeneration of nerve cells presenting complex obstacles due to disruptions in the essential cellular processes. This can lead to impaired cell function, impacting not only the nervous system, but other vital organs leading to life-altering symptoms and complications. But what if there was a way to target the root cause of these and other conditions at the cellular level and offer hope to millions of patients worldwide? In this episode of Vital Science, we sit down with Sarah Almond, head of pharmacology at Mission Therapeutics. We'll explore the company's world-leading DUB platform, innovative solutions to therapeutic challenges and the potential impact of their work on patients' lives.

Todd Poley (02:01):
Welcome to Vital Science, Sarah. We're honored to have you on our show. Why don't you tell us a little bit about yourself and your role at Mission Therapeutics?

Sarah Almond (02:10):
Hi, thank you Todd. I'm Sarah, and I'm currently the head of pharmacology at Mission Therapeutics. So I've been working for almost 30 years in this field, so in drug discovery and development. So in my day-to-day role, I manage and develop our pharmacology teams. I look after the kind of science on what they do, and then personally, I sit on some projects and look after the kind of pharmacology and translational aspects of those projects. And then I am responsible for all data that we produce in the kind of pharmacology area, both internally and externally.

Todd Poley (02:44):
So many hats.

Sarah Almond (02:46):
Many hats. Yeah.

Todd Poley(02:46):
Many hats. So at a high level Mission Therapeutics is a clinical stage biotech whose vision is to transform the treatment of serious diseases. How does Mission accomplish this?

Sarah Almond (03:03):
So we are a platform focused company, so we only work on a class of enzymes called deubiquitinating enzymes or DUBs. So really we achieve that kind of vision through the chemistry and assays and knowledge that helps us exploit that target class.

Todd (03:21):
And what would you say is driving that vision?

Sarah Almond (03:24):
I think two things, really. It's the science, and it's the patient. So our motivation is to treat significant and sometimes difficult to treat diseases. And this is underpinned by our knowledge around DUBs and what they do in those diseases, how affecting them might impact the disease, and how to actually hit or how to inhibit those enzymes.

Chris Garcia (03:52):
Mission Therapeutics research explores the function of DUBs, which play a vital role in cellular maintenance by removing ubiquitin tags from proteins. You can think of ubiquitin as a label to mark proteins for different tasks within the cell, such as controlling their activity and deciding if they should be cleared out. When proteins become dysfunctional ubiquitin signals for their removal. But DUBs step in to remove these tags. By blocking DUBs, the Mission Therapeutics team hopes to find ways to elevate ubiquitin levels. This would enhance the cell's ability to remove dysfunctional mitochondria and reduce the inflammation and cell death seen in neurodegeneration. Now let's hear more from Sarah on why DUBs are such a powerful foundation for therapy.

Todd Poley (04:38):
What makes DUBs such an attractive therapeutic target?

Sarah Almond (04:42):
I think there's several reasons. I think there's that broad biological function. So there's actually clear links with the pathology of a number of diseases. There are actually, although they're quite a big class of enzymes, there's kind of 100 DUBs. They've got quite a well-defined active site. There's often a clear catalytic domain, which means that actually for drugability, they're quite druggable and you can get good selectivity. So we know that even though there's a lot of them, we can actually inhibit one DUB and one DUB only. And often if you think of the biology of the condition, they're actually only active to a higher level in disease.

In Parkinson's Disease, you've actually got sort of genetic links to PINK and Parkin. And Parkin is an E3 ligase that puts ubiquitin onto cells. So it's actually only in that pathological condition that a DUB would have some impact. And USP30 is actually the only DUB associated with mitochondria. When things go wrong and the mitochondria being responsible for the power produced in the cell, the cells can't produce enough energy and then can't function effectively. And also, you get inflammation. So by targeting the USP30, we can selectively increase mitophagy and then have a key impact on neurodegenerative and other diseases.

Todd Poley (06:13):
And I'm sure it's also helpful that DUBs are ubiquitous, which we know since it's right there in the name. Given how widespread they are, I imagine there's a lot of potential here. What therapeutic areas do you think might benefit most from this approach?

Sarah Almond (06:28):
Yeah, if you think that there's 100 enzymes, as you say that the ubiquitin pathway is present in every cell and that each DUB might actually have more than one substrate, so it might deubiquitate one different type of protein or organelle. The potential in diseases is vast. If we look at USP30 alone, we're looking at Duchenne muscular dystrophy. We're looking at cardiac disease, so heart failure, myocardial infarction. We're looking at kidney disease, potentially both acute and chronic. And we're looking at neurodegenerative diseases, not just Parkinson's disease, but it could be Alzheimer's disease, ALS, Huntington's disease. There's multiple DUBs that potentially could impact in oncology. So yeah, massive disease potential.

Chris Garcia (07:21):
It's been historically challenging to make progress with DUBs as a therapy because of their complex chemistry. But Sarah and her team have developed a clever workaround, molecules that can bind to the catalytic site of DUBs. These molecules form strong yet reversible bonds which allow for precise targeting. To support this, Mission Therapeutics has developed a comprehensive suite of assays to accurately measure how well these molecules work. With expertise in screening dozens of DUBs, they can generate highly selective and potent molecules ensuring safety and efficacy in treating various diseases. Now let's hear from Sarah on Mission Therapeutics' upcoming clinical trial.

Todd Poley (08:01):
So Mission shared some exciting news recently on their MHRA clinical trial authorization for the treatment of Parkinson's disease. Can you share some details around that?

Sarah Almond (08:14):
Yeah, sure. Yeah, I mean, this is a great, great achievement for Mission. So we had approval to take our lead compound, our CNS penetrant sub-inhibitor, so MTX-115 325 into the clinic. And this is the first time that a USP30 inhibitor accessing the brain has actually gone into patients. So by the time people are listening to this, hopefully our phase one will be underway. So 325 is an inhibitor of USP30. It's very potent, it's very selective, and we've published recently a paper that shows that it's able to drive mitophagy able to increase ubiquitination of key substrates, and it's efficacious in animal models of Parkinson's disease.

Todd Poley (09:04):
So Parkinson's disease is a devastating degenerative condition that affects the central nervous system, and diagnosis has sadly become increasingly common. What potential does MTX-325 have as a possible disease modifying therapy for these patients?

Sarah Almond (09:23):
So 325, as we've mentioned, is inhibitor of USP30, and USP30 has strong target links with Parkinson's disease. I've mentioned about E3 ligase Parkin that actually ubiquitinates mitochondria and PINK mutations in Parkin and PINK which is the molecule that actually brings it to mitochondria, are actually really prevalent and a strong cause in the familial aspects of Parkinson's disease. And mitophagy is a pretty established hypothesis that there's defective mitophagy in Parkinson's neurons in Parkinsonian patients. So we'd expect to be neuroprotective. So you'd expect that if we treat patients with 325, that actually because you're improving the cell health, the neurons will survive longer, and that will lead to improvements in the cardinal symptoms of Parkinson's. So the motor symptoms of bradykinesia rigidity and tremor, but also potentially other symptoms because defective mitophagy and cellular dysfunction is not just prevalent in the dopaminergic neurons in Parkinson's disease, but also other symptoms that Parkinsonian patients get. Things like fatigue, sleep issues, cognitive are also driven by loss of neuronal cell loss. So potentially, we could actually be protecting all neuro populations and impacting the non-motor symptoms as well.

Todd Poley (10:58):
That's really exciting. So when do you expect to dose your first patient?

Sarah Almond (11:03):
So we expect as part of this phase one we're doing, which is currently going to be healthy volunteers, we expect a smaller patient cohort as actually part of that trial. That would be just to look at safety, tolerability, but also to maybe look at some biomarkers that might indicate that we are hitting our target, that we are actually inhibiting USP-30 and possibly impacting mitophagy, and that will take place this year.

Todd Poley (11:34):
I also want to talk a little bit more about as you reflect on this journey to where Mission Therapeutics has this specific program, there's a lot of considerations. Chief among them is finding the right partners and collaborative relationships that help reach these patients that you've been speaking to and the therapies that they need. How can collaborating with a contract research organization like Charles River help achieve this goal?

Sarah Almond (12:03):
I think it's essential to achieving. We're a biotech, we're not many people, we have to wear, I think you said at the beginning, you wear a lot of hats. We're trying to cover a lot of things. And you have to leverage the expertise that exists outside your organization. And CROs like Charles River, are really where we go to for that area. We haven't got the resources or the time and sometimes the expertise to deliver every assay and every model that we need. So we've partnered with Charles River on some of our Parkinson's models because they take years to validate, and we have to move very fast. So we need those up and running and really well understood in order to test our molecule in the best possible way.

Chris Garcia (12:55):
For Mission Therapeutics, collaborating with academic institutions has added momentum to their progress. These partnerships give them access to a wealth of specialized knowledge, rigorous scientific methodologies, and focused efforts to propel their research forward. But the benefits also extend to the larger scientific community. Mission Therapeutics recently teamed up with scientists at Harvard and Cambridge University on a publication to promote Parkinson's research and disease awareness. By joining forces with fellow scientists, the Mission team has expanded their understanding of various diseases and how to develop better treatments. These collaborations span the entire spectrum of research from preclinical investigations to clinical trials impacting everything from cellular studies to patient outcomes. Let's hear more from Sarah on what's on the horizon at mission.

Todd Poley (13:43):
I know your mantra is "Driven by the patient, built by the science." Now that we've covered the science, let's get into how your work will impact patients. I know Mission was granted IND status by the FDA, and given the green light for phase two clinical trials for acute kidney injury, can you tell us what's next in this process?

Sarah Almond (14:05):
Yeah, sure. So I mean, this is a trial in the planning stage. So this is another USP30 inhibitor, but this molecule doesn't enter the brain. And we've already completed a phase one trial. It sailed through that safe, beautiful pharmacokinetics in people so really, really good compound to test. And mitophagy is important in kidney disease, in protecting kidney tubules from damage and fibrosis. So we are looking to see in heart bypass patients where I think it's up to 50% can actually see kidney injury, whether giving a USP30 inhibitor could protect against developing that injury. So yeah, that trial's been given the go ahead, and we're in the planning stage as current.

Todd Poley (14:54):
That's great to hear. As we think about the future, in your opinion, what does it hold for drug discovery and the development in the neurodegeneration space?

Sarah Almond (15:06):
I think we are moving towards definitely an era of disease modification. So previously treatments have been quite focused on the symptoms, dopamine replacement, but now there's a few therapies moving forward that say either target the specific genetic links with Parkinson's disease, so LRRK2 inhibitors, GBA, or really focusing on protecting the neuron and dampening down inflammation in the brain. So we should be able to actually halt the progress of these neurodegenerative conditions. And the other area is actually clearing, similar that we're seeing in Alzheimer's disease with therapies being approved that actually clear amyloid. There's efforts on clearing the pathological protein synuclein that's also implicated in Lewy bodies in Parkinson's disease. So we'll see movement there towards actually clearing that pathology as well.

Todd Poley (16:04):
So a busy near-term future for Mission?

Sarah Almond (16:07):
Oh yeah, definitely. Yeah, yeah, yeah.

Todd Poley (16:10):
What do you hope Mission's legacy will be?

Sarah Almond (16:14):
I think furthering science, so bringing forward the breakthroughs in conditions we're looking at, but also hopefully that legacy will involve efficacious drugs on the market for some quite prevalent and devastating disease.

Todd Poley (16:30):
Well, we hope to be a small part of helping equip Mission Therapeutics for the future and bringing these therapies to the patients, driven by the patients built by science. I love it. So Sarah, thanks so much for the time.

Sarah Almond (16:43):
Okay. Thank you very much.

Chris Garcia (16:48):
Sarah Almond is the head of pharmacology at Mission Therapeutics. Our next episode of Vital Science will be coming to you in May. Until then, thanks for listening. Did you know that Vital Science recently launched a new limited series called Bold New Approaches? This series focuses on the voice of current perception of NAMs, the convergence of science and tech, alternative methods and regulatory, and the road ahead for therapeutic developers.

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