Hope in Action: Fighting SPG50 and Beyond with Elpida Therapeutics

Mary

Welcome to another episode of Sounds of Science. I'm your host, Mary Parker, and today we're diving into a story of resilience, innovation, and the power of community in rare disease research. So much has happened since we last spoke with today's guest, beginning with a major milestone being granted rare pediatric disease designation by the FDA for Melpida, an investigational treatment for Spastic Paraplegia Type 50 or SPG 50. I'm thrilled to welcome back Terry Pirovolakis, CEO of Elpida Therapeutics, who last joined us on the podcast in November, 2022 to share the deeply personal story of his son Michael, and his journey living with SPG 50. Terry, it's good to have you back.

Terry

Yeah, thank you for having me again. I really appreciate it.

Mary

We appreciate your time and your expertise. So can we begin by grounding our listeners in the story behind Elpida Therapeutics and the rare disease at the heart of the journey SPG 50?

Terry

I'll give you guys the Coles Notes. So again, going back to our original story, my son was diagnosed with SPG 50 on April 2, 2019. We were broken as a family. We found an incredible team. We made a gene therapy forum. We treated two children, and we thought we could hand over the license and all the drug and someone else would take it on. Unfortunately that wasn't the case.

We formed Elpida Therapeutics, we did a phase I/II in the US. We then opened up a compassion use site in Spain, actually two sites in Spain. And since then we've treated 10 children with SPG 50, mostly under the age of two, but children ranging from five months old all the way to 17 years old. We then took on two more programs. One was Charcot-Marie-Tooth (CMT) type 4J.  We received $5 million from the state of California. We did a natural history study. We've made plasmid, did toxicology, and we got approval from the FDA to move forward with that program last year. And we hope to be in the clinic sometime in January or February. And then our third program, CLN Seven Batten's Disease, we finally were able to make the drug product, it'll be ready in January, and we'll be opening up a phase I/II as well for that program. So things are moving along really well. And just add to that a little bit more. In December, after the PRV  went away at the FDA, we started a consulting division out of necessity, and we took on seven more programs through consultancy in order for us to help rare conditions get through an IND filing, a PLA filing, or even just a proof of concept. So we're really, really busy at Elpida therapeutics. 

Mary  
Yeah, that's a lot of ground to cover in just a few years, so that's pretty impressive. Could you catch us up on Michael? How's he doing? What's he been up to? 

Terry  

Yeah, Michael's good. I mean, relative to the condition obviously and relative to where he's at, but he's moving along, he is in school, he is happy and just in progressing with what he's going through. But obviously I didn't cure him, and that's kind of something that I have to live with and kind of get over. But he's doing better than where he would've been if we did nothing. 

Mary  

Good. And can you give us just a little bit of a thumbnail sketch of your first time here on the podcast? How was Elpida founded and how did you find Melpida? 

Terry  
Yeah, absolutely. So we were at a soccer tournament in Saint Sebastian that was funded and was done by Javier Garcia and Foundation Columbus. And I turned to Javier and I said, we need to do more. We need to see more children. Do you think we should? You'd help me start this nonprofit? He said, absolutely. So we formed Elpida Therapeutics with Sheila Mikhail. We moved it forward, and that's how we're here today. Elpida was formed by the word HOPE in Greek, and it was pun on words with Melpida, the drug we made for Michael, which was Michael's hope. 

Mary  

I love that. And for anyone unfamiliar with SPG 50, could you describe the condition and how it impacts children like Michael? 

Terry  
Absolutely. Yeah. So in general terms, children are paralyzed in the waist down by the age of 10, quadriplegic by the age of 20. Most of them never learned to walk or talk, and it's a neurodevelopmental neurodegenerative disease. 

Mary  
And how rare is it? 

Terry  
It's very rare. Michael was the only child in Canada. There is about 130 known cases worldwide. So as you can imagine, us treating 28 children by next year, we will have dosed almost 25 to 30% of the world's population. 

Mary  

Yeah, that's amazing. Obviously access to treatment can be a big issue for something as rare as that. 

Terry  

Yeah, we've been very fortunate that we had an amazing partner of Rogen who made us extra doses of drug, which we've been able to treat children, but unfortunately, that drug will run out in June of next, and then we have to find a way to make sure that every child receives it after that. 

Mary  

Well, speaking of collaborations, can we talk about how collaboration and innovation helped bring Melpida to life? So first, how does it work at the genetic level? 

Terry  

 So after locking myself in the room for 24 hours, we realized that we could do either an ASO or a gene therapy. We went down the AASO path and because at the time the technology wasn't going to work for our disease and our function, we went down the gene replacement therapy path. We were fortunate enough to meet Dr. Steven Gray, Dr. Xin Chen. They created a mouse, they created a cell line, they proved the vector worked in both. They also did a wild-type safety study that showed that it was relatively safe. We then moved to Charles River, who was our partner in toxicology. We did a rat safety study, GLP safety study there. From then, we filed our IND to the FDA manufactured the drug at Viralgen, treated Michael at Sick Kids, and then also two more children at UTSW in Dallas. 

Mary  

In your experience, how can partnerships with contract research organizations like Charles River and with Viralgen accelerate progress in rare disease programs like yours? 

Terry  

Honestly, in rare disease programs like mine, partnerships are fundamental. We're not a company, we don't have endless amounts of funds. We don't have the resources to understand the process, and we are relying on our partners to make sure that they help us understand the process thoroughly to help us make sure that we are aligned with what the FDA is looking for, and then help us align on the price as well. Because again, we don't have  endless funds. These funds come from events and blood, sweat, and tears, honestly. So these partnerships are fundamental and we're so grateful that Charles River has been an amazing partner of ours from the very beginning meeting Lauren Black at an event meeting the team in Quebec, and just seeing that they cared about Michael and these children really made a huge difference in how we move forward. 

Mary 

Built on blood, sweat, and tears sometimes literally when you're doing tissue banking, literally. Yeah, 

Terry  

Exactly. 

Mary 

So speaking of the regulatory angle, we know that small clinical trials like yours present a lot of unique challenges from literally getting to the patients since they're typically spread out all over the world. So in light of current public policy environments, how do you envision the approval pathway for these trials evolving? 

Terry  

So I'll be honest with you, when we started this journey, everybody was like, oh, the regulatory body is the worst. They're going to give you a hard time. We have had nothing but amazing supportive collaborations with Health Canada, the FDA, EMA, the MHRA in the UK. People want to see these programs move forward, and I think one of the things that we've always aligned with is safety is paramount for us. We do not skimp on anything that has to do with safety. And I think that's where we fully align our efficacy data may not be a hundred percent because it's never a hundred percent in these rare disease programs, but safety is always paramount. I think that's why we've always gone along with the regulatory bodies and have a good understanding, and they're people in the end, the reviewers are individuals, people that see these children, see the hardships of these families and really want to help. So we've been very fortunate. Now the second part to your question, which is this landscape that we're in now, I think we had a big loss with Dr. Marks leaving the FDA and Dr. 

Verdun and the changeups. And I'm really hoping that the new administration will see the pain that rare disease families go through. The difficulty it is to get a drug to a formal BLA and approval based on the current requirements by the FDA and will allow us to have exceptions to get to the end. Because the reality is we can't spend a quarter of a billion dollars on a manufacturing PPQ batch or the requirements to get to those items. We need leniency in order for us to get to the end. And I think what we're hearing from Dr. Makari and Dr. Prasad is that these things are going to be allowed and the publications that are being released are saying that as well. But we're almost there and we're hoping that when we get there, they will allow us to see these through. 

Mary  

And what do you think are some concrete steps that you or regulators could take to support the advancement of these clinical trials? 

Terry  

I think fundamentally, and it hasn't happened yet, but I think we need to lower the bar or set a different standard for ultra-rare conditions. We're not going to be able to meet the manufacturing requirements. It's just something that is just not possible. Three PPQ runs process validation. It's just the costs are just too exponential to put in perspective. It would take a hundred years of drug product to meet those requirements. And we can't leave an open IND because insurers are not paying for the trials. So we have to find a path to approval. I think the other thing we also need to do is bring back the PRV, the Priority Review Voucher. It has to come back. It's the fundamental core for rare diseases and how we get funding and not only just to fund our current programs, but to allow us to do R&D and to help us get more therapies to children. I think it's fundamental that it comes back. 

Mary  

Would you say that when it comes to a regulatory pathway for an ultra-rare disease, everything but safety should be flexible? 

Terry  

Yeah. I mean everything but safety should be paramount. I think also when we look at treating children, I mean, we also have to look at the risk versus reward, right? And if we are treating a 14-year-old that is immobile and they have some slight adverse events, we have to take that into account and understand what those look like. So even with safety, I think there has to be a sliding scale, especially around fatal conditions and what we might be looking at. But safety has to be paramount for sure. 

Mary  

Yeah, absolutely. Well, Melpida recently received both Rare Pediatric Disease Designation and Orphan Drug Designation from the FDA, which are important milestones. What do these designations mean in practical terms for a therapy like Melpida? 

Terry  

Yeah, I mean, initially for funding, while the P review was around, it helped us get funding from investors and philanthropists right now, because it's not around anymore or paused, it's been very difficult. I think what it does help is when you get to the end, it provides you a funding vehicle to pay back your debts and pay forward R&D. And then for the orphan disease designation, it allows you to recoup some tax breaks that may have been accrued over the years. But initially, it's really a vehicle for us to get investment or get loans to move things forward. 

Mary  

Have you seen these designations influence the project's momentum so far, or is it still too early to tell? 

Terry  

Again, they would've if the PRV continued, but because it's expiring in September, everybody's waiting on pins and needles to see if it gets renewed. So right now, if you need investment and your program is ultra rare, until that PRV gets renewed, it's almost impossible to receive funding. 

Mary  

Is there anything our listeners could do at home to help, obviously, besides donating to the cause, or could they write letters to their senators to try and make sure that this gets extended? 

Terry  

Yeah, I think the rare disease community has to come together as a whole. We can't be disparate parts all over the place anymore. We have to come together on two fundamental items. One is rare disease funding and rare disease laws and government agreements similar to the peer review voucher. We have to come together and basically say, this is important. We need it back as soon as possible, and that we are seeing the blowback from the biotech arctic winter that we're in right now, that it has to come back and we have to do something to move forward. The second thing we have to come together on is newborn screening. If we're ever going to get to the point of curing these kids early on, 

Terry  
We have to treat them at one week less than a month old. And we're not doing that by all of us advocating for our own diseases to be on the newborn screening panel. We need to come together as a whole and say, we have to get the whole exome sequence or genetic screening on the newborn screening panel. And that in turn will happen is it'll allow us to reduce the overall debt on society by reducing the amount of time that these children go into the hospital and all those things. So in the end, everybody benefits. More importantly, the children, the families benefit because they may never have the disease or they may have a light version of it. Whereas today they have no option but to go through this unfortunate path of finding out your child has a rare disease, God willing, there's a treatment, you get treated. But if not, then you have to go down the diagnostic odyssey, create a therapy, and just like what I did. 

Mary  

That's very true. I mean, especially once there is a gene therapy or an  SO available, so many of these diseases that I've heard of are so time-dependent, the sooner the better. 

Terry  
Yeah. Look at Zolgensma. You don't treat a child before two years of age. They miss out, right? 

Mary  

Absolutely. 

Terry  
Or Krabbe disorder. You have to treat the children within one month. These are the kind of things we really have to tackle. I know that countries like Spain are really ahead of us. For example, if a child goes into the doctor's office and they don't know what's going on with the child, the first thing they do is a whole exome sequence. Michael was an 18-month diagnostic odyssey. Those shouldn't happen anymore. It should be you go in seizures, microcephaly, spasticity, we don't know what it is, blood draw, whole exome sequence. But we do have to get a newborn screening so we can start saving these children. 

Mary  

So on a sort of cheerleading note, I know that some of the SPG 50 superheroes that you've met have obviously influenced getting this to clinical trial. So can you name names? Can you tell us about some of your contributors, scientists, biotech partners, and regulators who played a pivotal role in advancing Meplida? 

Terry  
Yeah, I mean, the FDA played a pivotal role in our phase I/II and our phase III approval. The Spanish government at AMPS was amazing in regards to allowing compassionate use, not just for children from Spain, but refugees and other children from around the world to be treated in Spain. They've been instrumental. The Italian regulator, AIFA, they've been amazing to us and they've been very supportive. The Denmark governments, all these individuals, all these governments have been instrumental. All the employees at Elpida, the consultants, all the people connected to us, all the family members that have raised millions of dollars in funds to pay the drug product, to fund the clinical research, to fund the hospital costs, we're all instrumental for us getting here. It's not a me, it's we. We're all working on this journey together and we're never going to get there unless we work together to do it. This is impossible otherwise. 

Mary  

Can you name some of the scientists who have contributed to Melpida? 

Terry  

Yeah, I mean, Lauren Black was instrumental from Charles River, Dr. Steven Gray, Dr. Xin Chen from UTSW, Dr Iannaccone from UTSW who treated these children, Dr. Bonne, Dr. Barry Burns. The problem is I'm going to forget someone and I'm going to be really upset about myself. So I don't like namedropping, but it's been Dr. Dan Balderson who has been there since day one, Sou, Keith, Rachel from my team, Caitlin, all instrumental people in this journey. And again, if I left someone out, it's not on purpose. I love you guys and you guys have supported us, but it is been a team effort. That's the way I got to say. It's been a team effort, and we would not have even got anywhere close to here without having an amazing team. 

Mary 

So with Melpida gaining momentum, can we look ahead at what the future holds for this therapy and for the rare disease innovation more broadly? So like what's next for Melpida? 

Terry  

Yeah. Our hope is that we are able to file to the FDA get approval for SPG 50, that the PRV is renewed. We're able to take those funds and exponentially grow how many programs we take on. So let's hope that we can get to 10 more programs, get them all into the clinic, get those 10 programs approved by the FDA, and then exponentially grow to 50 or a hundred. Because the reality is my team and I are not here to just make a dent in one program. We want to make a dent in the world, and we want to treat as many children as we can. So that's the only way to do that is exponentially grow through funding mechanisms, through grants, treat more children, get more therapies to children and get these approved. Because if we can get them approved, then they'll get to all the children in need. They'll get on the newborn screening panel, and everything will just be just free flowing in a cycle. 

Mary  

Do you see this journey as a model for other rare disease communities where families can kind of drive innovation from the ground up? 

Terry  

Absolutely. I mean, I hope people don't have to go through all you want we went through and the amount of money we have to raise and everything else. I hope it's a lot easier, but it is a model that if you don't give up and you are committed to seeing this through, it is a possibility you can do this. It is not impossible. I'm just a regular guy that did this, and so can you. But again, it takes a lot of willpower and you have to just sacrifice everything to get here. But it shouldn't be like this. It shouldn't be that a parent has to raise four and a half million dollars. It has to learn how to do all these things and project manage this and work while you're doing this. It shouldn't be like that. It should be some mechanism that is better than this to save these children. 

Mary  

Well, Elpida has a consulting branch, so what advice would you give to other parents or advocates who are beginning their own rare disease journey? 

Terry  

Yeah, I would say that unfortunately, you're starting off with the journey. You're not going to have that much money and try to do it on your own. And if you need help, reach out to me and I'm more than happy to help out. But at a certain point, you're going to need a team of people, FDA consultants, CMC consultants, toxicology consultants. You're going to need to know how to write your pre IND, and IND documents, and if you need help, we're here to help you and know that there's other people out there to see this through and help you get to the finish line. 

Mary  

If you could share a message with the scientific community, the industry or regulators, what would it be? 

Terry  

I think just work with urgency. I think that, I know that we're all busy and we all have a lot of things going on, but in a lot of these conditions, every day matters. Like for example, CLN 7 Batten’s Disease. We met a family in December. We told them, you only have about 12 months before your child is too far gone. The family quit. Their jobs raised $3 million in two months. They went all out, and now we're trying to quickly make this drug and every day matters to this child and these families. So I would just say, please work with urgency because these children just don't have time. And every day that we lose on one side, we lose 10 days on the other. So we just need to just work with urgency. 

Mary  

Oh, yeah, definitely agree. And what legacy do you hope to build for Michael for Elpida or the broader rare disease community? 

Terry  

I'm hoping that by publishing our documents and by showing a path forward with different regulatory bodies, that people can easily just copy what we're doing, that they don't need to be experts in this and that with our partnership with the FDA and the leniency they've given us and the support they've offered us, that people can easily follow our path. That's our goal, that our lessons learned and what we've done should make things a lot easier. That is our ultimate legacy that we hope for. 

Mary  

Making all of your data public is very generous, but it's also eminently practical. I mean, there's not going to be any more advancement if people don't start sharing their failures more often. 

Terry  

Yeah, I mean, the publishing the protocol allowed people to look and see these documents and be able to go and say, ‘Hey, I have a template that's easily usable right here’. 

Mary  

Finally, how can our listeners support your mission of helping to bring hope to families affected by SPG 50? 

Terry  

Yeah, I would say because now we're helping more families and more foundations, what I would say is if there's a family near you that's working on trying to make a therapy for their children, reach out to them, offer them help, offer them support, offer them to maybe do an event for them, because these families are working very, very hard to get there. They put their life on the line, they put themselves on the line, and they need support. So I would say, if there's a family in your community, please help them. The second thing I would say is if you have a friend, a family member, a neighbor that has a disabled child, buy them coffee, have a talk with them, because having a disabled is very difficult. And I think sometimes people just want to be heard. So if you have a neighbor or friend, a relative, anything like that, just be like, Hey, let's grab a coffee and let's move forward. 

Mary  

Well, thank you, Terry, for being on Sounds of Science and for sharing your powerful story and the incredible work of Elpida Therapeutics. Thanks for being here. 

Terry  

Thank you so much. I really appreciate it, and I'm honored to be on the podcast. Thank you. 

Mary  

Terry Pirovolakis is CEO of Elpida Therapeutics. Stay tuned for the next episode of Sounds of Science. Until then, you can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Thanks for listening.