S4, E02: A Father’s Race Against Time to Cure SPG50

Terry Pirovolakis (00:02):
So what I'm hoping for Michael is that maybe he can communicate and tell us that he's in pain or he wants to go to the bathroom or he is hungry, or maybe he'll continue not being spastic so he can climb on his bed or climb into the bathtub and we don't have to crane him into those places or have an elevator bringing up to the second level. Those are the kind of things I hope for my son. I hope more than anything that he ends up being cured. But I think the reality is that the statement of cured is for the youngest children as possible, not the children that are at a certain age where they've already lost or something has been taken from them that cannot be taken back.

Todd Poley (00:54):
Spastic Paraplegia 50 is a slowly progressing neurodegenerative and neurodevelopmental disorder that's often accompanied by developmental delays, intellectual disabilities, impaired or absent speech, small head size, seizures and progressive motor symptoms. It has no cure and only 80 patients in the world are known to carry the diagnosis. If your child is one of these 80, how far would you go to get them the treatment they need? Would you, for example, crash one of the largest gene therapy conferences in the world? I'm Todd Pulley, and in this episode of Vital Science, we speak with Terry Pirovolakis, the tenacious father of SPG50 patient Michael and founder of the CureSPG50 Foundation. We'll talk with Terry about his journey to find a cure for Michael, from his experience at the annual American Society for Cell and Gene Therapy Conference, to building his own team of scientists, to raising $2 million for therapy development.

Gina Mullane (01:59):
Okay. Welcome to Vital Science, Terry. We're really honored to have you here today. Could you tell us a little bit about yourself?

Terry Pirovolakis (02:06):
Yeah, so my name is Terry Pirovolakis and for the last four years I've been working on a gene therapy for my son. It's kind of interesting because I have a day job as well. I'm a director of a large bank for technology in Canada. So my last four years have been working during the day and then being a parent after work and then after work trying to run or trying to resolve a gene therapy for my son. But our story started on April 2nd, 2019 when my youngest little boy Michael, was diagnosed with a rare disease called Spastic Paraplegia type 50. And basically the doctors told us there's not much that can be done, go home and love him, that the disease is not really world categorized. So we went online and we started doing a lot of research and we found that the disease causes paralysis from the waist down by the first decade and then by the second decade it causes paralysis or quadriplegic paralysis in the children.

And then we also have severe cognitive development delays. So we were lucky that we met a team or a family in Boston on our first day of this journey and we found that they were working on a gene therapy for something similar. And it kind of sparked the fire to try to figure something out. And for me, my entire life has been around solving complex problems and I thought if I can't solve this problem for my son, then what have I been doing all my life?

So within one month we were at ASGCT with a poster that said, "Wanted a cure for Michael." So I met the seven world experts in gene therapy there. I met with the FDA, the NIH, and then I flew to London, England and I met the seventh world expert in gene therapy and the team that's been working on our gene for the last 20 years. And then I flew to Texas and I hired Dr. Steven Gray to make a gene therapy for us. And that's kind of where the journey all began.

Gina Mullane (04:10):
Wow, that's an incredible synopsis. I'm sure there was a lot of hard work to get to each of those stages. Can you tell us a little bit about starting CureSPG50, the organization, and what was involved in that and how you enabled that to happen and help to drive the mission to find a cure?

Terry Pirovolakis (04:31):
Yeah, so basically right after we hired Dr. Steven Gray and gave up our life savings to start the program, we realized that even if we sold our home, we wouldn't have enough money to run this program to the end, at least in a quick fashion. So what we did was we came out in our community with a video and within about 24 hours I had people knocking on my door telling us how sorry they are and how they want to help. And I think it was two weeks later that we had a beer works do an event for us and we raised about $25,000 and then it kind of just went viral and we were in the news and pretty much every news channel in Canada, the newspapers and people started just doing events for us. And we didn't even know these individuals. We'd show up and meet them for the first time and within the first year we raised about $2 million.

Todd Poley (05:22):
The expense to create novel therapeutic is immense, even for companies in the pharmaceutical industry who expect to make profit. It should be no surprise that for so many rare disease families, it is an insurmountable hurdle to seeking treatment at all. Terry's family gave up their life savings to kickstart treatment for Michael, but it was not nearly enough. The $2 million they needed was raised through golf tournaments, garage sales, and lemonade stands hosted by friends, neighbors and even strangers. Toronto's Greek community hosted an event where 1200 people came and in a single night a quarter million dollars was added to Michael's therapy fund. Let's hear more from Terry about SPG50 and why this disease so often flies under the radar.

Gina Mullane (06:11):
Let's talk a little bit about spastic paraplegia or SPG50. It's an ultra rare monogenetic neurodegenerative disorder, which I'm sure you've learned a lot about in a short amount of time. Can you tell us more about it?

Terry Pirovolakis (06:28):
Yeah, so just like you mentioned, it's a neurodegenerative, but it's also a neurodevelopmental disease as well. So the developmental piece of it is probably the first decade of life. And then the neurodegenerative is probably in combination with the neurodevelopmental around five years of age. And again, we were very fortunate that this family in Boston had set up a natural history study. So we understood the disease fairly well. We know there's about eight children in the US, about 87 in the world. And so what happens is the first six months of life, no one really notices anything is wrong with their children. And then what happens is that people start seeing that the children are able to raise their hands, they're not able to lift their head.

So in our scenario, we went to the doctor and they thought, okay, you know what? Don't worry. Even though he's on the 10th percentile for head growth, we've seen this before and he'll just catch up, don't worry about it. So we started physiotherapy and Michael started making gains. He started raising his hands and then we went back about, I think it was eight or 10 months into our journey and we went and saw a pediatrician. At that point, he was the third percentile for head growth. And then we started seeing that he was really falling behind and he was not crawling, he was not walking. So what happened was they sent us to infectious disease at SickKids because that was working a lot in Latin America and they thought maybe he contracted Zika. So we did all those tests and they didn't find anything wrong and Michael continued having difficulties. At this point he was minus one on the head growth scale of the World Health Organization.

So then we went to neurology, they did all the panels, they didn't find anything wrong with Michael in the panels and they decided to do a whole exome sequence. And that's when we found out that Michael had this disease. And currently he's at the negative two in the World Health Organization chart. So microcephaly is a big indicator, low muscle tone is a huge indicator. And then what happens is up until about three years of age, they're developing, some of them have seizures and then the spasticity starts kicking in around three to five years of age. And it starts with the toes and it works its way up. And usually by the time they're 10, they're fully wheelchair bound. Most children are nonverbal or speak very few words and we believe it's a life limiting disease. We're not sure because there's not many patients beyond 30.

But it would make sense if it ends up causing spasticity in your muscle, your lung and your heart is a muscle and your swallowing and everything else. So we feel that it's probably a life limiting disease, it's just not known at this time. We were very fortunate. I mean we talked, me and my wife the second day in, I said, If we're going to treat Michael, if we're going to give him a better life, then she needs to take care of the family and I need to take care of figuring this out. It was very simple and I said, "I'm going to be gone a lot and I'm going to be upstairs in my room reading a lot." Because that's kind of what I do for a living. I'm like, "I need to get deep down into the weeds and understand this in order for us to help Michael." And she's like, "Do whatever you need to do to help him."

Gina Mullane (09:47):
Wow. Thank you for sharing all that. That's got to be devastating to just continue to hear, everything's fine, not sure what it is, all of those types of diagnoses. But the impact to your family, I'm sure has been felt pretty strongly. Can you tell us a little bit about that and how the work that you're doing with CureSPG50 also involves your family?

Terry Pirovolakis (10:15):
Yeah. I'll tell you, the first two days were devastating. I mean, I remember getting a phone call from a friend the day after Michael was diagnosed and he was like, !You just called me crying. You were hysterical. You couldn't even be understood." And I think that's where people really saw that we really, really wanted to change Michael's life. And it was a bit difficult in our family because we also have two older children and taking away attention from them and doing all these events. Sometimes they were part of it, sometimes they weren't. And we try to keep them out of that kind of spotlight. But it was a really amazing experience I would say overall, just having this amazing journey that we were on in light of Michael's severe disability. We were very fortunate.

Todd Poley (11:05):
Thanks to Terry's efforts and the team of scientists he recruited all the work on Michael's therapy has paid off. In June of 2021 while in the midst of a rat GOP toxicology study with Charles River, Terry went to Health Canada and the FDA seeking approval for an inhuman trial. Due to the high dose injection Michael was to receive, they required additional studies to be performed. Within two months, the team kicked off an in vivo study with Charles River and by December they were able to deliver these safety results to the federal health agencies. On December 30th, 2021, Health Canada approved the first human SPG50 trial. Terry immediately called the CEO of the Hospital for Sick Children in Toronto and a PI was quickly assigned On March 24th, 2022, Michael became the first child to receive treatment for SPG50.

Gina Mullane (12:04):
So how has Michael been progressing? What's he like as a kid? Tell us a little bit about where things are at now.

Terry Pirovolakis (12:14):
Yeah, so Michael, he lights up a room when he comes in. He's a happy little boy. Unfortunately because we had to give him the immunosuppressants to protect him from the gene therapy, the Prednisone, Tacrolimus, Sirolimus, the first couple of about month and a half were very difficult trying to give him the drugs, all these medicines at the same time. He doesn't understand that he has to take these medicines and he was getting sick from them. And then we were seeing some gains and then unfortunately he got a stomach bug and then another bug. So we've kind of been like one step forward, two steps back. But he's doing okay. I mean we are seeing some items and some progression. We're cautiously optimistic that it's the gene therapy and from the drugs that he was on kind of thing.

Gina Mullane (13:05):
And so what's next after the first dose?

Terry Pirovolakis (13:09):
So the other thing that we also did was we applied on July 10th to the FDA and we received approval on August 10th to actually move forward with a full clinical trial. So sometime between November and December, the second child will be treated with Michael's gene therapy or the gene therapy. And Biogen was very kind to make more doses and we should have enough to treat 10 children.

Gina Mullane (13:33):
Wow, wonderful. I was going to ask about the broader outreach because I believe that Michael's the only known patient in Canada with SPG50 and I'm sure the rare disease community far and wide has been a part of the journey. But I was wondering what you foresaw the reach beyond Michael's access to the treatment would be?

Terry Pirovolakis (14:00):
Yeah, and that's one of the reasons why we never came out with our story until we got FDA approval. Because the last thing we wanted to do was be like, look, Michael got treated and what's happening with the other children? I felt that it was inappropriate. So what we did was we timed it so that when Michael got treated, when we announced it, that the FDA also gave us approval. And that weekend I had a meeting with about 25 SPG50 families to talk through what the gene therapy's going to look like, how it's going to go. And I think the community is super excited to start. Unfortunately, I think that my concern is we're not going to have enough drug to treat all the children. And then there's also the exclusion criteria of children that won't get treated. So it weighs heavy on me that some children will not get treated and we're working super hard to figure that out.

Gina Mullane (14:52):
That's wonderful. In a previous episode we talked about the access to treatment and high costs that are sometimes associated with therapies. And I was wondering from your perspective, how can we make therapies more accessible to patients who need them given the high cost of research and development and production and actually making that available to patients?

Terry Pirovolakis (15:19):
Unfortunately, I don't have the right answer. I mean, the reality is that gene therapy is so new and it costs an average between half a million and $750,000 per dose to actually manufacture it, forget the R&D cost to actually make it. And then you have about a quarter million dollars of safety testing that you have to do for the children, including the dosing because you have to have them come back every three months for 18 months and flying from their home town and staying in a hotel or whatever it may be. We thought about having an open IND, but again, only the rich or people that can raise money really well will treat their children. I think the only answer is getting the treatment as fast as humanly possible approved. That's the reality of it, because if we can get it approved, then we can get it to the insurable population in the countries that will pay for the drug.

And for the uninsurable children, what we'll do is the royalties that come back from whatever the sales of those drugs hopefully will be enough to fund purchasing the drug at cost and dosing those children. I think in all the ways of slicing and dicing it, that seems to be the only way to, after the drug is created.

We're working on a plan with a venture that we're starting called Alpeda and our goal is to create a model to get programs from proof of concept to the clinic in a manner that's quick, effective, safe and doesn't cause foundations to try to raise $7 million each time. Because the problem is if you're in this for three or five years, the well goes dry. Your family, your connections, the story's been told numerous times and there's no more money coming in and it's very stressful.

So our goal is to help families that are at proof of concept, bring it to the clinic and then get it from the clinic to approval as fast as possible so that we can not have the traditional two years for a phase one, two more years or three years for a phase two or more three years for a phase three. Half a decade goes by and then only a few children get treated and a number of them pass away. So our goal is to get it quickly to the clinic and I think that's the only way for us to treat these children.

Gina Mullane (17:38):
You mentioned that Michael was just 18 months old when he was diagnosed. How is SPG50 detected at this early age?

Terry Pirovolakis (17:48):
I think that if a child goes into a hospital or a pediatrician's office and they just don't know what's going on, just do WES report at a hundred bucks for a thousand dollars. So whole exome sequencing is basically a genetic test that tells you 90% of the rare diseases that are out there or the diseases that are out there, if your makeup is genetically applied to one of those diseases. So if your child is like SPG50 like ours, you'll know within six weeks if from this WES report if your child has this disease. So it's critically important. And then if they don't find it in a WES report, there's something called the whole genome sequencing. And that's a very more detailed test that actually is significantly more money, but it enables you to determine even more rare diseases than the whole exome sequence.

And the other problem that we have is maybe you'll bring this up as well, is everybody says, "Well why didn't you do an intravenous gene therapy?" Similar to spinal muscular atrophy. And I think that what people need to realize is that the way we're going to cure our kids is most likely through an intravenous gene therapy. So we get it to the kids intravenously, we inject it into their system as a whole, it goes to the brain. But the problem with that is that around two to two and a half years of age, your blood brain barrier, this protector, this filtering system that's between your body and your brain turns on. And at that point, if you injected something intravenously, it most likely will not get to your brain after two and a half years of age. The Catch 22 is that until you get a drug approved, it doesn't get onto the newborn screening program.

So if someone did a heel prick and that child had SPG50, they're going to have to go through the six months to wait to see if they start showing low muscle tone and then either get microcephaly or a seizure and then the doctor would most likely do a WES report. So you're losing about, let's say a year or two years in this scenario, before you would've lost eight years and that's where the Catch 22 happens. We can't get to the newborn screening program until we have a cure or treatment. So I think that if we can change it on its head and say if there's something in the clinic, then it gets put on the newborn screening program so that we can actually help the children because there's something potentially down the road coming. I think that's one of the things that we've been really pushing for.

And we've also been pushing for the panels. The panels are like if a child has epilepsy for example, or has microcephaly, then instead of doing a whole exome sequence, it was a cheaper way of doing a smaller test. But even those panels didn't have SPG50 on it for a while. So these are the kind of things that we need to change as a whole. A child goes in, we don't know what's going on, whole exome sequence and they know. Because if they would have done that for Michael, we would've known at six months, not at 18, and we would've saved a year and a half of injecting him before knowing.

Gina Mullane (21:05):
That's really helpful to hear that perspective. I can only imagine that collaboration is critical to ensuring that the speed happens at really every phase of development. And you did give us a view of what that has looked like for this particular gene therapy. Do you have any other advice for rare disease families who are racing the clock to get a treatment developed?

Terry Pirovolakis (21:29):
Finding the right team is critical. I mean, initially we thought we had the right team, but we had to pivot. And I think that if anybody's listening to this and you're stuck and you're not moving forward, you have to pivot. You cannot wait. Your time is of the essence. That's the one thing I tell people, that you can make money but you can't buy back time. That's one of the biggest things that I tell everybody. But yeah, finding the right team, making sure that the team is willing to go to war with you to save your child, and just making sure that you just do things as fast as possible. We took a significant risk for our program specifically in that we did everything concurrently. So we actually went to the FDA before we started the rat tox. We had our drug manufacturer before toxicology studies were finished.

So you can imagine if something happened in the rat tox and it wasn't safe, we would've thrown away $2 million. So I would say that if you have the funding and you're able to move quickly and you're fairly confident that you've done safety studies, I think things will go well, which they hardly ever do but you're willing to take the risk. Do things in series, because if you don't, you'll be spending five years making a therapy. But if your child's going to pass away in two years, then you have to do things in parallel. This is the reality of it.

Todd Poley (22:54):
Michael's swift treatment would not have been possible without recent advances in the adeno associated virus delivery system, which is now the leading platform for gene therapy delivery. In the case of Michael's SPG50 therapy, the virus package included the gene, but it was also accompanied by a promoter. The promoter tells the gene where to go, how much to express, and what cells to target. To create the treatment about 500 liters of this genetic material is put into a bio reactor to yield about a hundred milliliters of concentrated therapeutic for administration. This can be injected into the spinal column, so sternum magna or directly into the brain. Once administered the virus, releases the gene into the cell and permanently creates the protein that is missing. Now that we better understand the science, let's hear more from Terry on why his CRO collaboration was so successful.

Gina Mullane (23:51):
Is there anything in the collaborations that you've had with CROs that you think have really enabled things to progress in a way that maybe people said wasn't even possible?

Terry Pirovolakis (24:03):
I think it's that care. It's that understanding that we're not a company, it's that we're a foundation trying to save these children, that we don't have this unlimited amount of money and that things have to kind of go right. And we had an amazing team of individuals at Charles River that cared from the very beginning, that understood what we were going through, that worked with us, that made sure that our program was successful and only did what we needed to do to make sure that we got there.

If I can just thank the team at Charles River, thank the team at UTSW, at Boston Children's, at the NIH, at Biogen at SickKids, UTSW, and I know I missed a ton of people in that one statement, everybody that was involved in our journey to help us get here and to continue our journey to save more kids. I want to thank you from the bottom of our heart that you were part of this journey, that you supported us and you did something that everybody told us was impossible. So we did the impossible and now all we can do is hope that the drug works and changes the lives of children like my son.

Gina Mullane (25:12):
Wow. What an incredible journey. What does the future hold for rare disease research and drug discovery now that you've become an expert on this? What do you see on the horizon?

Terry Pirovolakis (25:26):
So for us specifically, we plan to get our treatment to the kids as fast as humanly possible. Not just to 10, but as many kids as we can. I've also been helping 30 other families do a gene therapy or an ASO or a drug screen, and we're hoping that they'll get to the clinic fairly quickly. I'm running a gene therapy 101 class because there's a huge unmet need to help families guide and do this journey.

And on top of that we're going to be hopefully starting up [inaudible 00:25:50] therapeutics that will hopefully make a path forward for families like mine to get to the clinic and not have to sell your home or liquidate your life savings like we did in order for you to get there and to help your child as quickly as possible. Not before they pass away, but at a time that will be beneficial. And unfortunately, there's been a lot of amazing families on this journey that got the drug, but then it was too late for their child. And I think that we're going to hopefully change that for the whole industry.

Gina Mullane (26:22):
What patient populations do you think Alpeda will be able to help?

Terry Pirovolakis (26:27):
The way I have always seen it is no patient population is too old. I think that it'll help any age. The reality is, and there's a huge uproar around cure, right? What the statement of cure means, and I'll tell you from my perspective what it means to me. If we would've dosed Michael between one and six months of age, I truly believe that this would've been a cure. Because it's the neural developmental portion of it.

Unfortunately, we dosed Michael at four years of age and he has microcephaly, he has severe cognitive delays. So what I'm hoping for Michael is that maybe he can communicate and tell us that he's in pain or he wants to go to the bathroom or he is hungry, or maybe he'll continue not being spastic so he can climb on his bed or climb into the bathtub and we don't have to crane him into those places or have an elevator bring him up to the second level. Those are the kind of things I hope for my son. I hope more than anything that he ends up being cured. But I think the reality is that the statement of cured is for the youngest children as possible, not the children that are at a certain age where they've already lost or something has been taken from them that cannot be taken back.

Gina Mullane (27:46):
How can our listeners help you to move forward on this journey and help you to reach all of the goals that you have?

Terry Pirovolakis (27:55):
So if you watched Intra Stella and you see the black hole that's there, the one thing that our families do not have is time. Right? Time is something that is taken away from us and we can never get back. And every minute that we lose is years on the horizon. So I would say if you're a scientist or a researcher listening to this, reach out to a family like ours, reach out to a rare disease family and offer them support. Offer them to help in any way you can.

If you're building IPSCs, maybe make them IPSCs. If you're making heroplasts, maybe make them heroplasts. If you are a tox consultant, offer your services. Just support a rare disease family because they can tell you we need it. We need it more than ever. For us specifically, if you can help us raise awareness to our cause, raise awareness for the company that we're going to be building so we can enable and get more partners and cure more children, that would be very helpful. So if you can donate, that's great if not, when you're around the dinner table tonight, tell our story. Get people aware of our cause. But if you can, please help another rare disease because I can tell you we definitely need it.

Gina Mullane (29:08):
That's very inspirational and love it. Everybody that's listening can relate to a piece of that for sure. So thank you for that.

Terry Pirovolakis (29:17):
Absolutely.

Todd Poley (29:20):
Terry Pirovolakis is the founder of CureSPG50. In our next episode of Vital Science, we'll be checking vitals by updating our listeners on a few of our most popular episodes from 2022. Until then, thanks for listening.