S3, E06: Are We One Shot Away?

Karin Agerman (00:01):
Being a patient with epilepsy that has not been able to get seizure freedom with a drug, means that your life is quite affected. If you, for example, are a mother to a newborn child, you might not actually want to hold your child in your arms because you are really, really scared of dropping your child if you get a seizure.

Chris Garcia (00:35):
The World Health Organization estimates, at least, 50 million people worldwide have epilepsy. The most common type is focal epilepsy, which affects a specific part of the brain and impacts one in 26 American adults. When we think of epilepsy, we often think of seizures that cause spasms, twitching, and other changes in motor function. However, a lesser known effect of focal epilepsy is non-motor seizures. That, depending on where the epileptic focus starts in the brain, can change how patients feel or think.

For example, a patient may have a sudden burst of intense emotion, a racing heart, goosebumps, or waves of heat or cold. While symptoms can vary, what all focal epilepsy patients have in common is the unexpected disruption of their daily lives. Many suffer from sleep problems, are unable to drive, must have special accommodations to work, and face challenges in raising a family. One in three of these patients have a type of focal epilepsy that is drug resistant, and are eagerly awaiting a treatment that can help them control their symptoms and gain stability in their lives. I'm Chris Garcia, and in this episode of Vital Science, Gina Mullane speaks with Karin Agerman, chief research and development officer at CombiGene AB. We'll discuss the epilepsy treatment landscape, the challenges of manufacturing biologics, and the laboratory discovery from more than 30 years ago that led Karin and her team to where they are today.

Gina Mullane (01:59):
I'm really interested to hear a little bit about you, your role at CombiGene, And how you got into the field of molecular neurobiology.

Karin Agerman (02:08):
Oh, that's a million dollar question, actually.

Gina Mullane (02:11):
It's quite a field, wow.

Karin Agerman (02:13):
Yeah it is. It is. So I would like to present myself with one word, and that's curious. I've always been curious to things. And already in high school, I loved biology, chemistry, but I also liked math and numbers. And I loved traveling. So when I was about to apply for university, I had two different things that I wanted to do. I wanted to study molecular biology at Stockholm University, or I wanted to study economy. And can you do two things more differently, actually?

Gina Mullane (02:50):
Right.

Karin Agerman (02:52):
And the day of the submission of my application to university, I actually flipped a coin.

Gina Mullane (02:56):
No. You did?

Karin Agerman (02:59):
And it ended up... Yeah.

Gina Mullane (03:00):
Wow.

Karin Agerman (03:00):
And it ended up being molecular biology at Stockholm University. And I have never, ever, ever been sorry about that choice. It was actually spot on to what I wanted to do, because the curiosity that I have within me every single day is about learning new things when it comes to science and molecular biology.

Chris Garcia (03:22):
In addition to her curiosity, it's clear another character trait has aided Karin in her work, and that's her work ethic. Her title may be Chief Research and Development Officer, but at a startup of just seven employees... That's right, seven. She's gotten used to wearing many hats. Leading the CG01 project at CombiGene, she has done everything from reviewing and negotiating contracts with CEOs to fetching coffee for her team. But long before there were contracts to sign and meetings to plan, there were countless hours spent in the lab. Let's hear more from Karin on how CG01 came to be.

Gina Mullane (03:58):
Thank you for sharing your story with us. Now I'd like to dive a little deeper into the story behind CG01 and what set it apart from other drug candidates?

Karin Agerman (04:09):
So, CG01 is a little different from a lot of other gene therapy vectors that we are using. And that is that we have actually two genes within our vector. We have both Neuropeptide Y, and one of its receptors, the Y2 receptor. And the reason why we have done that is because our scientists showed quite early, that you can reduce seizures by introducing NPY into the brains of rats that have epileptic seizures. But If you do that in combination with the Y2 receptor, then the effect is even greater. So that's why we choose to have two genes within our vector at the same time.

Gina Mullane (04:56):
And so how is this therapy different from other antiseizure medications?

Karin Agerman (05:01):
Well, epilepsy drug development has been quite limited I would say. A lot of companies are looking for new therapeutic drugs for epilepsy. But none has really, really found anything new within the last 20 years. The new thing that has come out within the field is just small tweaks of the previous molecules so that it stays longer in your system, it gives effect a little longer. And what we hoped to be able to do with CG01 is actually with the one shot treatment, injecting CG01 into the brain where the epileptic focus starts. And then the genes will be expressed there for a very, very long time and in that way, reduce the seizures. Hopefully forever for these patients. But this is something we have to prove, of course, in humans.

Chris Garcia (05:55):
Many pharmaceutical breakthroughs could be traced back to a single light bulb moment in the lab. And to pinpoint that moment for CG01 we have to go back 30 years. In the 90s two of CombiGene's founders, Merab Kokaia and David Woldbye of Lund University and Copenhagen University recognized that Neuropeptide Y, or NPY, could have an antiseizure effect in animals. They also recognized that this positive effect could be further strengthened by the addition of NPY receptor, Y2. At the time, there was no clear path to administering this treatment in humans. That is until a decade later, when it was discovered that if you took a safe, non pathogenic virus, removed its DNA and replaced it with functional DNA sequences, or AAV vectors, it could be used to transport gene therapeutic drugs.

This opened up a world of possibilities. And in the mid 2000's Kokaia and Woldbye founded CombiGene AB and submitted a patent application, for what subsequently became candidate drug, CG01. Over the course of the next 10 years, they began to build their team. And in 2015, drug development went into full swing as the company went public. In CombiGene's early drug development days, their goal was to determine which construct would have the best anti seizure effect in animals. The team then identified CG01 and were ready to begin toxicology studies in animals and then in patients. But realized that they had one major hurdle to overcome first.

In 2018, Karin joined the company and they began the challenging process of developing a manufacturing platform. No small feat given the complicated nature of producing in gene therapy. Once the company had this key piece of the puzzle, the rest began to fall into place.

Karin Agerman (07:43):
We had just been at the Cell and Gene Therapy Catapult in London that was helping us with producing, or making the manufacturing platform for us. And we were sitting very late, I think it was 10 or something in the evening at the Gatwick Airport and we both opened our emails to check what had happened during the day and we had been called for an interview at the EU, for a grant, for Horizon 2020. That was a really big memory for the both of us. One week later we had to show up at Brussels, to do the interview for this project, the CG01 project and a month later we got the message that we got financed with 3.36 million Euros-

Gina Mullane (08:28):
Wow.

Karin Agerman (08:28):
And that was a big milestone for us at CombiGene. One really big milestone in drug discovery is always the first clinical study. So this is something that we, at CombiGene, we had really worked hard at this for a very long time now. All we have in front of us before we can start the first clinical trial is the toxicology study's, that needs to be clean do that we can move into man. We at CombiGene have also been very fortunate with another really big milestone, and in our aim to move the CG01 project towards the clinical trial, and that is that in October last year, 2021, CombiGene and Spark Therapeutics signed a collaboration and licensing agreement for CG01. And in Spark, we have now found the perfect partner to take CG01 both through the clinical phase, and if data in humans looks good, also to full commercialization.

CombiGene will, in this collaboration with Spark, carry out the remaining parts of the preclinical program. Mainly the studies in toxicology that I talked about, as well as the bi distribution studies. And when these preclinical studies are completed, Spark will then assume full control of the program and around the clinical trial development from the first human study and onwards. This in my view is not only great news for us at CombiGene, but also for the patients in need. Because in Spark, we have a really good partner that can commercialize this all throughout the world and reach all the patients needed.

Gina Mullane (10:09):
So unlike many gene therapies, which are developed for the treatment of rare diseases. CG01 caters to a large population of patients. And epilepsy is a major global problem. Every year approximately 47,000 drug resistant patients with focal epilepsy are estimated to be added in the US, UK, EU, Japan and China. So how can this potential gene therapy be a potential game changer for drug resistant focal epileptic attacks?

Karin Agerman (10:37):
The major game changer for this is for the patients that are drug resistant. One third of all the patients that have epilepsy are drug resistant. And that means that they have tested at least two drugs and that they don't get enough seizure freedom from that. Being a patient with epilepsy that has not been able to get seizure freedom with a drug means your life is quite affected. If you, for example, are a mother to a newborn child, you might not actually want to hold your child in your arms because you are really, really scared of dropping your child if you get a seizure.

Chris Garcia (11:21):
This is just one example of how an everyday activity can take on a dangerous amount of risk for focal epilepsy patients, including those who experience non motor seizures. Car accidents are another. A 2020 study led by researchers at NYU's Grossman School of Medicine, found that among the patients who reported having one or multiple car accidents before their diagnosis, three quarters had non motor seizures, while one quarter had motor seizures. The researchers estimate that for every 13 early diagnosis, one car accident could be prevented. Or an estimated 1816 preventable accidents annually, worldwide. This goes to show just how disruptive and dangerous focal epileptic symptoms can be on an individuals health and safety.

Of the significant portion of patient whose focal epilepsy is drug resistant, a small subset are eligible for surgery. Which means removing the part of the brain where the epileptic focus starts. However, for patients whose epilepsy is centered in areas that control critical functions, like vision, hearing or multifunction, this may non be advantageous or even possible. This is why CG01 has the potential to be such a game changer for these patients. They will finally have the opportunity to stabilize their seizures in a way that allows them to lead a safer and more productive life.

Gina Mullane (12:40):
You mentioned earlier that a key piece of getting this treatment into the hands of patients is manufacturing. I know you're working with our team, and I was wondering if you could tell us a bit more about the challenges of manufacturing in gene therapy, and how you're working through them?

Karin Agerman (12:56):
We wanted a small partner. We wanted someone that was very tentative to our needs. And since we are a small company and works completely virtually, most of us are project leaders and we are generalists who know life science a lot. We know a little bit about, we have our own expertise areas, but we don't know everything. And being an expert in manufacturing is not something that you can take on in a small company because you don't only need one competences there-

Gina Mullane (13:30):
Mm-hmm (affirmative).

Karin Agerman (13:30):
... you need several different competences. And therefore it was very, very important for us to get a partner that actually challenged us and told us "Now you're doing the wrong things Karin. You have to think about it this way." And giving us feedback all the time, saying that, "This is the best way to work it." Or, "Possibly could you do it this, way rather than this. If we do it that way then it would be a lot better." And the work that we have done with Cobra Biologics has really been like that all the way along.

Chris Garcia (14:05):
Any drug development program can face challenges and uncertainties. But developing biologics often presents unique hurdles beyond those found in developing small molecule therapies. A lot of people think that because biologics are produced by living cells, that they are somehow more natural and require less stringent testing. In fact, the opposite is true. Because you're dealing with live cells, every manufacturing run is a little different than the one before. And you need to work with a partner who is committed to building a process that gets it right every time. This starts with a strong product, like the plasmids Cobra uses for CG01, to insure the makeup of the treatment is sound. Then you need to develop a standardized production process that will work not only as you move from milligrams to grams to kilos, but also as shift from small scale to large scale manufacturing. And with gene therapies, rigorous quality control measures are a must. Without them, your therapy could be at risk for structural changes, that can alter the molecules activity in the body. A very risk scenario for the patient receiving the treatment.

Gina Mullane (15:10):
It's clear a lot of work is being put in to bringing CG01 to fruition. And it sounds like it already has the potential to make a big impact for focal epilepsy patients. I was wondering if you see any potential for CG01 beyond epilepsy?

Karin Agerman (15:28):
We do believe that the thing we are focusing on when we do the therapy with NPY and Y2, is to reduce the excitatory transmission between the nerve cells. So basically, the neurons talking to each other. If they talk too much, that will give you a seizure. In other diseases you could also have this excitatory neuronal transmissions between the neurons and that is something we can limit, if we use NPY and Y2. The biggest challenge I would say, with using NPY and Y2, is the NPY. Because NPY you can find almost everywhere in the body and you don't want to interact too much all over the body. So its not something that you want to give systemically in to the whole body, but you want to give it into a specific defined area.

Gina Mullane (16:22):
So it sounds like there are some limitations, but also some opportunities for the application of this treatment to broaden in the future. Which patients do you see as being the best initial candidates for CG01?

Karin Agerman (16:36):
There are lots of patients that are not eligible for surgery due to that focus of the epileptic seizures in the eloquent area, an area of the brain which you cannot remove because the side effects by removing that part of the brain will be too detrimental for the patient.

Gina Mullane (16:57):
So CombiGene has some impressive milestones. Among them is the CGT2 development for treatment of partial lipodystrophy. Can you share some progress with us made on CGT2?

Karin Agerman (17:10):
Yes I can. CGT2 is a very early project. It's for partial lipodystrophy. Partial lipodystrophy does not have any cure or any medications at all at the moment. And this patient population is affected by excessive fat distribution at different parts of the body. And what it really does is that it accumulates a lot of fat into the liver and that means that you will get a lot of follow on diseases that is really detrimental for the body.

Chris Garcia (17:48):
Lipodystrophy is a life threatening disease with no known cure. The impact of lipodystrophy symptoms can vary greatly. But as Karin mentioned, the disease is associated with many short and longterm complications. These include an inability to breakdown glucose, higher levels of triglycerides in the blood, and diabetes. Patients also sometimes experience fat accumulation in the liver. Which can lead to liver disease that may require a transplant. Right now, most treatments are targeted at the specific symptoms and co-morbidities experienced by the patient. CombiGene has spent the last two years designing the best expression vector for CGT2 and are researching its effects in in vivo studies. They hope to soon select the drug candidate and proceed with proof of concept studies. A therapy like CGT2 that could be administered into the affected part of the body would be a novel approach to treating this rare disease.

Gina Mullane (18:44):
So how do CG01 and CGT2 compare to each other in their development and delivery?

Karin Agerman (18:52):
Well, they're quite different and they're quite similar. The big difference is that one is a rare disease. CG01 is as you know, a large patient population, where we will help a lot of patients. CGT2 is a small indication, with only a few new patients coming up every year. That means that for CGT2, we could potentially apply for an Orphan Drug designation.

Chris Garcia (19:22):
The Orphan Drug Act of 1983 was designed to promote the development of treatments for rare diseases or conditions. By definition, a disease or condition is classified as rare if affects fewer than 200,000 people in the United States. Or if the cost of developing and distributing a treatment in the United States will exceed any potential profits from its sale.

Gina Mullane (19:44):
Its incredible to think of all the work that has lead CombiGene to this point. And even still, the work that lies ahead. I'm wondering, with all the challenges and competing priorities how do you all stay focused on your goal? What motivates your team to keep going each day?

Karin Agerman (20:02):
To help the patients in the end, that's really the... If you have that in line and look at the patients, and actually get the chance to meet patients once in a while, you want to drop everything else and just do the work and work very efficiently to be able to help them and get something out to help them in the end.

Gina Mullane (20:23):
I'm sure you've crossed paths with many focal epilepsy patients over the years. Do you have any stories that can help illustrate the struggle for our listeners?

Karin Agerman (20:33):
Well one of the stories is that in my first year here at CombiGene, I had the privilege to meet up with a patient organization here in Stockholm. And I got the chance to present our work for them. And after the presentation one of the patients in the audience just stood up and said, "I'll do anything, if this can help me. I'll do anything. And really, as it is now, please remove my whole brain. Because I just want to get rid of this disease." And this is what really helps us every day at CombiGene, trying to help these patients.

Gina Mullane (21:14):
Wow. That's powerful. Well its been great speaking with you today, we've learned a lot and very impressed by the work at CombiGene, and your journey there. So thanks for sharing everything today.

Karin Agerman (21:31):
Thank you Gina, its been a true pleasure. Have a great day.

Gina Mullane (21:35):
You to.

Karin Agerman (21:36):
Bye-bye.

Gina Mullane (21:36):
Bye now.

Chris Garcia (21:38):
Karin Agerman is the Chief Research and Development Officer at CombiGene AB. Until next time. Thanks for listening.